Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6](=[O:19])[C:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([Br:18])[CH:11]=1)([CH3:9])[CH3:8])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][C:29]=1[N+:36]([O-:38])=[O:37].Cl>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][C:29]=1[N+:36]([O-:38])=[O:37])[C:6](=[O:19])[C:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([Br:18])[CH:11]=1)([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)CC(=O)C(C)(C)c1ccc(OC)c(Br)c1
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)C(C)(C)c1ccc(OC)c(Br)c1)c1ccc(C#N)cc1[N+](=O)[O-]
Temperature: 45 °C
Reaction time: 4 h

Procedure:
4-(3-Bromo-4-methoxy-phenyl)-4-methyl-3-oxo-pentanoic acid ethyl ester (Compound K3, 10.3 g, 30.01 mmol) was dissolved in DMF (80 mL), added with cesium carbonate (24.4 g, 2.5 eq.) and 4-chloro-3-nitro-benzonitrile (7.12 g, 1.3 eq.), and then stirred at 45° C. for 4 hr. The reaction solution was added to 1 N aqueous solution of hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The drying agent was removed by filtration, and after concentration under reduced pressure the title compound was obtained as a crude product (yellow oily substance).
Reaction SMILES: C[NH+]1CCOCC1.[NH2:8][C:9]1[C:14]([C:15]#[N:16])=[C:13]([C:17]2[CH:27]=[CH:26][C:20]([O:21][CH2:22][C:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)[C:12]([C:28]#[N:29])=[C:11]([SH:30])[N:10]=1.Br[CH2:32][C:33]([NH2:35])=[O:34].C([O-])(O)=O.[Na+]>CN(C=O)C>[NH2:8][C:9]1[C:14]([C:15]#[N:16])=[C:13]([C:17]2[CH:18]=[CH:19][C:20]([O:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:26][CH:27]=2)[C:12]([C:28]#[N:29])=[C:11]([S:30][CH2:32][C:33]([NH2:35])=[O:34])[N:10]=1
Reactant: N#Cc1c(N)nc(S)c(C#N)c1-c1ccc(OCC(=O)[O-])cc1
Reactant: NC(=O)CBr
Agent: C[NH+]1CCOCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(N)nc(SCC(N)=O)c(C#N)c1-c1ccc(OCC(=O)O)cc1

Procedure:
135 mg (0.316 mmol) of 2-[4-(2-amino-3,5-dicyano-6-sulfanyl-4-pyridinyl)-phenoxy]acetic acid N-methylmorpholinium salt together with 103.3 mg (0.474 mmol) of bromoacetamide and 106.1 mg (1.263 mmol) of NaHCO3 are stirred in 0.5 ml of DMF overnight. After filtration, the reaction solution is prepurified by preparative HPLC. The isolated fraction is reconcentrated under reduced pressure and the residue is purified by preparative thin-layer chromatography.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[C:7]([CH:8]=[O:9])[C:6]([OH:11])=[CH:5][CH:4]=1)=[O:2].S(C1C=CC(C)=CC=1)(O[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:24][CH:23]=1)(=O)=O>>[C:25]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:24]=[CH:23][C:22]([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][O:11][C:6]2[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:10][C:7]=2[CH:8]=[O:9])=[CH:27][CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCCCCc2ccc(-c3ccccc3)cc2)cc1
Reactant: O=Cc1ccc(O)c(C=O)c1
Product: O=Cc1ccc(OCCCCCCc2ccc(-c3ccccc3)cc2)c(C=O)c1

Procedure:
4-[6-(biphenyl-4-yl)hexyloxy]-1,3-benzenedicarboxaldehyde (MS: M+NH4+ =400) was prepared from 5-formyl salicylaldehyde and 6-(biphenyl-4-yl)hexyl tosylate at a temperature of 150° C. using the method in Example 1.
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:12]3[O:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH:21]([O:23]C)Cl.[Sn](Cl)(Cl)(Cl)Cl.[K+].[Br-]>>[CH:1]1([O:6][C:7]2[C:12]3[O:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[C:11]=3[C:10]([CH:21]=[O:23])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(Cl)Cl
Reactant: c1ccc2c(c1)oc1c(OC3CCCC3)cccc12
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Br-]
Agent: [K+]
Product: O=Cc1ccc(OC2CCCC2)c2oc3ccccc3c12
Yield: 31.5 %

Procedure:
Reaction of 4-cyclopentyloxydibenzo[b,d]furan (1.0 g, 3.96 mmol) with dichloromethylmethylether (456 mg, 3.96 mmol) in presence of tin(IV)chloride (1.55 g, 5.95 mmol), gave 350 mg (31.5%) of the product as white solid, IR (KBr)) 2960, 2730, 1686, 1565, 1276, 1099 cm−1. 1H NMR (300 MHz, CDCl3) δ 1.64-1.75 (m, 2H), 1.85-1.98 (m, 2H), 2.03-2.09 (m, 4H), 5.11 (quint, 1H), 7.07 (d, J=8.2 Hz, 1H), 7.38 (t, J=7.9H, 1H), 7.52 (t, J=7.8 Hz, 1H), 7.63 (d, J=8.4 Hz, 1H), 7.77 (d, J=8.2 Hz, 1H), 8.95 (d, J=8.4 Hz, 1H), 10.17 (s, 1H).
Reaction SMILES: [ClH:1].C([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:20][C:21]3[CH:26]=[C:25]([O:27][C:28]([O:30][CH3:31])=[O:29])[C:24]([CH3:32])=[CH:23][C:22]=3[F:33])=[N:15][CH:16]=[N:17]2)=[CH:12][CH:11]=1)C1C=CC=CC=1>[Pd].CO.CN(C=O)C.ClC(Cl)Cl>[ClH:1].[F:33][C:22]1[CH:23]=[C:24]([CH3:32])[C:25]([O:27][C:28]([O:30][CH3:31])=[O:29])=[CH:26][C:21]=1[NH:20][C:14]1[C:13]2[C:18](=[CH:19][C:10]([OH:9])=[CH:11][CH:12]=2)[N:17]=[CH:16][N:15]=1
Reactant: COC(=O)Oc1cc(Nc2ncnc3cc(OCc4ccccc4)ccc23)c(F)cc1C
Agent: [Pd]
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)Oc1cc(Nc2ncnc3cc(O)ccc23)c(F)cc1C
Reaction time: 0.75 h
Yield: 99.7 %

Procedure:
7-Benzyloxy-4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)quinazoline hydrochloride (1.53 g, 3.25 mmol) and 10% palladium-on-charcoal catalyst (1 80 mg) in a mixture of methanol/DMF/trichloromethane (75 ml, 6 ml, 30 ml) was stirred under hydrogen at 1.5 atmospheres for 45 minutes. The catalyst was removed by filtration through diatomaceous earth and the solvent removed from the filtrate by evaporation. The residue was triturated with ether, the resulting solid collected by filtration and dried under vacuum to give 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxyquinazoline hydrochloride (1.23 g, 84%) as an orange solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:19][CH2:18][CH2:17][CH:13]([C:14]([OH:16])=O)[CH2:12]1)=[O:4].Cl.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][NH2:35])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][NH:35][C:14]([CH:13]3[CH2:17][CH2:18][CH2:19][N:11]([C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[C:3]([O:2][CH3:1])=[O:4])[CH2:12]3)=[O:16])=[CH:30][CH:29]=2)=[CH:26][CH:27]=1
Reactant: COC(=O)c1ccccc1N1CCCC(C(=O)O)C1
Reactant: NCc1ccc(-c2ccc(Cl)cc2)cc1
Agent: Cl
Product: COC(=O)c1ccccc1N1CCCC(C(=O)NCc2ccc(-c3ccc(Cl)cc3)cc2)C1
Yield: 86.7 %

Procedure:
Using 1-[2-(methoxycarbonyl)phenyl]nipecotic acid (77.5 mg, 0.294 mmol) and (4′-chlorobiphenyl-4-yl)methylamine hydrochloride (72.2 mg, 0.284 mmol), the same procedure was followed as in Step 3a of Example 3 to give 114 mg (87%) of the desired compound as a colorless amorphous product.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][C:3]=1[CH2:10][CH2:11][C:12]([OH:14])=O.ClS(O)(=O)=O>O>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]2[C:3]=1[CH2:10][CH2:11][C:12]2=[O:14]
Reactant: O=C(O)CCc1cc(F)cc(F)c1Br
Agent: O=S(=O)(O)Cl
Solvent: O
Product: O=C1CCc2c(Br)c(F)cc(F)c21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96.6 %

Procedure:
3-(2-Bromo-3,5-difluorophenyl)propanoic acid (from Step 2, 3.0 g) is stirred with chlorosulfonic acid (10 mL) for 2 hours at ambient temperature. The mixture is then added dropwise to a vigorously stirred mixture of water and ice (200 mL) and further stirred for 15 minutes. Extraction with diethyl ether, subsequent washing of the organic layer with water, NaOH (0.2 M), and brine, drying (Na2SO4) and removal of the solvent under reduced pressure gives the crude product (Yield 2.7 g) that is used in the next step without further purification. LC (METHOD 7): tR=1.16 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O.C([Li])(CC)C.C1CCCCC1.C[O:45][B:46]([O:48]C)F>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]([F:10])([F:11])[F:12])=[CH:6][C:7]=1[B:46]([OH:48])[OH:45]
Reactant: COB(F)OC
Reactant: Fc1ccc(OC(F)(F)F)cc1
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: OB(O)c1cc(OC(F)(F)F)ccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the 4-fluoro(trifluoromethoxy)benzene (2.0 g, 11.1 mmol) in dry THF (30 ml) at −78° C., was added ethylenediaminetetraacetic acid (EDTA, 1.36 g, 11.7 mmol) followed by a 1.4 M solution of sec-butyllithium in cyclohexane (8.33 ml, 11.7 mmol) and the reaction stirred for 2 hours under nitrogen. To this reaction mixture at −78° C., was then added dropwise the preformed dimethoxyfluoroborane mixture. The reaction was stirred at −78° C. for 30 minutes, warmed to room temperature for 30 minutes, and then quenched with water (10 ml). The volume of the reaction mixture was reduced in vacuo, then the residue dissolved in diethyl ether (10 ml) and washed with an aqueous solution of 10% NaOH (50 ml). The aqueous layer was acidified and extracted with ethyl acetate (3×40 ml). The combined ethyl acetate extracts were dried over MgSO4 and concentrated in vacuo to afford the title compound as a single regioisomer (1.51 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[O:11][CH3:12].B.C1COCC1>C1COCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cc(C(=O)O)ccc1Cl
Agent: B
Solvent: C1CCOC1
Product: COc1cc(CO)ccc1Cl
Yield: 99.5 %

Procedure:
To a solution of 4-chloro-3-methoxybenzoic acid (4.88 g, 26.2 mmol) in THF (50 mL) was added borane-THF complex (52 mL 1M solution in THF, 52 mmol) via addition funnel over 10 min. The reaction mixture was refluxed for 2 hr, cooled, extracted with EtOAc, washed with water, 5% Na2CO3 and brine, dried and concentrated in vacuo to give (4-chloro-3-methoxyphenyl)methan-1-ol (4.5 g, 99%). ES-MS (M+H—H2O)+=155, 157 (Cl).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[O:37]CC1C=CC(OC)=C(OC)C=1)[C:5]([NH:7][C:8]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:23][C:9]=1[C:10]([NH:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22])=[O:11])=[O:6].C(O)(C(F)(F)F)=O.CCOC(C)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[OH:37])[C:5]([NH:7][C:8]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:23][C:9]=1[C:10]([NH:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22])=[O:11])=[O:6]
Reactant: COc1ccccc1CCNC(=O)c1cc(Oc2ccccc2)ccc1NC(=O)c1ccc(OCc2ccc(OC)c(OC)c2)c(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccccc1CCNC(=O)c1cc(Oc2ccccc2)ccc1NC(=O)c1ccc(O)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.9 %

Procedure:
A solution of 1E (27 mg, 0.04 mmol) in CH2Cl2 (2 mL) at 0° C. was treated with TFA (100 μL). The reaction was warmed to room temperature and stirred for three hours. The mixture was poured into EtOAc:buffer (1:1, pH 7, 40 mL) and the layers were separated. The organic layer was washed with pH 7 buffer (1×10 mL), dried (Na2SO4), filtered and concentrated to a yellow oil. The crude product was purified by preparative HPLC to afford 1F as a white solid (19 mg, 88%). 1H NMR (Acetone-d6) δ 8.80 (d, 1H, J=7.5 Hz), 8.17 (brs 1H), 8.01 (d, 1H, J=1.8 Hz), 7.81 (d, 1H, J=7.0 Hz), 7.45 (d, 1H, J=1.8 Hz), 7.36 (m, 2H), 7.15 (m, 5H), 6.97 (d, 1H, J=6.6 Hz), 6.89 (d, 1H, J=7.0 Hz), 6.79 (t, 1H, J=7.8 Hz), 3.77 (s, 3H), 3.64 (q, 2H, J=5.28 Hz), 2.93 (t, 2H, J=5.24 Hz). HPLC retention time=3.297 min. (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min gradient, monitored at 220 nm). m/z=516.9 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[O:23]([C:30]1[CH:31]=[C:32]([CH:34]=[CH:35][CH:36]=1)[NH2:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:15]=[CH:16][C:17]([C:20]([NH:33][C:32]2[CH:34]=[CH:35][CH:36]=[C:30]([O:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:31]=2)=[O:21])=[CH:18][CH:19]=1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: Nc1cccc(Oc2ccccc2)c1
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)Nc4cccc(Oc5ccccc5)c4)cc3)c2)o1

Procedure:
2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(3-phenoxyphenyl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and 3-phenoxyaniline using method I. LCMS; retention time 3.85 min, MH+ 462.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([C:16]#[N:17])[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[N:10]=1)=O)[CH3:2].[BrH:19]>CCOCC.C(Cl)Cl.CC(O)=O>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[N:10]=2)[NH:17][C:16]=1[Br:19])=[O:18])[CH3:2]
Reactant: Br
Reactant: CCOC(=O)C(C#N)CC(=O)c1ccnc(N)n1
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)c1cc(-c2ccnc(N)n2)[nH]c1Br
Reaction time: 0.5 h
Yield: 88 %

Procedure:
A solution of 4-(2-amino-pyrimidin-4-yl)-2-cyano-4-oxo-butyric acid ethyl ester (364 mg, 1.47 mmol) in anhydrous Et2O and DCM (1:1 10 mL) was added dropwise to 4.5 mL of 33% HBr in AcOH at 0° C. The mixture was left at 0° C. for 30 min and then at rt until disappearance of the starting material. The solid was filtered, washed with acetone and MeOH, neutralized with 7N NH3 in MeOH to afford 400 mg (88%) of the title compound.
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[Cl:19][C:20]1[N:25]=[CH:24][C:23]([C:26](Cl)=[O:27])=[CH:22][CH:21]=1.C(N(CC)CC)C.O1CCCC1>O>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:26]([C:23]2[CH:24]=[N:25][C:20]([Cl:19])=[CH:21][CH:22]=2)=[O:27])[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccc(Cl)nc2)CC1
Temperature: 25 °C

Procedure:
A mixture of 1-(2-tert-butylphenyl)piperazine dihydrochloride obtained in Reference Example 1 (0.5 g), 6-chloropyridine-3-carbonyl chloride (352 mg), triethylamine (0.835 mL), and tetrahydrofuran (30 mL) was stirred at room temperature for over-night. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by flash column chromatography (NH-silica gel, 0:100 hexane/ethyl acetate) to provide the title compound (635 mg, quant.) as a solid.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]3[N:17]=[N:18][N:19]([CH2:21][CH2:22][NH:23][C:24](OC(C)(C)C)=O)[N:20]=3)[CH2:15][C@@:9]1([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C@H:10]([O:31][CH2:32][C:33]1[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[C:35]([C:43]([F:46])([F:45])[F:44])[CH:34]=1)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:53]N(C)CCO>>[CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]3[N:17]=[N:18][N:19]([CH2:21][CH2:22][N:23]([CH3:24])[CH3:53])[N:20]=3)[CH2:15][C@@:9]1([C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)[C@H:10]([O:31][CH2:32][C:33]1[CH:34]=[C:35]([C:43]([F:44])([F:46])[F:45])[CH:36]=[C:37]([C:39]([F:40])([F:42])[F:41])[CH:38]=1)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)CCO
Reactant: CC(C)(C)OC(=O)NCCn1nnc([C@@H]2C[C@@]3(c4ccccc4)[C@H](OCc4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC[C@@H]2N3Cc2ccccc2)n1
Product: CN(C)CCn1nnc([C@@H]2C[C@@]3(c4ccccc4)[C@H](OCc4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC[C@@H]2N3Cc2ccccc2)n1

Procedure:
Prepared in analogous manner to (1R*,2R*,5S*,6R*)-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-(2-[2-(t-butoxycarbonylamino)ethyl]-2H-tetrazol-5-yl}-1-phenyl-8-azabicyclo[3.2.1]octane (Example 140) using N,N-dimethylethanolamine.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:37])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:14]=1)[N:11]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10](=[O:28])[C:9]([CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[CH:8]2)=[O:4].[NH2:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:21]([N:11]1[C:12]2[C:7](=[C:6]([OH:37])[C:5]([C:3]([NH:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42])=[O:4])=[N:14][C:13]=2[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:8]=[C:9]([CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:10]1=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1nc(-c2cccnc2)c2c(cc(CCc3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1nc(-c2cccnc2)c2c(cc(CCc3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 50.9 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenethyl-8-pyridin-3-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (42 mg, 0.086 mmol), β-alanine (610 mg, 6.8 mmol) and NaOMe solution (10 mL, 5.1 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (10-100% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3, and the resulting precipitate was isolated by filtration to give 24 mg of the title compound as a light yellow solid. MS: (+) m/z 549.50 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[CH2:22])[C:19]([OH:21])=[O:20])=[CH:14][CH:13]=1>>[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([CH:18]([CH2:22][S:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:19]([OH:21])=[O:20])=[CH:16][CH:17]=1
Reactant: C=C(C(=O)O)c1ccc(OC)cc1
Reactant: COc1cccc(S)c1
Product: COc1ccc(C(CSc2cccc(OC)c2)C(=O)O)cc1
Temperature: 125 °C
Reaction time: 21 h

Procedure:
3-Methoxybenzenethiol(2.5 ml, 20.1 mmol) was added to 2-(4-methoxyphenyl)acrylic acid (3 g, 16.8 mmol) and stirred for 21 hours with heating at 125° C. The reaction solution was extracted with diethyl ether, and the ether solution was washed with 0.1N iodine-potassium iodide solution, water and saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The residue was concentrated under reduced pressure to remove the organic solvent to obtain the title compound as a brown oil. The resulting compound was used in the next reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:21]([NH2:23])=[O:22])=[N:4][C:5]([C:14]2[CH:19]=[CH:18][C:17](=[O:20])[NH:16][CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.CI.[CH3:26]COC(C)=O.O>CN(C=O)C.CC([O-])(C)C.[K+]>[NH2:1][C:2]1[C:3]([C:21]([NH2:23])=[O:22])=[N:4][C:5]([C:14]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH3:26])[CH:15]=2)=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:7]=1
Reactant: CCOC(C)=O
Reactant: NC(=O)c1nc(-c2ccc(=O)[nH]c2)c(-c2ccccc2)nc1N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(-c2nc(C(N)=O)c(N)nc2-c2ccccc2)ccc1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Amino-6-(6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazinecarboxamide (61.4 mg) was dissolved in DMF (1 ml) To the solution were added 1M MeI solution in DMF (0.22 ml) and 0.1M t-BuOK solution in DMF (2.2 ml). The mixture was stirred at 20-30° C. for 2 hours. The reaction mixture was portioned EtOAc and water. The organic layer was separated. The aqueous layer was extracted with EtOAc. The combined organic solution was washed with brine and dried over MgSO4. Evaporation of solvent gave oily residue. The above residue was purified by chromatography on silica gel (EtOAc only-EtOAc:MeOH=93:7, v/v) to give 3-amino-6-(1-methyl-6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazinecarboxamide, which was crystallized from EtOAc (20 mg).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:29])[N:4]([C:18]2[CH:23]=[C:22]([C:24](=O)[C:25]#[CH:26])[CH:21]=[CH:20][C:19]=2[CH3:28])[C:5]([CH3:17])=[N:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=1.Cl.[OH:31][C:32]([CH3:37])([CH3:36])[C:33]([NH2:35])=[NH:34].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[C:3](=[O:29])[N:4]([C:18]2[CH:23]=[C:22]([C:24]3[CH:25]=[CH:26][N:35]=[C:33]([C:32]([OH:31])([CH3:37])[CH3:36])[N:34]=3)[CH:21]=[CH:20][C:19]=2[CH3:28])[C:5]([CH3:17])=[N:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=1
Reactant: CC(C)(O)C(=N)N
Reactant: C#CC(=O)c1ccc(C)c(-n2c(C)nc(OCc3cccc(C)n3)c(Br)c2=O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cccc(COc2nc(C)n(-c3cc(-c4ccnc(C(C)(C)O)n4)ccc3C)c(=O)c2Br)n1
Temperature: 75 °C
Yield: 41.9 %

Procedure:
To a solution of 5-bromo-2-methyl-3-(2-methyl-5-propynoyl-phenyl)-6-(6-methyl-pyridin-2-ylmethoxy)-3H-pyrimidin-4-one of Step D (54 mg, 0.12 mmol) in acetonitrile (1 mL) was added 2-hydroxy-2-methylpropionamidine HCl (25 mg, 0.18 mmol) and potassium carbonate (50 mg, 0.36 mmol) and the slurry was heated at 75° C. for eighteen hours. The reaction was returned to ambient temperature and filtered to remove excess salts. The filtrate was concentrated and purified via normal phase chromatography (ethyl acetate/heptane) to provide the title compound as a light yellow solid (27 mg, 42% yield). MS (M, M+2): 536, 538; 1H NMR (400 MHz, chloroform-d) δ ppm, 1.64 (s, 6H), 2.14 (s, 3H), 2.21 (s, 3H), 2.61 (s, 3H), 4.78 (s, 1H), 5.61-5.72 (m, 2H), 7.14 (d, J=7.83 Hz, 1H), 7.43 (d, J=7.44 Hz, 1H), 7.54-7.58 (m, 2H), 7.70 (s, 1H), 7.92 (s, 1H), 8.13 (d, J=7.82 Hz, 1H), 8.77 (d, J=5.09 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].[CH2:10]([O:12][C:13](=[O:17])[C:14]#[C:15][CH3:16])[CH3:11].N12CCCN=C1CCCCC2>O1CCCC1.ClCCl>[CH2:10]([O:12][C:13](=[O:17])[CH:14]=[C:15]([O:9][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[F:1])[CH3:16])[CH3:11]
Reactant: CC#CC(=O)OCC
Reactant: Cc1ccc(F)c(O)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)C=C(C)Oc1cc(C)ccc1F
Temperature: 130 °C
Reaction time: 8 h
Yield: 52.8 %

Procedure:
A mixture of 2-fluoro-5-methyl-phenol (0.97 mL, 8.91 mmol) and ethyl-2-butynoate (2.0 g, 17.8 mmol) in tetrahydrofuran (13.7 mL) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (1.33 mL, 8.91 mmol). The reaction was then heated at 130° C. for 4 h. At this time, the reaction was cooled to 25° C. and was stirred at 25° C. overnight. At this time, the reaction was diluted with dichloromethane (100 mL) and was washed with a 2N aqueous hydrochloric acid solution (1×100 mL), a 0.5N aqueous sodium hydroxide solution (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL). The organics were then dried over sodium sulfate, filtered and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 2% ethyl acetate/hexanes) afforded 3-(2-fluoro-5-methyl-phenoxy)-but-2-enoic acid ethyl ester (1.12 g, 52%) as a clear oil: HR-ES-MS m/z calculated for C13H15O3F [M+H]+ 239.1078, observed 239.1078; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.12 (t, J=7.0 Hz, 3H), 2.30 (s, 3H), 2.43 (s, 3H), 4.00 (q, J=7.0 Hz, 2H), 4.69 (s, 1H), 7.01-7.19 (m, 2H), 7.30 (dd, J=10.7, 8.3 Hz, 1H).