Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][O:8][C:9]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:10]=1[CH2:11][N:12]1[CH2:17][CH2:16][NH:15][C:14](=[O:18])[CH:13]1[CH3:19].F[B-](F)(F)F.[CH2:31]([O+](CC)CC)[CH3:32]>C(Cl)Cl.O>[CH3:7][O:8][C:9]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:10]=1[CH2:11][N:12]1[CH:13]([CH3:19])[C:14]([O:18][CH2:31][CH3:32])=[N:15][CH2:16][CH2:17]1
Reactant: CC[O+](CC)CC
Reactant: COc1ccc(CN2CCNC(=O)C2C)c(OC)c1
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC1=NCCN(Cc2ccc(OC)cc2OC)C1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Oven-dried (115° C.) sodium carbonate (18.6 g, 98 mmol, 2.25 eq.) was placed in a 500 mL round-bottom flask. The round-bottom flask was backfilled with Ar and then capped with a rubber septum. A solution of 4-(2,4-dimethoxybenzyl)-3-methylpiperazin-2-one 1.1a (20.6 g, 78 mmol, 1 eq.) in anhydrous DCM (250 mL) was added, followed by triethyloxonium tetrafluoroborate (18.6 g, 98 mmol, 1.25 eq.) in one portion. Thereafter, the reaction mixture was stirred further at RT for 1 h whereupon the reaction mixture was diluted with water (250 mL). The aqueous layer was extracted with DCM (3×150 mL). The organic layers were combined, dried over MgSO4, filtered and concentrated under reduced pressure. The crude compound was then purified on silica gel (EtOAc) to afford the desired product 1a as orange oil. Yield: 13.2 g, 58%. LCMS: P=93%, retention time=1.8 min, (M+H+H2O)+: 311; 1H-NMR (CDCl3): δ 7.23 (d, J=8.8 Hz, 1H), 6.48 (d, J=8.8 Hz, 1H), 6.44 (s, 1H), 4.02 (m, 2H), 3.92 (s, 3H), 3.91 (s, 3H), 3.86 (d, JAB=14.0 Hz, 1H), 3.46 (d, JAB=14.0 Hz, 1H), 3.44 (m, 2H), 3.10 (m, 1H), 2.79 (m, 1H), 2.32 (m, 1H), 1.35 (d, J=6.8 Hz, 3H), 1.24 (t, J=6.0 Hz, 3H).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1)[CH3:2].C(N(CC)C(C)C)(C)C.Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27]>O>[CH2:1]([N:3]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1)[CH3:2]
Reactant: OCCCCCCBr
Reactant: CCNc1ccc(Br)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CCCCCCO)c1ccc(Br)cc1
Temperature: 110 °C
Yield: 100 %

Procedure:
36.8 g (184.1 mmols) of N-ethyl-4-bromoaniline, 48.1 ml (1.5-fold equivalent weight) of N,N-diisopropylethylamine and 28.9 ml (1.2 equivalent) of 6-bromohexanol were mixed, and the mixture obtained was heated at 110° C. for 14 hours in an atmosphere of argon. Water was added to the reaction solution obtained, which was then extracted with ethyl acetate. The organic layer obtained was dried with anhydrous magnesium sulfate and then concentrated. The residue thus obtained was heated under reduced pressure (160° C./0.3 torr), and the components distilled out were removed to obtain 55.6 g of crude N-ethyl-N-(6-hydroxyhexyl)-4-bromoaniline (yield: 100%; a dark-brown oily liquid).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[N:4][N:3]=1.[F:21][C:22]1[C:30]([OH:31])=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[C:25]([CH3:32])[NH:26]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:21][C:22]1[C:30]([O:31][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][C:13]3[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)=[N:4][N:3]=2)=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[C:25]([CH3:32])[NH:26]2
Reactant: Cc1cc2c(F)c(O)ccc2[nH]1
Reactant: COc1ccc(Cc2nnc(Cl)c3ccccc23)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Cc2nnc(Oc3ccc4[nH]c(C)cc4c3F)c3ccccc23)cn1

Procedure:
Heating of a mixture of 1-chloro-4-[6-methoxy-(pyridin-3-yl)-methyl]phthalazine (Ex. 3e), 4-fluoro-5-hydroxy-2-methyl-1H-indole (preparation see WO 00/47212; Ex. 237) and K2CO3 in DMF yields the title compound.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C[O:12][C:13](=[O:17])[C@H:14]([CH3:16])[NH2:15]>>[CH:1]1([CH2:6][C:7]([NH:15][C@H:14]([C:13]([OH:17])=[O:12])[CH3:16])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)CC1CCCC1
Reactant: COC(=O)[C@H](C)N
Agent: Cl
Product: C[C@H](NC(=O)CC1CCCC1)C(=O)O

Procedure:
Following General Procedure A above using cyclopentylacetic acid (Aldrich) and L-alanine methyl ester hydrochloride (Sigma), the title compound was prepared as a solid having a melting point of 43-46° C. Purification was by recrystallization from ethyl acetate/hexanes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([OH:18])([CH2:15][CH2:16][OH:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[S:19](Cl)([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20].N12CCCN=C1CCCCC2>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([OH:18])([CH2:15][CH2:16][O:17][S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)C(O)(CCO)c1ccc(Cl)c(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CCOC(=O)C(O)(CCOS(=O)(=O)c1ccc(C)cc1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
To the solution of Example 135C (8.8 g, 30 mmol) in CH2Cl2 was added tosyl chloride (2 equivalents) and 1,8-diazabicyclo[5.4.0]undec-7-ene (2.5 equivalents) and the mixture stirred overnight at room temperature. Purification by column chromatography on silica gel provided title compound (3.3 g, 25%).
Reaction SMILES: [C:1]([OH:25])(=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[C:11][C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].CO.[CH:28](Cl)(Cl)Cl>S(=O)(=O)(O)O.C(O)C>[C:1]([O:25][CH3:28])(=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[C:11][C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: ClC(Cl)Cl
Reactant: CCCCCCCCCCC#CC#CCCCCCCCCC(=O)O
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: CO
Product: CCCCCCCCCCC#CC#CCCCCCCCCC(=O)OC
Temperature: 25 °C

Procedure:
10,12-tricosadiynoic acid (10 gm., GFS Chemicals) was dissolved in a solution containing 10 ml methanol (HPLC grade) and 10 ml chloroform (HPLC grade). The solution was stirred at room temperature and 10 drops of neat sulfuric acid was added drop wise. The solution was warmed to 100° F. for 2 hour. The reaction mixture was purified using column chromatography. The product (MeTDA) was dried using a Rotovap and the material stored in a chloroform solution. The solid form of MeTDA was very unstable to polymerization and therefore kept dissolved in organic solutions. Alcoholic solutions of MePDA and MeTDA: Solids MePDA or MeTDA were dissolved in reagent grade ethanol to a concentration of 150 mg/ml. A residual polymer was removed by filtration through Whatman No. 1 filter paper. The solutions were held at room temperature or slightly above (70-75° F.) to avoid crystallization or precipitation.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH2:19]([O:21][C:22]([CH:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)=[O:23])[CH3:20]>C1COCC1>[CH2:19]([O:21][C:22]([CH:24]1[CH2:28][CH2:27][N:26]([C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:25]1)=[O:23])[CH3:20]
Reactant: CCOC(=O)C1CCNC1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(C(=O)c2ccc(OC)cc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83 %

Procedure:
4-Methoxy-benzoyl chloride (185 mL, 1.36 mol) and triethylamine (259 mL, 1.86 mol) were added to a stirred solution of pyrrolidine-3-carboxylic acid ethyl ester (177.5 g, 1.24 mol) (see Preparation 1) in THF (2500 mL) at 10° C. The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched with 10% citric acid aqueous solution (2000 mL) then ethyl acetate (2000 mL) was added. The organic layer was washed with saturated aqueous NaHCO3 (2000 mL) and water (2000 mL), dried over magnesium sulphate then concentrated under reduced pressure to afford the title compound as a brown oil (285.3 g, 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([NH:6][C:7](=[O:9])[CH3:8])=[C:4]([F:12])[CH:3]=1.[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:11]([N+:13]([O-:15])=[O:14])=[CH:10][C:5]([NH:6][C:7](=[O:9])[CH3:8])=[C:4]([F:12])[CH:3]=1
Reactant: CC(=O)Nc1ccc(Cl)cc1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1cc([N+](=O)[O-])c(Cl)cc1F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A mixture of 4'-chloro-2'-fluoroacetanilide (51 g, 0.272 mol) in concentrated sulfuric acid (100 mL) is cooled to 0° C., treated with nitric acid (90% real, 14 mL, 0.300 mol) over 45 minutes, stirred for 10 minutes, and poured onto ice. The resultant aqueous mixture is filtered to obtain a tan solid which is washed with water, dried overnight, and recrystallized from a chloroform/hexanes (17:1) solution to give the title product as a yellow solid.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]#[CH:19].N>>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[O:1][N:2]=[C:3]([C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:19]=1
Reactant: C#Cc1ccccc1Cl
Reactant: ON=C(Cl)c1cccnc1
Agent: N
Product: Clc1ccccc1-c1cc(-c2cccnc2)no1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 1A (78 mg, 0.5 mmol) and 1-chloro-2-ethynylbenzene (Apollo, 68 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ 7.43-7.56 (m, 3H), 7.56-7.70 (m, 2H), 7.98 (dd, J=5.9, 3.6 Hz, 1H), 8.39 (dt, J=7.9, 2.0 Hz, 1H), 8.67 (dd, J=4.8, 1.6 Hz, 1H), 9.12 (d, J=2.4 Hz, 1H) ppm; MS (DCI/NH3) m/z 259 (M+H)+, 257 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][CH2:11][CH2:10][CH:9]1[C:15]([NH:17][C:18]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=O)=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.[CH2:32]([NH2:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C>[CH2:32]([NH:39][C:20]([C:19]1[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:18]=1[NH:17][C:15]([CH:9]1[CH2:10][CH2:11][CH2:12][C:13](=[O:14])[N:8]1[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:16])=[O:22])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(O)c1ccc(Cl)cc1NC(=O)C1CCCC(=O)N1Cc1ccccc1
Reactant: NCc1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(NCc1ccccc1)c1ccc(Cl)cc1NC(=O)C1CCCC(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Formula I where R1, R2, R4, R6, R7, R8 and R9 are H; R3 is Chloro; R5 is Benzyl, R10 is Benzyl; and V is CR′R″ where R′ and R″ are H: To a solution of 2-[(1-benzyl-6-oxo-piperidine-2-carbonyl)-amino]-4-chloro-benzoic acid (165 mg, 0.427 mmol) in 5 mL of DMF was added EDC (245 mg, 1.28 mmol) and the mixture stirred at room temperature. After 1 hour, benzylamine (140 μL, 1.28 mmol) was added, and the reaction mixture was stirred at room temperature for an additional 3 hours. After evaporating the solvents, the residue was dissolved in 100 mL of DCM, and washed with saturated sodium bicarbonate and brine. The organic layer was dried over sodium sulfate and filtered. The solvent was removed to afford crude 1-benzyl-6-oxo-piperidine-2-carboxylic acid (2-benzylcarbamoyl-5-chloro-phenyl)-amide, a compound of Formula 402. This was dried under vacuum and then added to a mixture of 10 mL of ethylene glycol and sodium hydroxide (17 mg, 0.425 mmol), followed by stirring at 130° C. for two days with monitoring by LC-MS. The mixture was then poured into 100 mL of water. After extraction with DCM, the resulting crude product was purified over silica gel (stepwise gradient 1:4, 1:2, 1:1, 2:1, 4:1 with ethyl acetate:hexanes as eluent) to give the desired pure product of Formula I, 3-benzyl-2-(1-benzyl-6-oxo-piperidin-2-yl)-7-chloro-3H-quinazolin-4-one (20 mg, 10%).
Reaction SMILES: Cl[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:8]2)[C:5]2[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=2[N:3]=1.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>CO>[CH:14]1([CH2:13][N:10]2[CH2:11][CH2:12][CH:7]([N:6]3[C:5]4[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=4[N:3]=[C:2]3[N:27]3[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]3)[CH2:8][CH2:9]2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Clc1nc2ccccc2n1C1CCN(CC2CCCC2)CC1
Reactant: CN1CCNCC1
Solvent: CO
Product: CN1CCN(c2nc3ccccc3n2C2CCN(CC3CCCC3)CC2)CC1
Temperature: 120 °C

Procedure:
The mixture of 1-(1-cyclopentylmethyl-4-piperidinyl)-1,3-dihydro-2H-benzimidazole-2-one(202 mg) and POCl3(5 ml) was heated at 120° C. for 2 h. After cooling down to room temperature, the reaction mixture was poured into NH4OH solution, and extracted with CH2Cl2. The extracts combined were washed with water, and dried (Na2SO4). After filtration, the filtrate was concentrated to give oil, which was purified by preparative TLC (1 mm thick plate×2, CH2Cl2/MeOH:15/1) to give 148 mg (69%) of 2-chloro-1-(1-cyclopentylmethyl-4-peridinyl)-1H-benzimidazole as colorless amorphous solid. To a solution of 2-chloro-1-(1-cyclopentylmethyl-4-piperidinyl)-1H-benzimidazole(148 mg, 0.466 mmol) in MeOH(5 ml) was added N-methylpiperazine(1 ml) and the resulting mixture was heated at 120° C. in a sealed tube for 2 days. After concentration, the residue was purified by preparative TLC (1 mm thick plate×2, CH2Cl2/MeOH:12/1, 2 developed) to give 161 mg of colorless amorphous solid. This was purified again by column chromatography(basic silica gel: 50 g; CH2Cl2/MeOH:200/1 to 50/1) to afford 52 mg (29%) of title compound as colorless amorphous solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][N:8]1[C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=[N:9]1.[Cl:16][C:17]1[C:18]([NH2:24])=[N:19][C:20]([NH2:23])=[CH:21][N:22]=1>ClCCl.CN(C)C=O>[NH2:24][C:18]1[N:19]=[C:20]([NH:23][C:13]([C:12]2[N:8]([CH3:7])[N:9]=[CH:10][CH:11]=2)=[O:15])[CH:21]=[N:22][C:17]=1[Cl:16]
Reactant: Cn1nccc1C(=O)O
Reactant: Nc1cnc(Cl)c(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1nccc1C(=O)Nc1cnc(Cl)c(N)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 35.7 %

Procedure:
Oxalyl chloride (0.288 ml, 3.32 mmol) was added to a suspension of 1-methyl-1H-pyrazole-5-carboxylic acid (0.279 g, 2.21 mmol) in dichloromethane (5 ml) followed by 1 drop of dimethylformamide. The mixture was stirred at room temperature for 4 hours before concentrating in vacuo and azeotroping with dichloromethane. The residue was taken up in pyridine (1 ml) and added to a solution of 3-chloro-pyrazine-2,6-diamine (Preparation 1) (0.16 g, 1.11 mmol) and the mixture heated at 60° C. for 3 hours before cooling to room temperature and concentrating in vacuo. The residue was purified by silica gel column chromatography, eluting with ethylacetate:heptane 1:1, to afford the product as a pale solid (100 mg).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][N:13]=1.COCN[C:23]([C:25]1[C:29]([CH3:30])=[C:28]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[N:27]([CH3:38])[N:26]=1)=[O:24].C(O)(=O)C>C1COCC1>[Cl:11][C:12]1[CH:17]=[C:16]([CH2:18][C:23]([C:25]2[C:29]([CH3:30])=[C:28]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[N:27]([CH3:38])[N:26]=2)=[O:24])[CH:15]=[CH:14][N:13]=1
Reactant: COCNC(=O)c1nn(C)c(-c2ccc(F)cc2)c1C
Reactant: Cc1ccnc(Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1c(C(=O)Cc2ccnc(Cl)c2)nn(C)c1-c1ccc(F)cc1
Temperature: -70 °C
Reaction time: 2 h

Procedure:
To 10 ml of dry THF cooled to −65° C. were added 1.35 ml of a 2M solution of Sodium-bis(trimethylsilyl)amide in THF. Then a solution of 0.32 g 2-Chlor-4-methyl pyridine in 1 ml of dry THF was added dropwise maintaining the temperature at −70° C. for 30 min. Then a solution of 0.50 g of 5-(4-Fluoro-phenyl)-1,4-dimethyl-1H-pyrazole-3-carboxylic acid methoxymethyl-amide in 5 ml of dry THF was added dropwise over a 10 min period maintaining the temperature below −65° C. The solution was stirred for 2 h at −60° C., and then allowed to warm up to 0° C. and stirred for 20 min at this temperature. Then 0.31 ml of Acetic acid was added dropwise at −50° C., and the solution was allowed to warm up to room temperature and stirred overnight. The mixture was concentrated in vaccuo. The residue was taken up in Ethyl acetate. The organic phase was washed with saturated bicarbonate solution and brine, dried over magnesium sulfate, filtered and evaporated. The crude product (0.67 g, yellow oil) was purified by chromatography on silica gel (Heptane/Ethyl acetate 4:1). The desired product was obtained as a white solid (0.27 g, 70%), MS: m/e=344.0 ([M+1]+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5](/[C:16](/[CH3:29])=[C:17](/[F:28])\[CH:18]=[CH:19]\[C:20](\[CH3:27])=[CH:21]\[C:22]([O:24]CC)=[O:23])=[CH:6][C:7]2[CH:8]=[CH:9][CH2:10][C:11]([CH3:15])([CH3:14])[C:12]=2[CH:13]=1)[CH3:2].[OH-].[Na+].Cl>C(O)C.C1COCC1>[CH2:1]([O:3][C:4]1[C:5](/[C:16](/[CH3:29])=[C:17](/[F:28])\[CH:18]=[CH:19]\[C:20](\[CH3:27])=[CH:21]\[C:22]([OH:24])=[O:23])=[CH:6][C:7]2[CH:8]=[CH:9][CH2:10][C:11]([CH3:15])([CH3:14])[C:12]=2[CH:13]=1)[CH3:2]
Reactant: CCOC(=O)/C=C(C)/C=C/C(F)=C(/C)c1cc2c(cc1OCC)C(C)(C)CC=C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1cc2c(cc1/C(C)=C(F)\C=C\C(C)=C\C(=O)O)C=CCC2(C)C
Temperature: 60 °C

Procedure:
To a solution of ethyl (2E,4E,6E)-7-(3-ethoxy-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-6-fluoro-3-methyl-octa-2,4,6-trienoate (Compound A-67, 4.0 mg, 0.01 mmol) in ethanol (0.2 mL) and THF (1 mL) was added 1M NaOH (0.05 mL, 0.05 mmol). The mixture was heated to 60° C. for 5 h and was cooled to room temperature, acidified with 1M HCl, extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 10% ethyl acetate in hexanes) to give the title compound as a white solid.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH3:5].C(=O)([O-])[O-].[K+].[K+].[CH3:12][C:13]1[CH:20]=[C:19]([OH:21])[CH:18]=[C:17]([CH3:22])[C:14]=1[CH:15]=[O:16]>C(C(C)=O)C>[CH2:2]([O:21][C:19]1[CH:18]=[C:17]([CH3:22])[C:14]([CH:15]=[O:16])=[C:13]([CH3:12])[CH:20]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCI
Reactant: Cc1cc(O)cc(C)c1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCOc1cc(C)c(C=O)c(C)c1
Reaction time: 20 h
Yield: 91.1 %

Procedure:
1-Iodobutane (9.2 g; 50 mmole) and potassium carbonate (6.9 g; 50 mmole) were added to a solution of 2,6-dimethyl-4-hydroxybenzaldehyde (7.5 g; 50 mmole) in methyl ethyl ketone (150 ml). The mixture was heated under reflux with stirring for 20 hours and then evaporated to dryness. The residue was dissolved in dichloromethane and washed with water, then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 4-butoxy-2,6-dimethylbenzaldehyde (9.4 g; 92.0%). The product was obtained as a yellow oil and was characterized by its proton magnetic resonance spectrum, the details of which are recorded in Table 2 below.
Reaction SMILES: C(O[CH2:10][CH2:11][CH2:12][CH:13]([CH2:23][S:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:14][NH:15][S:16]([CH2:19][CH2:20][CH2:21][Cl:22])(=[O:18])=[O:17])(=O)C1C=CC=CC=1.C[O-].[Na+].ClCCCS(NCC(CC(O)C)COC(=O)NCCCCCCCCCCCCCCCCCC)(=O)=[O:49]>CO>[Cl:22][CH2:21][CH2:20][CH2:19][S:16]([NH:15][CH2:14][CH:13]([CH2:12][CH:11]([OH:49])[CH3:10])[CH2:23][S:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])(=[O:18])=[O:17]
Reactant: CCCCCCCCCCCCCCCCSCC(CCCOC(=O)c1ccccc1)CNS(=O)(=O)CCCCl
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCCl)CC(C)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)CC(C)O
Yield: 54.5 %

Procedure:
A mixture of 1.24 g (2.0 mM) of 2-(benzoyloxypropan-1-yl)-1-(3-chloropropylsulfonylamino)-3-n-hexadecylthiopropane ml4 and 0.77 ml (2 mM) of 5.18 M/L sodium methoxide in methanol solution in 50 ml of methanol is allowed to react by the same procedure as described in (131) and 562 mg (54.5% yield) of the titled compound ml5 is obtained.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][C:12]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14]>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:14][C:13]1[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([F:20])([F:21])[F:22])[C:12]=1[CH3:11]
Reactant: Cc1c(N)cccc1C(F)(F)F
Reactant: Clc1nc2ccccc2[nH]1
Product: Cc1c(Nc2nc3ccccc3[nH]2)cccc1C(F)(F)F

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 2-methyl-3-(trifluoromethyl)aniline by Procedure A. The product was isolated by filtration and preparative LCMS to give the title compound as the free base (white solid, mp 204-206° C.). MS(ES+) m/z 292 ([M+1]+, 100).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:25][O:26][CH2:27][CH3:28])[N:14]([NH:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.O.[OH-].[Na+]>C(O)(C(F)(F)F)=O.[Pt](=O)=O>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:25][O:26][CH2:27][CH3:28])[N:14]([NH:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[C:10]=2[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1NCCCNC(=O)C(C)C
Agent: O=[Pt]=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCOCc1nc2c(N)nc3c(c2n1NCCCNC(=O)C(C)C)CCCC3
Temperature: 25 °C
Reaction time: 17 h
Yield: 52.1 %

Procedure:
A solution of N-(3-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]amino}propyl)-2-methylpropanamide (0.450 g, 1.17 mmol) in 25 mL of TFA was treated with platinum (IV) oxide (0.266 g, 1.17 mmol). The reaction mixture was shaken under an atmosphere of hydrogen (3.8×105 Pa) at ambient temperature. After 17 h, the reaction mixture was filtered through a pad of CELITE filter agent and rinsed with portions of 4:1 CHCl3:MeOH (1% TFA). The filtrate was concentrated under reduced pressure to yield a white oil. The oil was suspended in a minimum amount of H2O and treated with 50% NaOH solution until the pH was 13. A white solid precipitated and was triturated in the basic H2O for 1 h and then filtered to yield a sticky white solid. The solid was then triturated with Et2O for 2 h, filtered and dried to yield N-(3-{[4-amino-2-(ethoxymethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl]amino}propyl)-2-methylpropanamide (0.237 g) as a white solid. mp 163–165° C.; 1H NMR (500 MHz, DMSO-d6) δ 7.69 (t, J=5.5 Hz, 1H), 6.31 (t, J=5.9 Hz, 1H), 5.80 (s, 2H), 4.61 (s, 2H), 3.55 (q, J=7.0 Hz, 2H), 3.15–3.11 (m, 2H), 3.04–3.00 (m, 4H), 2.66 (t, J=5.7 Hz, 2H), 2.31 (h, J=6.8 Hz, 1H), 1.81–1.69 (m, 4H), 1.62 (p, J=7.1 Hz, 2H), 1.14 (t, J=7.0 Hz, 3H), 0.98 (d, J=6.9 Hz, 6H); 13C NMR (75 MHz, DMSO-d6) δ 176.3, 149.9, 149.3, 147.0, 137.6, 122.7, 105.4, 65.7, 63.3, 51.7, 36.6, 34.4, 32.5, 28.0, 23.3, 23.0, 22.4, 19.9, 15.3; MS (ESI) m/z 389 (M+H)+; Anal. Calcd for C20H32N6O2: C, 61.83; H, 8.30; N, 21.63; Found: C, 61.63; H, 8.23; N, 21.55.