Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.[CH2:9]([NH:11][CH2:12][C:13]([CH2:19][NH:20][C:21]1[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]2[C:22]=1[CH:23]=[N:24][N:25]2[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([OH:18])[C:14]([F:17])([F:16])[F:15])[CH3:10]>>[CH2:9]([N:11]([CH2:12][C:13]([OH:18])([CH2:19][NH:20][C:21]1[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]2[C:22]=1[CH:23]=[N:24][N:25]2[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:14]([F:17])([F:16])[F:15])[C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:8])[CH3:10]
Reactant: O=C(O)c1cccs1
Reactant: CCNCC(O)(CNc1cc(C)cc2c1cnn2-c1ccccc1)C(F)(F)F
Product: CCN(CC(O)(CNc1cc(C)cc2c1cnn2-c1ccccc1)C(F)(F)F)C(=O)c1cccs1

Procedure:
Prepared similarly to Example 11 from 2-thiophenecarboxylic acid and 3-(ethylamino)-1,1,1-trifluoro-2-{[(6-methyl-1-phenyl-1H-indazol-4-yl)amino]methyl}-2-propanol.
Reaction SMILES: COC[N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH:13][S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH:6]=[C:5]1[C:22]([NH2:24])=[O:23].I[CH:26]([CH3:28])[CH3:27].C(=O)([O-])[O-].[K+].[K+].O.O.C(O)(=O)C(O)=O>C(OCC)(=O)C.[Cl-].[Na+].O.O.CO.CN(C)C(=O)C>[CH:26]([N:13]([S:14]([C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)(=[O:15])=[O:16])[C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[NH:4][C:5]([C:22]([NH2:24])=[O:23])=[CH:6]2)([CH3:28])[CH3:27]
Reactant: CC(C)I
Reactant: COCn1c(C(N)=O)cc2cccc(NS(=O)(=O)c3cccs3)c21
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)N(c1cccc2cc(C(N)=O)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Yield: 34.2 %

Procedure:
A mixture of 1-(methoxymethyl)-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (1.0 g), 2-iodopropane (574 mg), potassium carbonate (1.13 g) and N,N-dimethylacetamide (5 ml) was stirred at room temperature for a week. The reaction mixture was diluted with ethyl acetate and saturated brine, and the organic layer was washed with aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate, and filtrated. The filtrate was concentrated, and the residue was subjected to basic silica gel column chromatography, and eluted with ethyl acetate-hexane (2:1) mixture to give a solid. A mixture of this solid, oxalic acid dihydrate (605 mg), methanol (15 ml) and water (15 ml) was stirred at 100° C. for 3.5 days. The reaction mixture was allowed to cool to room temperature, and the obtained solid was collected by filtration, washed successively with water, hexane-diisopropyl ether mixture and hexane. The obtained solid was subjected to basic silica gel column chromatography, and eluted with ethyl acetate-hexane mixture (2:1) to give the title compound (340 mg, yield 34%) as an amorphous solid.
Reaction SMILES: [C:1](/[N:4]=[CH:5]/[N:6]([CH3:8])[CH3:7])(=[S:3])[NH2:2].[C:9](Cl)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>ClCCl>[CH3:7][N:6]([CH3:8])/[CH:5]=[N:4]/[C:1](=[S:3])[NH:2][C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN(C)/C=N/C(N)=S
Solvent: ClCCl
Product: CN(C)/C=N/C(=S)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
(E)-N′-carbamothioyl-N,N-dimethylformimidamide (63) (5 g, 38 mmol), tritylchloride (11.6 g, 41.8 mmol) and trietheylamine (16 mL, 114 mmol) were refluxed in dichloromethane overnight. The reaction mixture was cooled to room temperature and filtered through a plug of celite. The resulting filtrate was washed with saturated sodium bicarbonate solution, followed with brine. The organic layer was dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel column (40%-100% EtOAc in hexanes) to afford (E)-N,N-dimethyl-N′-(tritylcarbamothioyl) formimidamide (64) as a white solid.
Reaction SMILES: N1C=CC([CH:7]2[CH2:12][NH:11][CH2:10][CH2:9][N:8]2[C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=CC=1.[H-].[Na+].Cl[C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][N:24]=1>CN(C=O)C>[N:24]1[CH:25]=[CH:26][C:31]([N:11]2[CH2:12][CH2:7][N:8]([C:13]3[CH:14]=[CH:15][C:16]([O:19][C:23]4[N:24]=[CH:25][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:31][CH:32]=4)=[CH:17][CH:18]=3)[CH2:9][CH2:10]2)=[CH:32][CH:23]=1
Reactant: Oc1ccc(N2CCNCC2c2ccncc2)cc1
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Oc2ccc(N3CCN(c4ccncc4)CC3)cc2)nc1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 94.5 %

Procedure:
To a suspension of 4-((4-pyridyl)piperazin-1-yl)phenol (1.13 g) in DMF (10 ml) was added a 60% dispersion of sodium hydride in oil (195 mg) and the resulting mixture was stirred for 20 minutes. A solution of methyl 6-chloronicotinate (758 mg) in DMF (2 ml) was added and the mixture was heated at 60° C. for 2 hours. The mixture was partitioned between ethyl acetate(100 ml) and water(20 ml). The organic layer was dried (MgSO4) and evaporated to give an oil which was purified by flash column chromatography on silica, eluting with methanol/dichloromethane (5:95 v/v) to give the title compound as a solid (815 mg): mp 143°-144° C. ; NMR (d6DMSO) δ3.2-3.35 (4H,m) 3.45-3.55 (4H,m), 3.85 (3H,s), 6.9 (2H,dd), 7.05-7.1 (4H,m), 8.15-8.3 (3H,m), 8.7 (2H,d); m/e 391 (M+H)+ ; calculated for C22H22N4O3.0.25H2O: C,66.9; H,5.7; N,14.2. Found: C,66.9; H,5.7; N,14.1%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[OH:63][CH:64]1[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:67]1[CH2:68][CH2:69][CH:64]([OH:63])[CH2:65][CH2:66]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: OC1CCNCC1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(Nc1ncnc2cc(C(=O)N3CCC(O)CC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 4-hydroxypiperidine in DMSO at ambient temperature.
Reaction SMILES: [N:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH2:11][NH2:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:15]([C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH:20]=[C:21]([CH3:28])[N:22]=[CH:23]2)=[C:16]=[O:17].N(C1C=CC=C2C=1C=CN=C2)=C=O>>[CH3:28][C:21]1[N:22]=[CH:23][C:24]2[C:19]([CH:20]=1)=[C:18]([NH:15][C:16]([NH:12][CH2:11][C:10]1[CH:13]=[CH:14][C:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[CH:8][CH:9]=1)=[O:17])[CH:27]=[CH:26][CH:25]=2
Reactant: NCc1ccc(N2CCCCC2)cc1
Reactant: Cc1cc2c(N=C=O)cccc2cn1
Agent: O=C=Nc1cccc2cnccc12
Product: Cc1cc2c(NC(=O)NCc3ccc(N4CCCCC4)cc3)cccc2cn1

Procedure:
The title compound was prepared using the procedure described in Example 61B using 4-(1-piperidinyl)benzylamine and the product from Example 154A instead of 4-cyanobenzyl alcohol and the product from Example 61A. 1H NMR (300 MHz, DMSO-d6) δ 9.69 (s, 1H), 9.60 (s, 1H), 8.68 (s, 1H), 8.57 (d, 1H, J=7.5 Hz), 8.00 (d, 1H, J=7.5 Hz), 7.85 7.55 (m, 4H), 7.43 (m, 2H), 4.40 (d, 2H, J=6 Hz), 3.44 (m, 4H), 2.77 (s, 3H), 1.90 (m, 4H), 1.65 (m, 2H); MS (ESI) 375 (M+H)+; Anal. Calcd for C23H26N4O.2.4HCl: C, 59.80; H, 6.20; N, 12.13. Found: C, 59.91; H, 6.45; N, 11.78
Reaction SMILES: [CH2:1]([C:5]1[N:9]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=O)[O:18]C(C)(C)C)=[CH:12][CH:11]=2)[N:8]=[N:7][C:6]=1[C:24]([NH:26][CH:27]1[CH2:29][CH2:28]1)=[O:25])[CH2:2][CH:3]=[CH2:4].FC(F)(F)C(O)=O.ClC(OC1C=C[C:44]([N+:47]([O-])=O)=[CH:43]C=1)=O.C(N)C>ClCCl.CN(C)C1C=CN=CC=1.O1CCCC1.C(OCC)(=O)C>[CH2:1]([C:5]1[N:9]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]([NH:47][CH2:44][CH3:43])=[O:18])=[CH:14][CH:15]=2)[N:8]=[N:7][C:6]=1[C:24]([NH:26][CH:27]1[CH2:29][CH2:28]1)=[O:25])[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(NC(=O)OC(C)(C)C)cc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: CCN
Agent: CN(C)c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(NC(=O)NCC)cc1
Temperature: 25 °C
Reaction time: 11 h
Yield: 70.3 %

Procedure:
To a solution of tert-butyl 4-{5-(3-buten-1-yl)-4-[(cyclopropylamino)carbonyl]-1H-1,2,3-triazol-1-yl}phenylcarbamate (1.58 g) obtained in Example 40d) in dichloromethane (20 ml) was added trifluoroacetic acid (5.0 ml). The reaction mixture was stirred at room temperature for 11 hr and the solvent was evaporated under reduced pressure. The residue was dissolved in chloroform, and washed with 1M aqueous sodium hydroxide solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated to give a brown solid. A solution of the obtained solid residue and N,N-dimethylpyridin-4-amine (0.60 g) in dichloromethane (15 ml) was added dropwise to a solution of 4-nitrophenyl chloroformate (1.17 g) in dichloromethane (15 ml) under ice-cooling. The reaction mixture was stirred at room temperature for 8 hr, and a solution (2M, 9.7 ml) of ethylamine in tetrahydrofuran was added. After further stirring for 1 hr, the reaction mixture was diluted with ethyl acetate, washed with 1M aqueous sodium hydroxide solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated. The residue was purified by silica gel column (hexane/ethyl acetate=2/3 to ethyl acetate), and the resultant product was recrystallized from ethyl acetate/hexane to give the title compound as colorless crystals (1.03 g, 73%).
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Br>O1CCCC1.C(OCC)(=O)C>[F:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][CH2:1][NH2:2]
Reactant: CN
Reactant: Fc1ccccc1CBr
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NCCc1ccccc1F
Reaction time: 1 h
Yield: 87 %

Procedure:
To tetrahydrofuran (5 ml) was added under ice-cooling with stirring 40% aqueous methylamine solution (5 ml) and 2-fluorobenzylbromide (1.00 g, 5.29 mmol) dissolved in tetrahydrofuran (2 ml), and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography to give the title compound (0.65 g, yield 87%) as a colorless oil.
Reaction SMILES: [OH-].[Na+].O1CCOCC1.[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15](S(C1C=CC=CC=1)(=O)=O)[C:14]([S:28]([N:31]1[CH2:36][CH2:35][NH:34][CH:33]([CH2:37][CH3:38])[CH2:32]1)(=[O:30])=[O:29])=[CH:13]2.[Cl-].[NH4+]>C(OCC)(=O)C.O>[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([S:28]([N:31]1[CH2:36][CH2:35][NH:34][CH:33]([CH2:37][CH3:38])[CH2:32]1)(=[O:30])=[O:29])=[CH:13]2
Reactant: CCC1CN(S(=O)(=O)c2cc3cc(Cl)ccc3n2S(=O)(=O)c2ccccc2)CCN1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CCC1CN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CCN1
Temperature: 80 °C
Reaction time: 11.5 h

Procedure:
A 1N aqueous solution (16 ml) of sodium hydroxide was added to a 1,4-dioxane solution (200 ml) of 1-[(5-chloro-1-phenylsulfonylindol-2-yl)sulfonyl]-3-(ethyl)piperazine (3.78 g) and the resulting mixture was stirred at 80° C. for 11.5 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture. Distilled water and ethyl acetate were then added and the water layer was extracted three time. The organic layers were combined, dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was subjected to chromatography on a silica gel column (methanol:methylene chloride=1:100), followed by crystallization from tetrahydrofuran—diethyl ether, whereby the title compound (2.54 g) was obtained as needle crystals.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH3:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:22]=[CH:21][CH:20]=[CH:19][C:12]=1[C:13]([NH:15][CH:16]([CH3:18])[CH3:17])=[O:14].C(N(C(C)C)CC)(C)C.COCCO>O>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:22]=[CH:21][CH:20]=[CH:19][C:12]=2[C:13]([NH:15][CH:16]([CH3:18])[CH3:17])=[O:14])[C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: CC(C)NC(=O)c1ccccc1N
Reactant: Cc1cnc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: COCCO
Product: Cc1cnc(Cl)nc1Nc1ccccc1C(=O)NC(C)C
Temperature: 130 °C
Reaction time: 36 h
Yield: 77 %

Procedure:
A vessel was charged with 2,4-dichloro-5-methylpyrimidine (5.0 g, 28 mmol), 2-amino-N-(1-methylethyl)benzamide (5.46 g, 34.3 mmol), di-isopropyl-ethylamine (7.0 mL, 42 mmol) and 2-(methyloxy)ethanol (30 mL) and sealed and heated with stirring at 130° C. for 36 hours. The reaction was cooled to room temperature and 50 mL water was added dropwise to afford a milky white solution, which was heated to 100° C. to induce precipitation. The solution was cooled and the solid collected by filtration. The collected solid was washed successively with water (2×50 mL) and hexane (3×50 mL). After drying, a white solid was collected (6.56 g, 77% yield) and identified as 2-[(2-chloro-5-methyl-4-pyrimidinyl)amino]-N-(1-methylethyl)benzamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.51 (1H, s) 8.56-8.63 (2H, m) 8.15 (1H, s) 7.81 (1H, dd, J=7.83, 1.52 Hz) 7.58 (1H, dd, J=15.66, 1.52 Hz) 7.17 (1H, dd, J=15.28, 1.14 Hz) 4.13 (1H, dd, J=14.02, 6.69 Hz) 2.18 (3H, s) 1.18 (6H, d, J=6.57 Hz).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([C:12]2[CH:13]=[N:14][C:15]([NH:18][C:19]3[C:24]4=[CH:25][N:26]([C:28]5[C:33]([C:34]#[N:35])=[CH:32][CH:31]=[CH:30][C:29]=5[Cl:36])[N:27]=[C:23]4[C:22]([F:37])=[CH:21][N:20]=3)=[CH:16][CH:17]=2)[CH2:9]1)=O)(C)(C)C>Cl>[ClH:36].[NH:8]1[CH2:9][CH:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[C:24]4=[CH:25][N:26]([C:28]5[C:29]([Cl:36])=[CH:30][CH:31]=[CH:32][C:33]=5[C:34]#[N:35])[N:27]=[C:23]4[C:22]([F:37])=[CH:21][N:20]=3)=[N:14][CH:13]=2)[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc(Nc3ncc(F)c4nn(-c5c(Cl)cccc5C#N)cc34)nc2)C1
Agent: Cl
Product: N#Cc1cccc(Cl)c1-n1cc2c(Nc3ccc(C4CNC4)cn3)ncc(F)c2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a round bottomed flask containing 3-{6-[2-(2-chloro-6-cyanophenyl)-7-fluoro-2H-pyrazolo[4,3-c]pyridin-4-ylamino]-pyridin-3-yl}-azetidine-1-carboxylic acid tert-butyl ester (98 mg, 0.19 mmol), was added a solution of HCl (1.25 N in propan-2-ol, 10 mL) and the suspension was stirred at room temperature for 16 hours and then heated at 50° C. for 4 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure and the resultant solid was triturated with diethyl ether, filtered and dried. The crude residue obtained was purified by HPLC [gradient: 20 to 98% MeOH (0.1% NH4OH) in water (0.1% NH4OH)] and freeze dried to afford the free base of the title compound which was dissolved in a solution of HCl (1.25 N in propan-2-ol, 5.0 mL), stirred for 4 hours and was then concentrated under reduced pressure. The resultant residue was triturated with diethyl ether, filtered and dried to yield the title compound as a white solid (30 mg, 35% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.00 (d, J=2.5 Hz, 1H), 8.50 (d, J=2.5 Hz, 1H), 8.31 (dd, J=8.7, 2.5 Hz, 1H), 8.26-8.22 (m, 2H), 8.18 (d, J=4.9 Hz, 1H), 7.96 (t, J=8.1 Hz, 1H), 7.75 (d, J=8.9, 1H), 4.39-4.28 (m, 3H), 4.24-4.14 (m, 2H). LCMS (Method B): RT=2.29 min, m/z: 420 [M+H+].
Reaction SMILES: C[O:2][C:3](/[CH:5]=[CH:6]/[C@@H:7]1[C@:15]2([CH3:16])[C@@:10]([OH:31])([CH2:11][C@@H:12]([C:17]3[CH:22]=[CH:21][C:20]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])=[CH:19][CH:18]=3)[CH2:13][CH2:14]2)[CH2:9][CH2:8]1)=O.CC(C[AlH]CC(C)C)C.OS(O)(=O)=O>C1COCC1>[OH:2][CH2:3]/[CH:5]=[CH:6]/[C@@H:7]1[C@:15]2([CH3:16])[C@@:10]([OH:31])([CH2:11][C@@H:12]([C:17]3[CH:22]=[CH:21][C:20]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:25])[CH3:26])=[CH:19][CH:18]=3)[CH2:13][CH2:14]2)[CH2:9][CH2:8]1
Reactant: COC(=O)/C=C/[C@H]1CC[C@]2(O)C[C@@H](c3ccc(O[Si](C)(C)C(C)(C)C)cc3)CC[C@]12C
Agent: CC(C)C[AlH]CC(C)C
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@]3(C)[C@@H](/C=C/CO)CC[C@]3(O)C2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
To a solution of 3.90 g of (1R,3aS,5S,7aR)-1-[(E)-2-methoxycarbonyl-1-ethenyl]-5-(4-tert-butyl-dimethylsilyloxyphenyl)-7a-methylperhydroinden-3a-ol in 50 ml of anhydrous THF, cooled at -78° C., 45 ml of 1N DIBAH in THF were added and the mixture was stirred at -78° C. for 1 hr, then at room temperature for 8 hrs. The reaction mixture was cooled to 0° C. and 100 ml of 1N H2SO4 were cautiously added and stirring was continued at room temperature for 1 hr. The mixture was then extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by flash chromatography (SiO2) with n-hexane/ethyl acetate 7:3 as the eluant to give 2.95 g of (1R,3aS,5S,7aR)-1-[(E)-3-hydroxy-1-propenyl]-5-(4-tert-butyldimethylsilyloxyphenyl)-7a-methylperhydroinden-3a-ol as a white solid.
Reaction SMILES: [H-].[Na+].[CH:3](=[O:11])[C:4]1[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[OH:6].[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>CN(C)C=O.CCCCCC>[CH2:22]([O:6][C:5]1[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=1[CH:3]=[O:11])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: O=Cc1ccccc1O
Reactant: CCCCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCCCCCCCCCCOc1ccccc1C=O

Procedure:
To a stirred suspension of sodium hydride (10.0 mmoles), which was prewashed with petroleum ether, in sieve dried dimethylformamide (10 ml) was added dropwise a solution of salicylaldehyde (10.1 mmoles) in dimethylformamide (1 ml). To the reaction mixture was then added undecyl bromide (10.0 mmoles) and the mixture stirred for 16 hours at ambient temperature under nitrogen. The reaction mixture was taken up in hexane (50 ml) and washed with 10 percent sodium hydroxide (2×50 ml) and saturated sodium chloride (50 ml). The organic phase was dried over anhydrous magnesium sulfate and charcoal. Evaporation of the volatiles yielded a colorless liquid which was purified by flash chromatography over silica gel with 2 percent ethyl acetate in hexane as eluant to afford the desired product as an oil.
Reaction SMILES: [NH2:1]C1C=NC2C(C=1NCCCCNC(=O)OC(C)(C)C)=CC=C(Br)C=2.C(Cl)(=O)CCC.[Br:32][C:33]1[CH:34]=[CH:35][C:36]2[C:37]3[N:45]([CH2:46][CH2:47][CH2:48][CH2:49][NH:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])[C:44]([CH2:58][CH2:59][CH3:60])=[N:43][C:38]=3[CH:39]=[N:40][C:41]=2[CH:42]=1>>[NH2:1][C:39]1[C:38]2[N:43]=[C:44]([CH2:58][CH2:59][CH3:60])[N:45]([CH2:46][CH2:47][CH2:48][CH2:49][NH:50][C:51](=[O:57])[O:52][C:53]([CH3:54])([CH3:55])[CH3:56])[C:37]=2[C:36]2[CH:35]=[CH:34][C:33]([Br:32])=[CH:42][C:41]=2[N:40]=1
Reactant: CCCc1nc2cnc3cc(Br)ccc3c2n1CCCCNC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)NCCCCNc1c(N)cnc2cc(Br)ccc12
Agent: CCCC(=O)Cl
Product: CCCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCCNC(=O)OC(C)(C)C

Procedure:
tert-Butyl [4-(3-amino-7-bromoquinolin-4-ylamino)butyl]carbamate was treated with butyryl chloride and cyclized according to the methods described in Part C and D of Examples 125-135. The resulting product, tert-butyl [4-(7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate was oxidized and aminated according to the methods described in Parts H and I of Example 1 to afford tert-butyl [4-(4-amino-7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate, which was coupled with 3-pyridylboronic acid according to the method described in Part J of Example 1. The reaction was heated at reflux for four hours, and the work-up procedure described in Part F of Examples 125-135 was followed. The crude product was recrystallized from toluene (1 mL/g) to provide tert-butyl {4-[4-amino-2-propyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}carbamate as a tan powder, mp 136-138° C.
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][N:18]([CH2:29][CH2:30][N:31]1[CH:35]=[CH:34][N:33]=[CH:32]1)[CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][N:18]([CH2:29][CH2:30][N:31]1[CH:35]=[CH:34][N:33]=[CH:32]1)[CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)n1c(CN(CCn2ccnc2)C2CCCc3cccnc32)nc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cnc2c(c1)CCCC2N(CCn1ccnc1)Cc1nc2ccccc2[nH]1
Yield: 91.5 %

Procedure:
A solution of 2-{[(2-imidazol-1-yl-ethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzimidazole-1-carboxylic acid tert-butyl ester (21 mg, 0.044 mmol) in 3:1 TFA/CH2Cl2 (4 mL) was stirred at room temperature for 30 minutes then concentrated in vacuo. The residue was partitioned between CH2Cl2 (20 mL) and 1 N NaOH(aq) (10 mL), and the aqueous phase was extracted with CH2Cl2 (10 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to afford COMPOUND 12 as a yellow foam (15 mg, 83%). 1H NMR (CDCl3) δ 1.73 (m, 2H), 1.99 (m, 1H), 2.20 (m, 1H), 2.69-2.88 (m, 2H), 2.92-3.08 (m, 2H), 3.82-3.98 (m, 2H), 4.04 (d, 1H, J=17 Hz), 4.09 (m, 1H), 4.19 (d, 1H, J=17 Hz), 6.70 (s, 1H), 6.93 (s, 1H), 7.18 (m, 3H), 7.42 (m, 2H), 7.57 (br s, 2H), 8.51 (d, 1H, J=3.9 Hz); 13C NMR (CDCl3) δ 21.55, 25.06, 29.36, 46.03, 50.34, 52.23, 62.59, 119.32, 122.26, 122.82, 129.55, 134.97, 137.93, 147.26, 155.42, 156.77. ES-MS m/z 373 (M+H). Anal. Calcd. for C22H24N6.0.2CH2Cl2.0.8CH4O: C, 66.55; H, 6.70; N, 20.25. Found: C, 66.64; H, 6.40; N, 20.06.
Reaction SMILES: [CH3:1][P:2]([CH3:11])([C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][CH:5]=1)=[O:3].[Li][N+:13]([O-:15])=[O:14]>CN1C(=O)N(C)CCC1.[Cl-].[Na+].O.CC(O)C>[CH3:1][P:2]([CH3:11])([C:4]1[CH:9]=[CH:8][C:7]([N+:13]([O-:15])=[O:14])=[CH:6][CH:5]=1)=[O:3]
Reactant: CP(C)(=O)c1ccc(F)cc1
Reactant: [Li][N+](=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCN(C)C1=O
Solvent: CC(C)O
Product: CP(C)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.12 h
Yield: 45.1 %

Procedure:
A sealed pressure flask, flushed with N2, containing a mixture of 3.90 g (22.7 mmol) of 1-(Dimethyl-phosphinoyl)-4-fluoro-benzene and 6.0 g (113.3 mmol) of LiNO2 (for prep see, W. C. Ball and H. H. Abram J. Chem. Soc. 1913, 103, 2130-2134) in 27 mL of DMPU (1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone) was stirred at ambient temperature for 5-10 min (to dissolve fluoro compound) then heated at 190° C. for 3 days. The resulting dark brown solution was cooled to ambient temperature, diluted with 300 mL of brine, then extracted with EtOAc (10×100 mL) until the aqueous layer showed little or no evidence of product by HPLC. The combined organics were dried over MgSO4 and concentrated. The excess DMPU was removed via short-path distillation (120° C./0.3 mm) to provide a semi-solid, which was dissolved in a minimum amount of iPrOH and purified by silica gel flash chromatography (eluted with 5% iPrOH/DCM, then 10% iPrOH/DCM, then 15% iPrOH/DCM) to provide 2.04 g of an yellow solid: 1H NMR (300 MHz, DMSO-d6) δ 8.34 (dd, J=8.7, 1.9 Hz, 2H), 8.07 (dd, J=10.6, 8.8 Hz, 2H), 1.75 (s, 3H), 1.70 (s, 3H). 31P NMR (121 MHz, DMSO-d6) δ 37.89.