Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][CH:14]([O:17][CH2:18][C:19]([OH:21])=O)[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:22]([F:25])([F:24])[F:23])([O-:3])=[O:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[Cl:55][C:56]1[CH:57]=[CH:58][C:59]2[O:63][CH:62]([C:64]([N:66]3[CH2:71][CH2:70][NH:69][CH2:68][CH2:67]3)=[O:65])[CH2:61][C:60]=2[CH:72]=1>ClCCl>[Cl:55][C:56]1[CH:57]=[CH:58][C:59]2[O:63][CH:62]([C:64]([N:66]3[CH2:67][CH2:68][N:69]([C:19](=[O:21])[CH2:18][O:17][CH:14]4[CH2:13][CH2:12][CH:11]([NH:10][C:7]5[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([C:22]([F:24])([F:25])[F:23])[CH:6]=5)[CH2:16][CH2:15]4)[CH2:70][CH2:71]3)=[O:65])[CH2:61][C:60]=2[CH:72]=1
Reactant: O=C(C1Cc2cc(Cl)ccc2O1)N1CCNCC1
Reactant: O=C(O)COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)N1CCN(C(=O)C2Cc3cc(Cl)ccc3O2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.4 %

Procedure:
To a solution of 2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]acetic acid (100 mg, 0.28 mmol) in dichloromethane (20 ml) was added EDAC.HCl (80 mg, 0.42 mmol 1.5 eq), HOBt (56 mg, 0.41 mmol, 1.5 eq), triethylamine (84 mg, 0.83 mmol, 3 eq) and 1-[(5-chloro-2,3-dihydro-1-benzofuran-2-yl)carbonyl]piperazine (74 mg, 0.28 mmol, 1 eq). The resulting solution was stirred overnight at room temperature and then concentrated under vacuum. The crude residue was purified by silica gel chromatography using 5-20% ethyl acetate in dichloromethane to elute. The product-containing fractions were combined and concentrated under vacuum to afford 1-[4-[(5-chloro-2,3-dihydro-1-benzofuran-2-yl)carbonyl]piperazin-1-yl]-2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]ethan-1-one as a yellow solid (34.9 mg, 19%). (ES, m/z): [M+H]+ 611.25; 1H NMR (300 MHz, CDCl3): δ 8.00 (d, J=9.0 Hz, 1H), 7.18 (s, 1H), 7.07 (d, J=8.4 Hz, 1H), 6.85 (d, J=2.1 Hz, 1H), 6.70 (d, J=8.7 Hz, 1H), 6.63 (dd, J=2.1 Hz, 9.0 Hz, 1H), 5.42 (dd, J=7.5 Hz, 9.0 Hz, 1H), 4.23 (s, 2H), 3.82-3.98 (m, 4H), 3.30-3.70 (m, 8H), 2.10-2.20 (m, 4H), 1.42-1.58 (m, 2H), 1.20-1.40 (m, 2H).
Reaction SMILES: C([Mg]Cl)(C)C.[Cl:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][C:13](I)=[CH:12]2.[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=[O:23]>O1CCCC1>[Cl:18][C:19]1[CH:20]=[C:21]([CH:22]([C:13]2[CH:14]=[N:15][C:16]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][C:7]=3[Cl:6])[OH:23])[CH:24]=[CH:25][CH:26]=1
Reactant: Clc1cccc2cc(I)cnc12
Reactant: O=Cc1cccc(Cl)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: OC(c1cccc(Cl)c1)c1cnc2c(Cl)cccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
iso-Propyl magnesium chloride (2M solution in tetrahydrofuran)(3.76 ml, 7.5 mmol) was added dropwise over 0.25 h to a stirred solution of 8-chloro-3-iodoquinoline (D1)(2.0 g, 6.9 mmol) in tetrahydrofuran (16 ml) at −40° C. under argon. After stirring the solution at this temperature for 0.5 h, 3-chlorobenzaldehyde (0.77 ml, 6.8 mmol) was added dropwise over 10 mins. The solution was allowed to warm to ambient temperature over 1 h and then quenched by the addition of a saturated solution of sodium chloride (100 ml). The mixture was extracted with ethyl acetate (2×100 ml). The combined extracts were dried (MgSO4) and concentrated in vacuo to give the title compound (D2) as a crude solid (1.84 g, 6.0 mmol, 88%) which was used directly in the next stage (see D3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:16][CH:17]([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:16][CH:17]([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])=[CH:4][CH:3]=1
Reactant: CCOC(CBr)OCC
Reactant: Sc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(CSc1ccc(Cl)cc1)OCC
Yield: 50 %

Procedure:
In a 250 mL 2-neck round flask, 4-chlorobenzenethiol (10.0 g, 69 mmol), K2CO3 (9.52 g, 69 mmol), and dimethylformamide (DMF) (100 mL) were poured and stirred, and then 2-bromo-1,1-diethoxyethane (16.3 g, 82.8 mmol) was dissolved in dimethylformamide (100 mL) and gradually added to the aforementioned mixture solution at 0° C. After the reaction, an organic solvent was extracted with ethyl acetate (EtOAc) (250 mL) and water (200 mL), and then dried over MgSO4. After column chromatography using ethyl acetate/petroleum ether (EtOAc/PE=1:60), the solution was distilled in vacuum to give 9.0 g of yellow oil (50% yield).
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:14](OCC)(=[O:17])[CH2:15][OH:16].CO.C[O-].[Na+]>CCOCC>[CH2:1]([NH:13][C:15](=[O:16])[CH2:14][OH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCN
Reactant: CCOC(=O)CO
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: CCCCCCCCCCCCNC(=O)CO
Yield: 74.9 %

Procedure:
181.4 g (1.0 mol) of dodecylamine, 104.1 g (1.0 mol) of ethyl glycolate and 7.5 g (40 mmol) of a methanol solution containing 28% sodium methylate were fed into a 500-ml four-necked flask equipped with a stirrer and a thermometer. The obtained mixture was stirred under a stream of nitrogen gas, and the temperature thereof was elevated to 100° C. At this temperature, the reaction mixture was stirred for 2 hr while distilling off formed methanol. The obtained reaction mixture was dissolved in 500 ml of ether at room temperature. The ether solution thus obtained was transferred to a separatory funnel, and washed with water. The ether phase was separated, and concentrated. The solid remaining after concentration was dried in a reduced pressure to thereby obtain 182.3 g of white powdery N-dodecylglycolamide (yield: 74.9%). The hydroxyl value of this N-dodecylglycolamide was 229.4 (calculated value: 230.5).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[CH3:14][OH:15].C[O-].[Na+].Cl>O>[CH3:14][O:15][S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:11])=[O:12]
Reactant: CO
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 10 °C
Reaction time: 0.83 h

Procedure:
A reaction vessel equipped with a stirrer, a thermometer, and a nitrogen inlet tube was charged with 856 g of 2-nitrobenzenesulfonyl chloride and 7 L of methanol, and then a mixed solution of 745 g of 28% sodium methylate and 600 ml of methanol was dropped for 45 minutes at a temperature of 10° C. or less. The mixture was then stirred for 50 minutes while maintaining the temperature at 10° C. The reaction mixture was acidified by adding 1.6 kg of 0.1 mol/l hydrochloric acid, and then adding 3 L of water, whereby crystals deposited. The crystals were filtered, washed with 2 L of water, and then dried under reduced pressure for 10 hours at 30° C. to obtain 702 g of 2-nitrobenzene sulfonic acid methyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[C@H:11]([CH2:23][CH2:24][CH2:25][OH:26])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH:27](Cl)(Cl)Cl>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:9][CH2:10][C@@H:11]([CH2:23][CH2:24][CH2:25][O:26][CH3:27])[N:12]2[S:13]([C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)(=[O:15])=[O:14])=[CH:6][CH:7]=1
Reactant: ClC(Cl)Cl
Reactant: Cc1ccc(S(=O)(=O)N2[C@H](CCCO)CC[C@H]2c2ccc(F)cc2)cc1
Product: COCCC[C@@H]1CC[C@H](c2ccc(F)cc2)N1S(=O)(=O)c1ccc(C)cc1

Procedure:
The title compound, colorless oil, MS: m/e=392.1 (M+H+) and [α]D20=−82.7° (c=0.2682 in chloroform), was prepared in accordance with the general method of example 8 from (2S,5S)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propan-1-ol.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:26][C:6]2[N:7]=[C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH:11]3[CH2:16][C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[NH:19][CH:18]=3)[S:9][C:5]=2[C:4](=[O:27])[CH2:3]1.[H-].[Na+].[CH3:31]I>CN(C=O)C>[CH3:1][C:2]1([CH3:28])[CH2:26][C:6]2[N:7]=[C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH:11]3[CH2:16][C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]([CH3:31])[CH:18]=3)[S:9][C:5]=2[C:4](=[O:27])[CH2:3]1
Reactant: CC1(C)CC(=O)c2sc(N3CCOCC3Cc3c[nH]c4ccccc34)nc2C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(CC2COCCN2c2nc3c(s2)C(=O)CC(C)(C)C3)c2ccccc21
Reaction time: 0.17 h
Yield: 78.1 %

Procedure:
To a stirred solution of Example 24 (0.10 g, 0.25 mmol) in DMF (5 mL) at 0° C. was added sodium hydride (0.01 g, 40% dispersion in oil, 0.28 mmol). After stirring at this temperature for 10 minutes, methyl iodide (0.02 mL, 0.28 mmol) was added. The reaction was stirred at r.t. for 1 h and then quenched by the addition of ice. The reaction mixture was then partitioned between EtOAc (15 mL) and water (10 mL) and the organic phase was dried over MgSO4 and concentrated in vacuo. Purification by column chromatography (SiO2, 1:1 EtOAc/hexanes) gave the title compound (0.08 g, 79%) as a white solid. δH (CDCl3) 7.79 (1H, d, J 7.7 Hz), 7.09-7.24 (3H, m), 6.90 (1H, s), 4.05 (2H, m), 3.82 (1H, d, J 12.0 Hz), 3.79 (1H, bs), 3.68 (3H, s), 3.57 (2H, m), 3.41 (2H, m), 2.95 (1H, m), 2.67 (2H, s), 2.34 (2H, s), 1.11 (6H, s). LCMS (ES+) 410.0 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[C:8]([Cl:27])=[C:9]([C:23]([Cl:26])=[CH:24][CH:25]=1)[CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([CH3:22])[CH:18]=[CH:17]2)[CH3:6])=[O:4].C(N(CC)CC)C.[C:35](Cl)(=[O:42])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>ClCCl>[Cl:27][C:8]1[C:7]([N:5]([C:3](=[O:4])[CH2:2][NH:1][C:35](=[O:42])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH3:6])=[CH:25][CH:24]=[C:23]([Cl:26])[C:9]=1[CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([CH3:22])[CH:18]=[CH:17]2
Reactant: CCCCCCC(=O)Cl
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)c2n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCC(=O)NCC(=O)N(C)c1ccc(Cl)c(COc2cccc3ccc(C)nc23)c1Cl
Reaction time: 0.5 h

Procedure:
To a mixture of 8-[3-(N-glycyl-N-methylamino)-2,6-dichlorobenzyloxy]-2-methylquinoline (100 mg), triethylamine (50 mg) and dichloromethane (2.0 ml) was added heptanoyl chloride (0.05 ml) in an ice-water bath. The mixture was stirred at the same temperature for 30 minutes and washed with water. The organic layer was collected and dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (dichloromethane--methanol) to give 8-[2,6-dichloro-3-[N-(heptanoylglycyl)-N-methylamino]benzyloxy]-2-methylquinoline (130 mg) as a pale yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[CH:6]=[CH:5]2.[C:19]([O:28][CH3:29])(=[O:27])[C:20]1[C:21](=[CH:23][CH:24]=[CH:25][CH:26]=1)[SH:22].C(N(CC)C(C)C)(C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([S:22][C:21]4[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=4[C:19]([O:28][CH3:29])=[O:27])[CH:3]=3)[N:8]=2)=[CH:13][CH:14]=1
Reactant: COC(=O)c1ccccc1S
Reactant: Fc1ccc(-c2ccc3cc(Br)ccc3n2)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(=O)c1ccccc1Sc1ccc2nc(-c3ccc(F)cc3)ccc2c1
Yield: 90 %

Procedure:
A mixture of 6-bromo-2-(4-fluorophenyl)quinoline (Example 19 Step 1; 758 mg, 2.51 mmol), methyl thiosalicylate (0.35 mL, 2.54 mmol), N,N-diisopropylethylamine (0.87 mL, 4.99 mmol), tris(dibenzylideneacetone)dipalladium(0) (58 mg, 0.063 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (74 mg, 0.128 mmol) in 1,4-dioxane (15 mL) was degassed then heated at reflux under nitrogen for 15 hours. The reaction mixture was allowed to cool, concentrated in vacuo and the residue purified by flash chromatography, eluting with 15-25% ethyl acetate/isohexane, to afford methyl 2-{[2-(4-fluorophenyl)quinolin-6-yl]thio}benzoate (0.876, 90%). 1H NMR (400 MHz, CDCl3) δ 8.20-8.14 (4H, m), 8.08 (1H, d, J 1.9 Hz), 8.01 (1H, dd, J 1.6, 7.8 Hz), 7.88 (1H, d, J 8.6 Hz), 7.76 (1H, dd, J 2.0, 8.7 Hz), 7.23-7.15 (4H, m), 6.91 (1H, dd, J 0.9, 8.0 Hz), 3.97 (3H, s); m/z (ES+) 390 [MH+].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:37]=[CH:36][C:20]([C:21]([N:23]([CH3:35])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH2:31][CH2:32][CH2:33]Br)=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:37]=[CH:36][C:20]([C:21]([N:23]([CH3:35])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH2:31][CH2:32][CH2:33][N:48]4[CH2:49][CH2:50][N:45]([CH3:44])[CH2:46][CH2:47]4)=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3OCCCBr)cc2)cc1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3OCCCN3CCN(C)CC3)cc2)cc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 33.5 %

Procedure:
To a solution of 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-[2-(3-bromopropoxy)phenyl]benzamide (520 mg) in N,N-dimethylformamide (15 ml) was added potassium carbonate (386 mg) and 1-methylpiperazine (280 mg) at ambient temperature. The reaction mixture was stirred at 60° C. for 12 hours. The reaction mixture was cooled and extracted with ethyl acetate and washed with water, saturated sodium hydrogen carbonate and brine. The organic solution was dried over sodium sulfate. The solvent was removed by evaporation and subjected to silica gel column chromatography (SiO2; 30 g, 10% methanol in chloroform) to give 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-[2-[3-(4-methylpiperazin-1-yl)propoxy]phenyl]benzamide (180 mg).
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[Sn](Cl)(Cl)Cl.[C:14]([O:20][CH2:21][CH3:22])(=[O:19])[CH2:15][C:16]([CH3:18])=[O:17].C([O-])(O)=O.[Na+]>C1C=CC=CC=1>[CH2:21]([O:20][C:14](=[O:19])[C:15](=[C:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:16](=[O:17])[CH3:18])[CH3:22]
Reactant: CCOC(=O)CC(C)=O
Reactant: N#Cc1ccccc1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: CCOC(=O)C(C(C)=O)=C(N)c1ccccc1
Yield: 45.4 %

Procedure:
To a solution of the benzonitrile (40 g, 388.3 mmol) in benzene (600 mL) were added SnCl4 (44.75 mL, 388.3 mmol) and ethyl acetoacetate (49.1 mL, 388.3 mmol) at r.t. with stirring. The mixture was stirred at r.t. for 40 min, and was then refluxed with stirring for 2 h. After cooling to r.t. sat. NaHCO3 solution (200 mL) was added, and the mixture extracted with EtOAc (4×200 mL). The combined organic phases were washed with sat. aq. NaCl solution and water, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel. Elution with 5-33% EtOAc/CH2Cl2 gave the title compound as a white solid (41.1 g): MS (m/z) 234.3 (M+1).
Reaction SMILES: Cl.[F:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[OH-].[Na+].[C:21](Cl)([CH3:23])=[O:22]>C(Cl)Cl>[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[C:21](=[O:22])[CH3:23])=[CH:17][CH:18]=1
Reactant: CC(=O)Cl
Reactant: Fc1ccc(CNCc2ccc(F)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(=O)N(Cc1ccc(F)cc1)Cc1ccc(F)cc1
Reaction time: 0.5 h
Yield: 54.5 %

Procedure:
Bis-(4-fluoro-benzyl)-amine hydrochloride (43 grams, 0.16 mole) was suspended in 200 mL of CH2Cl2. To this was added 730 mL of 1N NaOH. The reaction mixture was stirred vigorously while AcCl (20 mL, 0.28 mole) was slowly added. The reaction was stirred for 0.5 h, then the organic layer separated, washed with 1N HCl, dried over Na2SO4, filtered and the solvent removed under vacuum to yield 24 grams (55% yield) of N,N-bis-(4-fluoro-benzyl)-acetamide as an oil. MS (M+H) calcd for C16H16F2NO: 276.1. found: 276.0. Anal. calcd for C16H15F2NO: C, 69.80; H, 5.49; N, 5.08. found: C, 69.53; H, 5.41; N, 5.06. 1H NMR (500 MHz, DMSO) δ: 2.10 (s, 3), 4.45 (s, 2), 4.50 (s, 2), 7.11–7.27 (overlapping m, 8). 13C NMR (125 MHz, DMSO) δ: 21.34, 50.04, 54.80, 114.90, 115.07, 115.27, 115.45, 128.51, 128.58, 129.57, 129.64, 133.32, 133.34, 133.86, 133.89, 160.25, 160.33, 162.27, 170.22.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12]([OH:14])=O)[C:9]([OH:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[F:1][C:2]1[CH:11]=[C:10]([C:12]([NH:22][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([Cl:16])=[CH:18][CH:19]=2)=[O:14])[C:9]([OH:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: NCc1ccc(Cl)cc1
Reactant: O=C(O)c1cc(F)c2cccnc2c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1ccc(Cl)cc1)c1cc(F)c2cccnc2c1O
Temperature: 0 °C
Reaction time: 8 h
Yield: 41.7 %

Procedure:
To a solution of 5-fluoro-8-hydroxyquinoline-7-carboxylic acid (0.311 g) of reparation 4 and 4-chlorobenzylamine (0.219 g) in 20 mL DMF is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.305 g) and 1-hydroxybenzotriazole monohydrate (0.217 g). The mixture is stirred overnight. The solution is then poured into 30 mL ice-water. The resulting solid is collected and dried. The crude product is recrystallized from EtOAc/hexanes to yield 0.207 g of the title product as an off-white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][CH2:2]1.[C:16]([C:18]1[CH:34]=[CH:33][C:21]([C:22]([N:24]2[CH2:31][CH2:30][CH2:29][C@@:25]2([CH3:32])[C:26](O)=[O:27])=[O:23])=[CH:20][CH:19]=1)#[N:17].S(Cl)(Cl)=O>>[C:16]([C:18]1[CH:34]=[CH:33][C:21]([C:22]([N:24]2[CH2:31][CH2:30][CH2:29][C@@:25]2([CH3:32])[C:26]([N:1]2[CH2:2][CH2:3][CH:4]([O:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:6]2)=[O:27])=[O:23])=[CH:20][CH:19]=1)#[N:17]
Reactant: CC(C)(C)OC(=O)COC1CCNCC1
Reactant: C[C@@]1(C(=O)O)CCCN1C(=O)c1ccc(C#N)cc1
Solvent: O=S(Cl)Cl
Product: CC(C)(C)OC(=O)COC1CCN(C(=O)[C@]2(C)CCCN2C(=O)c2ccc(C#N)cc2)CC1

Procedure:
By reacting 1.67 g of t-butyl 4-piperidinyloxyacetate with 0.8 g of the acid chloride of 1-(p-cyanobenzoyl)-2-methyl-L-proline (obtained by treating the product of the previous step with thionyl chloride) there is obtained 0.89 g of t-butyl [[1-[1-(p-cyanobenzoyl)-2-methyl-L-prolyl]-4-piperidinyl]oxy]acetate. M.p. 180°-182° C. (ethyl acetate).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([SH:8])=[N:6][CH:7]=1.[H-].[Na+].Br[CH2:12][CH:13]1[CH2:15][CH2:14]1>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[N:6][CH:7]=1
Reactant: BrCC1CC1
Reactant: Sc1ccc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Brc1ccc(SCC2CC2)nc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-bromopyridine-2-thiol (3.9 g) in THF (100 mL) was added NaH (1.24 g) at 0° C. and the mixture was stirred at 0° C. for 0.5 h. Then (bromomethyl)cyclopropane (2.79 g) was added. The mixture was allowed to warm to r.t. and stirred for 6 hours. The mixture was poured into ice water (200 mL) and extracted with EA (100 mL×3). The combined organic phases were washed with brine (50 mL) and then dried over Na2SO4. After filtration and evaporation of the solvent, the residue was purified by SGC (eluent: PE) to provide the subtitle compound. MS ESI+: m/z=244 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH3:21].C(N(CC)CC)C.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN1CCCC1=O>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH3:21])[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:29](=[O:36])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CCOCCN
Reactant: O=C(Cl)c1ccccc1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Cc1nc2c(N)nc3ccccc3c2n1CCOCCNC(=O)c1ccccc1
Reaction time: 18 h
Yield: 26.5 %

Procedure:
A solution of the compound of Example 67, 1-[2-(2-aminoethoxy)ethyl]-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (1.47 g, 5.14 mmol) in 40 mL 1-methyl-2-pyrrolidinone was treated with triethylamine (1.43 mL, 10.3 mmol). With vigorous stirring, the solution was treated dropwise with benzoyl chloride (0.597 mL, 5.14 mmol). After 18 h, the reaction was concentrated. Purification by column chromatography (SiO2, 95:5:0.5 CHCl3:MeOH:NH4OH) gave a clear, colorless oil. The oil was triturated in ether and filtered to yield 531 mg of N-{2-[2-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethyl}benzamide as a white solid. mp 210-212° C.; 1H NMR (300 MHz, DMSO-d6) δ8.37 (t, J=7.0 Hz, 1 H), 8.05 (d, J=7.6 Hz, 1 H), 7.78-7.75 (m, 2 H), 7.61 (dd, J=1.1, 8.3 Hz, 1 H), 7.54-7.37 (m, 4 H), 7.21-7.16 (m, 1 H), 6.55 (s,2 H), 4.70 (t, J=5.0 Hz, 2 H), 3.90 (t, J=5.0 Hz, 2 H), 3.49 (t, J=6.1 Hz, 2 H), 3.34 (t, J=5.7 Hz, 2 H), 2.59 (s, 3 H); 13C NMR (75 MHz, DMSO-d6) δ166.7, 152.0, 151.1, 145.1, 134.8, 132.8, 131.4, 128.6, 127.4, 126.6, 121.3, 120.4,115.1, 69.4, 69.3, 45.8, 14.1; MS m/z 390 (M+H)+; Anal. Calcd for C22H23N5O2: C, 67.85; H, 5.95; N, 17.98. Found: C, 67.56; H, 5.81; N, 17.87.
Reaction SMILES: [F:1][C:2]([F:53])([F:52])[C:3]1[CH:4]=[C:5]([C:13]([CH3:51])([CH3:50])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:31]3[C@H:40]([CH2:41][O:42][Si](C(C)(C)C)(C)C)[CH2:39][N:38]4[C@H:33]([CH2:34][O:35][CH2:36][CH2:37]4)[CH2:32]3)=[CH:22][C:23]=2[C:24]2[CH:25]=[N:26][CH:27]=[CH:28][C:29]=2[CH3:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl>CO>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([C:13]([CH3:51])([CH3:50])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:31]3[C@H:40]([CH2:41][OH:42])[CH2:39][N:38]4[C@H:33]([CH2:34][O:35][CH2:36][CH2:37]4)[CH2:32]3)=[CH:22][C:23]=2[C:24]2[CH:25]=[N:26][CH:27]=[CH:28][C:29]=2[CH3:30])[CH3:17])=[O:15])[CH:4]=[C:3]([C:2]([F:1])([F:53])[F:52])[CH:8]=1
Reactant: Cc1ccncc1-c1cc(N2C[C@H]3COCCN3C[C@H]2CO[Si](C)(C)C(C)(C)C)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Solvent: CO
Product: Cc1ccncc1-c1cc(N2C[C@H]3COCCN3C[C@H]2CO)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
2-[3,5-bis(trifluoromethyl)phenyl]-N-{6′-[(7S,9aS)-7-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-4-methyl-3,4′-bipyridin-3′-yl}-N,2-dimethylpropanamide (D53, 86 mg) was dissolved in dry MeOH (4 mL), cooled in an ice/salt bath to ˜0° C. before adding c.HCl solution. The mixture was stirred at ˜0° C. for 45 mins before allowing to warm up to R.T. and stirring for a further 2 hrs. Placed on a 5 g SCX column, washed with MeOH×3, before eluting compound off with NH3 in MeOH. Solvent evaporated. Residue purified on a 5 g sek pak column eluting with Pent to EtOAc to 10% MeOH/EtOAc. Solvent evaporated to dryness in vacuo to afford a colourless gum of the title compound.