Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH2:12])=[N:6][C:7]=1[C:8]([F:11])([F:10])[F:9].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C[C:56]([N:58](C)C)=O>[C-]#N.[C-]#N.[Zn+2].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]>[NH2:12][C:5]1[CH:4]=[CH:3][C:2]([C:56]#[N:58])=[C:7]([C:8]([F:11])([F:10])[F:9])[N:6]=1
Reactant: CC(=O)N(C)C
Reactant: Nc1ccc(Br)c(C(F)(F)F)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: N#Cc1ccc(N)nc1C(F)(F)F
Temperature: 160 °C
Reaction time: 20 h

Procedure:
A mixture of 5-bromo-6-(trifluoromethyl)pyridin-2-amine (3.0 g, 12.3 mmol), Zn(CN)2 (0.81 g, 6.9 mmol), Pd2(dba)3 (0.57 g, 0.6 mmol), and Xantphos (0.72 g, 1.2 mmol) in DMA (12 mL) was placed in a sealed tube. The mixture was degassed with argon and stirred at 160° C. for 20 h. The mixture was poured into water and extracted with EtOAc (2×). The combined organic layers were dried over magnesium sulfate and concentrated to dryness. The residue was purified by column chromatography on silica gel eluting with 3:1 EtOAc/hexanes to afford 1.9 g of 6-amino-2-(trifluoromethyl)nicotinonitrile as a solid. 1H NMR (400 MHz, CDCl3) δ 7.74 (d, 1H), 6.67 (d, 1H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]([F:21])([F:20])[C:7]([N:9]1[CH2:15][CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[CH2:11][CH2:10]1)=[O:8].[Cl:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27](Cl)=[O:28]>ClCCCl>[Cl:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([C:18]1[CH:17]=[CH:16][C:13]2[CH2:14][CH2:15][N:9]([C:7](=[O:8])[C:6]([F:5])([F:20])[F:21])[CH2:10][CH2:11][C:12]=2[CH:19]=1)=[O:28]
Reactant: O=C(Cl)CCCCCl
Reactant: O=C(N1CCc2ccccc2CC1)C(F)(F)F
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C(CCCCCl)c1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Aluminum chloride (17 g, 130 mmol) was added by portions to a solution of 3-(trifluoroacetyl)-2,3,4,5-tetrahydro-1H-3-benzazepine (15.0 g) and 5-chlorovaleryl chloride (8.8 ml) in 1,2-dichloroethane (40 ml) under ice-cooling. After stirring at room temperature for 30 minutes, the reaction mixture was poured into ice (500 g), extracted with ethyl acetate, and washed with brine. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was crystallized from ethanol-diethyl ether to give a pale yellow solid (15.2 g). Further recrystallization from ethanol-diethylether afforded colorless crystals (13.2 g) as the title compound.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([OH:16])=O)=[CH:11][CH:12]=2)[C@H:7]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2].[NH3:31]>>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([NH2:31])=[O:16])=[CH:11][CH:12]=2)[CH:7]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([CH:24]3[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]3)=[CH:22][CH:23]=2)[CH2:6][CH:5]1[CH3:30])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(C(=O)O)cc2[C@H](Nc2ccc(C3CCCCC3)cc2)C[C@@H]1C
Reactant: N
Product: CC(=O)N1c2ccc(C(N)=O)cc2C(Nc2ccc(C3CCCCC3)cc2)CC1C

Procedure:
Reactions and treatments were carried out in the same manner as in Example 118, using 129.6 mg of (2S,4R)-1-acetyl-4-[(4-cyclohexylphenyl)amino]-2-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid instead of (2S,4R)-1-acetyl-2-methyl-4-(4-morpholinophenoxy)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid, and using aqueous ammonia instead of monomethylamine. Thus, 94.4 mg (72.9%, cis:trans=10:1) of the title compound was obtained as a white crystalline powder.
Reaction SMILES: [F:1][B-](F)(F)F.[CH2:6]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([N+]#N)=[CH:21][CH:20]=[C:19]([N:25]([C:29](=[O:31])[CH3:30])[CH:26]3[CH2:28][CH2:27]3)[N:18]=2)[CH2:13][CH2:12]1)=[O:10])[CH3:7].B([O-])([O-])[O-]>C1(C)C=CC=CC=1>[C:29]([N:25]([CH:26]1[CH2:28][CH2:27]1)[C:19]1[N:18]=[C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:6][CH3:7])=[O:10])[CH2:12][CH2:13]2)[C:22]([F:1])=[CH:21][CH:20]=1)(=[O:31])[CH3:30]
Reactant: CCOC(=O)N1CCN(c2nc(N(C(C)=O)C3CC3)ccc2[N+]#N)CC1
Reactant: F[B-](F)(F)F
Agent: [O-]B([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCN(c2nc(N(C(C)=O)C3CC3)ccc2F)CC1
Yield: 39.1 %

Procedure:
To 800 ml of refluxing toluene was added in portions, as a solid, 46.2 g (0.1 mole) of 2-[4-(ethoxycarbonyl)-1-piperazinyl]-6-(acetylcyclopropylamino)-3-pyridinediazonium tetrafluoroborate. borate. After the addition was complete, the reaction was refluxed for ten minutes and the toluene was decanted from the insoluble precipitate. The toluene was evaporated in vacuo and the residue was partitioned between chloroform and water. The chloroform layer was washed with 5% aqueous sodium bicarbonate, water, dried over magnesium sulfate and evaporated in vacuo to give 13.7 g of the title compound, as a viscous oil. An additional 10.2 g could be obtained by partitioning the original toluene insoluble material in chloroform and water. The organic layer was washed with 5% aqueous sodium bicarbonate, dried over magnesium sulfate, evaporated in vacuo and the residue was chromatographed on silica gel eluting with chloroform/ethyl acetate (6:4). This fraction was also a viscous oil which did not crystallize upon standing. Both fractions were of sufficient purity to be used as is in the ensuing steps.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:17])([F:16])[F:15])[NH:5][C:4](=O)[CH:3]=1.P(Cl)(Cl)([Cl:21])=O.C(N(CCC)CCC)CC>>[Cl:21][C:4]1[CH:3]=[C:2]([CH3:1])[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:17])([F:16])[F:15])[N:5]=1
Reactant: Cc1cc(=O)[nH]c(-c2ccccc2C(F)(F)F)n1
Reactant: O=P(Cl)(Cl)Cl
Agent: CCCN(CCC)CCC
Product: Cc1cc(Cl)nc(-c2ccccc2C(F)(F)F)n1
Temperature: 115 °C
Yield: 84.1 %

Procedure:
A solution of 6-methyl-2-(2-trifluoromethyl-phenyl)-3H-pyrimidin-4-one (10.7 g, 41.9 mmol) in phosphorous oxychloride (39 mL, 419 mmol) was treated with tri-n-propylamine (16 mL, 83.9 mmol) and refluxed at 110-120° C. for 1 hours. The solvent was evaporated, azeotroped three times with toluene, then dried in vacuo. The residue was taken up in ethyl acetate, washed sequentially with 1 N sodium hydroxide, water and brine, then dried over sodium sulfate and concentrated. Purification by flash chromatography [SiO2, ethyl acetate:hexanes (1:9)] provided the title compound (9.61 g, 84% yield) as an orange oil. 1H NMR (CDCl3, 500 MHz) δ 2.63 (3H, s), 7.26 (s, 1H), 7.61 (t, J=7.6 Hz, 1H), 7.67 (t, J=7.5 Hz, 1H), 7.76 (d, J=7.6 Hz, 1H), 7.82 (d, J=7.8 Hz, 1H) ppm; MS (FIA) 273.0 (M+H); Rt (Method A) 3.499 min.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][CH2:8][C:9]([O:11]C)=O)=[C:4]([Cl:15])[CH:3]=1.[CH2:16]([N:18]=[C:19]=[O:20])[CH3:17]>C(Cl)Cl>[Br:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:8][C:9](=[O:11])[N:18]([CH2:16][CH3:17])[C:19]2=[O:20])=[C:4]([Cl:15])[CH:3]=1
Reactant: COC(=O)CNCc1ccc(Br)cc1Cl
Reactant: CCN=C=O
Solvent: ClCCl
Product: CCN1C(=O)CN(Cc2ccc(Br)cc2Cl)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
Methyl 2-(4-bromo-2-chlorobenzylamino)acetate (2C3) (1.44 mmol, 420 mg) was dissolved in DCM (35 ml) and ethyl isocyanate (2C4) (2.87 mmol, 0.227 ml, 204 mg) added. The mixture was stirred at room temperature overnight. The mixture was concentrated and azeotroped with DCM three times and then re-dissolved in DCM (10 ml) and TFA (3 ml) added. The solution was stirred for 1.5 h then quenched with saturated sodium carbonate solution and the phases separated. The aqueous layer was washed with DCM twice and the combined organics dried over sodium sulphate, filtered and concentrated to give 1-(4-bromo-2-chlorobenzyl)-3-ethylimidazolidine-2,4-dione (2C5) 430 mg (90%); 1H NMR (400 MHz, CDCl3) δ 7.58 (s, 1H) 7.42 (d, 1H) 7.22 (d, 1H) 4.65 (s, 2H) 3.79 (s, 2H) 3.59 (q, 2H) 1.23 (t, 3H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([NH:11][C:12]1[C:21]([F:22])=[CH:20][C:15]([C:16](OC)=O)=[C:14]([NH:23][C:24]([CH3:31])([CH3:30])[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[N:13]=1)([CH3:10])([CH3:9])[CH3:8].C(OCC)(=O)C>O1CCCC1.O.C(O)C>[C:7]([NH:11][C:12]1[C:21]([F:22])=[CH:20][C:15]([CH3:16])=[C:14]([NH:23][C:24]([CH3:31])([CH3:30])[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[N:13]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: COC(=O)c1cc(F)c(NC(C)(C)C)nc1NC(C)(C)CC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Cc1cc(F)c(NC(C)(C)C)nc1NC(C)(C)CC(C)(C)C
Yield: 68.1 %

Procedure:
To 20 ml of tetrahydrofran was dispersed 850 mg of lithium aluminum hydride. The dispersion was water cooled and stirred simultaneously with the dropwise addition of 2.80 g of methyl 6-t-butylamino-5-fluoro-2-(1,1,3,3-tetramethylbut ylamino)nicotinate dissolved in 30 ml of tetrahydrofuran. The reactor was placed in an oil bath of 50° C., and the mixture was stirred for two and half hours. The reactor was then water cooled and 8 ml of ethyl acetate was added dropwise, and the mixture was stirred for 1 hour. 8 ml of ethanol was added dropwise, and the mixture was stirred for 1 hour, then 8 ml of distilled water was added dropwise, and the mixture was stirred overnight. The precipitate was separated by filtration, and the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography (silica gel, 40 g; eluent: chloroform:n-hexane, 1:1) to obtain 1.67 g of the title compound as a colorless oily residue.
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:22][C:21]([CH2:45][C:46]#[N:47])([N:23]2[CH:27]=[C:26]([C:28]3[C:29]4[CH:36]=[CH:35][N:34]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:30]=4[N:31]=[CH:32][N:33]=3)[CH:25]=[N:24]2)[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[OH-].[Na+]>C(O)C.O>[OH:18][CH:19]1[CH2:22][C:21]([CH2:45][C:46]#[N:47])([N:23]2[CH:27]=[C:26]([C:28]3[C:29]4[CH:36]=[CH:35][N:34]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:42])([CH3:44])[CH3:43])[C:30]=4[N:31]=[CH:32][N:33]=3)[CH:25]=[N:24]2)[CH2:20]1
Reactant: CC(C)(C)[Si](OC1CC(CC#N)(n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)C1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CC(O)C4)c3)ncnc21
Reaction time: 3 h
Yield: 88.7 %

Procedure:
To {3-{[tert-butyl(diphenyl)silyl]oxy}-1-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile (2.85 g, 4.30 mmol) in ethanol (120 mL) was added 5.0M sodium hydroxide in water (29 mL, 150 mmol). The reaction was stirred for 3 hours and diluted with water. The ethanol was removed under reduced pressure. The aqueous layer was extracted with ethyl acetate three times. The combine organic solutions were washed with brine, dried over Na2SO4, filtered and concentrated. The crude was purified with silica gel column eluting with a gradient from 0-10% MeOH/DCM to give of the product (1.62 g, 88%) as .off-white foam. LCMS (M+H)+: 425.2.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([O:14][CH:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)=[CH:12][CH:13]=2)=[CH:4][C:3]=1[O:28][C@@H:29]([C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[N:38]1[N:42]=[CH:41][CH:40]=[N:39]1)[CH3:30].Cl>CO>[F:37][C:35]1[CH:34]=[CH:33][C:32]([N:38]2[N:42]=[CH:41][CH:40]=[N:39]2)=[C:31]([C@H:29]([O:28][C:3]2[CH:4]=[C:5]([C:8]3[CH:9]=[N:10][C:11]([O:14][CH:15]4[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]4)=[CH:12][CH:13]=3)[CH:6]=[N:7][C:2]=2[NH2:1])[CH3:30])[CH:36]=1
Reactant: C[C@@H](Oc1cc(-c2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)nc2)cnc1N)c1cc(F)ccc1-n1nccn1
Agent: Cl
Solvent: CO
Product: C[C@@H](Oc1cc(-c2ccc(OC3CCNCC3)nc2)cnc1N)c1cc(F)ccc1-n1nccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.1 %

Procedure:
To a solution of the tert-butyl 4-[(6′-amino-5′-{(1R)-1-[5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]ethoxy}-3,3′-bipyridin-6-yl)oxy]piperidine-1-carboxylate (115 mg, 0.2 mmol) in MeOH (1 mL) was added HCl (4N in dioxane, 1 mL). The mixture was stirred at room temperature for 1 hr. The mixture was concentrated and the residue purified by a reversed phase prep-HPLC. The desired fractions were lyophillized to give the title compound (61 mg) as an off-white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]2[CH:12]=[C:13]([C:16]3[C:17]([C:40]4[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=4)=[N:18][N:19]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:20]=3)[CH:14]=[CH:15][C:10]2=[N:9][CH:8]=1.Cl.Cl[CH2:49][CH2:50][N:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1>>[N:51]1([CH2:50][CH2:49][O:46][C:43]2[CH:42]=[CH:41][C:40]([C:17]3[C:16]([C:13]4[CH:14]=[CH:15][C:10]5[N:11]([C:7]([C:2]6[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=6)=[CH:8][N:9]=5)[CH:12]=4)=[CH:20][N:19]([C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:18]=3)=[CH:45][CH:44]=2)[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1
Reactant: ClCCN1CCOCC1
Reactant: Oc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4ccccn4)n3c2)cc1
Agent: Cl
Product: c1ccc(C(c2ccccc2)(c2ccccc2)n2cc(-c3ccc4ncc(-c5ccccn5)n4c3)c(-c3ccc(OCCN4CCOCC4)cc3)n2)cc1
Yield: 58.8 %

Procedure:
90 mg 4-{4-[3-(pyridin-2-yl)imidazo[1,2-a]pyridin-6-yl]-1-trityl-1H-pyrazol-3-yl}phenol (compound in Example 353) and 42 mg N-(2-chloroethyl)morpholine hydrochloride were reacted under the same conditions as in Example 190, to give 63 mg of the title compound as a colorless amorphous matter.
Reaction SMILES: C[O-].[Na+].CO.C([S:9][CH:10]1[CH2:13][N:12]([C:14]2[S:15][CH2:16][CH2:17][N:18]=2)[CH2:11]1)(=O)C.Cl>CO>[SH:9][CH:10]1[CH2:13][N:12]([C:14]2[S:15][CH2:16][CH2:17][N:18]=2)[CH2:11]1
Reactant: CC(=O)SC1CN(C2=NCCS2)C1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: SC1CN(C2=NCCS2)C1
Reaction time: 0.17 h

Procedure:
770 mg of 28% sodium methoxide-methanol solution was added to a mixture solution of 862 mg of Compound (18) obtained in the step (b) in 20 ml of anhydrous methanol under ice-cooling and nitrogen gas atmosphere. Then the reaction mixture was stirred for 10 minutes under the same conditions. After reaction, 4 ml of 2N--HCl was added to the reaction mixture and the solvent was removed under reduced pressure to give crude 3-mercapto-1-(thiazolin-2-yl)azetidine [Compound (19)]. Then the crude Compound (19) was dissolved in 15 ml of a mixture solution of anhydrous acetonitrile-chloroform and to this solution were added 2430 mg of p-nitrobenzyl (1R,5R,6S)-2-(di-phenylphosphoryloxy)-6-[(R)-1-hydroxyethyl]-1-methyl-carbapen-2-em-3-carboxylate [Compound (20)] and 2.8 ml of diisopropylethylamine under ice-cooling and nitrogen gas atmosphere. After stirring the reaction mixture for 2 hours under the same conditions, ethyl acetate was added and the separated organic layer was washed with saturated sodium bicarbonate aqueous solution and saturated saline solution. The solvent was removed and the resulting residue was purified by silica gel column chromatography (chloroform: acetone =1:2) to give 1339 mg [65% yield from Compound (18)] of p-nitrobenzyl (1R,5S,6S)-2-[(1-(thiazolin-2-yl)azetidin-3-yl)thio]-6-[(R)-1-hydroxyethyl]-1-methyl-carbapen-2-em-3-carboxylate [Compound (21)].
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[CH:12]=[O:13].[BH4-].[Na+].[Cl-].[NH4+]>CO>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[CH2:12][OH:13]
Reactant: O=Cc1cnc2ccccc2c1Cl
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: OCc1cnc2ccccc2c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
To a 0° C. solution of 4-chloroquinoline-3-carbaldehyde (1.2 g, 6.3 mmol) in anhydrous methanol (20 mL) was added sodium borohydride (250 mg, 6.6 mmol). The reaction mixture was stirred at room temperature for 3 hours. Saturated ammonium chloride solution (20 mL) was added. The resultant mixture was extracted with dichloromethane (2×20 mL). The organic extracts were combined, dried over MgSO4, filtered, evaporated, and dried in vacuo, affording (4-chloroquinolin-3-yl)methanol (1.0 g, 85% yield). The product was used without further purification.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][CH2:7]2.B(O)O>>[N:6]1[CH:7]=[CH:8][C:3]([C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH2:4][CH2:5][NH:6][CH2:7]3)=[CH:4][CH:5]=1
Reactant: Brc1cccc2c1CCNC2
Agent: OBO
Product: c1cc2c(c(-c3ccncc3)c1)CCNC2

Procedure:
In close analogy to the procedure described above, 5-Bromo-1,2,3,4-tetrahydro-isoquinoline is reacted with the corresponding boronic acid to provide the title compound.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[Na+].[Na+].NC1C=CC2=NC(=O)N=C2C=1.O[C:19]1[C:20](C(Cl)=O)=[CH:21][C:22]2[C:27]([CH:28]=1)=C[CH:25]=[CH:24][CH:23]=2.OC1C(C(O)=O)=CC2C(C=1)=CC=CC=2>C1(C)C(C)=CC=CC=1.CN1CCCC1=O>[C:1]1(=[O:4])[C:27]2[C:22](=[CH:21][CH:20]=[CH:19][CH:28]=2)[CH:23]=[CH:24][CH2:25]1
Reactant: O=C([O-])[O-]
Reactant: O=C(Cl)c1cc2ccccc2cc1O
Agent: Nc1ccc2c(c1)=NC(=O)N=2
Agent: O=C(O)c1cc2ccccc2cc1O
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CN1CCCC1=O
Product: O=C1CC=Cc2ccccc21
Temperature: 100 °C
Reaction time: 6.5 h
Yield: 414.4 %

Procedure:
1750 ml of N-methylpyrrolidone are initially introduced into a 10 1 four-necked flask having a dropping funnel, reflux condenser, internal thermometer and stirrer. 291.5 g (2.75 mol) of sodium carbonate are added to this. 372.5 g (2.5 mol) of 5-aminobenzimidazolone are then added at about 25° C. 3181.8 g of 3-hydroxy-2-naphthoyl chloride (from 494.0 g (2.63 mol) of 3-hydroxy-2naphthoic acid) in xylene are metered into the suspension thus obtained with stirring in the course of 6.5 h at 25°-28° C. After addition is complete, the mixture is subsequently stirred at room temperature for 30 min. The precipitated product is filtered off with suction (suction time: 50 min) and the filter cake is washed in 10 portions with a total of 2150.0 g=2500 ml of xylene. 2500 ml of water are initially introduced into a 6 l four-necked flask having a stirrer, internal thermometer and distillation bridge having a 1 l one-necked flask as a receiver. The filter cake is then introduced. 200.0 g of sodium carbonate are then added and the mixture is heated to 100° C. Xylene and water distill off. The product is filtered off with suction at 100° C. and the suction filter cake is washed several times with a total of 6250 ml of water until neutral. 1571.4 g of naphthalone are obtained in water-moist form. After drying the filter cake at 100° C./100 mmHg, 681.7 g (2.135 mol) of 3-hydroxy-N-benzimidazolon-5-yl-2naphthamide are obtained; this corresponds to a yield of 85.4% of theory based on 5-aminobenzimidazolone.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([O:15][CH:16]3C[CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)[CH2:2][CH2:3][CH3:4].C(C1C=C2C(=C(F)C=1)N=CC=C2)CCC.C(OC(N1CC[C@@H](O)C1)=O)(C)(C)C.OC1CCN(C(OC(C)(C)C)=O)CC1>>[CH2:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([O:15][C@@H:16]3[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:20]3)[CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)c2ncccc2c1
Agent: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: CCCCc1cc(F)c2ncccc2c1
Product: CCCCc1cc(O[C@@H]2CCN(C(=O)OC(C)(C)C)C2)c2ncccc2c1
Reaction time: 1.5 h

Procedure:
This was prepared in an analogous manner to Intermediate 3, using 6-butyl-8-fluoroquinoline (for example, as prepared for Intermediate 2) and N-tert-butoxycarbonyl-(R)-(−)-3-pyrrolidinol (commercially available, for example, from Aldrich) instead of 1,1-dimethylethyl 4-hydroxy-1-piperidinecarboxylate. The reaction time was 3 h instead of 1.5 h. LCMS RT=3.56 min, ES+ve m/z 371 (M+H)+.
Reaction SMILES: [CH2:1]1[CH2:11][O:10][C:3]2([C:7]3([CH2:9][CH2:8]3)[CH2:6][NH:5][CH2:4]2)[O:2]1.[F:12][C:13]1[CH:14]=[C:15]([N+:21]([O-:23])=[O:22])[CH:16]=[C:17]([F:20])[C:18]=1F>C(#N)C>[F:12][C:13]1[CH:14]=[C:15]([N+:21]([O-:23])=[O:22])[CH:16]=[C:17]([F:20])[C:18]=1[N:5]1[CH2:4][C:3]2([O:2][CH2:1][CH2:11][O:10]2)[C:7]2([CH2:8][CH2:9]2)[CH2:6]1
Reactant: C1COC2(CNCC23CC3)O1
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Solvent: CC#N
Product: O=[N+]([O-])c1cc(F)c(N2CC3(CC3)C3(C2)OCCO3)c(F)c1
Temperature: 25 °C
Yield: 66 %

Procedure:
To a solution of 7,7-ethylenedioxy-5-azaspiro[2,4]heptane in acetonitrile (50 mL) was dropwise added 3,4,5-trifluoronitrobenzene (5.3 g, 31.6 mmol) and the reaction mixture was refluxed for 3 hours. After the reaction was terminated, the reaction mixture was cooled to room temperature and the solvent was removed therefrom by vacuum distillation. It was diluted with ethyl acetate and water, and the organic phase thus formed was dried over magnesium sulfate. The residue was filtered, concentrated in a vacuum, and purified through column chromatography (n-hexane/ethyl acetate=4:1) to afford the target compound (3.5 g, yield 66%).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[C:4]1=[O:20])[CH3:2].[H-].[Na+].Cl[C:24]1[N:28]([CH3:29])[C:27]2[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=2[N:25]=1.O>CN(C=O)C>[CH2:1]([N:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:24]3[N:28]([CH3:29])[C:27]4[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=4[N:25]=3)=[CH:15][CH:14]=2)[C:4]1=[O:20])[CH3:2]
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2ncc(F)cc21
Reactant: Cn1c(Cl)nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(=O)n(-c2ccc(Oc3nc4ccccc4n3C)cc2)c2ncc(F)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
To a stirred solution of 1-ethyl-6-fluoro-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (100 mg) in DMF (4 mL) was added 60% sodium hydride (13.2 mg) at room temperature. The mixture was stirred at room temperature for 30 min, and then 2-chloro-1-methyl-1H-benzimidazole (67.1 mg) was added. The mixture was exposed to microwave irradiation at 180° C. for 30 min, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on NH-silica gel eluting with AcOEt/Hexane. Crystallization from AcOEt/Hexane gave the title compound (104 mg).
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH2:8][N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[CH:25])=[CH:20][CH:19]=1>C(N(CC)CC)C.[Pd].[Cu]I>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[C:25][C:2]2[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH2:8][N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[CH:4][CH:3]=2)=[CH:20][CH:19]=1
Reactant: C#Cc1ccc(OC)cc1
Reactant: CCN(CC)CCOc1ccc(Br)cc1
Agent: [Cu]I
Agent: [Pd]
Solvent: CCN(CC)CC
Product: CCN(CC)CCOc1ccc(C#Cc2ccc(OC)cc2)cc1
Yield: 79.9 %

Procedure:
To a solution of 15 g (0.06 mole) of 1-(4-bromophenoxy)-2-diethylaminoethane and 8.2 g (0.062 mole) of 4-methoxyphenylacetylene in 150 ml of triethylamine are added, under nitrogen, 420 mg of the palladium complex PdCl2 [P(C6H5)2 ]2 and 228 mg of copper(I) iodide. The reaction mixture is subsequently refluxed for 24 hours, then concentrated, and the residue is taken up in water. After extraction with 200 ml of ether, the combined ethereal phases are washed 3 times with water, dried and evaporated to dryness. The crude product is chromatographed on silica gel, affording 15.5 g (80%) of 1-[4-(4-methoxyphenylethynyl)phenoxy]-2-diethylaminoethane with a melting point of 59°-60° C.