Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.FC(F)(F)S(O[C:20]1[CH2:25][CH2:24][NH:23][CH:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:21]=1)(=O)=O.C(OC(N1CCC(=O)CC1)=O)(C)(C)C.[Li+].CC([N-]C(C)C)C.C1C=CC(N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)=CC=1.C([O-])([O-])=O.[Na+].[Na+]>O.COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:20]1[CH2:25][CH2:24][NH:23][CH:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:21]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)C1C=C(OS(=O)(=O)C(F)(F)F)CCN1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(C)[N-]C(C)C
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)C1C=C(c2ccccc2C(F)(F)F)CCN1

Procedure:
The title compound was prepared according to the procedure described in Preparation A using 2-(trifluoromethyl)phenylboronic acid (Aldrich) (1.89 g, 10 mmol), tert-butyl 4-[(trifluoromethyl)sulfonyloxy]-1,2,5,6-tetrahydropyridinecarboxylate [prepared by the method of Wustrow, D. J. and Wise, L. D., Synthesis, 1991, 993-995, from tert-butyl-4-oxopiperidine-1-carboxylate (Aldrich), LDA (Aldrich) and N-phenyltrifluoromethanesulfonimide (Aldrich)] (3.64 g, 11 mmol), tetrakis(triphenylphosphine)palladium (0) (Strem Chemicals) (0.578 g, 0.5 mmol), LiCi (Aldrich) (1.27g, 30 mmol), and Na2CO3 (Aldrich) (2.46 g, 30 mmol) in water (15 mL) and DME (20 mL). Purification by silica gel chromatography (5:1 hexane:EtOAc) provided the title compound as a white foam (2.01 g). MS (ESI, pos. ion) m/z: 328 (M+1); MS (ESI, neg. ion) m/z: 326 (M−1). Calc'd for C17H20F3NO2: 327.34.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:20][CH2:21][O:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[C:4]2[C:9]([CH3:10])=[C:8]([CH3:11])[N:7]=[C:6](OC3C=CC=CC=3)[C:5]=2[N:19]=1.C([O-])(=O)C.[NH4+:36]>C(OCC)(=O)C>[CH3:1][C:2]1[N:3]([CH2:20][CH2:21][O:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[C:4]2[C:9]([CH3:10])=[C:8]([CH3:11])[N:7]=[C:6]([NH2:36])[C:5]=2[N:19]=1
Reactant: [NH4+]
Reactant: Cc1nc(Oc2ccccc2)c2nc(C)n(CCOCCCc3cccnc3)c2c1C
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Product: Cc1nc(N)c2nc(C)n(CCOCCCc3cccnc3)c2c1C
Temperature: 25 °C
Reaction time: 46.5 h

Procedure:
Under a nitrogen atmosphere, 2,6,7-trimethyl-4-phenoxy-1-[2-(3-pyridin-3-ylpropoxy)ethyl]-1H-imidazo[4,5-c]pyridine (4 g) from Part D and ammonium acetate (40 g) were heated in a sealed tube to 150° C. After 46.5 hours, NMR analysis indicated that only 7% of the starting material remained. The reaction mixture was cooled to ambient temperature, diluted with ethyl acetate, and washed 3 times with IN potassium hydroxide and once with water. The organic layers were dried with magnesium sulfate and concentrated under reduced pressure. The resulting oil was triturated with 90/10 diethyl ether/toluene and the filtered solids were dried under vacuum at 45° C. The pale yellow solid was dissolved in 10% hydrochloric acid and extracted 3 times with dichloromethane (DCM). Potassium hydroxide was added to the aqueous layer to bring the pH to 14, and this was subsequently washed 3 times with DCM. The combined organic layers were washed once with water, 3 times with brine, dried with magnesium sulfate, and concentrated under reduced pressure. The oil was purified by column chromatography over silica using 97/3 DCM/methanol as the eluant. The oil was then triturated with diethyl ether/toluene and the resulting solid was recrystallized from ethyl acetate/hexane to yield 2,6,7-trimethyl-1-[2-(3-pyridin-3-ylpropoxy)ethyl]-1H-imidazo[4,5-c]pyridin-4-amine, m.p. 108.6-109.5° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:8])[CH2:4][CH2:5][CH2:6][SH:7].Cl[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][OH:17])[C:11]=1[CH3:18]>CN(C=O)C.C(O)(=O)C>[OH:17][CH2:16][C:12]1[C:11]([CH3:18])=[C:10]([S:7][CH2:6][CH2:5][CH2:4][CH2:3][SH:8])[CH:15]=[CH:14][N:13]=1
Reactant: Cc1c(Cl)ccnc1CO
Reactant: SCCCCS
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Cc1c(SCCCCS)ccnc1CO
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4.2 g (145 mmol) of sodium hydride (80% in paraffin) are initially introduced in 100 ml of DMF with ice-cooling. 35.5 g (290 mmol) of 1,4-butanedithiol are slowly added dropwise. After the evolution of gas has ended, 15.3 g (97 mmol) of 4-chloro-2-hydroxymethyl-3-methylpyridine in 20 ml of DMF are added drop-wise. After about 30 minutes, the mixture is allowed to come to RT and is stirred at this temperature for 12 h. It is diluted with 800 ml of ice-water and neutralized with acetic acid. The mixture is extracted 3 times with dichloromethane. The combined organic phases are washed 4 times with water, dried over magnesium sulfate, filtered and concentrated. The crude product is chromatographed on silica gel using ethyl acetate/conc. ammonia=99/1. The title compound is obtained as a yellow crystallizate. M.p. 58°-63° C.; yield 13 g (55% of theory).
Reaction SMILES: [CH2:1]([CH:3]1[NH:12][C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:14])[CH3:2].O1CCOCC1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C([O-])(O)=O.[Na+].O>[CH2:1]([C:3]1[C:4](=[O:14])[NH:5][C:6]2[C:11]([N:12]=1)=[CH:10][CH:9]=[C:8]([F:13])[CH:7]=2)[CH3:2]
Reactant: CCC1Nc2ccc(F)cc2NC1=O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCc1nc2ccc(F)cc2[nH]c1=O
Yield: 94.8 %

Procedure:
To a homogeneous solution of 3-ethyl-7-fluoro-3,4-dihydroquinoxalin-2(1H)-one (60.61 g, 312.1 mmol) and 1,4-dioxane (1350 ml) was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (75.91 g, 327.7 mmol) and the mixture was stirred using an overhead stirrer at rt for 2.5 h. At this time, the mixture was concentrated under reduced pressure to give a brown residue. The brown residue was suspended in saturated aqueous NaHCO3 (2 L), stirred for 30 min, filtered, washed with saturated aqueous NaHCO3 (1 L) to give a light green solid. The light green solid was re-suspended in saturated aqueous NaHCO3 (500 mL), well mixed, filtered, and washed with saturated aqueous NaHCO3 (500 mL) to give an off-white solid. The off-white solid was suspended in water (500 mL), well mixed, filtered, washed with water (1 L), air-dried overnight, and dried under high vacuum at 22° C. for 2 h to give 3-ethyl-7-fluoroquinoxalin-2(1H)-one (56.87 g, 94.8% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.36 (br. S, 1H.), 7.76 (dd, J=9.0, 5.9 Hz, 1H), 7.11 (td, J=8.8, 2.7 Hz, 1H), 7.00 (dd, J=9.6, 2.7 Hz, 1H), 2.78 (q, J=7.4 Hz, 2H), 1.20 (t, J=7.4 Hz, 3H) Mass Spectrum (ESI) m/e=193.0 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[O:5][CH:6]=1.[CH:9]1(B(O)O)[CH2:11][CH2:10]1.ClC1C=CC(CC2C=C(C=O)SC=2)=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O>[CH:9]1([C:2]2[CH:3]=[C:4]([CH:7]=[O:8])[O:5][CH:6]=2)[CH2:11][CH2:10]1
Reactant: OB(O)C1CC1
Reactant: O=Cc1cc(Br)co1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=Cc1cc(Cc2ccc(Cl)cc2)cs1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=Cc1cc(C2CC2)co1
Yield: 30.9 %

Procedure:
The title compound was synthesized from 4-bromo-furan-2-carbaldehyde (300 mg, 1.71 mmol) and cyclopropylboronic acid (171 mg, 1.99 mmol), using the conditions to synthesize 4-(4-chlorobenzyl)thiophene-2-carbaldehyde, with the exception that the reaction was run in toluene (7.5 mL) and water (0.5 mL), and triphenylphosphine was replaced with tricyclohexylphosphine (48 mg, 0.17 mmol). Purification by flash chromatography (0-60% EtOAc in heptane) provided 4-cyclopropylfuran-2-carbaldehyde as an orange oil 72 mg (31%). 1H NMR (400 MHz, CDCl3) δ ppm 0.55-0.61 (m, 2H), 0.90-0.97 (m, 2H), 1.69-1.77 (m, 1H), 7.00 (d, J=0.78 Hz, 1H), 7.49 (d, J=0.59 Hz, 1H), 9.58 (d, J=0.49 Hz, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][C:13](O)=O)=[CH:6][CH:5]=1)([O-])=O.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.CCN=C=NCCCN(C)C.[ClH:33].C1C=CC2N(O)N=NC=2C=1.Cl.C(OCC)(=O)C>CN(C=O)C>[ClH:33].[ClH:33].[N:16]1([CH2:13][CH2:12][CH2:11][CH2:10][C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C(O)CCCc1ccc([N+](=O)[O-])cc1
Reactant: C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1ccc(CCCCN2CCCCC2)cc1

Procedure:
4-(4-nitrophenyl)butanoic acid and piperidine were allowed to undergo the reaction in DMF using WSC hydrochloride and HOBt, subjected to catalytic hydrogenation in the same manner as shown in Reference Example 3 to reduce the nitro group, and then reduced in the same manner as in Reference Example 2, and the resulting compound was subjected to salt formation using 4 M hydrogen chloride/ethyl acetate solution to obtain 4-(4-piperidin-1-ylbutyl) aniline dihydrochloride. F: 233.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][C:8]23[CH2:22][CH:15]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=42)[C:14]2[C:9]3=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:2]1.[CH:23]1([CH2:26]Br)[CH2:25][CH2:24]1.[NH2-].[Na+]>C1C=CC=CC=1.O>[CH:23]1([CH2:26][N:1]2[CH2:6][CH2:5][O:4][CH:3]([CH2:7][C:8]34[CH2:22][CH:15]([C:16]5[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=53)[C:14]3[C:9]4=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:2]2)[CH2:25][CH2:24]1
Reactant: BrCC1CC1
Reactant: c1ccc2c(c1)C1CC2(CC2CNCCO2)c2ccccc21
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: c1ccc2c(c1)C1CC2(CC2CN(CC3CC3)CCO2)c2ccccc21

Procedure:
A mixture of 9-(2-morpholinylmethyl)-9,10-dihydro-9,10-methanoanthracene (50 mg), cyclopropylmethyl bromide (40 mg) and sodium amide (15 mg) in dry benzene was refluxed for 10 hours. The reaction mixture was diluted with benzene and water. The benzene layer was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to give 9-(4-cyclopropylmethyl-2-morpholinylmethyl)-9,10-dihydro-9,10-methanoanthracene, M.P. 88° - 90° C.
Reaction SMILES: C([O:5][CH2:6][CH:7]([O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[N:13]=[CH:12][CH:11]=1)[CH3:8])(C)(C)C>C(O)(C(F)(F)F)=O>[CH3:21][O:20][C:16]1[CH:15]=[C:14]2[C:19]([C:10]([O:9][CH:7]([CH3:8])[CH2:6][OH:5])=[CH:11][CH:12]=[N:13]2)=[CH:18][CH:17]=1
Reactant: COc1ccc2c(OC(C)COC(C)(C)C)ccnc2c1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(OC(C)CO)ccnc2c1

Procedure:
A solution of 4-(1-tert-butoxypropan-2-yloxy)-7-methoxyquinoline in TFA (10 mL) was stirred for 45 min at 23° C. The solvent was removed under reduced pressure and the residue was partitioned between CH2Cl2 and 10% Na2CO3. The aqueous layer was extracted with CH2Cl2 (5 mL×4) and the combined organics were dried over MgSO4. The mixture was purified on 12 grams of silica eluting with 0-100% of 5% MeOH/CH2Cl2. MS (ESI pos. ion) m/z (MH+): 234. Calc'd exact mass for C13H15NO3: 233.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[CH:21]1([CH2:27][CH2:28][NH2:29])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C(O)C.C1OC1C>[CH:21]1([CH2:27][CH2:28][NH:29][C:2]2[N:3]=[C:4]([NH2:20])[C:5]3[N:6]=[CH:7][N:8]([C:18]=3[N:19]=2)[C@@H:9]2[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]2[OH:11])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: NCCC1CCCCC1
Agent: CC1CO1
Solvent: CCO
Product: Nc1nc(NCCC2CCCCC2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 2-chloroadenosine (15.05 g) and 2-cyclohexylethylamine (31.75 g) is stirred under nitrogen at 140° over 6 hours. The reaction mixture is cooled to room temperature, diluted with ethanol (500 ml), propylene oxide (50 ml) is added and the mixture is stirred at room temperature for 3 hours. The solid is collected by vacuum filtration, washed with ethanol, then ether, and dried at 80°/0.1 mm over 16 hours. The white solid obtained is recrystallized from ethanol to yield 2-(2-cyclohexylethylamino)-adenosine, the compound of example 4q, m.p. 142°-145°, [alpha]D25 -30.5° (c=1, dimethyl sulfoxide).
Reaction SMILES: C(OC(=O)[NH:7][C:8]([C:10]1[S:11][C:12]([S:26][CH3:27])=[C:13]([S:15]([C:18]2[CH:19]=[N:20][C:21](Cl)=[C:22]([Br:24])[CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])(C)(C)C.[NH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1.C(Cl)(Cl)Cl.[C:41]([OH:47])([C:43]([F:46])([F:45])[F:44])=[O:42]>C1COCC1>[F:44][C:43]([F:46])([F:45])[C:41]([OH:47])=[O:42].[Br:24][C:22]1[CH:23]=[C:18]([S:15]([C:13]2[CH:14]=[C:10]([C:8]([NH2:7])=[NH:9])[S:11][C:12]=2[S:26][CH3:27])(=[O:17])=[O:16])[CH:19]=[N:20][C:21]=1[NH:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cnc(Cl)c(Br)c1
Reactant: NCc1ccccn1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cnc(NCc2ccccn2)c(Br)c1

Procedure:
The reaction was conducted following the procedure for Example 164: step c, using {[4-(5-bromo-6-chloropyridine-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.035 g, 0.066 mmol), (example 164: step b), 2-aminomethylpyridine (0.014 g, 0.133 mmol), THF [3 mL], followed by chloroform/TFA (1:1) to yield the title compound. ESI-MS (m/z): Calcd. for C17H16BrN5O2S3: 499.44 (M+H); found 499.1, 501.0.
Reaction SMILES: [OH-].[Li+].[OH:3][CH:4]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=1)/[CH:5]=[CH:6]/[C@H:7]1[CH2:11][CH2:10][S:9](=[O:13])(=[O:12])[N:8]1[CH2:14][CH2:15][CH2:16][C:17]1[S:21][C:20]([C:22]([O:24]C)=[O:23])=[CH:19][CH:18]=1.C(O)(=O)C>O.C1COCC1>[OH:3][CH:4]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:35])[F:36])[CH:28]=1)/[CH:5]=[CH:6]/[C@H:7]1[CH2:11][CH2:10][S:9](=[O:12])(=[O:13])[N:8]1[CH2:14][CH2:15][CH2:16][C:17]1[S:21][C:20]([C:22]([OH:24])=[O:23])=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc(CCCN2[C@@H](/C=C/C(O)Cc3cccc(C(F)(F)F)c3)CCS2(=O)=O)s1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1ccc(CCCN2[C@@H](/C=C/C(O)Cc3cccc(C(F)(F)F)c3)CCS2(=O)=O)s1
Reaction time: 16 h
Yield: 41.4 %

Procedure:
Lithium hydroxide (0.25 mL of a 0.5N solution in H2O, 0.125 mmol) was added to a solution of the ester 13 (25 mg, 0.048 mmol) in THF (1.0 mL) at 23° C. The reaction mixture was stirred for 16 h, acidified with acetic acid and extracted with EtOAc. The organic portion was washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography (silica gel, 10% MeOH/CH2Cl2) afforded 10 mg (41%) of pure carboxylic acid 14.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[CH3:12])#[N:2].[NH:13]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[NH:17][CH2:16][CH2:15][CH2:14]1>>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:13]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[NH:17][CH2:16][CH2:15][CH2:14]2)=[O:9])=[CH:5][C:4]=1[CH3:12])#[N:2]
Reactant: c1ccc2c(c1)NCCCN2
Reactant: Cc1cc(C(=O)O)ccc1C#N
Product: Cc1cc(C(=O)N2CCCNc3ccccc32)ccc1C#N

Procedure:
The carboxylic acid from Example C (0.65 g, 4.03 mmol) was reacted with 2,3,4,5-tetrahydro-1H-1,5-benzodiazepine from Example 15A (0.50 g, 3.36 mmol) according to the procedure in Example 1A. The product was purified by flash chromatography on silica (eluant EtOAc:pet. ether 50:50); yield 0.36 g (37%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][C:19]([Cl:23])=[CH:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:24]([C:27]1[C:28]([CH:33]=O)=[N:29][CH:30]=[CH:31][CH:32]=1)([CH3:26])[CH3:25].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][C:19]([Cl:23])=[CH:18][N:17]=2)[CH2:33][C:28]2[C:27]([CH:24]([CH3:26])[CH3:25])=[CH:32][CH:31]=[CH:30][N:29]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)c1cccnc1C=O
Reactant: Cc1cc(Cl)cnc1CNC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(Cl)cnc1CN(Cc1ncccc1C(C)C)C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Using General Procedure B: Reaction of 4-[(5-Chloro-3-methyl-pyridin-2-ylmethyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester and 3-Isopropyl-pyridine-2-carbaldehyde with NaBH(OAc)3 in CH2Cl2 gave 4-[(5-Chloro-3-methyl-pyridin-2-ylmethyl)-(3-isopropyl-pyridin-2-ylmethyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a white solid. Deprotection with TFA using General Procedure F gave (5-Chloro-3-methyl-pyridin-2-ylmethyl)-(3-isopropyl-pyridin-2-ylmethyl)-piperidin-4-yl-amine as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:22][NH2:23].C1COCC1>>[CH3:22][NH:23][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CN
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cn1
Solvent: C1CCOC1
Product: CNc1nc(N(C)c2ccc(OC)nc2)c2ccccc2n1

Procedure:
The title compound was prepared from (2-chloro-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine (69 mg, 0.23 mmol) and 2.0 M methylamine in THF (4 ml, 8 mmol) by a procedure similar to example 122 to give 20 mg (30%) of yellow solids. 1H NMR (CDCl3): 8.02-8.01 (m, 1H), 7.48 (d, J=8.1 Hz, 1H), 7.42-7.34 (m, 2H), 6.97-6.94 (m, 1H), 6.76-6.70 (m, 2H), 5.01 (brs, 1H), 3.95 (s, 3H), 3.50 (s, 3H), 3.12 (d, J=5.1 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([N+:15]([O-])=O)=[C:4]([NH:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1>O.CCO.C1COCC1.[Ni]>[NH2:15][C:3]1[C:2]([Br:1])=[CH:7][CH:6]=[CH:5][C:4]=1[NH:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)CNc1cccc(Br)c1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CNc1cccc(Br)c1N
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Raney 2800 nickel, in water (Aldrich; 8 mL) was added to a solution of ethyl 2-((3-bromo-2-nitrophenyl)amino)acetate (14.12 g, 46.6 mmol) in EtOH (290 ml) and THF (290 ml); the mixture was placed under an atmosphere of H2 and was stirred at RT for 20 h. The mixture was filtered through a pad of wet Celite, topped with sand, and washed with DCM to give ethyl 2-((2-amino-3-bromophenyl)amino)acetate (210c) as a brown liquid. MS (ESI, pos. ion) m/z: 273.0/275.0 (M+1).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[Br:32][C:33]1[CH:38]=[C:37]([O:39][C:40]([F:43])([F:42])[F:41])[CH:36]=[C:35]([CH2:44][CH2:45]O)[C:34]=1[OH:47]>O1CCCC1>[Br:32][C:33]1[C:34]2[O:47][CH2:45][CH2:44][C:35]=2[CH:36]=[C:37]([O:39][C:40]([F:41])([F:42])[F:43])[CH:38]=1
Reactant: OCCc1cc(OC(F)(F)F)cc(Br)c1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: FC(F)(F)Oc1cc(Br)c2c(c1)CCO2
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a cooled (0° C.) of triphenylphosphine (6.11 g, 0.0234 mol) in tetrahydrofuran (40 ml) was added diethylazodicarboxylate (3.7 ml, 0.0234 mol). The solution was stirred for 30 min., whereupon a solution of 2-bromo-6-(2-hydroxyethyl)-4-trifluoromethoxyphenol (Desc 16.; 5.4 g, 0.018 mol) in tetrahydrofuran was added. The solution was stirred at room temperature for 15 h. and then the solvent was removed in vacuo. The residue was dissolved in ethyl acetate and the solution was washed with water, saturated brine, dried (MgSO4). After removal of the solvent in vacuo the residue was purified by chromatography on silica gel (eluting with 10% ethyl acetate in hexane) to give the title compound as a pink oil. 1H NMR (250 MHz, CDCl3) δ2.93 (2H, t, J 5.6 Hz), 3.98 (2H, t, J 5.4 Hz), 6.96 (1H, d, J 2.5 Hz), and 7.30 (1H, d, J 2.4 Hz).
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([NH:17][C:18]([N:20]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3[CH:27]=[C:28]([O:31][C:32]4[CH:37]=[C:36](Cl)[N:35]=[C:34]([NH2:39])[N:33]=4)[CH:29]=[CH:30][C:21]2=3)=[O:19])[CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1>CO.[Pd]>[F:41][C:2]([F:1])([F:40])[C:3]1[CH:4]=[C:5]([NH:17][C:18]([N:20]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3[CH:27]=[C:28]([O:31][C:32]4[CH:37]=[CH:36][N:35]=[C:34]([NH2:39])[N:33]=4)[CH:29]=[CH:30][C:21]2=3)=[O:19])[CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1
Reactant: CN1CCN(Cc2ccc(NC(=O)N3CCCCc4cc(Oc5cc(Cl)nc(N)n5)ccc43)cc2C(F)(F)F)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCN(Cc2ccc(NC(=O)N3CCCCc4cc(Oc5ccnc(N)n5)ccc43)cc2C(F)(F)F)CC1

Procedure:
250 mg (0.42 mMol) of 7-(2-amino-6-chloro-pyrimidin-4-yloxy)-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid [3-trifluoromethyl-4-(4-methylpiperazin-1-ylmethyl)-phenyl]-amide in 35 ml methanol are hydrogenated in the presence of 160 mg Pd/C (10%; Engelhard 4505). The catalyst is filtered off, the filtrate diluted with EtOAc and sat. Na2CO3/H2O 1:1 and the separated aqueous layer extracted twice with water. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Reversed phase MPLC (Gilson system) gives the title compound: MS: [M+1]+=556; HPLC: AtRet=9.0.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:23])=[C:4]([C:7]([OH:22])=[C:8]([CH:11]([OH:21])[CH2:12][CH:13]([CH3:20])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])[C:9]=1[OH:10])[CH:5]=[O:6].[H][H]>[Pd].C(O)C>[Cl:1][C:2]1[C:3]([CH3:23])=[C:4]([C:7]([OH:22])=[C:8]([CH:11]([OH:21])[CH2:12][CH:13]([CH3:20])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:18])[CH3:19])[C:9]=1[OH:10])[CH:5]=[O:6]
Reactant: CC(C)=CCCC(C)CC(O)c1c(O)c(Cl)c(C)c(C=O)c1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1c(Cl)c(O)c(C(O)CC(C)CCCC(C)C)c(O)c1C=O

Procedure:
An ethanol solution (1.5 ml) of 3-chloro-5-(1-hydroxy-3,7-dimethyl-6-octenyl)-4,6-dihydroxy-2-methylbenzaldehyde (220) (196 mg, 0.57 mmol) was stirred at 0° C. in the presence of 5% Pd/C (50 mg) in a hydrogen atmosphere for 2 hours. After the catalyst was separated by filtration with the use of Celite, the filtrate was concentrated to obtain a crude product (188 mg). This crude product was purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to obtain 3-chloro-5-(1-hydroxy-3,7-dimethyloctyl)-4,6-dihydroxy-2-methylbenzaldehyde (222, a diastereomeric mixture, red syrup 69 mg, crude yield 35%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH:12][C:13]([C:15]3[N:16]=[CH:17][S:18][CH:19]=3)=[O:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1.C(Cl)Cl>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:20][C:21]1[CH:26]=[C:25]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[C:5]([NH:12][C:13]([C:15]4[N:16]=[CH:17][S:18][CH:19]=4)=[O:14])[CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Nc1cccc2ccc(Cl)nc12)c1cscn1
Reactant: OB(O)c1cccc(F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: COCCOC
Product: O=C(Nc1cccc2ccc(-c3cccc(F)c3)nc12)c1cscn1
Temperature: 140 °C
Yield: 24.6 %

Procedure:
A solution of N-(2-chloroquinolin-8-yl)thiazole-4-carboxamide (29 mg, 0.100 mmol), 3-fluorophenylboronic acid (28 mg, 2 eq.), CsCO3 (65 mg, 2 eq.), Pd(dppf)Cl2.DCM (4 mg, 0.05 eq.) in DME (2 mL) was microwave heated (140° C.×15 min.). The reaction was filtered and concentrated. The residue was diluted with ethyl acetate, washed with saturated aqueous NaHCO3, dried (Na2SO4) and concentrated. The product was purified by column chromatography (0 to 100% EtOAc in Pentane) to obtain 8.6 mg of N-(2-(3-fluorophenyl)quinolin-8-yl)thiazole-4-carboxamide. MS (ESI) calcd for C19H13FN3OS (m/z): 350.08. found: 350.1 [M+1].