Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8].[Cl:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:17][C:16]2[CH:18]=[CH:19][C:13]([Cl:12])=[C:14]([N+:20]([O-:22])=[O:21])[CH:15]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(N=C=O)cc1Cl
Reactant: Nc1ccc(Cl)c([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=O)Nc2ccc(Cl)c([N+](=O)[O-])c2)cc1Cl

Procedure:
A solution of 29.8 mmol (5 g) of 3-chloro-4-methylphenyl isocyanate in 90 ml of toluene is heated to 70° C., and 29.8 mmol (5.15 g) of 4-chloro-3-nitroaniline are poured in. The solution is heated at reflux for 24 hours. The reaction mixture is cooled using ice, and the precipitate formed is filtered off and then rinsed with diethyl ether to yield the expected product.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:17][C:18]([F:29])([C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])[C:19](Cl)=[O:20]>ClCCl.Cl>[F:17][C:18]([F:29])([C:22]([F:27])([F:28])[C:23]([F:24])([F:25])[F:26])[C:19]([NH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)=[O:20]
Reactant: O=C(Cl)C(F)(F)C(F)(F)C(F)(F)F
Reactant: N#Cc1ccc(N)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(NC(=O)C(F)(F)C(F)(F)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.9 %

Procedure:
A mixture of 4-aminobenzonitrile (1.58 g), triethylamine (1.36 g), and dichloromethane (20 mL) was cooled in ice under a nitrogen atmosphere. To this mixture was added perfluorobutyryl chloride (3.11 g) in dichloromethane (10 mL) and the resulting mixture was allowed to warm to room temperature and was then stirred for three hours. The reaction mixture was diluted with HCl solution (1N, 50 mL) and the layers were partitioned in a separatory funnel. The organic phase was washed with a saturated brine solution, dried over MgSO4, filtered and concentrated with a rotary evaporator. The residue was dissolved in dichloromethane. Upon dilution with hexane the product precipitated to give 1.55 g of 2,2,3,3,4,4,4-heptafluoro-N-[4-(cyano)phenyl]butanamide, m.p. 116°-118° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.N1C=CN=C1.[C:15]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C>[Si:19]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:21])[CH3:20]
Reactant: OCc1cccc(O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cccc(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.3 %

Procedure:
To a solution of 79 g of 3-(hydroxymethyl)phenol in 300 mL of DMF cooled at 0° C. was added 50 g of imidazole followed by 101 g of tert-butyl(chloro)dimethylsilane. The reaction was warmed to rt and stirred overnight. The reaction was quenched with aqueous NH4Cl, extracted with EtOAc and washed with brine, dried over sodium sulfate, evaporated, and purified by flash chromatography (10–30% EtOAc/hexane) to afford 140 g of the title compound as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[CH3:30][O:31][C:32]1[CH:47]=[CH:46][C:35]([C:36]([NH:38][C:39]2[CH:40]=[N:41][CH:42]=[CH:43][C:44]=2[NH2:45])=[O:37])=[CH:34][CH:33]=1.N1C=CC=CC=1>ClCCl.CC=C(C)C.C(Cl)(Cl)Cl.CN(C=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:14]=1[C:15]([NH:45][C:44]1[CH:43]=[CH:42][N:41]=[CH:40][C:39]=1[NH:38][C:36](=[O:37])[C:35]1[CH:34]=[CH:33][C:32]([O:31][CH3:30])=[CH:47][CH:46]=1)=[O:17])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc(C(=O)Nc2cnccc2N)cc1
Reactant: COc1ccc(C(=O)O)c(OCCCNC(=O)OC(C)(C)C)c1
Agent: CC=C(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)Nc2cnccc2NC(=O)c2ccc(OC)cc2OCCCNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Yield: 80 %

Procedure:
2-(3-tert-Butoxycarbonylaminopropoxy)-4-methoxybenzoic acid (1.6 g, 4.94 mmol) was dissolved in dry dichloromethane (20 mL) and DMF (0.5 mL) under nitrogen atmosphere. Oxalyl chloride (0.475 mL, 5.43 mmol) was added via syringe. Vigorous bubbling occurred. The mixture was stirred until gas evolution ceased, then concentrated in vacuo. The residue was dissolved in amylene-stabilized chloroform (20 mL), transferred to an addition funnel, then added dropwise over 2 hours to an ice cold solution of N3-(4-methoxybenzoyl)-3,4-pyridinediamine (1.0 g, 4.11 mmol) in amylene-stabilized chloroform (30 mL) and pyridine (2 mL, 24.7 mmol). The mixture was allowed to warm to room temperature and stir for 2.5 days. The resulting slurry was diluted with dichloromethane (50 mL) and washed twice with saturated NaHCO3, once with brine, then dried and concentrated in vacuo. Purification on a 6 mm chromatotron rotor with isocratic 96:3:1 CHCl3:MeOH:triethylamine yielded about 80% pure material that was carried on directly.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:16])=[C:6]([C:8](=[O:15])[CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)[CH:7]=1.[CH3:17][Mg]Br>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:16])=[C:6]([C:8]([OH:15])([CH3:17])[CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)[CH:7]=1
Reactant: O=C(Cn1ccnc1)c1cc(F)ccc1O
Reactant: C[Mg]Br
Product: CC(O)(Cn1ccnc1)c1cc(F)ccc1O
Yield: 53.2 %

Procedure:
The general procedure of Example 1 was repeated using 1-(5-fluoro-2-hydroxyphenyl)-2-(1H-1-imidazolyl)-1-ethanone [compound (5-2)] and methylmagnesium bromide, to thereby yield 4-fluoro-2-(1-hydroxy-2-(1H-1-imidazolyl)-1-methylethyl)phenol as colorless crystals (yield: 53.2%).
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([O:10][CH:11]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]2)=[CH:6][CH:5]=1)([O-])=O>[Pd].CO>[NH2:1][C:4]1[N:9]=[CH:8][C:7]([O:10][CH:11]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2ccc([N+](=O)[O-])nc2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(Oc2ccc(N)nc2)C1
Reaction time: 2 h
Yield: 99.5 %

Procedure:
A 100-mL Parr hydrogenation bottle was purged with nitrogen and charged with 206b (1.07 g, 3.6 mmol), 10% palladium on carbon (50% wet, 0.30 g), and methanol (60 mL). The bottle was evacuated, charged with hydrogen gas to a pressure of 25 psi, and shaken for 2 h on a Parr hydrogenation apparatus. The hydrogen was then evacuated and nitrogen charged to the bottle. The catalyst was removed by filtration through a pad of CELITE® and the filtrate was concentrated under reduced pressure to afford 206c (0.95 g, 99%). MS-ESI: [M+H]+ 266.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[N:11]([CH:12]=[N:13][N:14]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[Br:20]Br.Cl>O>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[N:11]([C:12]([Br:20])=[N:13][N:14]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrBr
Reactant: CC(C)(C)OC(=O)N1CCc2nncn2CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2nnc(Br)n2CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.5 %

Procedure:
To a suspension of 4,5,7,8-tetrahydro-1,2,3a,6-tetraaza-azulene-6-carboxylic acid tert-butyl ester (200 mg, 0.839 mmol) in water was added 10N NaOH until a clear solution was formed. Br2 (0.432 mL, 8.39 mmol) was then added slowly while maintaining a pH of 12 by addition of conc. NaOH. The reaction was stirred at ambient temperature for 16 hours. The reaction mixture was then acidified to pH ˜4 with 6 M HCl. The organics were extracted three times with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title compound as a white solid (185 mg, 70% yield).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[NH:19][CH:20]=[CH:21][C:14]=23)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12].[CH2:22]([O:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]=1[C:35](Cl)=[O:36])[CH3:23]>CCCCCC.O1CCCC1>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[N:19]([C:35]([C:26]4[C:27]5[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH:33]=[CH:34][C:25]=4[O:24][CH2:22][CH3:23])=[O:36])[CH:20]=[CH:21][C:14]=23)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: CCOc1ccc2ccccc2c1C(=O)Cl
Reactant: COc1ccc(-c2ccnc3[nH]ccc23)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOc1ccc2ccccc2c1C(=O)n1ccc2c(-c3ccc(OC)c(OC)c3)ccnc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (60% dispersion in mineral oil, 39.9 mg, 0.997 mmol) was washed with hexane and put under an atmosphere of nitrogen, and 1 mL of tetrahydrofuran was added. 4-(3,4-dimethoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine (50, 195 mg, 0.767 mmol) in tetrahydrofuran (6.2 mL) was added, and the resulting mixture was stirred for 10 minutes at room temperature. 2-ethoxy naphthoyl chloride (202 mg, 0.844 mmol) in tetrahydrofuran was added. After two hours, the reaction was quenched with water, and the two layers were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded the crude material, which was purified by column chromatography (35-60% ethyl acetate in hexane) to yield the desired product in light yellow solid (48, 262 mg, 0.579 mmol). MS(ESI) [M+H+]+=453.2.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8](O)[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].C(Cl)[Cl:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>CCCCCCC>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([Cl:19])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: ClCCl
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCCCCCC
Product: COC(=O)[C@@H]1C[C@H](Cl)CN1C(=O)OC(C)(C)C
Temperature: 4 °C
Reaction time: 0.75 h
Yield: 89 %

Procedure:
A solution of 374 g (1.48 mol) (2S,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester in 1.61 CH2Cl2 was treated with 680 g (2.6 mol) triphenylphosphine, cooled to 3-5° C. and treated in 10 min with 1.24l (12.8 mol) CCl4, after 2 h at this temperature cooling was stopped, the reaction temperature was raised to 35° C. over a period of 2 h. It was cooled down to 20° C. and stirred for further 45 min. After addition of 4l of n-heptane, the reaction was evaporated to 2.9l, cooled to 0° C., filtered, the residue was treated twice the same way, the third time by dissolving the residue again in 2 of CH2Cl2. The solvents were evaporated and filtered through silicagel with hexane/tert.-buthyl-methylether 9:1 as eluent. Evaporation of the solvents gave 347 g (89%) of (2S,4S)-4-Chloro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester, MS: 246 (MH+).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]=[N:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:14]=2[OH:25])=[CH:7][CH:6]=1.[CH3:26][O:27][CH2:28]Cl.[Cl-].[NH4+]>O1CCCC1.CN(C)C=O>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]=[N:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([C:21]([CH3:22])([CH3:24])[CH3:23])[C:14]=2[O:25][CH2:26][O:27][CH3:28])=[CH:9][CH:10]=1
Reactant: COCCl
Reactant: COc1ccc(N=Nc2cc(OC)cc(C(C)(C)C)c2O)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COCOc1c(N=Nc2ccc(OC)cc2)cc(OC)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
To a suspension of 63 g of 62.5% sodium hydride and 2500 ml of dimethylformamide (DMF) was added dropwise under ice-cooling 3000 ml of a tetrahydrofuran (THF) solution containing 472 g of 2-(4-methoxyphenylazo)-4-methoxy-6-tert-butylphenol. After elevating the temperature to room temperature, the mixture was ice-cooled again, and 133 g of methoxymethyl chloride was added dropwise. After stirring at room temperature for 2 hours, 300 ml of an aqueous saturated ammonium chloride solution was gradually added dropwise to the mixture. THF was removed under reduced pressure, and a saturated saline solution was added to the residue. The mixture was extracted with ethyl acetate. The extract was washed and dried, and the solvent was removed under reduced pressure. The precipitated crystals were recrystallized from a mixed solution of hexane and ethyl acetate to give 520 g of [2-(4-methoxyphenylazo)-4-methoxy-6-tert-butylphenoxy]methoxymethane (yield: 97%, melting point: 102°-103° C., IR: 1610 cm-1).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([CH3:17])[N:14]=[C:15]([CH3:16])[C:3]=12.[CH3:18][NH2:19]>O1CCCC1.C(OCC)(=O)C>[CH3:17][N:13]1[C:4]2=[N:5][CH:6]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:2]([NH:19][CH3:18])=[C:3]2[C:15]([CH3:16])=[N:14]1
Reactant: CN
Reactant: CCOC(=O)c1cnc2c(c(C)nn2C)c1Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc2c(c(C)nn2C)c1NC
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
A mixture of 1.268 g (5 mmol) of ethyl 4-chloro-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate and 7.5 ml (15 mmol) of methylamine in tetrahydrofuran (2.0 molar solution) was stirred at room temperature overnight and refluxed for 2 hours. The solvent was removed to give a white solid. The solid was dissolved in ethyl acetate and the solution washed with H2O, 1M NaHCO3, brine and dried (Na2SO4). The solvent was removed to give a white solid. Crystallization from ethyl acetate gave 0.715 g of white solid; Mass spectrum (ES) 249.2 (M+H).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:12])[C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Cl.[CH2:13]([C:15]1([CH3:22])[NH:19][C:18](=[O:20])[NH:17][C:16]1=[S:21])[CH3:14]>>[CH3:2][N:3]([CH3:12])[C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][S:21][C:16]1[C:15]([CH2:13][CH3:14])([CH3:22])[NH:19][C:18](=[O:20])[N:17]=1
Reactant: CN(C)c1ccccc1CCl
Reactant: CCC1(C)NC(=O)NC1=S
Agent: Cl
Product: CCC1(C)NC(=O)N=C1SCc1ccccc1N(C)C

Procedure:
In the present Example, 2.3 g of 2-dimethylaminobenzylchloride hydrochloride and 1.5 g of 5-ethyl-5-methyl-4-thiohydantoin were reacted following the procedure used in Example 36. Crystallization from diethyl ether-n-hexane gave the desired compound in the form of a needle-like crystal. The yield of this compound was 1.9 g with a yield ratio of 68.6%, and the melting point was 111°-113° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([F:10])[C:3]=1[CH2:11][C:12]([OH:14])=[O:13].[C:15]([O-])(O)=O.[Na+]>CO.Cl>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([F:10])[C:3]=1[CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: COc1cc(F)c(CC(=O)O)c(F)c1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1c(F)cc(OC)cc1F
Yield: 92 %

Procedure:
A solution of PMW04140 (3.37 g, 16.7 mmol) in MeOH (70 mL) containing conc. HCl (15 drops) was heated at reflux overnight. The mixture was allowed to cool and was neutralised with sat aq. NaHCO3. The solvent was removed in vacuo and the residue was dissolved in EtOAc (100 mL) and washed with H2O (100 mL), sat. aq, NaHCO3 (100 mL) and brine (100 mL) then dried (MgSO4) and the solvent was removed in vacuo. The title compound (3.30 g, 92%) was obtained as a pale yellow oil; 1H NMR. (270 MHz, DMSO-d6) 3.61 (2H, s, CH2), 3.69 (3H, s, CH3), 3.76 (3H, s, CH3), 6.40-6.49 (2H, m, ArH); 19F NMR (376.4 MHz, DMSO-d6)-114.4 (d); HRMS (ES+) calcd, for C10H11F2O3 (M++H) 217.0657. found 217.0663; LC/MS (ES+) tr=1.69 min, m/z 216.8 (M+, 100%).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1[C:18]2[N:19]=[CH:20][N:21]([CH2:22][CH2:23][CH2:24][CH2:25][S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1)C1C=CC=CC=1.OS(C(F)(F)F)(=O)=O>ClCCl>[C:29]1([S:26]([CH2:25][CH2:24][CH2:23][CH2:22][N:21]2[C:17]3[C:16]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[N:10]=[C:9]([NH2:8])[C:18]=3[N:19]=[CH:20]2)(=[O:28])=[O:27])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=S(=O)(CCCCn1cnc2c(N(Cc3ccccc3)Cc3ccccc3)nc3ccccc3c21)c1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nc2ccccc2c2c1ncn2CCCCS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 47.2 %

Procedure:
A round bottom flask was charged with a magnetic stir bar, N,N-dibenzyl-1-[4-(phenylsulfonyl)butyl]-1H-imidazo[4,5-c]quinolin-4-amine (1.0 g, 1.78 mmol), triflic acid (2.68 g, 17.83 mmol), and anhydrous dichloromethane (14 mL) under a nitrogen atmosphere. The reaction was judged to be complete after stirring at ambient temperature for 24 hours. The solution was partitioned between chloroform and excess aqueous sodium hydroxide (20%). The layers were separated. The aqueous layer was extracted with chloroform (3×). The organic layers were combined and then concentrated under reduced pressure to afford a light brown solid. The material was purified by chromatography over silica gel (90/10 dichloromethane/methanol) to provide a fine white powder which was recrystallized from acetonitrile to give 1-[4-(phenylsulfonyl)butyl]-1H-imidazo[4,5-c]quinolin-4-amine (0.32 g, 0.84 mmol) as white needles, m.p. 175-177° C. Analysis. Calculated for C20H20N4O2S: % C 63.14; % H, 5.30; % N, 14.73. Found: % C 63.14; % H, 5.24; % N, 14.77
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]3[CH2:11][N:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[F:27])[NH2:23].Cl>CC(O)C.O1CCOCC1>[Cl:19][C:20]1[CH:21]=[C:22]([NH:23][C:2]2[C:3]3[C:10]4[CH2:11][N:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][C:9]=4[S:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:24]=[CH:25][C:26]=1[F:27]
Reactant: CCOC(=O)N1Cc2sc3ncnc(Cl)c3c2C1
Reactant: Nc1ccc(F)c(Cl)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: CCOC(=O)N1Cc2sc3ncnc(Nc4ccc(F)c(Cl)c4)c3c2C1
Temperature: 80 °C
Yield: 121.2 %

Procedure:
Ethyl 4-chloro-5,7-dihydro-6H-pyrrolo[3′,4′:4,5]thieno[2,3-d]pyrimidine-6-carboxylate from Example 21A (250 mg, 0.88 mmol) was dissolved in 2-propanol (2 mL). 3-Chloro-4-fluoroanilin (135 mg, 0.93 mmol) and a 4 M solution of gaseous hydrogen chloride in dioxane (11 μL, 0.04 mmol) were added, and the mixture was heated to 80° C. overnight. The precipitate was collected by suction filtration to yield 419 mg of the crude product (70% purity, 83% yield), which was used in the next step without purification.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH3:14][NH2:15].S(=O)(=O)(O)O>>[CH3:14][NH:15][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: CN
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Product: CNc1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 97.5 %

Procedure:
300 g (1.49 mol) of 4-chloro-3-nitrobenzoic acid were suspended in 836 mL of a 25-30% aqueous solution of methylamine. After heating to reflux temperature, an orange solution was obtained. The solution was kept at reflux temperature for 4 hours. The solution was cooled to room temperature, and pH was adjusted to about 2 by addition of 2M aqueous sulphuric acid. Precipitation of an orange solid was observed, which was isolated by filtration. The filtered cake was washed with 1.5 L of water and subsequently with 750 mL of ethanol. The solid was suspended in 1.6 L of ethanol and stirred at reflux temperature for 30 minutes. After cooling to room temperature, the solid was filtered and dried at 60° C. under vacuum to obtain 285 g of 4-(methylamino)-3-nitrobenzoic acid as an orange powder. Yield: 97.5%. Purity (HPLC, method 2): 97.7%.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][C:9]([F:21])=[CH:8][C:7]=1[N:22]1[CH2:34][CH2:33][C:32]2[N:31]3[C:26]([CH2:27][CH2:28][CH2:29][CH2:30]3)=[CH:25][C:24]=2[C:23]1=[O:35])(=[O:3])[CH3:2].I[C:37]1[N:45]=[C:44]2[C:40]([N:41]=[CH:42][N:43]2[CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])=[C:39]([NH:54][C:55]2[CH:60]=[CH:59][C:58]([N:61]3[CH2:66][CH2:65][N:64]([CH:67]4[CH2:70][O:69][CH2:68]4)[CH2:63][CH2:62]3)=[CH:57][CH:56]=2)[N:38]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:22]2[CH2:34][CH2:33][C:32]3[N:31]4[C:26]([CH2:27][CH2:28][CH2:29][CH2:30]4)=[CH:25][C:24]=3[C:23]2=[O:35])=[CH:8][C:9]([F:21])=[CH:10][C:11]=1[C:37]1[N:45]=[C:44]2[C:40]([N:41]=[CH:42][N:43]2[CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:51])([CH3:52])[CH3:53])=[C:39]([NH:54][C:55]2[CH:56]=[CH:57][C:58]([N:61]3[CH2:66][CH2:65][N:64]([CH:67]4[CH2:68][O:69][CH2:70]4)[CH2:63][CH2:62]3)=[CH:59][CH:60]=2)[N:38]=1)(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)CCOCn1cnc2c(Nc3ccc(N4CCN(C5COC5)CC4)cc3)nc(I)nc21
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCc2c(cc3n2CCCC3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2nc(Nc3ccc(N4CCN(C5COC5)CC4)cc3)c3ncn(COCC[Si](C)(C)C)c3n2)cc(F)cc1N1CCc2c(cc3n2CCCC3)C1=O
Temperature: 100 °C
Yield: 67.1 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 120f (400 mg, 0.82 mmol), 2-iodo-N-(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purin-6-amine 117f (604 mg, 0.99 mmol), PdCl2(dppf) (33 mg, 0.040 mmol), K3PO4 (347 mg, 1.64 mmol), and sodium acetate (134 mg, 1.64 mmol), acetonitrile (15 mL), and water (1 mL). The system was evacuated and refilled with N2. The reaction mixture was heated at 100° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 120g (460 mg, 66%) as a green solid. MS-ESI: [M+H]+ 836.4.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)[N:3]=1.[CH:23]1([OH:27])[CH2:26][CH2:25][CH2:24]1>>[CH:23]1([O:27][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[CH:5]=[C:4]([NH:16][C:17]3[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=3)[N:3]=2)[CH2:26][CH2:25][CH2:24]1
Reactant: OC1CCC1
Reactant: COc1cc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2cc1OC
Product: COc1cc2cc(Nc3cc(C)[nH]n3)nc(OC3CCC3)c2cc1OC

Procedure:
Similar procedure as described in example 10 was used, starting from (1-chloro-6,7-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and cyclobutanol to give (1-cyclobutoxy-6,7-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 355(MH+).
Reaction SMILES: [C:1]12([C:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[F:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18].C(N(CC)CC)C>C(Cl)(Cl)Cl.CCCCCC>[F:14][C:15]1[CH:16]=[C:17]([NH:18][C:11]([C:1]23[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]4)[CH2:2]2)[CH2:8]3)=[O:12])[CH:19]=[CH:20][CH:21]=1
Reactant: Nc1cccc(F)c1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: O=C(Nc1cccc(F)c1)C12CC3CC(CC(C3)C1)C2

Procedure:
Subject 3.6 g. (18 mmoles) of adamantane carboxylic acid chloride, 2.0 g. of m-fluoroaniline and 8.0 ml. of triethylamine to the process of Example 11. Crystallize the residue obtained thereby from a mixture of chloroform-hexane to obtain the title product, m.p. 174°-177° C.