Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3][CH2:4][CH:5]=[CH2:6].Br[C:15]1[CH:16]=[N:17][CH:18]=[C:19](SCC)[CH:20]=1.BrCCC=C.CN.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][N:2]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3][CH2:4][CH:5]=[CH2:6].[CH3:18][NH:17][CH2:16][CH2:15][CH:20]=[CH2:19]
Reactant: CCSc1cncc(Br)c1
Agent: C=CCCBr
Agent: C=CCCN(C)C(=O)OC(C)(C)C
Agent: CN
Solvent: CN(C)C=O
Product: C=CCCNC
Yield: 97 %

Procedure:
One representative compound, (E)-N-methyl-4-(3-[5-(ethylthio)pyridinyl])-3-buten-1-amine is prepared from N-methyl-N-(tert-butoxycarbonyl)-3-buten-1-amine and 3-bromo-5-(ethylthio)pyridine using the techniques set forth in W.C. Frank, et al., J. Org. Chem. 43(15):2947 (1978), and the tert-butoxy carbonyl protecting group is subsequently removed. Specifically, N-methyl-N-(tert-butoxycarbonyl)-3-buten-1-amine is prepared by (i) reacting 4-bromo-1-butene at 0.035 mole scale with a ten fold excess of condensed methylamine in N,N-dimethylformamide solvent in the presence of potassium carbonate to provide a 97% yield of N-mehtyl-3-buten-1-amine; (ii) the amine thus prepared is reacted at 0.030 mole scale with one equivalent of di-tert-butyldicarbonate in tetrahydrofuran to give N-methyl-N-(tert-butoxycarbonyl)-3-buten-1-amine in 68% yield. The 3-bromo-5-(ethylthio)pyridine is produced by the reaction of sodium ethanethiolate on 3,5-dibromopyridine in N,N-dimethylformamide in 86% yield. N-methyl-N-(tert-butoxycarbonyl)-3-buten-1-amine and 3-bromo-5-(ethylthio)pyridine are reacted using the Heck reaction on a 1.6 mmole scale in 2:1 acetonitrile:triethylamine using a catalyst consisting of one mole percent palladium acetate and four mole percent tri-o-tolylphosphine. N-methyl-N-(tert-butoxycarbonyl)-4-(3 -[5 -(ethylthio)pyridinyl])-3 -buten- 1-amine is obtained in 59% yield. Deprotection of the product may then be accomplished by 1:1 6N hydrochloric acid:tetrahdyrofuran.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11](=[O:13])[CH3:12])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:14](Cl)(=[O:16])[CH3:15].[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[C:14]([C:7]1[CH:8]=[C:9]2[C:4]([CH2:3][CH2:2][CH2:1]2)=[CH:5][C:6]=1[NH:10][C:11](=[O:13])[CH3:12])(=[O:16])[CH3:15]
Reactant: CC(=O)Cl
Reactant: CC(=O)Nc1ccc2c(c1)CCC2
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)Nc1cc2c(cc1C(C)=O)CCC2
Reaction time: 2 h
Yield: 48.3 %

Procedure:
To a stirred mixture of 10.5 g of N-(2,3-dihydro- 1H-inden-5-yl)acetamide and 4.7 ml of acetyl chloride in 100 ml of carbondisulfide were added portionwise 17.3 g of aluminum chloride at room temperature. After stirring for 2 hours at reflux temperature, the cooled reaction mixture was poured into 50 ml ice/HCl. The separated aqueous layer was extracted with dichloromethane. The extract was combined with the former organic layer, washed with water, dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; dichloromethane/methanol 99:1 ). The eluent of the desired fraction was evaporated and the residue was crystallized from 2,2'-oxybispropane. The crystallized product was filtered off and dried, yielding 6.3 g (48.3%) of N-(6-acetyl-2,3-dihydro- 1H-inden-5-yl)acetamide (interm. 1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[CH:11][CH2:12][CH3:13])[N:5]=[CH:4][N:3]=1.[NH:14]1[CH2:19][CH:18]=[CH:17][CH2:16][CH2:15]1>>[CH2:9]([O:8][C:6]1[CH:7]=[C:2]([N:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH2:19]2)[N:3]=[CH:4][N:5]=1)[C:10]#[C:11][CH2:12][CH3:13]
Reactant: C1=CCNCC1
Reactant: CCC=CCOc1cc(Cl)ncn1
Product: CCC#CCOc1cc(N2C=CC=CC2)ncn1
Reaction time: 3 h
Yield: 63.1 %

Procedure:
0.3 g of 4-chloro-6-(2-pentenyloxy)pyrimidine and 0.25 g of 1,2,3,6-tetrahydropyridine were mixed and left for 3 hours at room temperature. The reaction mixture was subjected to silica gel column chromatography to obtain 0.23 g of 1-(4-(2-pentynyloxy)pyrimidin-6-yl)pyridine (hereinafter, referred to as Compound (55)).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]([F:13])=[C:4]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[N:3]=1.[CH:19]1([NH2:22])[CH2:21][CH2:20]1>CC(N(C)C)=O.ClCCl>[CH:19]1([NH:22][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]([F:13])=[C:4]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[N:3]=2)[CH2:21][CH2:20]1
Reactant: NC1CC1
Reactant: CCOC(=O)c1cc(F)c(N2CCCC2)nc1Cl
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cc(F)c(N2CCCC2)nc1NC1CC1
Temperature: 90 °C

Procedure:
A solution of ethyl 2-chloro-5-fluoro-6pyrrolidinyl-3-pyridinecarboxylate (Example C-2, 500 mg, 1.83 mmol) and cyclopropylamine (2 mL) in DMA (1 mL) was sealed in a pressure bottle and heated at 90° C. for 1 day. The reaction mixture was diluted with dichloromethane (40 mL), washed with water and dried on sodium sulfate. Flash chromatography on a silica gel column using dichloromethane/hexane (3:2) as eluent provided 270 mg of the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([S:10](=[O:13])(=[O:12])[NH2:11])=[CH:5][C:3]=1[NH2:4].[CH3:14][C:15]1[CH:23]=[CH:22][C:18]([CH2:19][C:20]#N)=[CH:17][CH:16]=1>Cl>[Cl:9][C:7]1[C:6]([S:10](=[O:12])(=[O:13])[NH2:11])=[CH:5][C:3]2[NH:4][C:20]([CH2:19][C:18]3[CH:22]=[CH:23][C:15]([CH3:14])=[CH:16][CH:17]=3)=[N:1][C:2]=2[CH:8]=1
Reactant: Nc1cc(Cl)c(S(N)(=O)=O)cc1N
Reactant: Cc1ccc(CC#N)cc1
Agent: Cl
Product: Cc1ccc(Cc2nc3cc(Cl)c(S(N)(=O)=O)cc3[nH]2)cc1
Temperature: 25 °C
Yield: 11.2 %

Procedure:
To 150 ml of 6 N hydrochloric acid was added 17.7 g of 2-amino-4-chloro-5-sulfamylaniline followed by the addition of 15.7 g of 4-methylbenzyl cyanide; the mixture was then refluxed for 9 hours. The precipitate was collected by filtration and added to 300 ml of concentration ammonium hydroxide. After stirring for ten minutes at ambient temperature, the solid was collected and then added to 300 ml of water and stirred at 40° C. for ten minutes. The crude product was collected and dissolved in 1 liter of methanol which was brought to a boil; after stirring for five minutes, charcoal was added, and stirring continued for ten more minutes. The mixture was then filtered through two sheets of filter paper and then through Celite. Concentration in vacuo provided a solid which upon recrystallization from acetonitrile provided 3.0 g of pink crystals, m.p. 214°-217°.
Reaction SMILES: [CH2:1]1[O:7][CH2:6][C@@H:4](O)[C@H:2]1O.[Na].[CH2:9]([N:16]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([BH3-])#N.[Na+]>O.C(#N)C>[CH2:9]([N:16]1[CH2:20][CH2:19][C@@H:18]([N:21]2[CH2:4][CH2:6][O:7][CH2:1][CH2:2]2)[CH2:17]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O[C@@H]1COC[C@@H]1O
Reactant: N[C@@H]1CCN(Cc2ccccc2)C1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [Na]
Solvent: CC#N
Solvent: O
Product: c1ccc(CN2CC[C@@H](N3CCOCC3)C2)cc1
Reaction time: 16 h
Yield: 27.1 %

Procedure:
To a solution of 1,4-anhydroerythritol (1.9 g, 18 mmol) in water (10 ml) was added sodium periodiate (0.7 g, 18 mmol) and the reaction stirred for 16 h. Acetonitrile (10 ml) was added to the mixture and the reaction was filtered to remove precipitated salts. (R)-1-benzyl-pyrrolidin-3-ylamine (1.0 g, 6 mmol) was added as a solution in acetonitrile (5 ml) to the filtrate, followed by sodium cyanoborohydride (1.1 g, 18 mmol). The reaction was stirred for 10 minutes after which time the reaction the acetonitrile removed by evaporation, the mixture made basic by addition of NaHCO3, and repeatedly extracted with CH2Cl2. The combined organic extracts were dried (Na2SO4) and concentrated. Purification by flash column chromatography (CH2Cl2:MeOH 9:1) afforded the title product (0.4 g, 28%) as a brown gum. MS: 247.2 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH:12]([NH2:14])=O>>[CH3:11][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:2]=1[N:1]=[CH:12][NH:14][C:4]2=[O:5]
Reactant: Cc1cccc(C(=O)O)c1N
Reactant: NC=O
Product: Cc1cccc2c(=O)[nH]cnc12
Temperature: 25 °C

Procedure:
2-Amino-3-methylbenzoic acid (1.00 g, 0.0066 mol) and formamide (12 mL) were heated together at 130° C. for 20 hr. under nitrogen. After cooling to room temperature, the solid was filtered off, washed with diethyl ether and dried in vacuo to leave 8-methylquinazolin-4(3H)-one (1.19 g).
Reaction SMILES: [CH3:1][S:2]([C:5]1[C:10]2[O:11][CH2:12][O:13][C:9]=2[CH:8]=[CH:7][C:6]=1[CH2:14]O)(=[O:4])=[O:3].C(Br)(Br)(Br)[Br:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:17][CH2:14][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH2:12][O:11][C:10]=2[C:5]=1[S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1c(CO)ccc2c1OCO2
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1c(CBr)ccc2c1OCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.3 %

Procedure:
907 mg of [2-(methylsulfonyl)-3,4-methylenedioxyphenyl]methanol, 1.31 g of carbon tetrabromide and 1.03 g of triphenylphosphine were dissolved in 5 ml of dichloromethane, and the mixture was stirred at room temperature for 30 minutes. The solvent was evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:3), to give 1.10 g of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH3:22])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C@@H:13]([CH3:19])[CH2:14][C:15](OC)=[O:16])=[CH:10][CH:11]=2)[N:6]([CH3:20])[C:5]1=[O:21].CC(C[AlH]CC(C)C)C.C1COCC1.CCCCCCC>C1COCC1>[CH3:22][C:2]([CH3:1])([CH3:23])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C@H:13]([CH2:14][CH2:15][OH:16])[CH3:19])=[CH:10][CH:11]=2)[N:6]([CH3:20])[C:5]1=[O:21]
Reactant: COC(=O)C[C@H](C)c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: C[C@@H](CCO)c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 36-1 (0.46 g, 1.38 mmol) in THF (8 mL) chilled to −78° C. was added DIBAL 1.0M in THF heptane (4.22 mL, 4.22 mmol) dropwise. The resulting mixture was stirred at −78° C. for 3 hr, then quench with slow addition of Rochelle's salt solution (5 mL). The resulting mixture was allowed to warm to room temperature, diluted with water and extracted with ethyl acetate. The organic phase was concentrated and flash column separation using a 50-100% ethyl acetate/hexane gradient gave 36-2. (0.26 g, 64%). LRMS (ES) (M+H)+: observed=292.1, calculated=292.4.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[CH:14][C:15](Cl)=[O:16])=[CH:9][CH:8]=1.[CH3:21][NH2:22]>ClCCl.O>[F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[CH:14][C:15]([NH:22][CH3:21])=[O:16])=[CH:9][CH:8]=1
Reactant: O=C(Cl)C=Cc1ccc(OCc2cccc(F)c2)cc1
Reactant: CN
Solvent: O
Solvent: ClCCl
Product: CNC(=O)C=Cc1ccc(OCc2cccc(F)c2)cc1
Yield: 30 %

Procedure:
500 mg (1.72 mmol) of the crude 3-[4-(3-fluoro-benzyloxy)-phenyl]-acryloyl chloride is dissolved in 2 ml dichloromethane and 0.4 ml of a 41% solution of methylamine in water is added. The reaction mixture is heated under reflux for about 3 hours, cooled, filtered and washed with cold dichloromethane to yield 149 mg (30%) of a colorless solid. MS: m/e=286.2 (M+).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][C:10]1[N:11]=[C:12]([NH:15][C:16]2[CH:17]=[C:18]([CH:21]=[CH:22][N:23]=2)[CH:19]=[O:20])[S:13][CH:14]=1.C(OCC)(=O)C>CCOCC.C1COCC1>[CH3:9][C:10]1[N:11]=[C:12]([NH:15][C:16]2[CH:17]=[C:18]([CH:19]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[OH:20])[CH:21]=[CH:22][N:23]=2)[S:13][CH:14]=1
Reactant: Cc1csc(Nc2cc(C=O)ccn2)n1
Reactant: Br[Mg]c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1csc(Nc2cc(C(O)c3ccccc3)ccn2)n1
Reaction time: 0.5 h
Yield: 40 %

Procedure:
3.0 M Phenylmagnesium bromide (0.9982 mL, 2.995 mmol) in ether was added to THF (2 mL) at 0° C., and then 2-(4-methylthiazol-2-ylamino)isonicotinaldehyde (0.197 g, 0.8985 mmol) in THF (3 mL) was added. The reaction mixture was stirred for 30 minutes, then partitioned between saturated ammonium chloride and ethyl acetate. The organic layer was washed with brine, dried, and concentrated. The residue was purified via MPLC (Biotage) eluting with 2:3 hexane:ethyl acetate to afford (2-(4-methylthiazol-2-ylamino)pyridin-4-yl)(phenyl)methanol (0.107 g, 40.05% yield) as a white solid. 1H NMR (d6-DMSO) δ 11.10 (s, 1H), 8.14 (d, 1H), 7.24-7.37 (m, 5H), 7.11 (s, 1H), 6.81 (d, 1H), 6.50 (s, 1H), 6.09 (d, 1H), 5.64 (d, 1H), 2.22 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([CH:20]=[N:21][CH:22]=2)[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[C:6]([C:8]([OH:10])=O)[CH:7]=1.[CH3:23][C:24]1([CH3:32])[O:28][C@@H:27]([CH2:29][O:30][NH2:31])[CH2:26][O:25]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:23][C:24]1([CH3:32])[O:28][C@@H:27]([CH2:29][O:30][NH:31][C:8]([C:6]2[CH:7]=[C:2]([F:1])[C:3]3[N:4]([CH:20]=[N:21][CH:22]=3)[C:5]=2[NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[O:10])[CH2:26][O:25]1
Reactant: CC1(C)OC[C@H](CON)O1
Reactant: O=C(O)c1cc(F)c2cncn2c1Nc1ccc(I)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OC[C@H](CONC(=O)c2cc(F)c3cncn3c2Nc2ccc(I)cc2F)O1
Temperature: 25 °C
Reaction time: 72 h
Yield: 96.1 %

Procedure:
8-Fluoro-5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid (235 mg, 0.57 mmol), O—((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine (92 mg, 0.62 mmol), EDCI (120 mg, 0.62 mmol), HOBt (84 mg, 0.62 mmol) and DIPEA (0.1 mL, 0.62 mmol) were dissolved in DMF (10 mL) and the reaction mixture stirred at room temperature for 72 hours before being concentrated in vacuo. The resultant residue was dissolved in ethyl acetate (10 mL), washed with aqueous saturated sodium bicarbonate solution (10 mL) and the aqueous fraction extracted twice with ethyl acetate (2×10 mL). The combined organic fractions were washed with brine (20 mL), dried with MgSO4 and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-10% methanol in DCM) to yield the title compound as a pale yellow solid (298 mg, 97%). LCMS (Method B): RT=3.34 min, [M+H]+=545.
Reaction SMILES: [C:1]([C:3]1[CH:53]=[CH:52][C:6]2[N:7](COCC[Si](C)(C)C)[C:8]([C:10]([C:22]3[C:30]([CH2:31][CH3:32])=[CH:29][C:28]([CH3:33])=[C:27]4[C:23]=3[CH:24]=[CH:25][N:26]4S(C3C=CC(C)=CC=3)(=O)=O)([O:15][CH2:16][C:17]([O:19]CC)=[O:18])[C:11]([F:14])([F:13])[F:12])=[N:9][C:5]=2[CH:4]=1)#[N:2].C(C1C=CC2N=C(C(C3C(CC)=CC(C)=C4C=3C=CN4S(C3C=CC(C)=CC=3)(=O)=O)(OCC(OCC)=O)C(F)(F)F)N(COCC[Si](C)(C)C)C=2C=1)#N.Cl.[OH-].[K+]>CCO>[C:1]([C:3]1[CH:53]=[CH:52][C:6]2[NH:7][C:8]([C:10]([C:22]3[C:30]([CH2:31][CH3:32])=[CH:29][C:28]([CH3:33])=[C:27]4[C:23]=3[CH:24]=[CH:25][NH:26]4)([O:15][CH2:16][C:17]([OH:19])=[O:18])[C:11]([F:12])([F:13])[F:14])=[N:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: CCOC(=O)COC(c1c(CC)cc(C)c2c1ccn2S(=O)(=O)c1ccc(C)cc1)(c1nc2cc(C#N)ccc2n1COCC[Si](C)(C)C)C(F)(F)F
Agent: CCOC(=O)COC(c1c(CC)cc(C)c2c1ccn2S(=O)(=O)c1ccc(C)cc1)(c1nc2ccc(C#N)cc2n1COCC[Si](C)(C)C)C(F)(F)F
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: CCc1cc(C)c2[nH]ccc2c1C(OCC(=O)O)(c1nc2cc(C#N)ccc2[nH]1)C(F)(F)F
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A solution of a mixture of (±)-ethyl 2-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-(5-ethyl-7-methyl-1-tosyl-1H-indol-4-yl)-2,2,2-trifluoroethoxy)acetate and (±)-ethyl 2-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-(5-ethyl-7-methyl-1-tosyl-1H-indol-4-yl)-2,2,2-trifluoroethoxy)acetate (153 mg, 0.199 mmol) and HCl (1.25 M in MeOH) (1592 μL, 1.990 mmol) was allowed to stir at 60° C. for 0.5 h. The reaction was cooled to rt and concentrated. A suspension of the residue and KOH (112 mg, 1.99 mmol) in EtOH (2 mL) was allowed to stir at 100° C. for 1 h under microwave irradiation. The reaction mixture was concentrated. The crude was purified by HPLC (HC-A) to give the title compound. 1H NMR (TFA salt, 400 MHz, CD3OD) δ 8.05 (s, 1H), 7.71 (br. d, J=8.34 Hz, 1H), 7.61 (dd, J=1.51, 8.59 Hz, 1H), 7.06 (br. s, 1H), 6.92 (s, 1H), 6.11 (br. s, 1H), 4.17 (d, J=16.17 Hz, 1H), 3.95 (d, J=16.17 Hz, 1H), 2.70-2.85 (br. m, 1H), 2.49 (s, 3H), 2.33-2.44 (br. m, 1H) 1.06 (br. t, 3H). HRMS calcd. for C23H19F3N4O3 (M+H)+ 457.1488. found 457.1474.
Reaction SMILES: CC([N:5]([C@@H:9]1[C@H:13]([OH:14])[CH2:12][N:11]([CH2:15][CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[N:25]=3)[N:20]=[CH:19][CH:18]=2)[CH2:10]1)C(=O)[O-])(C)C.Cl.O1CCOCC1>CO>[NH2:5][C@@H:9]1[CH2:10][N:11]([CH2:15][CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[N:25]=3)[N:20]=[CH:19][CH:18]=2)[CH2:12][C@@H:13]1[OH:14]
Reactant: COc1ccc2nccc(CCN3C[C@@H](O)[C@@H](N(C(=O)[O-])C(C)(C)C)C3)c2n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc2nccc(CCN3C[C@@H](N)[C@@H](O)C3)c2n1
Reaction time: 12 h
Yield: 99.6 %

Procedure:
To a solution of 1,1-dimethylethyl((3S,4R)-4-hydroxy-1-{2-[6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)carbamate (327 mg, 0.843 mmol) in MeOH (4 mL) at 25° C. was added dropwise a 4M HCl in dioxane solution (1.5 mL, 5.9 mmol). After 12 h, the solution was concentrated and the residue neutralized with excess MP carbonate resin in DCM to afford the title compound (242 mg, quant.) as a yellow oil: LCMS (ES) m/e 289 (M+H).
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl[CH2:41][C:42]([N:44]1[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1)=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:33]=[CH:34][C:35]([O:38][CH2:41][CH2:42][N:44]2[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]2)=[CH:36][CH:37]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=C(CCl)N1CCCCC1
Product: CCN(Cc1ccc(OCCN2CCCCC2)cc1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 41.5 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (16 mg) and 2-chloro-1-piperidin-1-ylethanone (8.8 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (6.8 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:18][C:19]2[C:20]([N+:37]([O-])=O)=[C:21]([CH:34]=[CH:35][CH:36]=2)[O:22][C:23]2[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:24]=2[C:25]([O:27][CH3:28])=[O:26])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[H][H]>O1CCCC1.[Ni]>[NH2:37][C:20]1[C:19]([NH:18][CH:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:36][CH:35]=[CH:34][C:21]=1[O:22][C:23]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26]
Reactant: [H][H]
Reactant: COC(=O)c1ccc(F)cc1Oc1cccc(NC(c2ccc(OC)cc2)c2ccc(OC)cc2)c1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(F)cc1Oc1cccc(NC(c2ccc(OC)cc2)c2ccc(OC)cc2)c1N

Procedure:
To a solution of Example 44B (2.76 g) in tetrahydrofuran (125 ml) in a stainless steel bottle was added nickel catalyst (2.76 g). The mixture was stirred for 1 hour under 30 psi of hydrogen at ambient temperature. The mixture was filtered through a nylon membrane to remove the catalyst and the title compound was obtained upon evaporation of the solvent (2.54 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13](=[O:15])[CH3:14])[N:10]=[C:9]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[C:4]([Cl:23])[CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:34][C:35]([F:42])([F:41])[C:36](OCC)=[O:37]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13](=[O:15])[CH2:14][C:36](=[O:37])[C:35]([F:42])([F:41])[F:34])[N:10]=[C:9]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[C:4]([Cl:23])[CH:3]=1
Reactant: CC(=O)c1cn(-c2ccc(Br)cc2Cl)c(-c2ccccc2Cl)n1
Reactant: CCOC(=O)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(CC(=O)C(F)(F)F)c1cn(-c2ccc(Br)cc2Cl)c(-c2ccccc2Cl)n1
Temperature: -78 °C
Yield: 15.2 %

Procedure:
To a dry N2 purged 50 mL round bottom flask attached with addition funnel was added 1-(1-(4-bromo-2-chlorophenyl)-2-(2-chlorophenyl)-1H-imidazol-4-yl)ethanone (640 mg, 1.56 mmol) and anhydrous THF (12 mL). The reaction solution was cooled to −78° C. prior to dropwise addition of a 1.0 M LHMDS solution in THF (1.72 mL). The enolate solution was allowed to stir, warming to −200C over 1 h. The reaction solution was cooled to −600C, and ethyl trifluoroacetate (370 μL, 3.12 mmol) was added. The reaction solution was stirred at room temperature for 16 h. The reaction solution was quenched with H2O and diluted with EtOAc (100 mL). The EtOAc phase was partitioned, dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was chromatographed through a 12 g SiO2 column using a 100% hexane to 60% EtOAc gradient to yield 120 mg (86% yield) of title compound. MS (ESI) 507.0, 509.0 [M+H]+.
Reaction SMILES: CN(C(ON1N=NC2C=[CH:13][CH:14]=[N:15][C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C@H:26]([O:29][C:30]1[CH:31]=[C:32]([O:45][C:46]2[N:47]=[CH:48][C:49]([C:52]([OH:54])=O)=[N:50][CH:51]=2)[CH:33]=[C:34]([C:36]([NH:38][C:39]2[CH:43]=[CH:42][N:41]([CH3:44])[N:40]=2)=[O:37])[CH:35]=1)[CH2:27][CH3:28].Cl.N1CCC1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C.CCOCC>[N:15]1([C:52]([C:49]2[N:50]=[CH:51][C:46]([O:45][C:32]3[CH:33]=[C:34]([CH:35]=[C:30]([O:29][C@@H:26]([CH3:25])[CH2:27][CH3:28])[CH:31]=3)[C:36]([NH:38][C:39]3[CH:43]=[CH:42][N:41]([CH3:44])[N:40]=3)=[O:37])=[N:47][CH:48]=2)=[O:54])[CH2:14][CH2:13][CH2:10]1
Reactant: CC[C@H](C)Oc1cc(Oc2cnc(C(=O)O)cn2)cc(C(=O)Nc2ccn(C)n2)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C1CNC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC[C@H](C)Oc1cc(Oc2cnc(C(=O)N3CCC3)cn2)cc(C(=O)Nc2ccn(C)n2)c1
Reaction time: 16 h
Yield: 32.2 %

Procedure:
HATU (34 mg, 0.89 mmol) was added to 5-[(3-{[(1S)-1-methylpropyl]oxy}-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyrazine-2-carboxylic acid (190 mg, 0.4 mmol) and azetidine hydrochloride (84 mg, 0.89 mmol) in DMF (5 mL). DIPEA (0.311 mL, 1.79 mmol) was added and the reaction was stirred for 16 hours. The reaction mixture was added to ethyl acetate (20 mL), washed with water (10 mL), 2N citric acid (10 mL), saturated aqueous sodium hydrogencarbonate (10 mL) and brine (10 mL), then dried (MgSO4), filtered and evaporated under reduced pressure to a gummy residue. The residue was purified by chromatography on silica, eluting with 50-100% ethyl acetate in hexane, to give a gum which was taken up in 50% ethyl acetate in ether and washed twice with water, brine (10 mL) then dried (MgSO4) to give the desired product as a foam (58 mg).