Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH2:1].[O-]CC.[Na+].[Si:6]([CH2:16][CH2:17][CH2:18][NH:19][C:20]([NH:22][CH2:23][CH2:24]Cl)=[O:21])([O:13][CH2:14][CH3:15])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9]>C(O)C>[Si:6]([CH2:16][CH2:17][CH2:18][NH:19][C:20]([NH:22][CH2:23][CH2:24][SH:1])=[O:21])([O:13][CH2:14][CH3:15])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9]
Reactant: S
Reactant: CCO[Si](CCCNC(=O)NCCCl)(OCC)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCO[Si](CCCNC(=O)NCCS)(OCC)OCC
Temperature: 25 °C
Yield: 99 %

Procedure:
To a solution of NaSH in ethanol [prepared by introducing H2S (15.21 g, 0.45 mol, 1.07 eq) into a sodium ethoxide solution (prepared from Na (10.55 g, 0.46 mol, 1.10 eq) in EtOH (300 mL))] is added, by metered addition at 52° C., (EtO)3Si—CH2CH2CH2—NH—CO—NH—CH2CH2—Cl (138.90 g, 0.42 mol, 1.00 eq) in ethanol (300 ml), and the mixture is heated to 78° C. After a reaction time of 5 h, the mixture is cooled to room temperature and the suspension is filtered. The filtrate is freed of the solvent on a rotary evaporator and dried under reduced pressure. The (EtO)3Si—CH2CH2CH2—NH—CO—NH—CH2CH2—SH product (134.96 g, 97.9% of theory) is obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:19][O:20][CH2:21][CH3:22])[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([OH:23])=[CH:5][C:4]=2[N:3]=1.[CH3:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Br.C(=O)([O-])[O-].[Cs+].[Cs+].CN1CCCC1=O>CN(C=O)C>[CH2:21]([O:20][CH2:19][C:13]1[N:14]([CH2:15][CH:16]([CH3:17])[CH3:18])[C:10]2[C:9]3[CH:8]=[CH:7][C:6]([O:23][CH2:24][C:25]4[CH:32]=[CH:31][CH:30]=[C:27]([CH3:28])[CH:26]=4)=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=1)[CH3:22]
Reactant: Cc1cccc(CBr)c1
Reactant: CCOCc1nc2c(N)nc3cc(O)ccc3c2n1CC(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Product: CCOCc1nc2c(N)nc3cc(OCc4cccc(C)c4)ccc3c2n1CC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.1 %

Procedure:
The general method described for Examples 22-32 was followed using the following modifications. 4-Amino-2-ethoxymethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-ol (310 mg, 0.97 mmol) was dissolved in DMF (15 mL) with heating but precipitated from the solution as it cooled to room temperature. A solution of 3-methylbenzyl bromide (197 mg, 1.07 mmol) in DMF (0.5 mL) was added followed by solid cesium carbonate (643 mg, 1.97 mmol). N-Methylpyrrolidone (1 mL) was added to the reaction, and the reaction was stirred overnight. The crude product was purified by column chromatography on silica gel (eluting with chloroform:methanol), triturated with acetonitrile, and isolated by filtration to provide 175 mg of 2-ethoxymethyl-7-(3-methylbenzyloxy)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, mp 207.0-208.0° C.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:3]=1[CH:4]([OH:20])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:6]=1.[CH:26](=O)[C:27]1[O:31][CH:30]=[CH:29][CH:28]=1.C(O)(=O)C.[BH4-].C([Na])#N>CO>[Cl:25][C:22]1[CH:23]=[CH:24][C:2]([NH:1][CH2:26][C:27]2[O:31][CH:30]=[CH:29][CH:28]=2)=[C:3]([CH:21]=1)[CH:4]([OH:20])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[CH:6]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(C(O)c2cc(Cl)ccc2N)c1
Reactant: O=Cc1ccco1
Agent: N#C[Na]
Agent: [BH4-]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCc1cccc(C(O)c2cc(Cl)ccc2NCc2ccco2)c1
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 98.3 %

Procedure:
In methanol (15 ml) were dissolved 2-amino-5-chloro-α-(3-tert-butoxycarbonylaminomethylphenyl)benzyl alcohol (0.5 g) produced in Example (1) and furfural (0.15 g). To the solution were added acetic acid (0.1 g) and cyano sodium borohydride (0.11 g). The mixture was stirred for 40 minutes at 60° C. The reaction mixture was concentrated, to which were added water (30 ml) and ethyl acetate (50 ml), followed by subjecting the mixture to extraction. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by means of a silica gel column chromatography to give 5-chloro-2-(furan-2-ylmethyl)amino-α-(3-tert-butoxycarbonylaminomethylphenyl)benzyl alcohol (0.6 g) as a colorless oily product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:11]1[CH:12]=[N:13][C:14]([O:17]C)=[CH:15][CH:16]=1)O.[I-].[Na+].C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O.C[Si](Cl)(C)C.[O-]S([O-])=O.[Na+].[Na+]>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:11]1[CH:16]=[CH:15][C:14](=[O:17])[NH:13][CH:12]=1
Reactant: COc1ccc(C(O)c2ccc(F)cc2F)cn1
Agent: CC[SiH](CC)CC
Agent: C[Si](C)(C)Cl
Agent: O=S([O-])[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: O=c1ccc(Cc2ccc(F)cc2F)c[nH]1
Temperature: 25 °C

Procedure:
A mixture of (2,4-difluoro-phenyl)-(6-methoxy-pyridin-3-yl)methanol 2 (2.28 g, 9.1 mmol), sodium iodide (5.45 g, 36.4 mmol), triethylsilane (2.2 ml, 13.6 mmol) in anhydrous acetonitrile (21 ml) and was stirred at room temperature. TFA (1.1 ml, 14.3 mmol) was added at a rate that maintained the temperature below 30° C.; TMSCl (5.8 ml, 45.5 mmol) was added, and the batch was heated at 70° C. for 3 h. Upon cooling to 55° C., a 0.8 M Na2SO3 (11.4 ml) was added, and the reaction mixture was concentrated in vacuo to 20 ml. A solution of 0.15 M Na2SO3 (11.4 ml) was added, the mixture was stirred at room temperature overnight. A solution of 1.4 M K2CO3 (13.6 ml) was added and cooled to 0° C. The crude product was extracted with ethyl acetate (60 ml) and washed with 0.15 M Na2SO3 (20 ml) and water (60 ml) and dried over anhydrous sodium sulfate. The mixture was distilled, and the residue was purified by flash column chromatography on silica gel (chloroform:methanol, 90:10). Yield 1.89 g (94%). 1H NMR (CDCl3, 500 MHz): δ 13.35 (s, 1H), 7.36-6.79 (m, 7H), 6.53 (d, 1H, J=9.2 Hz), 3.71 (s, 2H). 13C NMR (CDCl3, 125 MHz): δ 164.7, 162.4, 160.4, 143.2, 132.7, 131.2, 122.3, 120.3, 118.4, 111.4, 104.1, 30.3.
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([C:10]2[O:11][CH:12]=[C:13]([C:15](=[O:35])[NH:16][C@H:17]3[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=4)=[O:23])[CH2:18]3)[N:14]=2)[CH2:7]1)(=O)=O.[C:36]([O-:39])(=[S:38])[CH3:37].[K+]>CN(C)C=O>[C:36]([S:38][CH:6]1[CH2:9][N:8]([C:10]2[O:11][CH:12]=[C:13]([C:15](=[O:35])[NH:16][C@H:17]3[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=4)=[O:23])[CH2:18]3)[N:14]=2)[CH2:7]1)(=[O:39])[CH3:37]
Reactant: CS(=O)(=O)OC1CN(c2nc(C(=O)N[C@H]3CCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)co2)C1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(C(=O)N[C@H]3CCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)co2)C1
Temperature: 80 °C
Reaction time: 10.5 h
Yield: 73.1 %

Procedure:
To a solution of 3-methanesulfonyloxy-1-{4-[(3S)-1-(p-nitrobenzyloxycarbonyl)pyrrolidin-3-ylcarbamoyl]-1,3-oxazol-2-yl}azetidine (760 mg, 1.49 mmol) (obtained as described in Reference Example 76(3)) in dimethylformamide (38 ml) was added potassium thioacetate (1.02 g, 8.95 mmol) at room temperature and was stirred in an oil bath (80° C.) for 10.5 hours. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane: ethyl acetate (1:6)→ethyl acetate as the eluant to afford 3-acetylthio-1-{4-[(3S)-1-(p-nitrobenzyloxycarbonyl)pyrrolidin-3-ylcarbamoyl]-1,3-oxazol-2-yl}azetidine (533 mg, yield 73%) as a pale brown solid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[NH:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[C:10]([O:12][CH3:13])=[O:11].Cl[C:15]([CH3:18])([CH3:17])[CH3:16]>ClC(Cl)C>[C:15]([C:9]1[NH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: COC(=O)c1ccc[nH]1
Reactant: CC(C)(C)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: COC(=O)c1ccc(C(C)(C)C)[nH]1
Reaction time: 2 h
Yield: 91.2 %

Procedure:
Aluminum chloride (0.710 g, 5.33 mmol, 2.2 equiv) is added in one portion to a solution of methyl pyrrole-2-carboxylate (0.30 g, 2.42 mmol) in dry dichloroethane (12 mL) under N2 at rt. Subsequently, 2-chloro-2-methylpropane (0.26 mL, 2.42 mmol, 1.0 equiv) is added in one portion via syringe. After 2 h, the orange solution is quenched by slowly pouring into a saturated sodium bicarbonate solution. The resulting white suspension is extracted with diethyl ether (2×). The combined organic layers are dried (Na2SO4) and concentrated in vacuo to give 0.40 g of methyl 5-t-butylpyrrole-2-carboxylate as an off-white solid. Flash chromatography (40% hexane in dichloromethane) gives 0.3 6 g of the desired material as a white amorphous solid (81%). 1H NMR (CDCl3) d 8.82 (br s, 1H), 6.81 (t, 1H, J=3.3 Hz), 6.00 (t, 1H, J=3.3 Hz), 3.83 (s, 3H), 1.31 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:3](B(O)O)=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.Br[C:14]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:15]=1[C:16]#[N:17]>>[Cl:22][C:20]1[CH:21]=[CH:14][C:15]([C:16]#[N:17])=[C:18]([C:3]2[C:2]([Cl:1])=[CH:7][N:6]=[C:5]([O:8][CH3:9])[CH:4]=2)[CH:19]=1
Reactant: COc1cc(B(O)O)c(Cl)cn1
Reactant: N#Cc1ccc(Cl)cc1Br
Product: COc1cc(-c2cc(Cl)ccc2C#N)c(Cl)cn1

Procedure:
5.36 g (purity 91%, 26.03 mmol) of 5-chloro-2-methoxypyridin-4-ylboronic acid and 5.12 g (23.66 mmol) of 2-bromo-4-chlorobenzonitrile in the presence of [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride/dichloromethane monoadduct were reacted according to General Method 2A. After work-up, the crude product was then purified by flash chromatography (silica gel 60, cyclohexane/dichloromethane mixtures). Yield: 4.11 g (purity 91%, 52% of theory)
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[OH:13].Cl[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH2:22][CH2:23][CH2:24][OH:25])[N:16]=1>CN(C=O)C>[Cl:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[O:13][C:19]1[CH:20]=[CH:15][N:16]=[C:17]([NH:21][CH2:22][CH2:23][CH2:24][OH:25])[N:18]=1
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Reactant: OCCCNc1nccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccnc(NCCCO)n2)c(Cl)c1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
370 mg (14.7 mmol) sodium hydride was given to a solution of 2.31 g (13.3 mmol) 2-chloro-4-nitrophenol in 25 ml DMF. Stirring was continued for 30 min. at room temperature. 2.50 g (13.3 mmol) 3-(4-Chloro-pyrimidin-2-ylamino)-propan-1-ol were added and the mixture heated to 140° C. for 24 h. The reaction mixture was evaporated, taken up with water and extracted with dichloromethane. The organic phase was extracted with sodium carbonate solution, dried (sodium sulphate) and evaporated. The obtained material was dissolved in 3 ml dichloromethane and purified by chromatography over silica (dichloromethane/ethanol 95:5) to give 2.92 g (67%) 3-[4-(2-chloro-4-nitro-phenoxy)-pyrimidin-2-ylamino]-propan-1-ol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:9][CH2:10]Cl)=[CH:4][CH:3]=1.[CH3:18][NH:19][CH3:20]>>[CH3:18][N:19]([CH2:10][CH:9]=[C:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[CH3:20]
Reactant: ClCC=C(c1ccc(Br)cc1)c1cccnc1
Reactant: CNC
Product: CN(C)CC=C(c1ccc(Br)cc1)c1cccnc1
Reaction time: 2 h

Procedure:
The brown solution of the chloride from step 3 (from 0.1 moles ketone) in ca 160 ml of solvent was stirred at ca 0° C. and 26 g dimethylamine were added in one portion. This solution was stirred at 0°-5° C. for 2 hours. The solvent was then evaporated. A crude brown oil of the desired end product was obtained.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([N:5]([C:7](=O)[C@H:8]([CH2:17][OH:18])[NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[NH2:6])=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:13]([O:12][C:10]([NH:9][C@H:8]1[CH2:7][N:5]([C:3](=[O:4])[C:2]([F:21])([F:20])[F:1])[NH:6][C:17]1=[O:18])=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)N(N)C(=O)C(F)(F)F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CN(C(=O)C(F)(F)F)NC1=O
Yield: 85.8 %

Procedure:
N-(t-Butoxycarbonyl) (L)-serine trifluoroacetyl hydrazide (3.78 g, 12 mmol) and triphenylphosphine (3.46 g, 13.2 mmol) were dissolved in THF (50 ml). To the solution was added a THF solution (10 ml) of 95% diethyl azodicarboxylate (2.42 g, 2.19 ml, 13.2 mmol). The resultant mixture was stirred at room temperature for six hours and then the solvent was removed in vacuo. The residue was dissolved in ethyl acetate (100 ml) and then the solution was washed with aqueous sodium bicarbonate solution (33 ml, 3×). The sodium bicarbonate extracts were combined, aqueous saturated brine solution (70 ml) was added and the resultant mixture was extracted with ethyl acetate (120 ml, 3×). The sodium bicarbonate solution was then layered with additional ethyl acetate (200 ml) and 1N hydrochloric acid (approx. 80 ml) was added until the sodium bicarbonate solution had a pH of 2.5. The ethyl acetate layer was separated and the aqueous layer was extracted with additional ethyl acetate (4×, 125 ml). The ethyl acetate extracts were combined, washed with saturated aqueous brine (125 ml, 2×), dried over sodium sulfate, filtered, and taken to dryness in vacuo. The resultant residue was dissolved in acetonitrile (100 ml) then the acetonitrile was removed in vacuo. Treatment of the residue with acetonitrile was repeated to yield 3.06 g, 96% yield of 4-(S)-(t-butoxycarbonylamino)-1-(trifluoroacetyl)-3-oxo-1,2-diazolidine: n.m.r (300 MHz, CDCl3): δ 5.25 (d, 1, J=6), 4.81 (t, 1), 4.6 (m, 1), 4.06 (t, 1), 1.46 (s, 9); i.r. (CHCl3): 1722, 1682, 1518 cm-1 ; f.d.m.s. (m/e): M+ =297; specific rotation: [α]D25 =-88.14° (10.03 mg/ml in methanol);
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[N:10]1([C:15]2[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=2)[CH:14]=[CH:13][CH:12]=[N:11]1.N1CCCCC1.C(O)(=O)C>C1C=CC=CC=1.O>[N:10]1([C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[C:3]([C:2](=[O:1])[CH2:8][CH3:9])[C:4]([O:6][CH3:7])=[O:5])=[CH:17][CH:16]=2)[CH:14]=[CH:13][CH:12]=[N:11]1
Reactant: CCC(=O)CC(=O)OC
Reactant: O=Cc1ccc(-n2cccn2)cc1
Solvent: c1ccccc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CCC(=O)C(=Cc1ccc(-n2cccn2)cc1)C(=O)OC
Temperature: 23 °C
Reaction time: 4 h

Procedure:
A mixture containing methyl 3-oxopentanoate (2.2 g, 17 mmol), 4-(1H-pyrazol-1-yl)benzaldehyde (2.5 g, 14 mmol), piperidine (0.3 mL, 3.0 mmol), and acetic acid (0.16 mL, 2.8 mmol) in benzene (70 mL) was heated to 90° C. with removal of water (Dean-Stark trap). After 4 hours, the mixture was cooled to 23° C. and then concentrated to provide the title compound. The residue (mixture of alkene isomers) was taken onto the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]([CH3:31])[C:10]([NH:12][CH2:13][C:14]2[C:15]([C:24]3[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=3)=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].[BH4-].[Na+]>C(O)C.C(OCC)(=O)C.[NiH6-5]Cl>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([CH:9]([CH3:31])[C:10]([NH:12][CH2:13][C:14]2[C:15]([C:24]3[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=3)=[N:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)C(C)c2cccc(C#N)c2)c1
Agent: Cl[NiH6-5]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)C(C)c2cccc(CN)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 5.9 %

Procedure:
To a stirred solution of 2-(3-cyanophenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide (217 mg, 5.13 mmol) in dry ethanol (15 mL), cooled to 0° C., were added nickel(II) chloride hexahydride (121 mg, 5.13 mmol). Sodium borohydride (136 mg, 35.9 mmol) was added in small portions over 10 min. The reaction mixture was allowed to warm to room temperature and left to stir for a further 1 h. The purple residue was dissolved in ethyl acetate (50 mL) and extracted with saturated NaHCO3. The organic layer was dried over magnesium sulfate and the solvent removed in vacuo to yield 2-(3-(aminomethyl)phenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide (130 mg, 60%).
Reaction SMILES: [OH:1][C:2]1[C:6]([CH:7]([CH3:9])[CH3:8])=[C:5]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[O:4][N:3]=1.[C:16]([O:20][C:21]([NH:23][CH2:24][CH2:25]O)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([NH:23][CH2:24][CH2:25][O:1][C:2]1[C:6]([CH:7]([CH3:9])[CH3:8])=[C:5]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[O:4][N:3]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)c1c(O)noc1-c1cccnc1
Reactant: CC(C)(C)OC(=O)NCCO
Product: CC(C)c1c(OCCNC(=O)OC(C)(C)C)noc1-c1cccnc1
Yield: 72.2 %

Procedure:
3-Hydroxy-4-isopropyl-5-(3-pyridyl)isoxazole (0.12 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.09 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 9(a) to obtain the title compound (0.14 g, 74%) as a colorless powder.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([N+:15]([O-])=O)[CH:9]=1)(C)(C)C.[S:19]1[CH:23]=[C:22]([C:24](O)=O)[N:21]=[CH:20]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>CN(C)C=O>[S:19]1[CH:23]=[C:22]([C:24]2[NH:15][C:10]3[CH:9]=[C:8]([NH2:7])[CH:13]=[CH:12][C:11]=3[N:14]=2)[N:21]=[CH:20]1
Reactant: O=C(O)c1cscn1
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)c([N+](=O)[O-])c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ccc2nc(-c3cscn3)[nH]c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of (4-Amino-3-nitro-phenyl)-carbamic acid tert-butyl ester (1-3, 0.409 g, 1.832 mmol), thiazole 4-carboxylic acid (0.226 g, 1.832 mmol) and diisopropylethylamine (0.81 mL, 4.03 mmol) in N,N-dimethylformamide (10 mL) was reacted at the ambient temperature with benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBop, 1.05 g, 2.02 mmmol). After 3 h stirring at the same temperature, the reaction mixture was concentrated under the reduced pressure and the residue was partitioned between ethyl acetate (100 mL) and aqueous 0.5N-NaOH solution (70 mL). The organic layer was washed with brine, separated, dried (MgSO4) and concentrated in vacuo. The resulting crude product was triturated with ethyl acetate (5 mL), collected by filtration, and dried under the reduced pressure. The mixture of the intermediate products (1-4a and 1-4b) was dissolved in aqueous 20%(v/v)-acetic acid (50 mL) and heated at reflux for 2 h. The reaction mixture was cooled to the ambient temperature and concentrated in vacuo. The resulting crude thick oil was partitioned between ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate solution (70 mL). The organic layer was washed with brine, separated, dried (MgSO4) and concentrated in vacuo. The crude product was triturated with ethyl acetate (15 mL) and hexanes (2 mL). The resulting solid, 2-thiazol-4-yl-3H-benzoimidazol-5-ylamine (1-5), was collected by filtration and dried under the reduced pressure; 1H NMR (500 MHz, DMSO-d6) δ 12.34 (s, 1H), 9.27 (s, 1H), 8.24 (s, 1H), 7.27 (bs, 1H), 6.66 (s, 1H), 6.54 (d, 1H, J=7.5 Hz), 4.96 (bs, 2H).
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([O:6][C:7]2[CH:8]=[C:9]([NH:13][C:14]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]4[C:23]5[C:30]([CH3:31])=[CH:29][NH:28][C:24]=5[N:25]=[CH:26][N:27]=4)[CH2:18][CH2:17]3)=O)[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:1][C:2]1[CH:33]=[CH:32][C:5]([O:6][C:7]2[CH:8]=[C:9]([NH:13][CH2:14][CH:16]3[CH2:21][CH2:20][N:19]([C:22]4[C:23]5[C:30]([CH3:31])=[CH:29][NH:28][C:24]=5[N:25]=[CH:26][N:27]=4)[CH2:18][CH2:17]3)[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: Cc1c[nH]c2ncnc(N3CCC(C(=O)Nc4cccc(Oc5ccc(F)cc5)c4)CC3)c12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c[nH]c2ncnc(N3CCC(CNc4cccc(Oc5ccc(F)cc5)c4)CC3)c12
Temperature: 25 °C

Procedure:
A solution of 1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidine-4-carboxylic acid [3-(4-fluoro-phenoxy)-phenyl]-amide (52 mg, 0.12 mmol) in anhydrous THF (tetrahydrofuran) (10 mL) was cooled in an ice bath for 15 minutes with stirring. To this a solution of LAH (lithium aluminum hydride) in THF (1.0 M, 1.2 mL, 1.2 mmol) was added slowly. The reaction mixture was warmed to room temperature and stirred for 15 minutes, and then heated to reflux for 2 hours. The mixture was cooled to room temperature and then Na2SO4.10H2O was added until bubbling stopped. After stirring for 2 hours, the precipitate was filtered off and the filtrate concentrated. The residue was dissolved in acetonitrile (1.5 mL) and 30% aqueous TFA (trifluoroacetic acid) (0.5 mL), filtered, and chromatographed using reverse-phase high-pressure liquid chromatography. The clean fractions were pooled and concentrated and then lyophilized to remove water to yield [3-(4-fluoro-phenoxy)-phenyl]-[1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-ylmethyl]-amine as a white solid (7.9 mg, 15%, (M+H)+:432).
Reaction SMILES: [CH:1]([O:4][CH2:5][C@H:6]([NH:25]C(=O)OCC1C=CC=CC=1)[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:21]3[C:16](=[CH:17][N:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]([CH3:23])[C:13]=2[CH:24]=1)([CH3:3])[CH3:2].N#N>CO.[Pd]>[NH2:25][C@@H:6]([CH2:5][O:4][CH:1]([CH3:3])[CH3:2])[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:21]3[C:16](=[CH:17][N:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]([CH3:23])[C:13]=2[CH:24]=1
Reactant: CC(C)OC[C@@H](COc1ccc2c3ccncc3c(=O)n(C)c2c1)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: N#N
Solvent: CO
Product: CC(C)OC[C@H](N)COc1ccc2c3ccncc3c(=O)n(C)c2c1
Reaction time: 12 h
Yield: 83.1 %

Procedure:
A solution of (S)-benzyl (1-isopropoxy-3-((6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)propan-2-yl)carbamate (220 mg, 0.130 mmol) in MeOH (12 mL) was degassed with N2 for 5 min. Pd/C (68.9 mg, 0.065 mmol) was added and the mixture stirred under a balloon of H2 for 12 h. The reaction mixture was filtered through diatomaceous earth (Celite®), eluting with methanol and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase HPLC (10 MM ammonium acetate in water/AcCN) to afford (S)-8-(2-amino-3-isopropoxypropoxy)-6-methylbenzo[c][2,7]naphthyridin-5(6H)-one (90 mg, 0.108 mmol, 83% yield) as an off-white solid. LC/MS (ESI) m/e 342.2, [(M+H)+, calcd for C19H24N3O3, 342.2]; LC/MS retention time (method C): tR=1.50 min. HPLC retention time (method A): tR=7.20 min; HPLC retention time (method B): tR=8.00 min. 1H NMR (400 MHz, MeOD) δ ppm 9.54 (s, 1H), 8.23 (d, J=4.4 Hz, 1H), 8.52 (d, J=8.8 Hz, 1H), 8.44 (d, J=6.0 Hz, 1H), 7.20 (s, 1H), 7.18 (d, J=6.0 Hz, 1H), 4.52 (dd, J=10.4, 3.6 Hz, 1H), 4.43 (dd, J=10.4, 6.8 Hz, 1H), 3.88-3.75 (m, 7H), 1.26 (d, J=6.4 Hz, 3H), 1.25 (d, J=6.4 Hz, 3H).