Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].CCOCC.[CH3:7][N:8]1[CH2:40][CH2:39][C@:10]2([N:14](C(OC(C)(C)C)=O)[C@@H:13]([C:22]3[N:27]=[C:26]([CH3:28])[CH:25]=[C:24]([C:29]4[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=4)[N:23]=3)[CH2:12][CH2:11]2)[C:9]1=[O:41]>C(Cl)Cl>[ClH:1].[CH3:7][N:8]1[CH2:40][CH2:39][C@:10]2([NH:14][C@@H:13]([C:22]3[N:27]=[C:26]([CH3:28])[CH:25]=[C:24]([C:29]4[CH:30]=[CH:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=4)[N:23]=3)[CH2:12][CH2:11]2)[C:9]1=[O:41]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc([C@H]2CC[C@@]3(CCN(C)C3=O)N2C(=O)OC(C)(C)C)n1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc([C@H]2CC[C@@]3(CCN(C)C3=O)N2)n1
Reaction time: 0.08 h
Yield: 89.2 %

Procedure:
1M HCl in Et2O (3.07 mL, 3.07 mmol) was added to a solution of the (2R,5S)-7-methyl-2-[4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]-1,7-diazaspiro[4.4]nonan-6-one (1.2 g, 3.07 mmol) in DCM (20 mL) at 20° C. and the reaction stirred for 5 mins. The solvent was evaporated and the residue was triturated from Et2O and dried under vacuum at 40° C. to afford the (2R,5S)-7-methyl-2-[4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]-1,7-diazaspiro[4.4]nonan-6-one hydrochloride (E7) (1.07 g, 2.7408 mmol, 89.2% yield) as an off white solid with 5 mol % ether present;
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]=[CH:7][N:6]([CH3:12])[C:5]2=[O:13].[CH2:14]([S:16]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)(=[O:18])=[O:17])[CH3:15]>COCCO>[CH2:14]([S:16]([N:19]1[CH2:20][CH2:21][N:22]([C:2]2[N:3]=[C:4]3[C:9](=[N:10][CH:11]=2)[N:8]=[CH:7][N:6]([CH3:12])[C:5]3=[O:13])[CH2:23][CH2:24]1)(=[O:18])=[O:17])[CH3:15]
Reactant: Cn1cnc2ncc(Br)nc2c1=O
Reactant: CCS(=O)(=O)N1CCNCC1
Solvent: COCCO
Product: CCS(=O)(=O)N1CCN(c2cnc3ncn(C)c(=O)c3n2)CC1
Temperature: 100 °C
Yield: 64.8 %

Procedure:
A solution of 6-bromo-3-methyl-pteridin-4-one (5.516 g, 22.88 mmol) in 2-methoxyethanol (50.81 mL) was treated with 1-ethylsulfonylpiperazine (6.118 g, 34.32 mmol) and the resulting suspension heated for 2 hours at 100° C. The reaction mixture was cooled in an ice-water bath and resultant precipitate collected and washed with cold methanol to give the product as a yellow solid (5.02 g, 65% Yield). 1H NMR (400.0 MHz, DMSO) d 1.25 (t, 3H), 3.10 (q, 2H), 3.34 (m, 4H), 3.49 (s, 3H), 3.85 (m, 4H), 8.37 (s, 1H), 8.84 (s, 1H) ppm; MS (ES+) 339
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:31][C:32]2[CH:37]=[C:36]([Cl:38])[CH:35]=[C:34]([Cl:39])[CH:33]=2)=[C:7]([S:9]([N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH:13]2[CH2:25][N:26]2[CH:30]=[N:29][CH:28]=[N:27]2)(=[O:11])=[O:10])[CH:8]=1)#[N:2].Cl>C(Cl)Cl.O1CCOCC1>[ClH:38].[Cl:39][C:34]1[CH:33]=[C:32]([CH:37]=[C:36]([Cl:38])[CH:35]=1)[O:31][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][C:7]=1[S:9]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH:13]1[CH2:25][N:26]1[CH:30]=[N:29][CH:28]=[N:27]1)(=[O:11])=[O:10]
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cc(C#N)ccc2Oc2cc(Cl)cc(Cl)c2)C(Cn2cncn2)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: N#Cc1ccc(Oc2cc(Cl)cc(Cl)c2)c(S(=O)(=O)N2CCNCC2Cn2cncn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 179.3 %

Procedure:
To a solution of tert-butyl 4-{[5-cyano-2-(3,5-dichlorophenoxy) phenyl]sulfonyl}-3-(1H-1,2,4-triazol-1-ylmethyl)-1-piperazinecarboxylate (37 mg, 0.06 mmol) in CH2Cl2 (1 ml) was added 4N HCl in 1,4-dioxane (1 ml). The mixture was stirred for 2 hours at room temperature. The solvent was evaporated in vacuo, the residue was triturated with Et2O and the white solid was collected by filtration to give 4-(3,5-dichlorophenoxy)-3-{[2-(1H-1,2,4-triazol-1-ylmethyl)-1-piperazinyl]sulfonyl}benzonitrile hydrochloride (28.5 mg, 86.3%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[OH:29])[N:3]=1.[C:30](OCC)(=[O:37])[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].N1CCCCC1>C(O)C>[C:19]([O:18][C:16]([N:12]1[CH2:13][CH2:14][CH2:15][CH:10]([C:6]2[CH:5]=[C:4]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[OH:29])[N:3]=[C:2]3[C:7]=2[CH:8]=[C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:30](=[O:37])[NH:1]3)[CH2:11]1)=[O:17])([CH3:21])([CH3:22])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3ccccc3O)nc(N)c2C=O)C1
Reactant: CCOC(=O)CC(=O)OCC
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)c1cc2c(C3CCCN(C(=O)OC(C)(C)C)C3)cc(-c3ccccc3O)nc2[nH]c1=O
Temperature: 25 °C
Yield: 70.5 %

Procedure:
To a suspension of tert-butyl 3-[2-amino-3-formyl-6-(2-hydroxyphenyl)-4-pyridinyl]-1-piperidinecarboxylate (0.86 g, 2.16 mmol) in ethanol (25 mL) were added diethyl malonate (6.93 g, 43.27 mmol) and piperidine (2.14 mL, 21.64 mmol) and, and the mixture was heated at reflux overnight. The mixture was allowed to cool to room temperature, and then diluted with ethanol. The resulting precipitate was collected by filtration, washed with ethanol and dried under reduced pressure to give ethyl 5-[1-(tert-butoxycarbonyl)-3-piperidinyl]-7-(2-hydroxyphenyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate as a yellow solid (0.752 g, yield; 71%).
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1.[O:14]1[CH:16]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:15]1>>[ClH:1].[OH:14][CH:16]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:15][NH:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH2:13])(=[O:11])=[O:12])=[CH:8][CH:9]=1
Reactant: CCCCC1CO1
Reactant: NCc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Product: CCCCC(O)CNCc1ccc(S(N)(=O)=O)cc1

Procedure:
In the same manner as in Example 452, Step 1, the title compound was synthesized from 4-aminomethylbenzenesulfonamide hydrochloride and 1,2-epoxyhexane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]2[CH:7]([CH3:11])[CH2:8][CH2:9][O:10][C:5]=2[CH:4]=1.[C:14](O)(=[O:16])[CH3:15]>C1C=CC=CC=1>[C:14]([C:13]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[O:10][CH2:9][CH2:8][CH:7]([CH3:11])[C:6]=2[CH:12]=1)(=[O:16])[CH3:15]
Reactant: COc1ccc2c(c1)OCCC2C
Reactant: CC(=O)O
Solvent: c1ccccc1
Product: COc1cc2c(cc1C(C)=O)C(C)CCO2
Reaction time: 8 h
Yield: 95 %

Procedure:
The methyl ether of step (c) (58.0 g) was dissolved in dry benzene (1 l) and glacial acetic acid (22.3 ml) was added. Boron trifluoride gas was bubbled through the reaction mixture for 1 hour and then stirring was continued overnight. The reaction mixture was poured into water, the organic layer was separated and the aqueous phase was extracted with more ether. The organic extracts were washed with sodium bicarbonate solution, then water, and dried. Evaporation gave 67.8 g of the desired product (95%). MS and NMR analysis were correct for the required compound.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:27]=[CH:28][CH:29]=1)[O:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[C:16]=2[CH3:24])=[CH:11][CH:10]=1)[CH:2]=[CH2:3].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:27]=[CH:28][CH:29]=1)[O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[C:16]=2[CH3:24])=[CH:25][CH:26]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1cccc(Oc2ccc(CNc3cccc([N+](=O)[O-])c3C)cc2)c1
Reactant: BrCc1ccccc1
Product: C=CCOc1cccc(Oc2ccc(CN(Cc3ccccc3)c3cccc([N+](=O)[O-])c3C)cc2)c1

Procedure:
The product from Example 61D and benzyl bromide were processed as described in Example 6B to provide the title compound
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8](=O)[CH2:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH:26]([CH3:28])[NH:25][CH2:24][CH:23]1[CH3:29])=[O:21])([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C>[C:15]([O:19][C:20]([N:22]1[CH:23]([CH3:29])[CH2:24][N:25]([C:8]2[C:7]3[C:12](=[CH:13][C:4]([Cl:3])=[CH:5][CH:6]=3)[N:11]=[CH:10][CH:9]=2)[CH:26]([CH3:28])[CH2:27]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC1CN(C(=O)OC(C)(C)C)C(C)CN1
Reactant: O=C1CC=Nc2cc(Cl)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1CN(c2ccnc3cc(Cl)ccc23)C(C)CN1C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
Sodium hydride (72 mg, 3 mmol) is added to a solution of 7-chloro-4-quinolone (359 mg, 2 mmol) in DMF. After 1 h at 40° C. N-phenyl(trifluoromethylsulfon)imide (1.0 g, 2.8 mmol) and, 1 h later, 1-tert-butoxycarbonyl-2,5-dimethylpiperazine (1.8 g, 8 mmol) is added. The reaction mixture is stirred at 80° C. for 2 days, concentrated, diluted with EtOAc, washed with water and brine, dried (Na2SO4), and concentrated. The residue is purified by reversed phase HPLC with water-MeCN-TFA to give 4-[4-(tert-butoxycarbonyl)-2,5-dimethylpiperazin-1-yl]-7-chloroquinoline (188 mg, 0.5 mmol) which is deprotected with TFA in CH2Cl2 and transformed after being washed with base into the product with 4-fluorophenyl isocyanate (31 μL, 0.27 mmol) according to method C giving the title product as a colorless solid.
Reaction SMILES: [F:1][C@@:2]1([CH2:15][NH:16][C:17]2[N:26]=[C:25]([C:27]3[CH:28]=[N:29][N:30]([CH2:32][O:33][CH3:34])[CH:31]=3)[CH:24]=[C:23]3[C:18]=2[CH:19]=[CH:20][CH:21]=[N:22]3)[CH2:7][CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C@@:2]1([CH2:15][NH:16][C:17]2[C:18]3[CH:19]=[CH:20][CH:21]=[N:22][C:23]=3[CH:24]=[C:25]([C:27]3[CH:28]=[N:29][N:30]([CH2:32][O:33][CH3:34])[CH:31]=3)[N:26]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1
Reactant: COCn1cc(-c2cc3ncccc3c(NC[C@]3(F)CCCN(C(=O)OC(C)(C)C)C3)n2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCn1cc(-c2cc3ncccc3c(NC[C@]3(F)CCCNC3)n2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.5 %

Procedure:
To 1,1-dimethylethyl (3R)-3-fluoro-3-{[(7-{1-[(methyloxy)methyl]-1H-pyrazol-4-yl}-1,6-naphthyridin-5-yl)amino]methyl}-1-piperidinecarboxylate (813 mg, 1.728 mmol) in DCM (10 ml) was added trifluoroacetic acid (2 ml, 26.0 mmol) and stirred at room temperature for 2 h. LCMS showed product as the main peak. The solvent was removed and dissolved in methanol and loaded onto a pre-equilibrated 50 g SCX cartridge. Washed with methanol and eluted with 2M methanolic ammonia. The solvent from the ammonia fractions was removed and the residue dried under high vacuum overnight. The residue was purified on the large scale high pH MDAP (Method D). Appropriate fractions were combined and the solvent removed. The resulting product was dried under high vacuum for 1 h to give the title compound as a yellow solid (349 mg).
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH2:14][CH:15]([O:21][CH:22]([CH3:24])[CH3:23])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:6]1)(O)=[O:2].C(N(CC)CC)C.ClC(OCC)=O>O1CCCC1>[OH:2][CH2:1][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH2:14][CH:15]([O:21][CH:22]([CH3:23])[CH3:24])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:6]1
Reactant: CCOC(=O)C(Cc1cn(CC(=O)O)c2ccccc12)OC(C)C
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(Cc1cn(CCO)c2ccccc12)OC(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 49.8 %

Procedure:
0.3 g of Ethyl 3-(1-carboxymethyl-1H-indol-3-yl)-2-isopropoxypropionate was dissolved in 10 ml of tetrahydrofuran, and 0.2 ml of triethylamine was added under ice-cooling, followed by 0.1 ml of ethyl chloroformate, then the mixture was stirred at 0° C. for 15 minutes. After filtering off the precipitated insoluble substances, the reaction solution was again cooled with ice, and 60 mg of sodium borohydride and water were added, and stirring was continued at room temperature for 1 hour. The reaction solution was cooled with ice, acidified with diluted hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was subjected to silica gel column chromatography (33% ethyl acetate-hexane), to give 143 mg of the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@H:4]([OH:21])[C@@H:5]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH3:22][CH:23]([CH3:28])[CH2:24][C:25](Cl)=[O:26].C(N(CC)CC)C>C(Cl)Cl>[CH3:22][CH:23]([CH3:28])[CH2:24][C:25]([NH:1][CH2:2][CH2:3][C@H:4]([OH:21])[C@@H:5]([NH:13][C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:6][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1)=[O:26]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H](O)CCN
Reactant: CC(C)CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CC(=O)NCC[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To (3S,4S)-1-amino-3-hydroxy-4-t-butyloxycarbonylamino-5-cyclohexylpentane (30.8 mg, 0.102 mmol) in dry methylene chloride (3 mL) at 0° C. was added 3-methyl-butyroyl chloride (0.123 mmol) and triethylamine (20.0 microliters, 0.143 mmol). The mixture was stirred at 0° C. for 1 hour, evaporated, taken up in methanol (3 mL) and treated with 1M NaOH (1 mL). After stirring for 1 hour, the mixture was diluted with ether, washed sequentially with 0.5M H3PO4, saturated NaHCO3 solution, and brine, and then dried over Na2SO4 and evaporated to afford the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C@:10]2([CH2:27][N:28]3[CH:32]=[CH:31][N:30]=[CH:29]3)[O:14][C@H:13]([CH2:15]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:12][O:11]2)=[CH:4][CH:3]=1.[N-:33]=[N+:34]=[N-:35].[Na+]>CN(C)C=O.O>[N:33]([CH2:15][CH:13]1[CH2:12][O:11][C:10]([CH2:27][N:28]2[CH:32]=[CH:31][N:30]=[CH:29]2)([CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[O:14]1)=[N+:34]=[N-:35]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CO[C@@](CCc3ccc(Cl)cc3)(Cn3ccnc3)O2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCC1COC(CCc2ccc(Cl)cc2)(Cn2ccnc2)O1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
To a mixture of QC-16 (201 mg, 0.42 mmol) in N,N-dimethylformamide (3 mL) was added sodium azide (546 mg, 8.40 mmol, 20 equiv). The mixture was heated at 110° C. with stirring for 2 h. The reaction mixture was cooled to room temperature, diluted with H2O, extracted with EtOAc (3×), and the combined organic extracts were washed sequentially with a saturated aqueous solution of Na2CO3, and 1120, and then dried (Na2SO4). The solution was concentrated and the golden oily residue purified by flash column chromatography on silica gel (EtOAc) to give the free base as an oil (Rf=0.29, EtOAc). High-vacuum drying left 121 mg (0.35 mmol, 83%) of QC-112 as a colorless oil: [α]D24=+6.6° (c=0.7, CDCl3); 1H NMR (400 MHz, CDCl3): δ 1.90-2.05 (m, 2H), 2.66-2.81 (m, 2), 3.20 (dd, J=13.2, 5.2 Hz, 1H), 3.39 (dd, J=13.2, 4.0 Hz, 1H), 3.44-3.51 (m, 1H), 3.64 (t, J=8.0 Hz, 1H), 3.78 (dd, J=8.0, 6.4 Hz, 1H), 4.02 (s, 2H), 6.98 (br s, 1H), 7.05 (br s, 1H), 7.12 (d, J=8.4 Hz, 2H), 7.25 (d, J=8.4 Hz, 2H), 7.49 (br s, 1H); 13C NMR (100 MHz, CDCl3): δ 29.0, 38.7, 51.8, 53.0, 67.9, 76.1, 109.9, 120.9, 128.8, 129.3, 129.8, 132.1, 138.7, 139.6; HRMS (EI) [M+H]+ Calcd. for C16H19ClN5O2: 348.1227. Found: 348.1234.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[CH3:17][O:18][C:19]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[CH3:17][O:18][C:19]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:20]=1[C:21]([NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)=[O:22]
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Reactant: NCCc1ccc(-c2ccc(O)cc2)cc1
Product: COc1ccc(C(=O)NCCc2ccc(-c3ccc(O)cc3)cc2)c(OC)c1
Yield: 80 %

Procedure:
4-[2-(2,4-Dimethoxy-benzamido)-ethyl]-4'-hydroxy-biphenyl was prepared analogous to Example I from 4-[2-amino-ethyl]-4'-hydroxy-biphenyl and 2,4-dimethoxybenzoyl chloride.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]([CH2:14][CH3:15])[N:5]([CH:16]([CH3:18])[CH3:17])[C:4]=2[N:3]=1.[C:19]1([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][C:30]=2B2OC(C)(C)C(C)(C)O2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:14]([C@H:6]1[N:5]([CH:16]([CH3:18])[CH3:17])[C:4]2[N:3]=[C:2]([C:30]3[CH:29]=[CH:28][N:27]=[CH:26][C:25]=3[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:11]=[CH:10][C:9]=2[N:8]([CH3:12])[C:7]1=[O:13])[CH3:15]
Reactant: CC1(C)OB(c2ccncc2-c2ccccc2)OC1(C)C
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C(C)C
Product: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccncc3-c3ccccc3)nc2N1C(C)C

Procedure:
The title compound was prepared similarly to the methods described in Example 5, with Intermediate C instead of Intermediate B and with 3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Boronic Acid 2) instead of pyridin-4-ylboronic acid. LCMS: 388.2 m/z (M+H)+; ret. Time: 6.56 min (Analytical Method C).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:13])[CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:40])[CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32]/[CH:33]=[CH:34]\[CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH3:39].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:18]([NH:17][CH2:16][CH2:15][NH:14][C:10](=[O:12])[CH2:9][N:8]([CH3:13])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])(=[O:40])[CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32]/[CH:33]=[CH:34]\[CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH3:39]
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NCCNC(=O)CN(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 94.5 %

Procedure:
2-((tert-Butoxycarbonyl)(methyl)amino)acetic acid (240 mg, 1.27 mmol) was taken up in 5 mL of CH2Cl2 along with (4Z,7Z,10Z,13Z,16Z,19Z)—N-(2-aminoethyl)docosa-4,7,10,13,16,19-hexaenamide (470 mg, 1.27 mmol), HATU (724 mg, 1.27 mmol). The resulting reaction mixture was stirred at room temperature for 20 h. The organic layer was washed with saturated NH4Cl, brine, dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to afford 650 mg of tert-butyl (2-((2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)ethyl)amino)-2-oxoethyl)(methyl)carbamate (56% yield).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH:21]1[CH2:25][NH:24][C:23](=[O:26])[CH2:22]1.N(C(OCC)=O)=NC(OCC)=O.[C:39]([OH:42])(=[S:41])[CH3:40]>O1CCCC1>[C:39]([S:41][CH:21]1[CH2:25][NH:24][C:23](=[O:26])[CH2:22]1)(=[O:42])[CH3:40]
Reactant: CC(O)=S
Reactant: O=C1CC(O)CN1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)SC1CNC(=O)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
20-(1) 15.6 g of triphenylphosphine were added to a suspension of 3 g of 4-hydroxy-2-pyrrolidinone in 200 ml of tetrahydrofuran, and then the mixture was stirred at room temperature for 5 minutes, after which it was cooled to -20° C. A solution of 9.3 ml of diethyl azodicarboxylate in 9 ml of tetrahydrofuran was added dropwise, whilst cooling at -12° C. to -20° C., to the previous solution. The mixture was then stirred at 0°-5° C. for 5 minutes, after which it was again cooled to -20° C. 4.2 ml of thioacetic acid were then added dropwise to the mixture, whilst cooling at -18° C. to -20° C. The mixture was then warmed to 0°-5° C. and stirred at that temperature for 2 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure. The residue was purified first by column chromatography through silica gel, eluted with a 10:1 by volume mixture of ethyl acetate and methanol, and then by column chromatography through silica gel, eluted with a 2:1 by volume mixture of acetonitrile and benzene, to give 2.45 g of 4-acetylthio-2-pyrrolidinone as colorless crystals.
Reaction SMILES: CO.[C:3]1([CH2:9][N:10]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:11]2[C:20]3[N:21]=[C:22]([CH2:28][CH2:29][CH2:30][CH2:31][Cl:32])[N:23](COCC)[C:19]=3[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>Cl>[C:3]1([CH2:9][N:10]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:11]2[C:20]3[N:21]=[C:22]([CH2:28][CH2:29][CH2:30][CH2:31][Cl:32])[NH:23][C:19]=3[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOCn1c(CCCCCl)nc2c(N(Cc3ccccc3)Cc3ccccc3)nc3ccccc3c21
Agent: Cl
Solvent: CO
Product: ClCCCCc1nc2c(N(Cc3ccccc3)Cc3ccccc3)nc3ccccc3c2[nH]1
Yield: 93.8 %

Procedure:
Methanol (several mL) was added to a suspension of N,N-bis(phenylmethyl)-2-(4-chlorobutyl)-1-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine (0.76 g, 1.5 mmole) in 3N hydrochloric acid (20 mL). The reaction mixture was heated on a stream bath for 4 hours then partitioned between methylene chloride and aqueous saturated sodium bicarbonate. The methylene chloride layer was separated, dried over magnesium sulfate and then concentrated under vacuum to provide 0.64 g of N,N-bis(phenylmethyl)-2-(4-chlorobutyl)-1H-imidazo[4,5-c]quinolin-4-amine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C@@H:8]1[CH2:14][CH:13]=[C:12]([CH2:15]Cl)[CH2:11][N:10]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]1=[O:25])([CH3:4])([CH3:3])[CH3:2].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>C(#N)C>[C:1]([O:5][C:6](=[O:26])[NH:7][C@@H:8]1[CH2:14][CH:13]=[C:12]([CH2:15][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH2:11][N:10]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]1=[O:25])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC=C(CCl)CN(OCc2ccccc2)C1=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H]1CC=C(CN2CCOCC2)CN(OCc2ccccc2)C1=O
Temperature: 65 °C

Procedure:
To a solution of 234 mg of (1-Benzyloxy-6-chloromethyl-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-(R)-yl)-carbamic acid tert-butyl ester in 10 mL of acetonitrile was added 0.5 mL of morpholine. The mixture was heated to 65° C. for 2 hours. The reaction was cooled and the mixture was extracted with ethyl acetate. The organic layer was washed with NaHCO3(aq.) and NaCl (aq.) solutions. The aqueous layers were re-extracted with ethyl acetate, and the organic layers were combined and dried over Na2SO4(s). Filtration and solvent removal gave 270 mg of a clear oil. MS: 454 (M+Na), 432 (M+H).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=O.C(=O)(O)O.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH2:29])=[NH:28])=[CH:22][CH:21]=1>C(O)(C)C>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([NH:26][C:27]2[N:29]=[C:5]([C:7]3[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][N:28]=2)=[CH:24][CH:25]=1
Reactant: COc1ccc(NC(=N)N)cc1
Reactant: CN(C)C=CC(=O)c1ccncc1
Agent: O=C(O)O
Solvent: CC(C)O
Product: COc1ccc(Nc2nccc(-c3ccncc3)n2)cc1

Procedure:
A 14.4 g amount of 3-dimethylamino-1-(4-pyridinyl)-2-propen-1-one (U.S. Pat. No. 4,281,000) and 16.1 g of 4-methoxyphenylguanidine carbonate in 200 ml of isopropanol was heated at reflux for 24 hours. The solvent was evaporated to 1/3 volume, then the mixture was cooled in an ice-bath to crystallize the crude product. The product was collected by filtration and washed with water, then with isopropanol. The material was recrystallized from isopropanol/ethylene glycol monomethyl ether to give 16.7 g of the desired product as yellow crystals, mp 174°-175° C.