Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[O:5][CH:6]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[N:8]=2)[CH2:3][CH2:2]1.C1C(=O)N([Br:20])C(=O)C1.C(Cl)(Cl)(Cl)Cl>CCOC(C)=O>[Br:20][C:6]1[O:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[N:8][C:7]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1coc(C2CC2)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(C2CC2)oc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.2 %

Procedure:
Into a 5000-mL 3-necked round-bottom flask were placed methyl 2-cyclopropyloxazole-4-carboxylate (140 g, 838.32 mmol, 1.00 equiv.), NBS (224 g, 1.26 mol, 1.50 equiv.), CCl4 (1400 mL) and BPO (20 g, 82.64 mmol, 0.10 equiv). The resulting solution was stirred overnight at room temperature, then it was diluted with 2000 mL of EtOAc. The solid was filtrated out. The filtrate was dried over anhydrous calcium chloride and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:50˜1:20). This resulted in 120 g (58% yield) of methyl 5-bromo-2-cyclopropyloxazole-4-carboxylate as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:16])[N:8]=[CH:9][C:10]=1[C:11]([O:13]CC)=[O:12])=[O:5])[CH3:2].[OH-].[Na+]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:16])[N:8]=[CH:9][C:10]=1[C:11]([OH:13])=[O:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(C)c1C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)c1c(C(=O)O)cnn1C
Reaction time: 18.5 h
Yield: 75 %

Procedure:
X-Zyme 6134 (20%, 90 mg) was added to a suspension of 2-methyl-2H-pyrazole-3,4-dicarboxylic acid diethyl ester (as prepared in Example 10, Step 1, 4.5 g, 19.5 mmol) in KPI (100 mM, pH 7.2, 450 ml). Sodium hydroxide solution (1 M, total amount 23.2 ml) was added slowly as needed to keep the pH constantly at 7.2 over the course of the reaction. After 18.5 h, the reaction mixture was extracted with tert-butyl methyl ether (TBME) to remove unwanted byproducts. The water layer was then acidified (pH 3.9) by addition of H2SO4, and extracted several times with TBME. During these extractions, the pH of the water layer was adjusted by addition of H2SO4 to a pH range between 4.2 and 3.8. After drying (Na2SO4) and evaporating the combined organic layers, a first crop of title compound (2.90 g, 74%) was obtained as a light grey solid. An additional crop of title compound (0.21 g, 5.3%) was obtained by adding brine to the water layer, repeated extraction with TBME, drying (Na2SO4) of the combined organic layers, and evaporation.
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:12](C=O)[C:5]2[O:6][C:7]([CH3:11])([CH3:10])[O:8][CH2:9][C:4]=2[CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:24])C=1.[OH-].[K+].C([O-])(O)=O.[Na+]>ClC(Cl)C.C(OCC)(=O)C>[F:1][C:2]1[CH:13]=[C:12]([OH:24])[C:5]2[O:6][C:7]([CH3:11])([CH3:10])[O:8][CH2:9][C:4]=2[CH:3]=1
Reactant: CC1(C)OCc2cc(F)cc(C=O)c2O1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: CC1(C)OCc2cc(F)cc(O)c2O1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 6-fluoro-2,2-dimethyl-4H-1,3-benzodioxine-8-carbaldehyde (20 g, 95 mmol) in dichloroethane (100 mL) was treated with m-CPBA (70% pure, 28.1 g, 114 mmol) at 70° C. for 20 min. After cooling to rt, ethyl acetate (300 mL) was added. The organic mixture was then washed with 10% aqueous sodium thiosulfate followed by 1 N KOH (114 mmol) followed by 3 washes with aqueous NaHCO3 (sat). The organic phase was then dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in THF (100 mL), and then 1 M KOH (100 mL) was added. The mixture was stirred for 20 min at rt. The pH was adjusted to 6 by the slow addition of 1 N HCl (aq). Ethyl acetate was then added, and the layers were partitioned. The aqueous phase was extracted with ethyl acetate. The organic extracts were combined, dried over magnesium sulfate, filtered, and concentrated in vacuo. 6-Fluoro-2,2-dimethyl-4H-1,3-benzodioxin-8-ol was isolated as a brown liquid (17.2 g, 86.6 mmol, 91% yield). 1H NMR (400 MHz, CDCl3): δ 6.56 (dd, 1H), 6.28-6.25 (m, 1H), 5.57 (br s, 1H), 4.79 (s, 2H), 1.56 (s, 6H); GCMS for C10H11FO3: 198 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[O:12])[N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:15][CH:14]=3)[C:9](=[S:25])[NH:8][C:7]=2[N:26]=1.C(=O)([O-])O.[Na+].I[CH2:33][CH3:34].C(#N)C>C(OCC)(=O)C>[CH2:33]([S:25][C:9]1[N:10]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:17][CH:18]=2)[C:11](=[O:12])[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[N:26][C:7]=2[N:8]=1)[CH3:34]
Reactant: CCI
Reactant: COc1ccc2c(=O)n(-c3ccc(OCC(F)(F)F)cc3)c(=S)[nH]c2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCSc1nc2nc(OC)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of 7-methoxy-2-thioxo-3-[4-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one (383 mg), 1M aqueous sodium hydrogen carbonate solution (1.0 ml), iodoethane (0.4 ml) and acetonitrile (10 ml) was stirred at 100° C. for 1 hr. The reaction mixture was allowed to be cooled, diluted with ethyl acetate (80 ml), washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (375 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].C([O-])([O-])=O.[K+].[K+].F[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 105 %

Procedure:
To a solution of 4-chloro-3-(trifluoromethyl)phenol (31.5 g, 160 mmol) in DMSO (200 ml) was added K2CO3 (46.5 g, 337 mmol) at room temperature under nitrogen. After 5 minutes stirring, 4-fluorobenzonitrile (19.4 g, 160 mmol) was added to the mixture in one portion and the resulting mixture was stirred at 100° C. for 18 hours. The reaction mixture was allowed to cool to room temperature and poured into ice-cold 1N aqueous NaOH solution with vigorous stirring. The precipitated solid was collected by filtration and under vacuum to afford 50 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:5]=[C:4](OS(C(F)(F)F)(=O)=O)[C:3]=1[C:26]([N:28]1[CH2:33][CH2:32][CH:31]([N:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)[CH2:30][CH2:29]1)=[O:27].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:85][O:86][C:87]1[CH:94]=[CH:93][C:90]([CH2:91][NH2:92])=[CH:89][CH:88]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:85][O:86][C:87]1[CH:94]=[CH:93][C:90]([CH2:91][NH:92][C:4]2[C:3]([C:26]([N:28]3[CH2:29][CH2:30][CH:31]([N:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)[CH2:32][CH2:33]3)=[O:27])=[C:2]([CH3:1])[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=3)[N:5]=2)=[CH:89][CH:88]=1
Reactant: COc1ccc(CN)cc1
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)nc(OS(=O)(=O)C(F)(F)F)c1C(=O)N1CCC(N2CCCC2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Product: COc1ccc(CNc2nc(-c3cccc(C(F)(F)F)c3)cc(C)c2C(=O)N2CCC(N3CCCC3)CC2)cc1

Procedure:
In analogy to the procedure described for the preparation of example 6, trifluoro-methanesulfonic acid 4-methyl-3-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-6-(3-trifluoromethyl-phenyl)-pyridin-2-yl ester (intermediate 10) was reacted with [rac]-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, palladium(II) acetate and 4-methoxy-benzylamine to give the title compound as yellow oil. MS: 553.4 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([OH:17])[CH:16]=1)[C:12]#[N:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.C1COCC1.Cl.C([O-])(O)=O.[Na+]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([OH:17])[CH:16]=1)[CH2:12][NH2:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cc(O)cc(OCc2ccccc2)c1
Agent: B
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: NCc1cc(O)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
3-benzyloxy-5-hydroxybenzonitrile (225 mg, 1 mmol) was dissolved in 2 mL THF. 2 mL of BH3-THF (1.5 M in THF and ether) was added dropwise, then the mixture was heated at reflux temperature for 3 hours. After cooling, the mixture was carefully poured to 3M HCl (ice cooled) and allowed to stir for 20 hours at room temperature. The mixture was neutralized with solid NaHCO3, thus the product precipitated as a white solid. The product was collected by filtration, washed with water, and dried (140 mg, 61%): MP 164-166° C. (dec); 1H NMR (DMSO-d6, 400 MHz) δ 9.28 (br, 1H), 7.41 (d, 2H, J=6.9 Hz), 7.36 (dd, 2H, J=7.0 and 7.6 Hz), 7.30 (dd, 1H, J=7.0 and 6.6 Hz), 6.43 (s, 1H), 6.32 (s, 1H), 6.21 (dd, 1H, J=2.2 and 2.0 Hz), 4.99 (S, 2H), 3.57 (S, 2H).
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[O:10][CH:11]=[C:12]3[C:20]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[NH:14][C:13]=23)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1OCCOCCOCCOCCOC1.[Br:36][C:37]1[CH:45]=[CH:44][CH:43]=[CH:42][C:38]=1[C:39](Cl)=[O:40]>C1COCC1>[Br:36][C:37]1[CH:45]=[CH:44][CH:43]=[CH:42][C:38]=1[C:39]([N:14]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=2[C:12]2=[CH:11][O:10][C:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[C:13]12)=[O:40]
Reactant: O=C(Cl)c1ccccc1Br
Reactant: c1ccc(-c2occ3c2[nH]c2ccccc23)cc1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(c1ccccc1Br)n1c2ccccc2c2coc(-c3ccccc3)c21
Reaction time: 1 h

Procedure:
2.1 g (52.5 mmol) of NaH (60% in mineral oil) are dissolved in 500 ml of THF under a protective-gas atmosphere. 11.5 g (50 mmol) of 3-phenyl-4H-furo[3,4-b]indole and 11.5 g (52.5 mmol) of 15-crown-5, dissolved in 200 ml of THF, are added. After 1 h at room temperature, a solution of 12 g (55 mmol) of 2-bromobenzoyl chloride in 250 ml of THF is added dropwise.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:22])[CH:8]=2)[N:3]=1.[CH3:23][NH:24][CH3:25]>CC(O)C>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([N:12]([CH3:13])[C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([CH3:22])[CH:8]=3)[N:3]=[C:2]([N:24]([CH3:25])[CH3:23])[N:11]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccc(C)cc23)cc1
Reactant: CNC
Solvent: CC(C)O
Product: COc1ccc(N(C)c2nc(N(C)C)nc3ccc(C)cc23)cc1
Temperature: 25 °C
Yield: 26.4 %

Procedure:
A solution of (2-chloro-6-methyl-quinazolin-4-yl)-(4-methoxyphenyl)-methyl-amine (64.4 mg, 0.21 mmol) and dimethylamine (2.0 M in THF, 1.0 mL, 2.0 mmol) in i-PrOH (2 mL) was heated to 100° C. overnight. After cooling to room temperature the reaction was concentrated onto SiO2 and purified by gradient MPLC (SiO2, 0 to 10%, MeOH/CH2Cl2, 20 min). 17.9 mg (26%) of the title compound was obtained: 1H NMR (DMSO-d6) δ 7.17-7.28 (m, 2 H), 7.12-7.16 (m, 2 H), 6.95-7.01 (m, 2 H), 6.51-6.54 (m, 1 H), 3.77 (s, 3 H), 3.44 (s, 3 H), 3.19 (s, 6 H), 1.94 (s, 3 H). HRMS (ES) calcd for C19H23N4O [(M+H)] 323.1866, found 323.1951.
Reaction SMILES: [Br:1]Br.[CH:3]([O:6][C:7]([N:9]1[CH2:15][CH2:14][CH2:13][CH:12]([N:16]([C:32](=[O:34])[CH3:33])[CH2:17][C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=2)[C:11]2[CH:35]=[CH:36][C:37]([CH3:39])=[CH:38][C:10]1=2)=[O:8])([CH3:5])[CH3:4]>C(O)(=O)C.C(OCC)(=O)C>[CH:3]([O:6][C:7]([N:9]1[CH2:15][CH2:14][CH2:13][CH:12]([N:16]([C:32](=[O:34])[CH3:33])[CH2:17][C:18]2[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[C:20]([C:28]([F:29])([F:30])[F:31])[CH:19]=2)[C:11]2[CH:35]=[C:36]([Br:1])[C:37]([CH3:39])=[CH:38][C:10]1=2)=[O:8])([CH3:4])[CH3:5]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(C)ccc21
Reactant: BrBr
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(C)c(Br)cc21
Temperature: 50 °C
Yield: 100.3 %

Procedure:
Add bromine (0.016 mL, 0.303 mmol) dropwise to a solution of isopropyl-5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-8-methyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (0.153 g, 0.288 mmol) in glacial acetic acid (2.8 mL) and heat at 50° C. under nitrogen for 18 h. Cool the mixture to room temperature, dilute with ethyl acetate (50 mL) and wash with saturated sodium bicarbonate (2×50 mL) and 10% aqueous sodium thiosulfate (50 mL), then dry the organic layer over sodium sulfate, filter and remove the solvent under reduced pressure to provide the title compound as a white solid (0.176 g, >99%): ESI MS 609 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1Br.[CH3:12][N:13](C)C=O.O>ClCCl>[C:8]([C:5]1[CH:4]=[C:3]([C:12]#[N:13])[C:2]([NH2:1])=[CH:7][CH:6]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(N)c(Br)c1
Reactant: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CC(=O)c1ccc(N)c(C#N)c1
Reaction time: 0.33 h

Procedure:
A stirred mixture of 35.5 g of 4'-amino-3'bromoacetophenone, 17.8 g of cuprous cyanide and 180 ml of dry dimethylformamide was heated at reflux, under nitrogen for 6 hours. After cooling, the mixture was treated with 180 ml of a solution of ferric chloride (prepared from 400 g of ferric chloride hexahydrate, 100 ml of concentrated hydrochloric acid and 600 ml of water) and stirred for 20 minutes at 60°-70° C. A 500 ml portion of water and 400 ml of dichloromethane were added. To facilitate phase separation, the mixture was filtered and then the filtrate was extracted with two 400 ml portions of dichlorometbane. The organic extracts were combined, washed with 200 ml of water and 200 ml of saturated sodium bicarbonate solution and the solvent removed in vacuo at 80° C. The residue was evaporated twice from 100 ml portions of toluene, giving a yellow solid, which was crystallized from ethanol, giving 14.35 g of the desired compound, mp 155°-159° C.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:19])=[C:11]([F:18])[C:12]=3[O:14]C(C)C)[C:7](=[O:20])[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1.[N+:26]([O-])([O-:28])=[O:27].[K+]>OS(O)(=O)=O>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([N+:26]([O-:28])=[O:27])[C:10]([F:19])=[C:11]([F:18])[C:12]=3[OH:14])[C:7](=[O:20])[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])[O-]
Reactant: CCOC(=O)c1cn(C2CC2)c2c(OC(C)C)c(F)c(F)cc2c1=O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOC(=O)c1cn(C2CC2)c2c(O)c(F)c(F)c([N+](=O)[O-])c2c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
A solution of ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-isopropoxy-4-oxoquinoline-3-carboxylate (600 mg, 1.71 mmol) in concentrated H2SO4 (5 mL) was treated portion wise with solid KNO3 (242 mg, 2.39 mmol) at 0° C. After stirred at 0° C. for 30 min and at room temperature for 1 h, the reaction mixture was poured into ice-water and the resulting precipitate was collected by filtration, washed with water and dried to yield ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-hydroxy-5-nitro-4-oxoquinoline-3-carboxylate (393 mg, 65%) as a pale brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([NH:12][C:13]([CH3:21])([CH:18]([CH3:20])[CH3:19])[C:14]([O:16]C)=O)=[O:11].C[C:23]([O-:26])(C)C.[K+].O>C1(C)C=CC=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:26][CH3:23])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14](=[O:16])[C:13]([CH:18]([CH3:20])[CH3:19])([CH3:21])[NH:12][C:10]1=[O:11]
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)C(C)(NC(=O)Cc1ccc(F)cc1Cl)C(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C2C(=O)NC(C)(C(C)C)C2=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85.4 %

Procedure:
71.4 g (0.226 mol) of methyl N-(2-chloro-4-fluorophenyl-acetyl)-2-amino-2,3-dimethyl-butyrate, dissolved in 450 ml of absolute toluene, are added dropwise to a suspension of 56 g (0.498 mol) of potassium tert-butylate in 150 ml of absolute tetrahydrofuran at the boil, and stirring is continued for 90 minutes at reflux temperature. After the reaction mixture has cooled to room temperature, 700 ml of water are added, the organic phase is separated off and washed again using 340 ml of water. The combined aqueous phases are acidified at 15-20° C. using separately 80 ml of concentrated hydrochloric acid, and the product is filtered off with suction. After drying, 57.1 g (85% of theory) of 3-(2-chloro-4-methoxyphenyl)-5-isopropyl-5-methyl-pyrrolidine-2,4-dione of m.p. 130-140° C. are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[C:21]([N:22]3[CH2:26][C@H:25]([S:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:36]([F:39])([F:38])[F:37])(=[O:29])=[O:28])[CH2:24][C@H:23]3[C:40]([O:42]C)=[O:41])=[CH:20][C:19]([CH3:44])=[N:18]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+]>>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([N:17]2[C:21]([N:22]3[CH2:26][C@H:25]([S:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:36]([F:37])([F:38])[F:39])(=[O:29])=[O:28])[CH2:24][C@H:23]3[C:40]([OH:42])=[O:41])=[CH:20][C:19]([CH3:44])=[N:18]2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C)nn1C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Li+]
Agent: [OH-]
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccccc3C(F)(F)F)C[C@H]2C(=O)O)n(C2CCN(C(=O)OCc3ccccc3)CC2)n1

Procedure:
In analogy to the procedure described in example 253e, 4-{5-[(2S,4R)-2-methoxycarbonyl-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidin-1-yl]-3-methyl-pyrazol-1-yl}-piperidine-1-carboxylic acid benzyl ester was saponified in the presence of lithium hydroxide to give the title compound as yellow solid. MS (ESI): m/z=619.4 [M−H]−.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:26][CH2:27][CH3:28])[C:7]2[C:16]3[CH:15]=[CH:14][C:13]([O:17][CH:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)=[CH:12][C:11]=3[N:10]=[C:9]([NH2:24])[C:8]=2[N:25]=1)[CH3:2].[C:29](OC(=O)C)(=[O:31])[CH3:30].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[C:29]([N:21]1[CH2:20][CH2:19][CH:18]([O:17][C:13]2[CH:14]=[CH:15][C:16]3[C:7]4[N:6]([CH2:26][CH2:27][CH3:28])[C:5]([CH2:4][O:3][CH2:1][CH3:2])=[N:25][C:8]=4[C:9]([NH2:24])=[N:10][C:11]=3[CH:12]=2)[CH2:23][CH2:22]1)(=[O:31])[CH3:30]
Reactant: CCCn1c(COCC)nc2c(N)nc3cc(OC4CCNCC4)ccc3c21
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCCn1c(COCC)nc2c(N)nc3cc(OC4CCN(C(C)=O)CC4)ccc3c21
Reaction time: 36 h
Yield: 48.8 %

Procedure:
2-(Ethoxymethyl)-7-(piperidin-4-yloxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine (0.500 g, 1.3 mmol) was slurried in dichloromethane (13 mL). Acetic anhydride (0.122 mL, 1.3 mmol) was added dropwise to the slurry and the mixture was stirred for 36 hours. Saturated aqueous sodium carbonate (5 mL) was added and the reaction was stirred for 1 hour. The layers were separated and the organic fraction was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 1-22% CMA in chloroform). The resulting amorphous solid was triturated with boiling acetonitrile. Filtration afforded 0.270 g of 7-[(1-acetylpiperidin-4-yl)oxy]-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine as an off-white solid, mp 178-179.5° C.
Reaction SMILES: Br[C:2]1[C:3](=[O:20])[N:4]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6](Br)[N:7]=1.[CH:21]1[CH2:26][CH:25]=[CH:24][CH2:23][CH:22]=1>[Pd].O1CCCC1>[CH3:5][N:4]([CH3:9])[CH2:3][CH2:2][N:7]([CH2:6][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:2]1[C:3](=[O:20])[N:4]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:6][N:7]=1
Reactant: COC(=O)c1ccc(C)c(-n2cc(Br)nc(Br)c2=O)c1
Reactant: C1=CCC=CC1
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C)c(-n2ccnc(N(CCN(C)C)Cc3ccccc3)c2=O)c1
Temperature: 100 °C

Procedure:
A mixture of 3-(3,5-dibromo-2-oxo-2H-pyrazin-1-yl)-4-methyl-benzoic acid, methyl ester (Example 1b, 129 mg), W-benzyl-N,N-dimethylethylenediamine (0.1 mL), N,N-diisopropylethylamnie (0.1 mL) and tetrahydrofuran (1 mL) was heated within a microwave for 15 minutes at 100° C. before being cooled to room temperature. The mixture was transferred to a mixture of palladium on carbon (10%, 50 mg) and tetrahydrofuran (1 mL) and 1,4-cyclohexadiene (1 mL) was added. The mixture was heated within a microwave for 60 minutes at 120° C. before being cooled to room temperature. The mixture was filtered and the filtrated concentrated in vacuo. Purification by preparative HPLC (Gemini column, 0.1% ammonia:acetonitrile eluent) afforded the title compound as a solid (50 mg).
Reaction SMILES: [C:1]([NH:20][CH:21]([CH2:24][C:25]1[N:26]=[CH:27][N:28]([C:30]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:29]=1)[CH2:22][OH:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:52]1[C:56]2[CH:57]=[C:58]([Cl:61])[CH:59]=[CH:60][C:55]=2[O:54][N:53]=1.O>CN(C)C=O.C(OCC)(=O)C>[Cl:61][C:58]1[CH:59]=[CH:60][C:55]2[O:54][N:53]=[C:52]([O:23][CH2:22][CH:21]([NH:20][C:1]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:24][C:25]3[N:26]=[CH:27][N:28]([C:30]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:29]=3)[C:56]=2[CH:57]=1
Reactant: Clc1ccc2onc(Cl)c2c1
Reactant: OCC(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Clc1ccc2onc(OCC(Cc3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)NC(c3ccccc3)(c3ccccc3)c3ccccc3)c2c1

Procedure:
A solution of 2.0 g of 2-tritylamino-3-(1-trityl-4-imidazolyl)-1-propanol in 10 ml of N,N-dimethylformamide is dropwise added to a suspension of 0.14 g of 60% (w/w) sodium hydride in 15 ml of N,N-dimethylformamide at room temperature over 15 minutes, and the temperature is then elevated gradually to 80° C., after which this is added to a solution of 0.6 g of 3,5-dichloro-1,2-benzoisoxazole in 10 ml of N,N-dimethylformamide. They are subjected to reaction at the same temperature for six hours. After cooling, water and ethyl acetate are added and shaken, and the organic layer is separated. The separated organic layer is washed with a saturated saline solution and dried over anhydrous magnesium sulfate, after which the solvent is removed by distillation under reduced pressure. The residue obtained is purified by a column chromatography [eluant:n-hexane:ethyl acetate=3:1], to obtain 1.12 g of colorless, crystalline 5-chloro-3-[2-tritylamino-3-(1-trityl-4-imidazolyl)propoxy]-1,2-benzoisoxazole having a melting point of 113.4°-114.7° C.