Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][CH:9]([O:11][CH2:12][CH2:13][O:14][C:15]1[N:23]=[C:22]2[C:18]([N:19]=[C:20]([O:24][CH3:25])[NH:21]2)=[C:17]([NH2:26])[N:16]=1)[CH3:10].C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:38][CH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1)(=O)=O>CN(C)C=O.C(OCC)(=O)C>[CH3:10][CH:9]([O:11][CH2:12][CH2:13][O:14][C:15]1[N:23]=[C:22]2[C:18]([N:19]=[C:20]([O:24][CH3:25])[N:21]2[CH2:38][CH:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[C:17]([NH2:26])[N:16]=1)[CH3:8]
Reactant: CS(=O)(=O)OCC1CCOCC1
Reactant: COc1nc2c(N)nc(OCCOC(C)C)nc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2c(N)nc(OCCOC(C)C)nc2n1CC1CCOCC1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 112.7 %

Procedure:
To a solution of 2-({2-[(1-methylethyl)oxy]ethyl}oxy)-8-(methoxy)-9H-purin-6-amine trifluoroacetate salt (400 mg) in dry N,N-dimethylformamide (6.4 ml) was added potassium carbonate (579 mg). The reaction was stirred at 60° C. for 1.5 hours. The reaction was cooled and tetrahydro-2H-pyran-4-ylmethyl methanesulfonate (224 mg) was added. The reaction was stirred at 90° C. for 4 hours. The reaction was cooled and taken up in ethyl acetate and washed twice with water. The organic layer was separated, dried over magnesium sulphate, filtered and concentrated in vacuo to yield a yellow oil (432 mg). The product was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid)-acetonitrile (containing 0.05% formic acid) as eluant (20-50%) to afford the title compound as a clear viscous oil (166 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[Br:16]Br.[CH2:18](O)[CH3:19]>>[Br:16][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:9]([O:11][CH2:18][CH3:19])=[O:10]
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: CCO
Reactant: BrBr
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C(Br)c1ccc(Cl)cc1

Procedure:
By the method of E. Schwenk and D. Papa, J. A. C. S. 70, 3626 (1948), incorporated herein by reference, 86.8 g (0.509 mole) of p-chlorophenylacetic acid was treated with 100 ml of thionyl chloride. Subsequent reaction with 83.2 g (0.52 mole) of bromine followed by 100 ml of ethanol produced 78.9 g of ethyl alphabromo-(4-chlorophenyl)acetate as an oil.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:6]([NH:8][CH2:9][C:10]([NH:12][C@H:13]([C:15]([N:17]1[CH2:28][CH2:27][CH2:26][C@H:18]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])[CH3:14])=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4].[H][H].C(Cl)(Cl)Cl.CO>CO.[Pd]>[NH2:1][C@H:2]([C:6]([NH:8][CH2:9][C:10]([NH:12][C@H:13]([C:15]([N:17]1[CH2:28][CH2:27][CH2:26][C@H:18]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])[CH3:14])=[O:11])=[O:7])[CH:3]([CH3:4])[CH3:5]
Reactant: [H][H]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NCC(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)[C@H](N)C(=O)NCC(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C

Procedure:
533 mg of Z-Val-Gly-Ala-Pro-OtBu are hydrogenated in 10 ml of methanol in the presence of 300 mg of Pd on charcoal (10%) at room temperature. The hydrogen uptake has ended after 20 minutes. The catalyst is filtered off and the filtrate evaporated in a waterpump vacuum at 30°C to give an oil. Rf = 0.52 in the system chloroform-methanol (1:1) on silica gel.
Reaction SMILES: [C@H:1]1([NH2:8])[CH2:6][CH2:5][C@H:4]([NH2:7])[CH2:3][CH2:2]1.[C:9]1([CH2:15][O:16][C:17](ON2C(=O)CCC2=O)=[O:18])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1CCOCC1>[NH3:7].[C:9]1([CH2:15][O:16][C:17](=[O:18])[NH:7][C@H:4]2[CH2:5][CH2:6][C@H:1]([NH2:8])[CH2:2][CH2:3]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: C1COCCO1
Product: N
Product: N[C@H]1CC[C@H](NC(=O)OCc2ccccc2)CC1
Reaction time: 2 h

Procedure:
A solution of trans 1,4-cyclohexanediamine (22.8 g, 200 mmol) in dry dioxan (100 ml) was cooled to 5°-10° and treated dropwise with 1-[[(phenylmethoxy)carbonyl]oxy]-2,5-pyrrolidinedione (4.98 g, 20 mmol) in dioxan (50 ml) over 3 h. The mixture was warmed to 21° then stirred for a further 2 h and filtered. The filtrate was evaporated to give a solid which was purified on silica eluted with dichloromethane:ethanol:0.88 ammonia (30:8:1) to give the title compound (2.58 g) as a white solid. MH+ =249.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[CH3:16][NH:17][CH3:18]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:17]([CH3:18])[CH3:16])(=[O:10])=[O:9])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1C(F)(F)F
Reactant: CNC
Product: CN(C)S(=O)(=O)c1ccc(Br)cc1C(F)(F)F
Yield: 80 %

Procedure:
In an analogous manner to General Procedure A, 4-Bromo-2-trifluoromethylbenzenesulfonyl chloride (0.50 g, 1.54 mmol) and dimethylamine (10 mL, 33% in ethanol) were stirred in sealed tube for 16 hours. 4-bromo-N,N-dimethyl-2-(trifluoromethyl)benzenesulfonamide (0.41 g, 80%) was provided after purification. MS (ESI) m/z 332. HPLC purity 100.0% at 210-370 nm, 9.3 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [NH2:1][C:2]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:3]=1[C:4]([N:6]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=1)[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1)=[O:5].Br[CH2:36][C:37]#[N:38].[Na].[H][H]>C(O)C>[C:26]([C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:6]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:10]=2)[C:4](=[O:5])[C:3]2[CH:30]=[C:31]([Cl:34])[CH:32]=[CH:33][C:2]=2[NH:1][CH2:36][C:37]#[N:38])=[CH:21][CH:22]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)c1ccc(CN(CCc2cccc(C(F)(F)F)c2)C(=O)c2cc(Cl)ccc2N)cc1
Reactant: [H][H]
Reactant: N#CCBr
Agent: [Na]
Solvent: CCO
Product: CC(C)(C)c1ccc(CN(CCc2cccc(C(F)(F)F)c2)C(=O)c2cc(Cl)ccc2NCC#N)cc1
Temperature: 100 °C
Yield: 30 %

Procedure:
2-Amino-N-(4-tert-butyl-benzyl)-5-chloro-N-[2-(3-trifluoromethyl-phenyl)-ethyl]-benzamide (80 mg, 0.164 mmol), bromo-acetonitrile (21 mg, 0.172 mmol) and sodium hydrogen catbonat (17 mg, 01.96 mmol) were suspended in ethanol (21 ml) and heated to 100° C. for 3 days. The reaction mixture was cooled to RT, filtered and the precipitate was washed with ethanol. The solvent of the filtrate was concentrated in vacuo to give a residue which was purified by flash column chromatography (heptane/ethyl acetate 7:3) to yield the desired product (26 mg, 30%) as a yellow solid. MS (ISP) 526.2 (M−H)−.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[CH3:12].[NH3:13]>>[Cl:11][C:4]1[C:3]([CH3:12])=[C:2]([NH2:13])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: Cc1c(Cl)ccc([N+](=O)[O-])c1Cl
Reactant: N
Product: Cc1c(Cl)ccc([N+](=O)[O-])c1N
Temperature: 130 °C
Reaction time: 18 h
Yield: 76 %

Procedure:
A suspension of 2,6-dichloro-3-nitrotoluene (6.0 g, 29 mmol) in 50% methanolic ammonia (60 mL) was stirred at 130° C. (340 lb pressure) for 18 hours. The autoclave was cooled to -30° C., opened, and the precipitate was filtered off and washed with methanol to give 4.14 g (76%) of 3-chloro-2-methyl-6-nitrobenzenamine.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-])=O.[C:14](OC(=O)C)(=[O:16])[CH3:15]>CO.CN(C=O)C.[Pd]>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([NH:11][C:14](=[O:16])[CH3:15])[CH:4]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)c1ccc(O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(C(C)=O)ccc1O

Procedure:
A solution of 1-(4-hydroxy-3-nitro-phenyl)-ethanone (10 g) in methanol, DMF (50 ml) and acetic anhydride (10 ml) was hydrogenated using 10% Pd—C (0.45 g) for 2 h at 30 psi. The catalyst was filtered off. The filtrate was concentrated (5 ml) and treated with EtOAc (100 ml) to obtain the title compound, which was filtered, washed with EtOAc (10 ml) and dried. Yield, 9.1 g (85%); mp, >215° C.; MS (EI): 193 (M+), 151, 136, 108.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH3:11][C:12]1[CH:16]=[CH:15][NH:14][C:13]=1[CH:17]=O>N1CCCCC1.C(O)C>[CH3:11][C:12]1[CH:16]=[CH:15][NH:14][C:13]=1[CH:17]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]1=[O:10]
Reactant: O=C1Cc2ccccc2N1
Reactant: Cc1cc[nH]c1C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc[nH]c1C=C1C(=O)Nc2ccccc21
Temperature: 90 °C
Reaction time: 3 h
Yield: 67.4 %

Procedure:
A reaction mixture of 133.0 mg of oxindole, 130.9 mg of the 3-methylpyrrole-2-carboxaldehyde, and 3 drops of piperidine in 2 mL of ethanol was stirred at 90° C. for 3 h. After cooling, the precipitate was filtered, washed with cold ethanol, and dried to yield 150.9 mg (67%) of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[N:16][C:5]2[NH:6][C:7]3[CH2:8][CH2:9][N:10]4[CH:14]([C:15]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12][CH2:11]4.[OH-].[K+].[F:20][C:21]([F:31])([F:30])[C:22]1[CH:27]=[CH:26][C:25]([CH:28]=[CH2:29])=[CH:24][N:23]=1>CN1C(=O)CCC1.O>[CH3:1][C:2]1[CH:17]=[N:16][C:5]2[N:6]([CH2:29][CH2:28][C:25]3[CH:24]=[N:23][C:22]([C:21]([F:31])([F:20])[F:30])=[CH:27][CH:26]=3)[C:7]3[CH2:8][CH2:9][N:10]4[CH:14]([C:15]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12][CH2:11]4
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Reactant: Cc1cnc2[nH]c3c(c2c1)C1CCCN1CC3
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cnc2c(c1)c1c(n2CCc2ccc(C(F)(F)F)nc2)CCN2CCCC12
Reaction time: 16 h

Procedure:
A solution of 10-methyl-2,3,5,6,7,11c-hexahydro-1H-pyrido[3′,2′:4,5]pyrrolo[2,3-g]indolizine (80 mg, 0.352 mmol) and powdered KOH (138 mg, 2.46 mmol) in NMP (2 mL) was stirred at RT for 5 min. 2-(Trifluoromethyl)-5-vinylpyridine (122 mg, 0.704 mmol) was added into the reaction mixture and stiffing continued for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by silica gel flash chromatography to yield 10-methyl-7-(2-(6-(trifluoromethyl) pyridin-3-yl)ethyl)-2,3,5,6,7,11c-hexahydro-1H-pyrido[3′,2′:4,5]pyrrolo[2,3-g]indolizine;
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].[C:12](=O)([O-])[O-].[Cs+].[Cs+].C1(C)C(S(O[CH2:28][CH2:29][O:30][S:31]([C:34]2[C:35](C)=[CH:36][CH:37]=[CH:38][CH:39]=2)(=[O:33])=[O:32])(=O)=O)=CC=CC=1>CN(C=O)C>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:2]([O:1][CH2:28][CH2:29][O:30][S:31]([C:34]2[CH:39]=[CH:38][C:37]([CH3:12])=[CH:36][CH:35]=2)(=[O:32])=[O:33])=[C:3]([CH:6]=1)[CH:4]=[O:5]
Reactant: Cc1ccccc1S(=O)(=O)OCCOS(=O)(=O)c1ccccc1C
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(O)c(C=O)c1
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(OCCOS(=O)(=O)c2ccc(C)cc2)c(C=O)c1
Temperature: 70 °C
Reaction time: 5 h
Yield: 75 %

Procedure:
To a vigorously stirred solution of 15,2 g (100 mmol) 2-hydroxy-5-methoxy-benzaldehyde and 42.4 g (130 mmol) caesium carbonate in 350 ml DMF at 0° C. was added 46.3 g (125 mmol) ethylene glycol bis-toluene sulfonate (Aldrich) in 50 ml DMF dropwisely. The reaction mixture was stirred vigorously at 70° C. for 5 h. The solvent was evaporated. 200 ml water and 200 ml ethyl acetate were added. The organic phase was separated. The aqueous phase was extracted three times with 100 ml ethyl acetate each. The combined organic phases were washed with 50 ml water and 50 ml brine. The organic phase was dried with magnesium sulfate and evaporated. The crude product was purified by silica column chromatography (gradient ethylacetate:hexane 1:6, ethyl acetate→1:2). The desired product 5a was obtained in 75% yield (26.3 g, 75 mmol) as yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[C:14](=[O:15])[C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[O:11][C:10]2[CH:20]=[CH:21][C:22]([CH:24]=[O:25])=[CH:23][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-].[Mg+2].[Br-].[N+:29]([C:32]1[CH:50]=[CH:49][C:35]([CH2:36][O:37][C:38]([C:40]2[N:41]3[C@H:44]([S:45][CH:46]=2)[C@@H:43]([Br:47])[C:42]3=[O:48])=[O:39])=[CH:34][CH:33]=1)([O-:31])=[O:30].C(N(CC)CC)C.[C:58](OC(=O)C)(=[O:60])[CH3:59]>C(#N)C.CN(C1C=CN=CC=1)C.C1COCC1>[N+:29]([C:32]1[CH:50]=[CH:49][C:35]([CH2:36][O:37][C:38]([C:40]2[N:41]3[CH:44]([S:45][CH:46]=2)[C:43]([CH:24]([O:25][C:58](=[O:60])[CH3:59])[C:22]2[CH:21]=[CH:20][C:10]4[O:11][C:12]5[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=5[C:14](=[O:15])[N:8]([CH2:1][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)[C:9]=4[CH:23]=2)([Br:47])[C:42]3=[O:48])=[O:39])=[CH:34][CH:33]=1)([O-:31])=[O:30]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)C1=CS[C@@H]2[C@@H](Br)C(=O)N12
Reactant: O=Cc1ccc2c(c1)N(Cc1ccccc1)C(=O)c1ccccc1O2
Agent: CN(C)c1ccncc1
Agent: [Br-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)OC(c1ccc2c(c1)N(Cc1ccccc1)C(=O)c1ccccc1O2)C1(Br)C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CSC21
Temperature: -20 °C
Reaction time: 4 h
Yield: 41 %

Procedure:
10-benzyl-11-oxo-10,11-dihydro-dibenzo[b,f][1,4]oxazepine-8-carbaldehyde (0.250 g, 0.759 mmole) in acetonitrile was added to magnesium bromide (0.419 g, 2.28 mmole) under N2 at room temperature. The dry THF solution of (5R,6S)-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitrobenzyl ester (0.292 g, 0.758 mmole) then was added to the mixture. After 15 minutes the reaction mixture was cooled to −20° C., and triethylamine (0.317 mL, 2.27 mmole) was added. The reaction flask was covered with foil to exclude light. After 4 hours at −20° C., treated with acetic anhydride (0.358 mL, 3.795 mmole) and DMAP (0.00927 g, 0.0759 mmole). Warmed up the reaction mixture to 0° C. and placed it in freezer overnight. Reaction solution was concentrated and dissolved with ethyl acetate and washed with 5% of citric acid aqueous solution, saturated NaHCO3, water and brine. Organic layer was dried in sodium sulfate and filtered and concentrated. Purified with silica gel column and 1:15 ethyl acetate/CH2Cl2. Obtained the desired compound (light yellow oil) in 41% yield.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:40]1[CH:45]=[CH:44][N:43]=[CH:42][N:41]=1)[S:7]([C:10]1[C:37]([F:38])=[CH:36][C:13]([O:14][C@H:15]2[CH2:20][CH2:19][CH2:18][CH2:17][C@@H:16]2[C:21]2[C:22]([NH:32][C:33](=[O:35])[CH3:34])=[N:23][N:24](C3CCCCO3)[CH:25]=2)=[C:12]([CH3:39])[CH:11]=1)(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O.ClCCl>CO>[F:38][C:37]1[C:10]([S:7](=[O:9])(=[O:8])[NH:6][C:40]2[CH:45]=[CH:44][N:43]=[CH:42][N:41]=2)=[CH:11][C:12]([CH3:39])=[C:13]([CH:36]=1)[O:14][C@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@@H:16]1[C:21]1[C:22]([NH:32][C:33](=[O:35])[CH3:34])=[N:23][NH:24][CH:25]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(C)c(O[C@H]3CCCC[C@@H]3c3cn(C4CCCCO4)nc3NC(C)=O)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1n[nH]cc1[C@H]1CCCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1C
Yield: 62.7 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 22c by using the N-{4-[(1R*,2S*)-2-{4-[(2,4-dimethoxybenzyl)(pyrimidin-4-yl)sulfamoyl]-5-fluoro-2-methylphenoxy}cyclohexyl]-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl}acetamide (78 mg, 0.108 mmol) prepared in Example 96b, triethylsilane (0.10 mL), trifluoroacetic acid (0.50 mL), dichloromethane (2.0 mL) and methanol (1.0 mL), to yield the title compound (33.1 mg, 63%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][C:5]2([CH3:13])[CH3:12].Br[C:15]1[CH:16]=[N:17][CH:18]=[C:19]([N:21]2[CH2:25][CH2:24][C@H:23]([O:26][Si](C(C)(C)C)(C)C)[CH2:22]2)[CH:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([C:15]1[CH:16]=[N:17][CH:18]=[C:19]([N:21]3[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22]3)[CH:20]=1)[C:5]2([CH3:13])[CH3:12]
Reactant: CC1(C)NC(=O)c2ccc(Cl)cc21
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCN(c2cncc(Br)c2)C1
Product: CC1(C)c2cc(Cl)ccc2C(=O)N1c1cncc(N2CC[C@H](O)C2)c1

Procedure:
In analogy to the procedure described for the preparation of example 137, 5-chloro-3,3-dimethyl-2,3-dihydro-isoindol-1-one (intermediate A-12), 3-bromo-5-[(S)-3-(tert-butyl-dimethyl-silanyloxy)-pyrrolidin-1-yl]-pyridine was used (step C) to yield the title compound as a white solid. MS: 358.1 (M+H+).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH:20](N(C(C)C)CC)(C)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[C:44]1([C:50]2[CH:51]=[CH:52][C:53]3[O:57][CH:56]=[N:55][C:54]=3[CH:58]=2)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C(Cl)(Cl)Cl>[CH2:20]=[C:56]1[N:55]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:54]2[CH:58]=[C:50]([C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[CH:51]=[CH:52][C:53]=2[O:57]1
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: CCN(C(C)C)C(C)C
Reactant: c1ccc(-c2ccc3ocnc3c2)cc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: C=C1Oc2ccc(-c3ccccc3)cc2N1CCCCCCCCCCCCCCCCCC
Reaction time: 8 h
Yield: 76.1 %

Procedure:
Powdered 1-octadecanol (15.4 g, 56.9 mmol) and diisopropylethylamine (9.9 mL, 56.9 mmol) are dissolved in 200 mL CHCl3 (dried over molecular sieves). To the above stirred solution is added trifluoromethanesulfonic anhydride (10.4 mL) dropwise over a period of 1 hours. Powdered 5-phenylbenzoxazole (16.7 g, 79.7 mmol) is then added portion-wise over a period of 10 minutes. After stirring overnight, the solution is washed with water and dried with anhydrous Na2SO4. The solution is loaded onto a large silica column and eluted with MeOH/CHCl3. The product is obtained as a colorless solid (20 g, 77%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][O:22][CH2:23][CH3:24].C(N(CC)CC)C.[CH:32]([S:35](Cl)(=[O:37])=[O:36])([CH3:34])[CH3:33].O>C(Cl)Cl>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH2:21][O:22][CH2:23][CH3:24])[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][S:35]([CH:32]([CH3:34])[CH3:33])(=[O:37])=[O:36])[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CCOCCN
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCOCCNS(=O)(=O)C(C)C
Reaction time: 18 h
Yield: 23.7 %

Procedure:
A solution of the compound of Example 53, 1-[2-(2-aminoethoxy)ethyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine (980 mg, 2.98 mmol) in 20 mL CH2Cl2 was treated with triethylamine (1.04 mL, 7.45 mmol) and chilled in an ice water bath. With vigorous stirring, the solution was treated dropwise with isopropylsulfonyl chloride (0.351 mL, 3.13 mmol). After 18 h, the reaction was treated with 25 mL CH2Cl2 and 25 mL water and the layers were separated. The organic portion was washed with 1% Na2CO3 solution, water, brine, dried over Na2SO4, filtered and concentrated to yield a yellow foam. Purification by column chromatography (SiO2, 90:10:0.5 CHCl3:MeOH:NH4OH) followed by recrystallization from CH2Cl2/hexanes gave 308 mg of N-(2-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)propane-2-sulfonamide as a light yellow solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:9][C:10]1[C:11]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C@@H:19]2[CH3:28])=[N:12][C:13]([Cl:17])=[N:14][C:15]=1[CH3:16]>CN(C)C=O>[ClH:17].[CH3:9][C:10]1[C:11]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C@@H:19]2[CH3:28])=[N:12][C:13]([N:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH3:1])=[N:14][C:15]=1[CH3:16]
Reactant: CNc1ccccc1
Reactant: Cc1nc(Cl)nc(N2CCc3ccccc3[C@@H]2C)c1C
Solvent: CN(C)C=O
Product: Cc1nc(N(C)c2ccccc2)nc(N2CCc3ccccc3[C@@H]2C)c1C
Product: Cl
Yield: 36.9 %

Procedure:
After N-methylaniline(1.04 ml, 9.6 mmol) was added to a mixture solution of (S)-5,6-dimethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-chloropyrimidine(1.4 g, 4.8 mmol) and dimethylformamide(10 ml), 0.70 g of the titled compound was obtained in accordance with the same procedure as in Step 2 of Example 1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Br[CH2:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCOc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 70 h
Yield: 75.8 %

Procedure:
A partial suspension of m-nitrophenol (6.0 g; 43.0 mmoles), N-(3-bromopropyl)phthalimide (10.0 g; 37.0 mmoles) and potassium carbonate (8.0 g; 58.0 mmoles) in 50 ml of DMF was stirred at ambient temperature for 70 hours. The reaction mixture was diluted with 80 ml of water and filtered to give product. Recrystallization from 2-methoxyethanol yielded 9.15 g of the title compound, mp 149°-152°.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[C:35]([NH:37][CH3:38])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[C:35]([NH:37][CH3:38])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCN(C(=O)NC)c1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c2c1
Solvent: O=C(O)C(F)(F)F
Product: CCCCCN(C(=O)NC)c1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)O)cc3)c2c1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(N-methylaminocarbonyl-n-pentylamino)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid,
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([O:15][CH2:16][C:17]([OH:19])=O)[C:12]2[C:7](=[CH:8][C:9]([CH3:20])=[CH:10][CH:11]=2)[N:6]=1)=[O:4].FC1C(O)=C(F)C(F)=C(F)C=1F.[CH3:33][O:34][CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.C(N1CCOCC1)C>CN(C=O)C.C(Cl)Cl.C(Cl)CCl>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([O:15][CH2:16][C:17]([N:38]2[CH2:39][CH2:40][CH:35]([O:34][CH3:33])[CH2:36][CH2:37]2)=[O:19])[C:12]2[C:7](=[CH:8][C:9]([CH3:20])=[CH:10][CH:11]=2)[N:6]=1)=[O:4]
Reactant: COC1CCNCC1
Reactant: COC(=O)c1cc(OCC(=O)O)c2ccc(C)cc2n1
Agent: CCN1CCOCC1
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1cc(OCC(=O)N2CCC(OC)CC2)c2ccc(C)cc2n1

Procedure:
To a solution of 1000 mg 4-Carboxymethoxy-7-methyl-quinoline-2-carboxylic acid methyl ester in 5 ml DMF were added 956 mg pentafluorophenol and 994 mg EDC. The mixture was stirred under exclusion of moisture until LCMS indicated complete conversion to the corresponding pentafluorophenolester. 4-methoxypiperidine (379 mg) was mixed with 1.3 ml N-ethylmorpholine and 10 ml DMF and this mixture added dropwise to the solution of the pentafluorophenolester. After 12 h the reaction mixture was diluted with DCM and washed with aqueous LiCl (4%) and saturated aqueous NaHCO3. The crude product obtained after evaporation of the solvent was purified by flash chromatography on silica eluting with ethyl acetate/heptane gradient. Yield: 980 mg.