Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH3:41][O:42][NH:43][CH3:44]>C(Cl)Cl>[CH3:41][O:42][N:43]([CH3:44])[C:10](=[O:12])[CH2:9][NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CNOC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CON(C)C(=O)CNC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 53.6 %

Procedure:
8.75 g (50 mmol) of BOC-glycine dissolved in 150 ml DCM and 6.95 ml (50 mmol) of TEA was added to the solution, and stirred. 17.42 g (50 mmol) BOP reagent (Richelieu Biotechnologies, QC, Canada) was added, followed a few minutes later with O,N-dimethylhydroxylamine hydrochloride (5.6 g, 55 mmol) and TEA (7.67 g, 55 mmol). The reaction was complete in 60 min, and the result was verified by TLC monitoring. A small amount of TEA was used to neutralize the mixture (adjust the pH to above 7.0) in order to allow the reaction go to completion. The mixture was diluted to 500 ml with DCM. The solution was washed in turn with 3N HCl (3×100 ml), saturated NaHCO3 (3×100 ml), and brine (3×100 ml). The DCM layer was dried over MgSO4 and concentrated to obtain the crude product. Recrystallization from water afforded 5.85 g Nα -(BOC)-glycine N-methoxy-N-methylamide (m.p. 92°-95° C.). This product was dried thoroughly in vacuo over P2O5 before use in the following reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](Cl)=[O:11])=[CH:5][CH:4]=1.C(#N)C.C[Si]([CH:20]=[N+:21]=[N-:22])(C)C.C(OCC)C>C1COCC1>[N+:21](=[CH:20][C:10](=[O:11])[CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[N-:22]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COc1ccc(CC(=O)Cl)cc1
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(CC(=O)C=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Under an argon atmosphere, 4-methoxyphenylacetyl chloride (61) (952 mg, 5.16 mmol) was dissolved in THF (2.5 mL) and acetonitrile (2.5 mL) and cooled to 0° C. To this was slowly added a solution of trimethylsilyldiazomethane in diethyl ether (2.0 M, 5.00 mL, 10.0 mmol), which was stirred overnight (15 hours) after warming up to room temperature. After concentrating under reduced pressure, the residue was purified by silica gel flash column chromatography (n-hexane/diethyl ether=1/1) to give 1-diazo-3-(4-methoxyphenyl)propan-2-one (62) as a pale yellow oily substance (692 mg, 3.64 mmol, 70.6%).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]1([CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCN1CCOCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCOCCOCCOCCN1CCOCC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 99 %

Procedure:
To a solution of 1 g of tert-butyl 3-{2-[2-(2-morpholin-4-yl-ethoxy)-ethoxy]-ethoxy}-propanoate in 50 ml of DCM was added 4 ml of TFA. The mixture was stirred for 10 hours at room temperature and then concentrated under reduced pressure and purified on a Mega BE-SCX, 25GM 150ML cartridge (Varian), using washing with MeOH and detachment of the expected product with a 2N solution of ammonia in MeOH. The fractions containing the desired product were combined and concentrated under reduced pressure. 830 mg of 3-{2-[2-(2-morpholin-4-yl-ethoxy)-ethoxy]-ethoxy}-propanoic acid were obtained. LC/MS (E): tr (ELSD)=0.16 min; [M+H]+: m/z 292
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[NH2:9].[F:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[C:13]([O:20][CH3:21])[CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)(O)[O-].[Na+]>COCCOC.C(OCC)(=O)C>[Cl:8][C:6]1[N:5]=[N:4][C:3]([NH2:9])=[C:2]([C:14]2[CH:15]=[CH:16][C:11]([F:10])=[CH:12][C:13]=2[O:20][CH3:21])[CH:7]=1
Reactant: Nc1nnc(Cl)cc1Br
Reactant: COc1cc(F)ccc1B(O)O
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1cc(F)ccc1-c1cc(Cl)nnc1N
Reaction time: 0.25 h

Procedure:
To a solution of 4-bromo-6-chloropyridazin-3-amine (2.5 g, 12.0 mmol, CAS RN 446273-59-2) in 1,2-dimethoxyethane (30 mL) was added 4-fluoro-2-methoxyphenylboronic acid (2.45 g, 14.4 mmol, CAS RN 179899-07-1) and 2M aqueous sodium carbonate solution (10 mL). The reaction mixture was stirred under argon atmosphere for 15 minutes. Pd(II)acetate (135 mg, 600 μmol) and triphenylphosphine (315 mg, 1.2 mmol) was added. The dark red reaction mixture was stirred at 90° C. for 8 hours and then poured on 10% aqueous sodium bicarbonate solution (200 mL) and ethyl acetate (200 mL), filtered over dicalite and the layers were separated. The aqueous layer was extracted a second time with ethyl acetate (200 mL). The organic layers were washed with 200 mL brine, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography on a 120 g column using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 0:100). Light red solid (1.71 g, 56.2%). MS (ESI+): m/z=254.050 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[OH:9].O[CH:11]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:12][CH2:13][N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[O:9][CH:11]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:12][CH2:13][N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20]
Reactant: Oc1cc(Cl)ccc1Cl
Reactant: CCCCC(O)CCN(C)C(=O)OC(C)(C)C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCCCC(CCN(C)C(=O)OC(C)(C)C)Oc1cc(Cl)ccc1Cl
Temperature: 50 °C
Reaction time: 20 h
Yield: 51.2 %

Procedure:
2,5-Dichlorophenol (163 mg, 1.00 mmol) and (3-hydroxyheptyl)methylcarbamic acid, 1,1-dimethylethyl ester (360 mg, 1.47 mmol) were dissolved in tetrahydrofuran (10 ml). To the resulting solution was added tributylphosphine (0.380 ml, 1.50 mmol) and then 1,1′-(azodicarbonyl)dipiperidine (380 mg, 1.50 mmol). The solution was then heated to 50° C. under nitrogen for 3 h, and then allowed to stir at room temperature for a further 20 h. The mixture was then filtered and poured into sodium hydrogen carbonate solution. The mixture was extracted with diethyl ether three times and the combined organic fractions were washed with brine, then dried over magnesium sulfate. The solvent was evaporated and the residue eluted down a flash chromatography column using 10% ethyl acetate/isohexane as eluent to give 200 mg (51%) of the title compound as an oil.
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C@H:6]([C:13]2[CH:14]=[CH:15][C:16]([Cl:20])=[C:17]([Cl:19])[CH:18]=2)[CH2:5][CH2:4]1.[NH2:21][C@H:22]([C:27]([OH:29])=[O:28])[CH2:23][C:24]([OH:26])=[O:25].O>C(OCC)(=O)C>[CH3:1][NH:2][C@@H:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C@H:6]([C:13]2[CH:14]=[CH:15][C:16]([Cl:20])=[C:17]([Cl:19])[CH:18]=2)[CH2:5][CH2:4]1.[NH2:21][C@H:22]([C:27]([O-:29])=[O:28])[CH2:23][C:24]([O-:26])=[O:25]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: CN[C@H]1CC[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Product: N[C@@H](CC(=O)[O-])C(=O)[O-]
Reaction time: 24 h

Procedure:
Sertraline free base (the compound of Preparation AA, 200.3 mg) was dissolved in ethyl acetate (800 μL, which had previous been saturated with water). L-aspartic acid (95.53 mg) was suspended in ethyl acetate (3 mL, which had previously been saturated with water). The aspartic acid suspension was added to the sertraline free base solution. The reaction mixture was stirred for 24 hours. The solids were filtered, washed with ethyl acetate saturated with water and then dried at 40° C. in a vacuum oven for 48 hours. The yield of sertraline L-aspartate was 96.4%. mp 247° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]([NH:7][CH2:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=O)[CH3:2].P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[C:10]([C:9]1[O:14][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:15])=[N:7][CH:8]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CCOC(=O)C(=O)NCC(=O)C(C)(C)C
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ncc(C(C)(C)C)o1
Temperature: 120 °C
Yield: 87.6 %

Procedure:
To a mixture of ethyl[(3,3-dimethyl-2-oxobutyl)amino](oxo)acetate (40 g, 162 mmol) in toluene (350 mL) is added phosphorous oxychloride (75 g, 488 mmol). The reaction mixture is heated at 120° C. for 14 h. Then the solvent is removed and the residue is diluted with ether. The ether layer is washed with saturated aqueous NaHCO3 solution, brine, dried (Na2SO4) and concentrated to afford the title compound (28 g, 87%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[NH2:9].[F:10][C:11]([F:24])([F:23])[CH2:12][O:13][C:14]1[C:19](B(O)O)=[CH:18][CH:17]=[CH:16][N:15]=1>>[Cl:8][C:6]1[N:5]=[N:4][C:3]([NH2:9])=[C:2]([C:19]2[C:14]([O:13][CH2:12][C:11]([F:23])([F:10])[F:24])=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:7]=1
Reactant: OB(O)c1cccnc1OCC(F)(F)F
Reactant: Nc1nnc(Cl)cc1Br
Product: Nc1nnc(Cl)cc1-c1cccnc1OCC(F)(F)F

Procedure:
The title compound was prepared in analogy to example 1, intermediate b, from 4-bromo-6-chloro-pyridazin-3-ylamine (CAS RN 446273-59-2) and 2-(2,2,2-trifluoroethoxy)pyridine-3-boronic acid (CAS RN 1218790-79-4) after a reaction time of 18 hours. Brown solid (43%). MS (ESI+): m/z=305.041 ([M+H]+).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1)=[O:10])(C)(C)C.[ClH:27].O1CCOCC1>>[ClH:27].[NH2:7][C@@H:8]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)[C:9]([N:11]1[CH2:12][CH2:13][CH:14]([OH:17])[CH2:15][CH2:16]1)=[O:10]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)cc1)C(=O)N1CCC(O)CC1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H](Cc1ccc(F)cc1)C(=O)N1CCC(O)CC1
Reaction time: 2 h
Yield: 97 %

Procedure:
[(S)-1-(4-Fluoro-benzyl)-2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester (20.2 g, 55 mmol) was dissolved in 4M HCl-dioxane (25 mL) at 25° C. After 3 hours a thick syrup had precipitated, and an additional 4M HCl-dioxanes (10 mL) was added. The mixture was stirred for 2 hours, concentrated and the solid residue suspended in 4M HCl-dioxanes. After 2 hours at 25° C., the mixture was concentrated and the residue coevaporated twice with ether. The resulting solid was stirred in a mixture of ether (75 mL) and hexanes (10 mL) at 25° C. for 18 hours, the mixture filtered, and the filtered solid washed with 1:1 ether-hexanes and dried giving hygroscopic solid (16.3 g, 97%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(N2CCN(c3ccc([N+](=O)[O-])cc3)CC2)cc1
Yield: 67 %

Procedure:
A mixture of 1-(4-methoxyphenyl)piperazine dihyclrochloride (0.050 mol), 1-chloro-4-nitrobenzene (0.050 mol) and potassium carbonate (10.0 g) in N,N-dimethylform-amide (100 ml) was stirred and refluxed overnight. The reaction mixture was diluted with water and extracted twice with trichloromethane. The organic layers were combined, dried (MgSO4), filtered and evaporated in vacuum. The residue was successively triturated in 4-methyl-2-pentanone and recrystallized from 1,4-dioxane. The product was filtered off and dried, yielding 10.5 g (67%) of 1-(4-methoxyphenyl)-4-(4-nitrophenyl)-piperazine; mp. 195.1° C. (interm. 1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][Si](C(C)C)(C(C)C)C(C)C)=[CH:4][C:3]=1[N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:4]=1)#[CH:9]
Reactant: CC(C)[Si](C#Cc1ccc(F)c(N2CCOCC2)c1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccc(F)c(N2CCOCC2)c1
Yield: 99.1 %

Procedure:
A 25 mL round bottom flask was charged with 4-(2-fluoro-5-((triisopropylsilyl)ethynyl)phenyl)morpholine (0.540 g, 1.50 mmol), diluted with tetrahydrofuran (THF, 1.5 ml) at room temperature. A 1M solution of tetrabutylammonium fluoride in THF (2.0 mL) was added. After 105 minutes reaction the mixture was partitioned between ethylacetate and water, separated, dried with sodium sulfate, and concentrated to an oil by rotary evaporation to yield 0.305 g of 4-(5-ethynyl-2-fluorophenyl)morpholine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[C:11](OS(C(F)(F)F)(=O)=O)[C:10]=2[N+:23]([O-:25])=[O:24])=[C:5]([CH3:26])[CH:4]=1.Cl.[CH3:28][O:29][CH2:30][CH:31]([NH2:33])[CH3:32]>>[CH3:28][O:29][CH2:30][CH:31]([NH:33][C:11]1[C:10]([N+:23]([O-:25])=[O:24])=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[CH3:26])[CH:14]=[CH:13][N:12]=1)[CH3:32]
Reactant: COc1ccc(-c2ccnc(OS(=O)(=O)C(F)(F)F)c2[N+](=O)[O-])c(C)c1
Reactant: COCC(C)N
Agent: Cl
Product: COCC(C)Nc1nccc(-c2ccc(OC)cc2C)c1[N+](=O)[O-]
Yield: 48.9 %

Procedure:
Trifluoro-methanesulfonic acid 4-(4-methoxy-2-methyl-phenyl)-3-nitro-pyridin-2-yl-ester (0.332 g, 0.74 mmol), prepared substantially as described in Part C of Example 67a, and 2-methoxy-1-methyl-ethylamine HCl (0.263 g, 67 mmol) were treated substantially as described in Part C of Example 67a to produce 0.120 g (54%) of (2-methoxy-1-methyl-ethyl)-[4-(4-methoxy-2-methyl-phenyl)-3-nitro-pyridin-2-yl]amine; MS(AP) m/z 332.1 [(M+H)+, 94].
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]2[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16][CH3:17])=[CH:8][C:6]=2[N:7]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[CH3:17][O:16][C:9]1[C:10]([O:14][CH3:15])=[C:11]([O:12][CH3:13])[C:5]2[O:4][C:3]([CH2:2][N:18]3[CH2:23][CH2:22][N:21]([CH2:2][C:3]4[O:4][C:5]5[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16][CH3:17])=[CH:8][C:6]=5[N:7]=4)[CH2:20][CH2:19]3)=[N:7][C:6]=2[CH:8]=1
Reactant: C1CNCCN1
Reactant: COc1cc2nc(CCl)oc2c(OC)c1OC
Product: COc1cc2nc(CN3CCN(Cc4nc5cc(OC)c(OC)c(OC)c5o4)CC3)oc2c(OC)c1OC

Procedure:
2-Chloromethyl-5,6,7-trimethoxybenzoxazole (156 mg) and piperazine (23 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9]#[N:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(N(CC)CC)C.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>C1C=CC=CC=1>[C:22]1([O:21][C:19]([O:1][N:2]=[C:3]([C:9]#[N:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:20])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)C(C#N)=NO
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C#N)=NOC(=O)Oc1ccccc1
Temperature: 0 °C
Yield: 124.8 %

Procedure:
In dry benzene (50 ml), ethyl 2-hydroxyimino-2-cyanoacetate (7.1 g) and triethylamine (7.0 ml) are dissolved, and the obtained solution is cooled with ice-water. A solution of phenyl chloroformate (7.8 g) in dry benzene (50 ml) is dropwise added thereto while stirring, and the resulting mixture is stirred for 1 hour and allowed to stand over night. The reaction mixture is filtered, and the filtrate is washed with water, dried and concentrated to give ethyl 2-phenyloxycarbonyloxyimino-2-cyanoacetate (16.3 g) as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:4][CH:3]=1.C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[F:29][C:30]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOCC.C(O)C>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([C:34]2[CH:33]=[CH:32][CH:31]=[C:30]([F:29])[C:35]=2[F:36])=[CH:3][CH:4]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCOc1ccc(Br)cc1
Reactant: OB(O)c1cccc(F)c1F
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCO
Solvent: CCOCC
Product: CCCCCCCCOc1ccc(-c2cccc(F)c2F)cc1

Procedure:
To a mixture of 4.2 g of the 4-bromo-1-n-octyloxybenzene, 0.5 g of tetrakis(triphenylphosphine) palladium(0), 53 ml of benzene, and 53 ml of an aqueous sodium carbonate solution (2 mol/liter), 26 ml of ethanol containing 3.0 g of 2,3-difluorophenyl boronic acid synthesized by the same method as in [1] in Example 1 was added dropwise, and then the solution thus formed was heated to reflux for 5 hours. After the solution was cooled, it was added with 200 ml of an ether to extract the product, washed with water and dried. The solvent was distilled off under a reduced pressure. The residue thus obtained was purified by a silica gel column chromatography using a mixed solvents of n-hexane and diethyl ether (10:2) to obtain 2.8 g of 4-n-octyloxy-2', 3'-difluorobiphenyl.
Reaction SMILES: [N:1]([C:4](=[CH:10][N:11]([CH3:13])[CH3:12])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:2]=[O:3].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[C:5]([C:4]([NH:1][C:2]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:3])=[CH:10][N:11]([CH3:12])[CH3:13])([O:7][CH2:8][CH3:9])=[O:6]
Reactant: Nc1ccccc1
Reactant: CCOC(=O)C(=CN(C)C)N=C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CN(C)C)NC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of Ethyl 2-isocyanato-3-(dimethylamino)-propenoate (5.52 g) in toluene (250 mL) was added aniline (2.79 g). The reaction was stirred at room temperature for 30 min. The resulting solid was collected and dried to yield N-(1-Carboethoxy-2-dimethylaminovinyl)-N'-phenyl urea as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]([OH:18])=O)[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.[C:22]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)(=[O:26])[CH:23]([CH3:25])[CH3:24]>O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH:10]1[CH2:11][CH2:12][CH:13]([C:16]([N:30]2[CH2:31][CH2:32][N:27]([C:22](=[O:26])[CH:23]([CH3:24])[CH3:25])[CH2:28][CH2:29]2)=[O:18])[CH2:14][CH2:15]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CC(C)C(=O)N1CCNCC1
Solvent: ClCCl
Solvent: O
Product: CC(C)C(=O)N1CCN(C(=O)C2CCC(CNC(=O)OC(C)(C)C)CC2)CC1
Reaction time: 2 h
Yield: 80.2 %

Procedure:
To a solution of trans-4-(tert-Butoxycarbonylamino-methyl)-cyclohexanecarboxylic acid (8.5 g, 32.8 mmol) in DCM (100 mL) 1,1-carbonyldiimidazole (4.87 g, 30.1 mmol) was added and the reaction was left stirring for 2 hours. Then isobutyryl-piperazine (6.95 g, 27.3 mmol) was also added and the reaction was left stirring for 16 h at room temperature. The mixture was diluted with 50 mL of H2O, the organic phase collected and the solvent removed under reduced pressure. The residue was washed with 1N NaOH solution and the precipitate was filtered, affording 8.7 g (21.9 mmol) of [4-(4-Isobutyryl-piperazine-1-carbonyl)-cyclohexylmethyl]-carbamic acid tert-butyl ester. The product obtained was dissolved in 100 mL of DCM and H2SO4 (2.92 mL, 54.9 mmol) was added. The reaction was stirred for 18 hours and the mixture was washed with 50 mL of 15% NaOH solution, the organic phase was collected and concentrated under reduced pressure. 3.85 g of the titled product were obtained (yield=48%).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:9](=[O:11])C)[S:7][CH:8]=1)([CH3:3])[CH3:2].[OH-:12].[Na+]>O1CCOCC1.Cl[O-].[Na+]>[CH:1]([C:4]1[CH:5]=[C:6]([C:9]([OH:11])=[O:12])[S:7][CH:8]=1)([CH3:2])[CH3:3]
Reactant: [OH-]
Reactant: CC(=O)c1cc(C(C)C)cs1
Agent: [Na+]
Agent: [O-]Cl
Solvent: C1COCCO1
Product: CC(C)c1csc(C(=O)O)c1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
A solution of 1-(4-isopropylthiophen-2-yl)ethanone (example 74, step a) (1 g) in 1,4-dioxane (10 mL) was cautiously added to a solution of sodium hydroxide (1.19 g) in aqueous sodium hypochlorite (8%, 50 mL) at 60° C. The resulting mixture was heated to 75° C. and stirred for 1 h. The reaction was allowed to cool and the aqueous phase washed with DCM (50 mL). The aqueous phase was treated with aqueous sodium bisulphite solution (10%, 20 mL) and carefully acidified with concentrated hydrochloric acid. The resulting mixture was extracted with DCM (3×50 mL). The combined organic solutions were dried over sodium sulphate, filtered and evaporated to give a yellow oil. Purification was by preparative HPLC (Sunfire™, Gradient: 5-95% acetonitrile in 0.2% aqueous TFA). The fractions containing product were combined, evaporated and dried under high vacuum to give the subtitled compound as a white solid. Yield 0.5 g.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH3:18])[N:14]([CH2:15][CH2:16]O)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.S(Cl)([Cl:21])=O>ClCCCl>[Cl:21][CH2:16][CH2:15][N:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=[C:13]1[CH3:18]
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CCO
Reactant: O=S(Cl)Cl
Solvent: ClCCCl
Product: Cc1nc2c(N)nc3ccccc3c2n1CCCl
Yield: 45.3 %

Procedure:
Using the general method of Example 6 Part A except that a solvent (55 mL of 1,2-dichloroethane) was included, 2-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethanol (4.0 g, 16.51 mol) was chlorinated using thionyl chloride (2.41 mL, 33.02 mmol) to provide 3.9 g of 1-(2-chloroethyl)-2-methyl-1H-imidazo[4,5-c]quinoline-4-amine as a fine, white powder.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:38])=[C:21]([NH:26][S:27]([C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[F:37])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=2[F:25])[CH:5]=[CH:4][N:3]=1.[NH4+:39].[OH-]>>[NH2:39][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:38])=[C:21]([NH:26][S:27]([C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[F:37])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=2[F:25])[CH:5]=[CH:4][N:3]=1
Reactant: [NH4+]
Reactant: O=S(=O)(Nc1ccc(F)c(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1cc(F)ccc1F
Agent: [OH-]
Product: Nc1nccc(-c2sc(N3CCOCC3)nc2-c2c(F)ccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 21 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}-2,5-difluorobenzenesulfonamide (150 mg, 0.256 mmol) and NH4OH (2.5 mL, 17.97 mmol) heated in a microwave reactor at 130° C. for 30 min the title compound was obtained as a light yellow solid (127 mg, 83% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.74 (br. s., 1H), 7.90 (d, J=5.3 Hz, 1H), 7.46-7.58 (m, 4H), 7.25 (t, J=8.8 Hz, 1H), 6.62 (br. s., 2H), 5.61 (d, J=5.1 Hz, 1H), 3.69-3.74 (m, 4H), 3.42-3.47 (m, 4H). MS (ESI): 566 [M+H]+.