Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@:2]12[C@H:11]3[CH2:12][CH2:13][C@:14]4([CH3:20])[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]4[C@@H:10]3[CH2:9][CH2:8][C@H:7]1[CH2:6][C@@H:5]([OH:21])[CH2:4][CH2:3]2.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>N1C=CC=CC=1>[S:28]([O:21][C@H:5]1[CH2:4][CH2:3][C@@:2]2([CH3:1])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:11]2[CH2:12][CH2:13][C@@:14]2([CH3:20])[C@H:15]3[CH2:16][CH2:17][C:18]2=[O:19])[CH2:6]1)([C:25]1[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=1)(=[O:30])=[O:29]
Reactant: C[C@]12CC[C@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O[C@H]2CC[C@@]3(C)[C@@H](CC[C@@H]4[C@@H]3CC[C@]3(C)C(=O)CC[C@@H]43)C2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87 %

Procedure:
In a 25 mL round bottom flask, trans-androsterone (1.00 g, 3.44 mmol) and p-toluenesulfonyl chloride (1.51 g, 7.91 mmol) was dissolved in in pyridine (4.30 mL). The reaction mixture was stirred continuously at room temperature. After 24 h, the reaction mixture was quenched by adding H2O (10 mL) and it was extracted with CH2Cl2 (3×20 mL). All organic layers were collected, combined together and washed over HCl (3×20 mL, 2 M), brine solution (3×20 mL), and H2O (3×20 mL), dried over Na2SO4, and concentrated under reduced pressure afforded 3β-tosyloxy-5α-androstan-17-one (1.33 g, 87%) as a white solid. 1H NMR (300 MHz, CDCl3): d 7.79 (dt, J=8.3, 1.9 Hz, 2H), 7.33 (dd, J=8.0, 0.5 Hz, 2H), 4.42 (h, J=5.9 Hz, 1H), 2.44 (s, 3H), 2.38-2.47 (m, 1H), 1.99-2.11 (m, 1H), 1.86-1.95 (m, 1H), 1.78-1.80 (m, 1H), 1.71-1.77 (m, 2H), 1.65-1.69 (m, 1H), 1.56-1.64 (m, 3H), 1.44-1.55 (m, 3H), 1.30-1.31 (m, 1H), 1.28-1.29 (m, 2H), 1.22-1.24 (m, 1H), 1.18-1.20 (m, 1H), 1.04-1.16 (m, 1H), 0.85-1.00 (m, 2H), 0.84 (s, 3H), 0.80 (s, 1H), 0.60-0.69 (m, 1H).
Reaction SMILES: [CH2:1]([C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C@@H:24]([OH:26])[CH3:25])=[CH:18][CH:17]=2)=[N:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH2:27]([O:30][CH:31]([CH3:35])[C:32](O)=[O:33])[CH2:28][CH3:29]>>[CH2:1]([C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH:24]([O:26][C:32](=[O:33])[CH:31]([O:30][CH2:27][CH2:28][CH3:29])[CH3:35])[CH3:25])=[CH:18][CH:17]=2)=[N:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCOC(C)C(=O)O
Reactant: CCCCCCCCCc1ccc(-c2ccc(OC[C@H](C)O)cc2)nc1
Product: CCCCCCCCCc1ccc(-c2ccc(OCC(C)OC(=O)C(C)OCCC)cc2)nc1

Procedure:
(S)-5-nonyl-2-(4'-(2"-hydroxypropoxy)phenyl)pyridine (m.p. 77.6°-80.3° C.) was reacted with 2-propoxypropionic acid prepared in Example 3 in the same manner as in Example 3 to obtain 5-nonyl-2-(4'-(2"-(2"'-propoxypropionyloxy)-propoxy)phenyl)pyridine (m.p. 58.0° C.).
Reaction SMILES: N1([C:7](=[N:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH3:8])CCOCC1.[N:20]([CH2:23][CH2:24][CH3:25])=[C:21]=[O:22]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:8][C:7]1[N:20]([CH2:23][CH2:24][CH3:25])[C:21](=[O:22])[N:10]([C:11]2[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)[N:9]=1
Reactant: CCCN=C=O
Reactant: CC(=NNc1ccc([N+](=O)[O-])cc1)N1CCOCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCn1c(C)nn(-c2ccc([N+](=O)[O-])cc2)c1=O
Reaction time: 3 h
Yield: 65 %

Procedure:
A mixture of 13 parts of 1-[1-(4-morpholinyl)ethylidene-2-(4-nitrophenyl)hydrazine, 8.5 parts of 1-isocyanatopropane, 1 part of N,N-dimethyl-4-pyridinamine and 39 parts of dichloromethane was stirred and refluxed for 2 hours. The whole was evaporated and 90 parts of dimethylbenzene were added to the residue. Stirring at reflux was continued for 3 hours. The reaction mixture was cooled and filtered over diatomaceous earth. The filtrate was saturated with petroleum ether. The precipitated product was filtered off and crystallized from 2-propanol, yielding 8.5 parts (65%) of 2,4-dihydro-5-methyl-2-(4-nitrophenyl)-4-propyl-3H-1,2,4-triazol-3-one; mp. 125.4° C. (int. 20).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[OH:15][C:16]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:17]=1[CH:18]=[O:19]>CN(C=O)C.O>[CH2:1]([O:15][C:16]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:17]=1[CH:18]=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc(Br)ccc1OCc1ccccc1
Temperature: 80 °C
Yield: 92.2 %

Procedure:
Benzyl bromide (18 mL, 14.9 mmol) and cesium carbonate (8.1 g, 24.9 mmol) were added to a solution of 2-hydroxy-5-bromo benzaldehyde 2 g, 9.95 mmol) in anhydrous DMF (25 mL) at room temperature. The reaction was heated to 80° C. for two hours, cooled and diluted with water (50 mL). The mixture was extracted with ethyl acetate (3×40 mL) and the combined organic layers were washed with water (1×50 mL) and brine (1×50 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (10% ethyl acetate/hexane) to afford 2.67 g of the title compound as a colorless oil (92%). MS: 291 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.94 (s, 1H); 7.6 (dd, 1H, J=8.9, 2.7 Hz); 7.39 (m, 6H); 6.92 (d, 1H, J=8.9 Hz); 5.18 (s, 2H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[N:7]=1.[OH:26][CH2:27][CH2:28][NH2:29]>>[OH:26][CH2:27][CH2:28][NH:29][C:2]1[N:3]=[C:4]([N:19]2[CH2:20][CH2:21][S:22](=[O:25])[CH2:23][CH2:24]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:6]=2[N:7]=1
Reactant: O=S1CCN(c2nc(Cl)nc3c(Sc4ccccc4)ncnc23)CC1
Reactant: NCCO
Product: O=S1CCN(c2nc(NCCO)nc3c(Sc4ccccc4)ncnc23)CC1

Procedure:
This compound was prepared analogous to Example 1 from 2-chloro-4-(1-oxido-thiomorpholino)-8-phenylthiopyrimido[5,4-d]pyrimidine (melting point: 253°-255° C.) and 2-hydroxyethyl-amine.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=[O:30])[C@@H:7]1[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([C@@H:22]([OH:26])[CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:27])[CH2:17][CH2:18]2)[C:13]([Cl:28])=[CH:12]3)[CH2:9][C@H:8]1[CH3:29])(=[O:3])[CH3:2].O1CCCC1.Br.[NH+]1C=CC=CC=1>CC(C)=O>[C:1]([O:4][CH2:5][C:6](=[O:30])[C@@H:7]1[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([C@@H:22]([OH:26])[CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:27])[CH:17]=[CH:18]2)[C:13]([Cl:28])=[CH:12]3)[CH2:9][C@H:8]1[CH3:29])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)[C@H]1[C@H](C)C[C@H]2[C@@H]3C=C(Cl)C4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Agent: Br
Agent: c1cc[nH+]cc1
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CC(=O)OCC(=O)[C@H]1[C@H](C)C[C@H]2[C@@H]3C=C(Cl)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C

Procedure:
A solution of 10.45 g. of 21-acetoxy-6-chloro-11β-hydroxy-16α-methyl-4,6-pregnadiene-3,20-dione in 80 ml. of tetrahydrofuran is combined with 6.5 g. of pyridinium hydrobromide perbromide in 26 ml. of tetrahydrofuran and agitated for 20 minutes at 25°. Subsequently, 0.6 ml. of acetone is added thereto and the mixture is filtered. The filtrate is concentrated under vacuum to a volume of 10 ml., and combined with 80 ml. of dimethylformamide, 4.5 g. of lithium carbonate, as well as 1.62 g. of lithium bromide. The mixture is heated for 2.5 hours to 105° and concentrated under vacuum at 60° to a volume of 40 ml. The mixture is combined with 10 ml. of acetic acid and 14 ml. of water and stirred into 350 ml. of ice water. The thus-obtained precipitate is filtered off, washed with water, and dried in the air. The crude product, 9.4 g., is chromatographed on silica gel. With 40% ethyl acetate-hexane and after recrystallization from acetone-diisopropyl ether, 1.81 g. of 21-acetoxy-6-chloro-11β-hydroxy-16α-methyl-1,4,6-pregnatriene-3,20-dione is obtained, m.p. 192° [α]D25 =+136° (pyridine). UV: ε228 =11,100, ε256 =10,500, ε299 =9,800 (methanol).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:9][C:10]([F:19])([F:18])[C:11](=[O:17])C(OCC)=O)[C:5]([N+:26]([O-])=O)=[CH:4][N:3]=1.Cl>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:26][C:11](=[O:17])[C:10]([F:19])([F:18])[CH2:9][N:8]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:6]=2[N:7]=1
Reactant: CCOC(=O)C(=O)C(F)(F)CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCCC1
Agent: [Fe]
Agent: Cl
Solvent: CC(=O)O
Product: O=C1Nc2cnc(Cl)nc2N(C2CCCCC2)CC1(F)F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 60.4 %

Procedure:
In a round bottom flask compound ethyl 4-((2-chloro-5-nitropyrimidin-4-yl)(cyclohexyl)amino)-3,3-difluoro-2-oxobutanoate (11.85 g, 31.35 mmol) was dissolved in acetic acid (30 mL), and added iron powder (3.51 g, 62.7 mmol) to it. Then cooled the round bottom flask to 0° C. in an ice bath. After 10 min, added conc.HCl (12 mL) dropwise using addition funnel and continued the reaction at 60° C. on a preheated oil bath until starting material disappear. It was then concentrated in vacuo, diluted with EtOAc, basified with 10% NaOH solution at 0° C. The whole was filtered through celite, washed with EtOAc. The filtrate was then separated. The organic layer was dried over Na2SO4. The solution was concentrated in vacuo followed by precipitation from ether to afford the desired compound (6.0 g, 62% yield) as yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.96-1.85 (m, 10 H) 4.02 (t, J=11.37 Hz, 2 H) 4.47 (m, 1 H) 8.11 (s, 1 H) 11.02 (br. s., 1 H). [M+H] calc'd for C13H15ClF2N4O, 317; found 317.
Reaction SMILES: [CH3:1][S:2]([O-:4])=[O:3].[Na+].[Br:6][C:7]1[C:8]([Cl:15])=[N:9][CH:10]=[C:11]([CH2:13]Br)[CH:12]=1>CN(C)C=O.O>[Br:6][C:7]1[C:8]([Cl:15])=[N:9][CH:10]=[C:11]([CH2:13][S:2]([CH3:1])(=[O:4])=[O:3])[CH:12]=1
Reactant: Clc1ncc(CBr)cc1Br
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)Cc1cnc(Cl)c(Br)c1
Temperature: 65 °C
Yield: 84.4 %

Procedure:
Sodium methanesulfinate (0.748 g, 7.32 mmol) and the product from Example 143A (1.9 g, 6.66 mmol) were combined in N,N-dimethylformamide (4.44 mL) and heated at 65° C. for 1 hour. The reaction mixture was cooled and diluted with 200 mL of cold water producing a precipitate that was collected by filtration and dried to constant mass affording the title compound (1.6 g, 84%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[NH:10][NH2:11].C([O:14][C:15]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C:18]1=O)=O)C>C(O)(=O)C>[Cl:8][C:6]1[C:5]([OH:9])=[CH:4][C:3]([N:10]2[C:15](=[O:14])[CH:17]3[C:18]([CH2:19][CH2:20][CH2:21][CH2:22]3)=[N:11]2)=[C:2]([F:1])[CH:7]=1
Reactant: CCOC(=O)C1CCCCC1=O
Reactant: NNc1cc(O)c(Cl)cc1F
Solvent: CC(=O)O
Product: O=C1C2CCCCC2=NN1c1cc(O)c(Cl)cc1F
Yield: 85.9 %

Procedure:
A solution of 2-fluoro-4-chloro-5-hydroxyphenylhydrazine (8 g) and 2-ethoxycarbonylcyclohexanone (8 g) in acetic acid (30 ml) was heated under reflux for 4 hours. After cooling, the precipitated crystals were collected by filtration and washed with ether to give 11 g of 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-2,3a,4,5,6,7-hexahydroindazol-3-one. m.p., 273°-275° C. (decomp.).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[NH2:13][C:14]1[C:23]2[N:24]=[C:25]([CH2:32][O:33][NH2:34])[N:26]([CH2:27][C:28]([CH3:31])([OH:30])[CH3:29])[C:22]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1>CN(C=O)C>[NH2:13][C:14]1[C:23]2[N:24]=[C:25]([CH2:32][O:33][NH:34][S:9]([CH3:8])(=[O:11])=[O:10])[N:26]([CH2:27][C:28]([OH:30])([CH3:31])[CH3:29])[C:22]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: CC(C)(O)Cn1c(CON)nc2c(N)nc3ccccc3c21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(O)Cn1c(CONS(C)(=O)=O)nc2c(N)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 4.6 %

Procedure:
Triethylamine (0.634 mL, 4.55 mmol) and methanesulfonyl chloride (0.211 mL, 2.73 mmol) were added to a solution of 1-{4-amino-2-[(aminooxy)methyl]-1H-imidazo[4,5-c]quinolin-1-yl}-2-methylpropan-2-ol (prepared as described in Example 100, 685 mg, 2.27 mmol) in DMF (5 mL). A solid formed immediately. The mixture was stirred for 3.5 hours at room temperature, then additional triethylamine (0.634 mL) and methanesulfonyl chloride (0.211 mL) were added. The reaction mixture was stirred for an additional 1.5 hours, then was partitioned between water (20 mL) and dichloromethane (30 mL). The aqueous layer was extracted with dichloromethane (2×30 mL). The organic layers were combined and allowed to stand overnight at room temperature. Crystals formed and were isolated by filtration to provide 40 mg of N-{[4-amino-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl]methoxy}methanesulfonamide. Additional crystals were isolated from the mother liquor after a seed crystal was added. The two crops were combined and dried in a vacuum oven to provide 160 mg of N-{[4-amino-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl]methoxy}methanesulfonamide as pale yellow crystals, mp 232-234° C.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([O:24][CH3:25])=[C:11]([CH:23]=1)[C:12]([NH:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:13]>ClCCl>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([O:24][CH3:25])=[C:11]([CH:23]=1)[C:12]([NH:14][CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:21][CH:22]=1)=[O:13]
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccc(Cl)cc1C(=O)NCCc1ccccc1
Solvent: ClCCl
Product: COc1ccc(Cl)cc1C(=O)NCCc1ccc(S(=O)(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.5 ml chlorosulfonic acid were added in one portion to 6.5 g 5-Chloro-2-methoxy-N-phenethyl-benzamide. The reaction mixture was stirred at room temperature for one hour, then 100 ml dichloromethane were added and the reaction mixture was poured on ice water. The organic layer was separated washed twice with 50 ml brine and then dried over MgSO4. The solvent was removed in vacuo to obtain 5.53 g 4-[2-(5-Chloro-2-methoxy-benzoylamino)-ethyl]-benzenesulfonyl chloride.
Reaction SMILES: [C:1]1([P:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:17]=2[NH:16][CH:15]([CH3:18])[CH:14]=[CH:13]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OO.[O-:27]S([O-])=O.[Na+].[Na+]>C(Cl)Cl>[C:19]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:17]=2[NH:16][CH:15]([CH3:18])[CH:14]=[CH:13]3)=[O:27])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=S([O-])[O-]
Reactant: CC1C=Cc2cccc(P(c3ccccc3)c3ccccc3)c2N1
Agent: OO
Agent: [Na+]
Solvent: ClCCl
Product: CC1C=Cc2cccc(P(=O)(c3ccccc3)c3ccccc3)c2N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 8-diphenylphosphino-2-methyl-1,2-dihydroquinoline (2) (10.5 g, 32 mmol) in CH2Cl2 (100 mL) was added H2O2 (6.6 mL, 30% w/w in H2O, 63.9 mmol) at 0° C. and the solution was stirred at room temperature for 1 hour. The solution was then cooled to 0° C., saturated aqueous Na2SO3 solution (10 mL) was added and the mixture was warmed to room temperature. Products were extracted with EtOAc, washed with water and saturated aqueous NaCl, dried (MgSO4) and evaporated to give 5 as a yellow oil (11 g, quantitative). 1H NMR (400.13 MHz, CDCl3) δ 7.7-7.6 (m, 4H, Ph-H), 7.6-7.5 (m, 2H, Ph-H), 7.5-7.4 (m, 4H, Ph-H), 6.97 (bs, 1H, N1—H), 6.87 (d, 1H, J=7.2 Hz, C5—H), 6.55 (ddd, 1H, J=14.0, 8.0, 1.6 Hz, C7—H), 6.36 (ddd, 1H, J=10.0, 7.6, 2.8 Hz, C6—H), 6.22 (d, 1H, J=10.0 Hz, C4—H), 5.51 (ddd, 1H, J=10.0, 4.0, 2.0 Hz, C3—H), 4.43 (m, 1H, C2—H), 1.17 (d, 3H, J=6.8 Hz, C1′—CH3) ppm; 13C NMR (100.61 MHz, CDCl3) δ 148.2 (d, J=5.1 Hz), 146.0 (d, J=6.1 Hz), 135.7 (d, J=8.1 Hz), 134.8, 132.4, 131.3 (d, J=5.1 Hz), 131.0 (d, J=11.1 Hz), 130.8 (d, J=10.1 Hz), 130.7 (d, J=10.1 Hz), 130.1, 129.2, 127.2 (d, J=12.1 Hz), 126.6 (d, J=13.1 Hz), 126.3, 125.0 (d, J=8.1 Hz), 124.1 (d, J=13.1 Hz), 122.8, 121.1, 119.7 (d, J=8.1 Hz), 113.6 (d, J=14.1 Hz), 107.3, 106.2, 46.9, 23.5 ppm; 31P NMR (161.97 MHz, CDCl3) δ 36.0 ppm.
Reaction SMILES: [OH:1][CH:2]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3][NH:4][CH2:5][CH2:6][NH:7][CH2:8][CH2:9][NH2:10].[CH:25]([CH2:27][CH:28]([CH3:34])[C:29](OCC)=[O:30])=O>>[OH:1][CH:2]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3][NH:4][CH2:5][CH2:6][N:7]1[C:29](=[O:30])[CH:28]([CH3:34])[CH2:27][CH:25]=[N:10][CH2:9][CH2:8]1
Reactant: CCOC(=O)C(C)CC=O
Reactant: CCCCCCCCCCCCCCC(O)CNCCNCCN
Product: CCCCCCCCCCCCCCC(O)CNCCN1CCN=CCC(C)C1=O

Procedure:
Into an apparatus similar to that in Example 1, were charged 339.5 g (1 mole) of N-(2-hydroxy)hexadecyldiethylenetriamine and 144.2 g (1 mole) of ethyl 3-formyl-2-methylpropionate. At 140° to 160° C., 18 g of water and 46 g of ethanol were distilled off to obtain 4-(2-hydroxyhexadecyl)aminoethyl-6-methyl-2,3,6,7-tetrahydro-1,4-diazocin-5-one.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]1[CH2:11][CH2:12][CH2:13][CH:14]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]1=[CH:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:28][C:29]1[CH:30]=[C:31]([CH:34]=[C:35]([O:37][C:38]([F:41])([F:40])[F:39])[CH:36]=1)[C:32]#[N:33]>CN(C=O)C>[C:32]([C:31]1[CH:30]=[C:29]([CH:36]=[C:35]([O:37][C:38]([F:39])([F:41])[F:40])[CH:34]=1)[CH2:28][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]1[CH2:11][CH2:12][CH2:13][CH:14]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]1=[CH:5]2)#[N:33]
Reactant: N#Cc1cc(CCl)cc(OC(F)(F)F)c1
Reactant: CCOC(=O)CC1CCCn2c1cc1cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1CCCn2c1cc1cc(OCc3cc(C#N)cc(OC(F)(F)F)c3)ccc12
Temperature: 75 °C
Yield: 83.4 %

Procedure:
To a mixture of ethyl 2-(2-hydroxy-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate (75 mg, 0.274 mmol) and cesium carbonate (134 mg, 0.412 mmol) in DMF (2 mL) was added 3-(chloromethyl)-5-(trifluoromethoxy)benzonitrile (78 mg, 0.329 mmol). The reaction was heated at 75° C. for 15 h and cooled down. The solid was filtered and washed with ethyl acetate. The combined solvent was evaporated, and the residue was purified by silica gel column chromatography to give the title compound (108 mg). LCMS m/z=473.6 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.30 (t, J=7.1 Hz, 3H), 1.51-1.62 (m, 1H), 2.00-2.10 (m, 1H), 2.10-2.24 (m, 2H), 2.55 (dd, J=15.6, 8.6 Hz, 1H), 2.93 (dd, J=15.6, 5.5 Hz, 1H), 3.45-3.54 (m, 1H), 3.85-3.93 (m, 1H), 4.10-4.17 (m, 1H), 4.22 (q, J=7.1 Hz, 2H), 5.14 (s, 2H), 6.18 (s, 1H), 6.87 (dd, J=8.8, 2.4 Hz, 1H), 7.05 (d, J=2.4 Hz, 1H), 7.18 (d, J=8.8 Hz, 1H), 7.44 (s, 1H), 7.58 (s, 1H), 7.71 (s, 1H).
Reaction SMILES: [CH2:1]([S:9][C:10]1[CH:19]=[CH:18][C:13]([C:14](OC)=[O:15])=[CH:12][C:11]=1[C:20]([F:23])([F:22])[F:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].O.[NH2:25][NH2:26]>CO>[CH2:1]([S:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([NH:25][NH2:26])=[O:15])=[CH:12][C:11]=1[C:20]([F:23])([F:22])[F:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCSc1ccc(C(=O)OC)cc1C(F)(F)F
Reactant: NN
Solvent: CO
Solvent: O
Product: CCCCCCCCSc1ccc(C(=O)NN)cc1C(F)(F)F
Temperature: 80 °C
Reaction time: 1 h

Procedure:
The crude methyl 4-(octylthio)-3-(trifluoromethyl)benzoate was dissolved in 2 mL of MeOH and treated with 2 mL of hydrazine hydrate. The reaction mixture was left to stir at 80° C. for 1 hour, poured into ice-water. The solid was filtered, washed with H2O and dried under vacuum to provide the 4-(octylthio)-3-(trifluoromethyl)benzohydrazide 3a as a yellow solid. HPLC retention time on a C18 column (30×4.6 mm, 3.5μ) was 2.69 min with gradient 10-95% acetonitrile-H2O (0.1% TFA) in 3.5 min as mobile phase. MS (ESI, M+H+)=349.3; 1H NMR (400 MHz, CDCl3) δ 9.99 (s, 1H), 8.13 (d, 1H, J=1.6 Hz), 8.03 (dd, 1H, J=8.2 Hz, J=1.6 Hz), 7.67 (d, 1H, J=8.8 Hz), 4.59 (s, 2H), 3.13 (t, 2H, J=7.2 Hz), 1.61 (pentet, 2H, J=6.8 Hz), 1.44-1.36 (m, 2H), 1.30-1.20 (m, 8H), 0.85 (t, 3H, J=6.8 Hz).
Reaction SMILES: [Br:1][C:2]1[C:11]([O:12]C)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:14])=[N:7]2>Br>[Br:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:14])=[N:7]2
Reactant: COc1ccc2nc(C)ccc2c1Br
Agent: Br
Product: Cc1ccc2c(Br)c(O)ccc2n1
Temperature: 5 °C
Reaction time: 1 h
Yield: 122.2 %

Procedure:
A mixture of 5-bromo-2-methyl-6-methoxyquinoline (30 g, 0.12 mol) in 48% HBr (135 mL) was heated to reflux for 7 h then cooled to 5° C. in 1 hour to give a brown and thick slurry. The slurry was stirred at 0-5° C. for 1 hour then filtered, washed with EtOAc (2×50 mL) and dried in a vacuum oven to give 34.9 g (92%) of the hydrobromide of the title compound as a brown solid. 1H NMR (DMSO) δ 8.26 (d, J=8.7 Hz, 1H), 7.85 (d, J=9.1 Hz, 1H), 7.56 (d, J=9.1 Hz, 1H), 7.45 (d, J=8.7 Hz, 1H), 2.64 (s, 3H). A slurry of the hydrobromide salt of 5-bromo-2-methyl-6-quinolinol (3.4 g, 10.5 mmol) and Amberlyst A-21 ion-exchange resin (1.7 g, pre-washed with MeOH then dried in oven) in MeOH (35 mL) was stirred at room temperature for 3 h. The mixture was then filtered and concentrated in vacuo to give 2.5 g (100%) of a yellow solid. Rf=0.36 (1:1) EtOAc:heptane; 1H NMR (DMSO) δ 8.26 (d, J=8.4 Hz, 1H), 7.82 (d, J=9.3 Hz, 1H), 7.47 (t, J=9.1 Hz, 2H), 2.66 (s, 3H).
Reaction SMILES: C(N(CC)CC)C.Cl[C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11].[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:19][CH:18]=1
Reactant: CCOC(=O)C(=O)Cl
Reactant: Nc1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Triethylamine (1.52 ml) and ethyl chlorooxoacetate (1.11 ml) were successively added to a solution of 4-chloroaniline (1.16 g) in methylene chloride (26 ml), and the mixture was stirred at room temperature for 14 hours. After a saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture to conduct liquid separation, the resultant organic layer was successively washed with a 10% aqueous solution of citric acid and saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After the solvent was concentrated under reduced pressure, hexane was added to the residue to deposit crystals, and the crystals were collected by filtration and dried to obtain the title compound (1.89 g).
Reaction SMILES: [C:1]([C:3]([CH3:30])([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][OH:29])=[CH:22][CH:21]=1)[C:4]([N:6]([CH:16]1[CH2:18][CH2:17]1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=1[Cl:15])=[O:5])#[N:2].[Cl:31][C:32]1[C:37]([F:38])=[CH:36][CH:35]=[C:34]([F:39])[C:33]=1O.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>CCOCC.C1(C)C=CC=CC=1>[Cl:31][C:32]1[C:37]([F:38])=[CH:36][CH:35]=[C:34]([F:39])[C:33]=1[O:29][CH2:28][CH2:27][CH2:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][C:3]([C:1]#[N:2])([CH3:30])[C:4]([N:6]([CH:16]2[CH2:18][CH2:17]2)[CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=2[Cl:15])=[O:5])=[CH:25][CH:24]=1
Reactant: Oc1c(F)ccc(F)c1Cl
Reactant: CC(C#N)(Cc1ccc(CCCO)cc1)C(=O)N(Cc1cccc(Cl)c1Cl)C1CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(C#N)(Cc1ccc(CCCOc2c(F)ccc(F)c2Cl)cc1)C(=O)N(Cc1cccc(Cl)c1Cl)C1CC1
Temperature: 80 °C

Procedure:
2-Cyano-N-cyclopropyl-N-(2,3-dichlorobenzyl)-3-[4-(3-hydroxypropyl)phenyl]-2-methylpropanamide from the previous step (1 eq.) and 2-chloro-3,6-difluorphenol (4 eq.) were taken up in freshly deoxygenated toluene (0.05 M). To this solution was then added 1,1′-(azodicarbonyl)-dipiperidine (4 eq.) and finally tributylphosphine (4 eq.). The resulting yellow solution was heated at 80° C. for 3 h. The reaction mixture was cooled to RT, diluted with ether, and washed with 1 N aq. NaOH. The aqueous wash was back extracted with ether and the combined organic extracts were dried over MgSO4. Filtration and concentration of the filtrate in vacuo afforded a yellow semi-solid. Purification of the crude product thus obtained by way of flash chromatography (SiO2, Hex→3:2 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil.