Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][N:30]([CH3:43])[C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]([CH:41]=O)=[CH:33][CH:32]=1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:41][C:34]3[C:35]4[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:31]([N:30]([CH3:29])[CH3:43])=[CH:32][CH:33]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)c1ccc(C=O)c2ccccc12
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: CN(C)c1ccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c2ccccc12

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 4-dimethylamino-naphthalene-1-carbaldehyde according to the procedure of Example 66. MS (ESI) m/z 562.
Reaction SMILES: CC(C)([O-])C.[K+].C1(C)C=CC(S([CH2:16][N+:17]#[C-])(=O)=O)=CC=1.[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[C:23]([O:29][CH3:30])[CH:22]=1.CO>COCCOC>[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][C:16]#[N:17])=[C:23]([O:29][CH3:30])[CH:22]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: COc1cc(Br)ccc1C=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: COCCOC
Product: COc1cc(Br)ccc1CC#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
To a solution of potassium tert-butoxide (6.5 g, 0.058 mol) in 1,2-dimethoxyethane (150 mL) was added p-toluenesulfonylmethyl isocyanide (5.6 g, 0.029 mol) portionwise at −78° C. Then a solution of 4-bromo-2-methoxybenzaldehyde (6.3 g, 0.029 mol) in 1,2-dimethoxyethane was added dropwise and the reaction mixture was warmed to room temperature. The mixture was stirred at room temperature for 1 hour and methanol (150 mL) was added, then heated to reflux and stirred for 2 hours. Solvent was evaporated, and saturated ammonium chloride (100 mL) was added and extracted with ethyl acetate (100 mL×2). The organic layers were combined, dried over sodium sulfate and concentrated in vacuo to give a residue, which was purified by combiflash (Petroleum ether/EtOAc=10:1 to 5:1) to give the title compound (5.4 g, 82%) as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.25 (d, 1H), 7.12 (d, 1H), 7.03 (s, 1H), 3.87 (s, 3H), 3.63 (s, 2H)
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[F:6][C@@H:7]1[CH2:11][NH:10][C@H:9]([C:12]#[N:13])[CH2:8]1.C(N(CC)CC)C.S(=O)(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][CH2:2][C:3]([N:10]1[CH2:11][C@@H:7]([F:6])[CH2:8][C@H:9]1[C:12]#[N:13])=[O:4]
Reactant: N#C[C@@H]1C[C@H](F)CN1
Reactant: O=C(Cl)CCl
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CCl
Temperature: 0 °C
Yield: 55.4 %

Procedure:
Chloroacetyl chloride (11.13 g, 98.5 mmol) was dissolved in 120 mL of dichloromethane with stirring under argon atmosphere. Upon cooling to 0° C., (2S,4S)-4-fluoropyrrolidine-2-carbonitrile 13f (11.4 g, 75.7 mmol) was dissolved in 400 mL of dichloromethane followed by addition of triethylamine (16.1 g, 158.97 mmol). To a solution of chloroacetyl chloride in dichloromethane was added the above mentioned mixture in 30 minutes. The reaction mixture was reacted at 0° C. for 2 hours and diluted with 200 mL of ice water and 150 mL of dichloromethane. The separated organic phase was neutralized with saturated sodium bisulfate, washed with 300 mL of water and 300 mL of saturated brine successively, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (2S,4S)-1-(2-chloroacetyl)-4-fluoropyrrolidine-2-carbonitrile 13g (8 g, yield 60%) as a white crystal.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19](Cl)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.[OH-].[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2Cl)CC1
Reactant: C1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2nccnc2N2CCCCC2)CC1
Temperature: 180 °C
Yield: 98.8 %

Procedure:
Place 3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid t-butyl ester (0.4 g, 1.34 mmol, 1 eq) and piperidine (662 μL, 6.69 mmol, 5 eq) in a microwave vial, seal and heat in a CEM™ microwave to 180° C. with up to 300 Watt power for 1 hr. (Caution—pressure build up). Add 2 M aqueous sodium hydroxide solution (5 mL) and DCM (5 mL), and then pass through a hydrophobic frit to separate. Extract the aqueous layer twice with DCM (5 mL) combine the organic extracts and concentrate to give 3′-piperidin-1-yl-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid t-butyl ester (0.46 g, 99%). MS (m/z): 348.3 (M+1).
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][CH2:13]/[CH:14]=[CH:15]/[CH:16]=[CH:17][CH2:18][CH2:19][CH3:20])[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[C:21]([C:23]#[C:24][C:25]#[N:26])#[N:22]>O1CCCC1.C1(C=CC(O)=CC=1)O>[C:21]([C:23]1[CH:17]([CH2:18][CH2:19][CH3:20])[CH:16]=[CH:15][CH:14]([CH2:13][CH2:12][C@H:9]2[CH2:8][CH2:7][C@H:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:11][CH2:10]2)[C:24]=1[C:25]#[N:26])#[N:22]
Reactant: N#CC#CC#N
Reactant: CCCC=C/C=C/CC[C@H]1CC[C@H](CCCCC)CC1
Agent: Oc1ccc(O)cc1
Solvent: C1CCOC1
Product: CCCCC[C@H]1CC[C@H](CCC2C=CC(CCC)C(C#N)=C2C#N)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 61.1 %

Procedure:
9.5 g of 1-(trans-4-pentylcyclohexyl)-3,5-trans-nonadiene were dissolved in 62 ml of tetrahydrofuran in a round flask and treated with 14 mg of hydroquinone. A solution of 3.2 g of dicyanoacetylene in 18 ml of tetrahydrofuran was subsequently added by means of a pipette and the pipette was rinsed twice with 9 ml of tetrahydrofuran each time. The mixture was stirred at room temperature for 2.5 hours and then overnight at 40°-45° C. (bath temperature) under nitrogen. The dark brown solution was thereafter concentrated in vacuo. The resulting dark brown oil (10.9 g) was chromatographed on silica gel using hexane, hexane/toluene (volume ratio 1:1) and toluene, there being obtained 4.2 g of unreacted 3-cis, 5-trans-diene as a colourless oil and 7.4 g of 1,2-dicyano-3-[2-(trans-4-pentylcyclohexyl)ethyl]-6-propyl-1,4-cyclohexadiene as a slightly yellowish oil.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:9]=[C:10]3[CH:16]=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[F:19][C:20]1[C:25]([CH:26]=[O:27])=[C:24]([F:28])[CH:23]=[CH:22][C:21]=1[NH:29][S:30]([CH2:33][CH2:34][CH3:35])(=[O:32])=[O:31]>CO>[F:19][C:20]1[C:25]([CH:26]([OH:27])[C:16]2[C:10]3[C:11](=[N:12][CH:13]=[C:8]([NH:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH:9]=3)[NH:14][CH:15]=2)=[C:24]([F:28])[CH:23]=[CH:22][C:21]=1[NH:29][S:30]([CH2:33][CH2:34][CH3:35])(=[O:32])=[O:31]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C=O)c1F
Reactant: c1ccc(Nc2cnc3[nH]ccc3c2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(O)c2c[nH]c3ncc(Nc4ccccc4)cc23)c1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To phenyl-(-1H-pyrrolo[2,3-b]pyridine-5-yl)-amine (70, 17.0 mg, 0.09 mmol) in methanol (5.0 mL) were added potassium hydroxide (92.0 mg, 1.6 mmol) and propane-1-sulfonic acid (2,4-difluoro-3-formyl-phenyl)-amide (73, 19.0 mg, 0.072 mmol, prepared as described in Example 7) under an atmosphere of nitrogen. The reaction was stirred for 12 hours at room temperature. The reaction was concentrated and purified by silica gel column chromatography eluting with 1% methanol in dichloromethane to give the compound (71, 17 mg, 50%). MS (ESI) [M+H+]+=473.5.
Reaction SMILES: [Cl:1][C:2]1[C:12]([CH:13]=O)=[CH:11][CH:10]=[C:9]([Si:15]([CH3:18])([CH3:17])[CH3:16])[C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5].[N+:19]([CH3:22])([O-:21])=[O:20].[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[C:12](/[CH:13]=[CH:22]/[N+:19]([O-:21])=[O:20])=[CH:11][CH:10]=[C:9]([Si:15]([CH3:18])([CH3:17])[CH3:16])[C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5]
Reactant: CCNC(=O)c1c([Si](C)(C)C)ccc(C=O)c1Cl
Reactant: C[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCNC(=O)c1c([Si](C)(C)C)ccc(/C=C/[N+](=O)[O-])c1Cl
Yield: 26.2 %

Procedure:
To a solution of the compound of Example 223 (0.199 g, 0.7 mmol) in methanol (5 mL) at 0° C. was added nitromethane (0.3 mL, 5.0 mmol) and 2.5 N NaOH (2.3 mL, 5.8 mmol) portionwise over 2 h. The suspension was dissolved by addition of ice-cold water and cold 2N HCl (10 mL) was added. The precipitate was filtered and washed with water to afford the crude title compound. The crude product was purified by recrystallization from aq methanol to afford the title compound as a light yellow fluffy solid (60 mg, 26%). m.p. 104°-106° C.
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][C:7]3[CH2:13][CH2:12][C@@H:11]([CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])[C:8]=32)=[N:3]1.[Br:20]N1C(=O)CCC1=O>C(#N)C>[Br:20][C:10]1[N:2]([CH3:1])[N:3]=[C:4]2[C:9]=1[C:8]1[C@H:11]([CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])[CH2:12][CH2:13][C:7]=1[CH:6]=[CH:5]2
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)NCC[C@@H]1CCc2ccc3nn(C)cc3c21
Solvent: CC#N
Product: CC(=O)NCC[C@@H]1CCc2ccc3nn(C)c(Br)c3c21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.4 %

Procedure:
To a solution of N-{2-[(8S)-2-methyl-2,6,7,8-tetrahydrocyclopenta[e]indazol-8-yl]ethyl}acetamide (50 mg, 0.194 mmol) in acetonitrile (2.0 mL) was added N-bromosuccinimide (34.6 mg, 0.194 mmol), and the mixture was stirred at room temperature for 15 min. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→5/95) to give the title compound (60.3 mg, yield 92%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:15]C)=[CH:4][C:5]2[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[S:7][C:6]=2[C:13]=1[Cl:14].Cl.N1C=CC=CC=1>>[Cl:1][C:2]1[C:3]([OH:15])=[CH:4][C:5]2[CH:9]=[C:8]([CH:10]([CH3:11])[CH3:12])[S:7][C:6]=2[C:13]=1[Cl:14]
Reactant: COc1cc2cc(C(C)C)sc2c(Cl)c1Cl
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)c1cc2cc(O)c(Cl)c(Cl)c2s1
Reaction time: 4.5 h
Yield: 98.5 %

Procedure:
A mixture of 6.00 g of 6,7-dichloro-2-isopropyl-5-methoxybenzo[b]thiophene and 50 g of pyridine hydrochloride, is heated under nitrogen with stirring in a 185° bath for 4.5 hours and at 200° for one hour. The reaction is cooled, triturated with 500 ml of water and extracted with three 150 ml-portions of ether. The combined ether extracts are washed with one 150 ml-portion of 2 N hydrochloric acid, two 150 ml-portions of water and one 50 ml-portion of saturated sodium chloride solution and dried over magnesium sulfate to give 5.61 g of 6,7-dichloro-5-hydroxy-2-isopropylbenzo[b]thiophene as an amber oil which crystallized on standing to a product having mp 44.5-46.5. A sample recrystallized twice from hexane melts at 44.5°-46.5°.
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1.[CH2:16]([NH2:18])[CH3:17]>C1COCC1>[CH2:16]([NH:18][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1)[CH3:17]
Reactant: CCN
Reactant: COc1ccc2nc(Cl)c(C=O)cc2c1
Solvent: C1CCOC1
Product: CCNc1nc2ccc(OC)cc2cc1C=O
Temperature: 160 °C
Reaction time: 6 h
Yield: 76 %

Procedure:
To a stirred solution of 2-chloro-6-methoxyquinoline-3-carbaldehyde (1.51 g, 6.80 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added ethylamine (2 M in THF, 33.8 mL, 67.6 mmol) and the mixture was stirred at 160° C. for 6 h under microwave irradiation. After cooling to RT, the volatiles were removed under vacuum at 40° C. and the resulting yellow oil was taken up in a mixture of THF:1 N aq. HCl=1:1 (50 mL) and stirred for 15 min at RT. THF was removed at 40° C. under vacuum and the residue was then neutralised with a saturated NaHCO3 aqueous solution before to be extracted with CH2Cl2 (100 mL). The organic phase was washed with brine (20 mL), dried over MgSO4, filtered, and concentrated at 40° C. under vacuum to give 2-(ethylamino)-6-methoxyquinoline-3-carbaldehyde SLA 28162 as an orange oil (1.19 g, 76% yield).
Reaction SMILES: [C:1]([C:4]1[CH:19]=[CH:18][C:7]([O:8][CH2:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[CH:13]=O)=[C:6]([CH2:20][CH2:21][CH3:22])[C:5]=1[OH:23])(=[O:3])[CH3:2].[S:24]1[CH2:30][C:28](=[O:29])[NH:27][C:25]1=[S:26].C([O-])(=O)C.[Na+]>C(O)(=O)C>[C:1]([C:4]1[CH:19]=[CH:18][C:7]([O:8][CH2:9][C:10]2[CH:11]=[C:12](/[CH:13]=[C:30]3/[C:28](=[O:29])[NH:27][C:25](=[S:26])[S:24]/3)[CH:15]=[CH:16][CH:17]=2)=[C:6]([CH2:20][CH2:21][CH3:22])[C:5]=1[OH:23])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCc2cccc(C=O)c2)ccc(C(C)=O)c1O
Reactant: O=C1CSC(=S)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCc1c(OCc2cccc(/C=C3\SC(=S)NC3=O)c2)ccc(C(C)=O)c1O

Procedure:
Under a nitrogen atmosphere in a three-neck round bottom flask 3-[(4-acetyl-3-hydroxy-2-propylphenoxy)methyl]benzaldehyde (0.73 g, 2.34 mmol), rhodanine (0.34 g, 2.55 mmol), sodium acetate (0.23 g, 2.80 mmol) and acetic acid (20 ml) were combined and then heated to reflux. The reaction mixture was allowed to reflux. The progress of the reaction was monitored by thin layer chromatography.
Reaction SMILES: C[O:2][C:3](=[O:24])[CH2:4][C@@H:5]1[C:17]2[NH:16][C:15]3[C:10](=[CH:11][C:12]([F:22])=[CH:13][C:14]=3[S:18]([CH3:21])(=[O:20])=[O:19])[C:9]=2[C:8](=[O:23])[CH2:7][CH2:6]1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][C:30]([C@H:33](O)[CH3:34])=[CH:29][CH:28]=1>>[F:22][C:12]1[CH:11]=[C:10]2[C:15](=[C:14]([S:18]([CH3:21])(=[O:19])=[O:20])[CH:13]=1)[N:16]([C@H:33]([C:30]1[CH:29]=[CH:28][C:27]([C:26]([F:25])([F:36])[F:37])=[CH:32][CH:31]=1)[CH3:34])[C:17]1[C@@H:5]([CH2:4][C:3]([OH:2])=[O:24])[CH2:6][CH2:7][C:8](=[O:23])[C:9]2=1
Reactant: COC(=O)C[C@H]1CCC(=O)c2c1[nH]c1c(S(C)(=O)=O)cc(F)cc21
Reactant: C[C@@H](O)c1ccc(C(F)(F)F)cc1
Product: C[C@@H](c1ccc(C(F)(F)F)cc1)n1c2c(c3cc(F)cc(S(C)(=O)=O)c31)C(=O)CC[C@@H]2CC(=O)O

Procedure:
The procedures described in Example 1 were followed using compound of Step 1 and (1R)-1-[4-(trifluoromethyl)phenyl]ethanol to provide the title compound following the hydrolysis of the corresponding methyl ester. MS (+APCI) m/z 511.9 (M)+
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([NH:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:14]([CH:16]=1)[NH2:15].[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1.OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]2[N:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:29]([C:28]3[CH:31]=[CH:32][C:25]([Cl:24])=[CH:26][CH:27]=3)=[N:15][C:14]=2[CH:16]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NC1CCOCC1
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ccc(-c2nc3cc(-c4nc5ccccc5o4)ccc3n2C2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.2 %

Procedure:
To a solution of 5-(benzoxazol-2-yl)-2-(tetrahydropyran-4-yl)aminoaniline (see Working Example 20-2) (150 mg, 0.485 mmol) in dimethylformamide (3 mL) was added p-chlorobenzaldehyde (81.8 mg, 0.582 mmol) and oxone (179 mg, 0.291 mmol), and this was stirred at room temperature for 2 hours. After the reaction was complete, aqueous potassium carbonate solution was added, and after this was filtered and washed with water, drying yielded the title compound (188 mg, 90% yield) as colorless crystals.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:21])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].CC1(C)C(C)(C)OB([C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=2)O1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[CH3:8][C:7]1[C:2]([C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=2)=[CH:3][C:4]([NH:9][C:10](=[O:21])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[CH:5][CH:6]=1
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1I
Reactant: CC1(C)OB(c2ccc([N+](=O)[O-])cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1ccc([N+](=O)[O-])cc1
Temperature: 90 °C
Yield: 95.6 %

Procedure:
To N-(3-iodo-4-methylphenyl)-3-(trifluoromethyl)benzamide (400.0 mg, 0.99 mmol) was added 4,4,5,5-tetramethyl-2-(4-nitrophenyl)-1,3,2-dioxaborolane (270 mg, 1.1 mmol) followed by toluene (8.2 mL), then ethanol (1.15 mL), and K2CO3 (270 mg, 2.0 mmol in 1.1 mL water). The reaction was degassed with N2, then tetrakis(triphenylphosphine)palladium(0) (60 mg, 0.05 mmol) was added. The reaction was degassed again, and then heated at reflux under N2 atmosphere at 90° C. until LCMS and TLC indicated complete reaction, about 16 hours. The reaction was then cooled to ambient temperature, transferred to a separatory funnel and partitioned between water and EtOAc. The phases were separated and the organic phase was washed with water, then saturated aqueous NaCl, dried (MgSO4) and then evaporated to dryness to leave the crude product, which was purified by column chromatography to give the product (379 mg, 95.79%). 1H NMR (400 MHz, CDCl3): δ 8.29 (m, 2H), 8.12 (s, 1H), 8.07 (d, 1H), 7.82 (m, 2H), 7.5-7.7 (m, 5H), 7.33 (d, 1H), 2.26 (s, 3H). MS (EI) m/z=401 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH:10]([NH2:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([O-])([O-])=O.[K+].[K+].ClC(OCC)=O.B>C1COCC1.O>[CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[C@H:10]([NH:21][CH3:22])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Reactant: O=C([O-])[O-]
Agent: B
Agent: CCOC(=O)Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CN[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 51.5 %

Procedure:
To a solution of rac-(3S,4R)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylamine (0.54 g, 1.68 mmol) in THF (5 ml) was added a solution of K2CO3 (0.46 g, 3.36 mmol) in H2O (3 ml). After 10 minutes, ethyl chloroformate (0.18 ml, 1.85 mmol) was added and stirring was continued at RT for an additional 2 h. The intermediate carbamate was then extracted with Et2O, dried over Na2SO4 and concentrated under vacuo to give viscous oil. The oil was taken up in THF (5 ml) and a solution of borane in THF (1M) was added (6.7 ml). The reaction mixture was then heated at 65° C. over night, cooled to RT and carefully quenched with conc. HCl (5 ml). The mixture was then heated at 80° C. for 2 h, cooled to RT, concentrated under vacuo, diluted with Et2O (20 ml) and neutralized with an aqueous solution of NaHCO3. The organic phases were dried over Na2SO4 and the product purified by flash chromatography (SiO2, CH2Cl2/MeOH 9:1) to afford 0.29 g (51%) of rac-[(3S,4R)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-amine as a colorless oil. ES-MS m/e: 335.3 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21]C)[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH2:23][CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:5][C:4]=2[N:3]=1>ClCCl>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][OH:21])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH2:23][CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:5][C:4]=2[N:3]=1
Reactant: COCc1nc2c(N)nc3cc(CCS(C)(=O)=O)ccc3c2n1CC(C)(C)O
Solvent: ClCCl
Product: CC(C)(O)Cn1c(CO)nc2c(N)nc3cc(CCS(C)(=O)=O)ccc3c21
Temperature: 25 °C
Reaction time: 18 h
Yield: 38.2 %

Procedure:
A stirring solution of 1-{4-amino-2-(methoxymethyl)-7-[2-(methylsulfonyl)ethyl]-1H-imidazo[4,5-c]quinolin-1-yl}-2-methylpropan-2-ol (340 mg, 0.84 mmol) in dichloromethane (40 mL) was sealed with a septum and purged with nitrogen gas. The solution was cooled in an ice/water bath and a 1.0 M solution of boron tribromide in dichloromethane (4.2 mL) was added via syringe. The resulting mixture was stirred for 18 hours while warming to ambient temperature. The mixture was cooled back to 0° C. in an ice/water bath and the second portion of boron tribromide (1.0 M, 4.2 mL) was added. The reaction was stirred for 3 hours while warming to ambient temperature. Methanol (30 mL) was added and the mixture was concentrated to a purple foam. The foam was dissolved in 10% aqueous hydrochloric acid (30 ml) and washed with chloroform (2×25 mL). The aqueous fraction was neutralized by the slow addition of solid potassium carbonate until the pH reached 11. The aqueous fraction was extracted with chloroform (2×50 mL) and allowed to stand overnight. The resulting solid was recovered by filtration to provide 126 mg of 1-{4-amino-2-(hydroxymethyl)-7-[2-(methylsulfonyl)ethyl]-1H-imidazo[4,5-c]quinolin-1-yl}-2-methylpropan-2-ol
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7](Cl)[N:6]=1)[CH:2]=[CH2:3].[CH2:19]([NH2:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>O>[CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7]([NH:26][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCNc1nc(Cl)nc2ccc([N+](=O)[O-])cc12
Reactant: CCCCCCCN
Solvent: O
Product: C=CCNc1nc(NCCCCCCC)nc2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
A mixture of 200 mg (0.76 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline and 1.55 g (13.49 mmol) of heptylamine was stirred at room temperature for 2 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate, washing brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 228 mg (87.8%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15](=O)[C:16]2[CH:21]=[CH:20][C:19]3[O:22][CH2:23][O:24][C:18]=3[CH:17]=2)=[O:8])=[CH:5][CH:4]=1.CC(C)=O.C(=O)=O.[NH3:35]>>[OH:8][C:7]1([C:6]2[CH:26]=[CH:27][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:15]([C:16]2[CH:21]=[CH:20][C:19]3[O:22][CH2:23][O:24][C:18]=3[CH:17]=2)=[N:35]1
Reactant: N
Reactant: COc1ccc(C(=O)c2ccccc2C(=O)c2ccc3c(c2)OCO3)cc1
Agent: O=C=O
Solvent: CC(C)=O
Product: COc1ccc(C2(O)N=C(c3ccc4c(c3)OCO4)c3ccccc32)cc1
Temperature: 70 °C
Yield: 90 %

Procedure:
A bomb was charged 1-(4-methoxybenzoyl)-2-(3,4-methylenedioxybenzoyl)benzene (1.0 g, 2.8 mmol) was cooled to -78° C. (acetone/dry ice bath), and liquid ammonia (20 ml) was added and the vessel was sealed. The reaction was heated at 70° C. reaching a steady pressure of 300 psi for 24 h. The pressure was slowly released after the mixture had cooled to room temperature, and the brown residue was partitioned between ethyl acetate and water. The organic extract was acidified with 3N HCl. The resulting aqueous layer (containing the hydrochloride salt) was washed with ethyl acetate, then basified by treatment with concentrated ammonium hydroxide and extracted with ethyl acetate. The combined organic extract was successively washed with water brine and dried (MgSO4). Removal of the solvent under reduced pressure gave an isomeric mixture of the title compound as a brown foam (0.900 g, 90%).