Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH3:12])=[C:8]([CH2:10]Cl)[CH:9]=1)=[O:4].[F:13][CH:14]([F:29])[O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH3:12])=[C:8]([CH2:10][NH:28][C:25]2[CH:26]=[CH:27][C:22]([C:19]3[CH:20]=[CH:21][C:16]([O:15][CH:14]([F:13])[F:29])=[CH:17][CH:18]=3)=[CH:23][CH:24]=2)[CH:9]=1)=[O:4]
Reactant: Nc1ccc(-c2ccc(OC(F)F)cc2)cc1
Reactant: COC(=O)c1cc(CCl)c(C)o1
Solvent: CC#N
Product: COC(=O)c1cc(CNc2ccc(-c3ccc(OC(F)F)cc3)cc2)c(C)o1

Procedure:
Compound (170) was prepared from compounds (159) and (169) by adapting the procedure of Example 38(d). (420 mg). LC/MS System A; Rt=4.00 mins, m/z (ES+)=388 (M+H) and 429 (M+H acetonitrile adduct) for C21H19F2NO3.
Reaction SMILES: Cl.N[OH:3].[OH-].[K+].[CH2:6]([CH:13]([CH:17]=[CH2:18])[C:14](Cl)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CO.C1COCC1>[CH2:6]([CH:13]([CH:17]=[CH2:18])[C:14]([OH:3])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NO
Reactant: C=CC(Cc1ccccc1)C(=O)Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=CC(Cc1ccccc1)C(=O)O

Procedure:
A solution of hydroxylamine hydrochloride (0.455 g, 6.55 mmole) in 25 ml of absolute methyl alcohol and a solution of potassium hydroxide (0.85 g, 12.8 mmole) in 25 ml of absolute methyl alcohol were cooled to 0° C. and mixed together. A solution of 2-benzylbut-3-eneoic acid chloride, prepared as described in A above, in 10 ml of dry THF was added at 0° C. to the mixed solutions with stirring. The cooling bath was removed and the mixture was stirred at room temperature for 20 minutes. The pH of the mixture was adjusted to 4.0 with 5% hydrochloric acid and the mixture was evaporated to remove methyl alcohol. The aqueous concentrate was saturated with sodium chloride and extracted four times with 75 ml portions of ethyl acetate. The extracts were combined, washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness. The 2-benzylbut-3-eneoic acid N-hydroxamide obtained as a pale brownish yellow oil was used without further purification in the following step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[CH3:10][S:11](Cl)(=[O:13])=[O:12]>N1C=CC=CC=1>[CH3:10][S:11]([O:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[Cl:1])(=[O:13])=[O:12]
Reactant: CS(=O)(=O)Cl
Reactant: Oc1ccc(F)cc1Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Oc1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
To a mixture of 2-chloro-4-fluorophenol (14.7 g) and methylsulfonyl chloride (11.5 g), under ice-cooling, pyridine (30 g) was added dropwise. The resulting mixture was stirred at room temperature for 30 minutes to complete the methylsulfonylation, after which the pyridine was distilled off under reduced pressure. Toluene and water were added to the residue and the mixture was washed with a dilute aqueous hydrochloric acid, then with water. The toluene layer as separated was dried over anhydrous sodium sulfate and then the toluene was distilled off to afford the titled compound (20.8 g) as a pale yellow oil. After purification by silica gel chromatography, the oil was made colorless with a refractive index nD23 =1.5117.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3[CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[C:15](=[O:17])[O:16][C:5]=2[CH:4]=1.C(N(CC)CC)C.Cl.Cl[CH2:27][CH2:28][N:29]1[CH2:36][CH:35]2[CH2:37][CH:31]([CH2:32][CH2:33][CH2:34]2)[CH2:30]1>>[CH:35]12[CH2:37][CH:31]([CH2:32][CH2:33][CH2:34]1)[CH2:30][N:29]([CH2:28][CH2:27][N:12]1[CH2:13][CH2:14][C:9]3[C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[O:16][C:15](=[O:17])[C:10]=3[CH2:11]1)[CH2:36]2
Reactant: ClCCN1CC2CCCC(C2)C1
Reactant: COc1ccc2c3c(c(=O)oc2c1)CNCC3
Agent: Cl
Solvent: CCN(CC)CC
Product: COc1ccc2c3c(c(=O)oc2c1)CN(CCN1CC2CCCC(C2)C1)CC3
Yield: 48.3 %

Procedure:
Prepared by the method described for Example 13 from 1,2,3,4-tetrahydro-8-methoxy-5H-[1]benzopyrano[3,4-c]pyridin-5-one (3.0 g, 0.013 moles), triethylamine (7.2 ml, 0.052 moles), and 3-(2-chloroethyl)-3-azabicyclo-[3.3.1]nonane hydrochloride (3.25 g, 0.015 moles). Recrystallization from ethanol gave the product (2.4 g), mp 102°-103° C.
Reaction SMILES: [NH2:1][C:2]([NH2:19])=[N:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[C:8]([C:15]#[CH:16])=[CH:7][C:6]=1[CH3:17].CC1C=C(Br)C(S(C)(=O)=O)=CC=1C(OC)=O.CC1C=C(C#C)C(S(C)(=O)=O)=CC=1C(OC)=O.NC(N)=N.[H][H]>CN(C=O)C.[Pd].C([O-])([O-])=O.[Ca+2]>[NH2:19][C:2]([NH2:1])=[N:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:12])=[O:13])[C:8]([CH:15]=[CH2:16])=[CH:7][C:6]=1[CH3:17]
Reactant: C#Cc1cc(C)c(C(=O)N=C(N)N)cc1S(C)(=O)=O
Reactant: [H][H]
Agent: [Pd]
Agent: C#Cc1cc(C)c(C(=O)OC)cc1S(C)(=O)=O
Agent: COC(=O)c1cc(S(C)(=O)=O)c(Br)cc1C
Solvent: CN(C)C=O
Product: C=Cc1cc(C)c(C(=O)N=C(N)N)cc1S(C)(=O)=O

Procedure:
6.0 g of N-diaminomethylene-2-methyl-4-ethynyl-5-methylsulfonylbenzamide, m.p. 223°-226° [obtainable by reaction of methyl 2-methyl-4-bromo-5-methylsulfonyl-benzoate with Li acetylide to give methyl 2-methyl-4-ethynyl-5-methylsulfonyl-benzoate and subsequent reaction with guanidine] are dissolved in 300 ml of DMF and hydrogenated in the presence of 450 mg of Pd-CaCO3 (Lindlar catalyst) for 15 minutes in a stream of hydrogen (p=1 bar). Customary working up gives N-diaminomethylene-2-methyl-4-ethenyl-5-methylsulfonyl-benzamide).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1.[NH3:15].C(O)C.[BH4-].[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:15])[CH3:13])[C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: N
Reactant: CC(=O)c1cc(Cl)cc2c1OCCO2
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CCO
Product: CC(N)c1cc(Cl)cc2c1OCCO2
Temperature: 0 °C
Yield: 61 %

Procedure:
1-(6-Chloro-2,3-dihydrobenzo[b][1,4]dioxin-8-yl)ethanone (248 mg, 1.17 mmol), titanium(IV) isopropoxide (0.84 mL, 2.33 mmol) and 2 M solution of ammonia in ethanol (2.90 mL, 5.83 mmol) were stirred at room temperature for 6 h. The reaction was cooled to 0° C. and sodium borohydride was added portionwise during 10 min. (0.66 mg, 1.76 mmol); the resultant mixture was stirred at rt for an additional 3 h. The reaction was quenched by pouring it into ammonium hydroxide (2 M, 20 mL), the precipitate that formed was filtered off and washed with ethyl acetate (10 mL×3). The organic layer was separated and the remaining aqueous layer was extracted with ethyl acetate (10 mL×2). The combined organic extracts were washed with 1 M HCl (10 mL). The acidic aqueous extracts were washed with ethyl acetate (25 mL), then treated with aqueous sodium hydroxide (2 M) to pH 10-12, and extracted with ethyl acetate (25 mL×3). The combined organic extracts were washed with brine (10 mL), dried (Na2SO4), and concentrated in vacuo to afford the desired product (130 mg, 61% yield). 1H NMR (400 MHz, CDCl3): δ 6.87 (d, 1H), 6.75 (d, 1H), 4.24 (m, 5H), 1.35 (d, 3H).
Reaction SMILES: [C:1]([NH:5][C:6]([NH:8][C:9]1[C:10]([CH3:28])=[CH:11][C:12]2[O:16][CH2:15][C@H:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=3)[C:13]=2[C:26]=1[CH3:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:29](OCC)(=[O:31])C.CCCCCC>C(Cl)(Cl)Cl>[C:1]([NH:5][C:6]([NH:8][C:9]1[C:10]([CH3:28])=[C:11]([CH:29]=[O:31])[C:12]2[O:16][CH2:15][C@H:14]([C:17]3[CH:18]=[CH:19][C:20]([CH:23]([CH3:24])[CH3:25])=[CH:21][CH:22]=3)[C:13]=2[C:26]=1[CH3:27])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(C)=O
Reactant: Cc1cc2c(c(C)c1NC(=O)NC(C)(C)C)[C@@H](c1ccc(C(C)C)cc1)CO2
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: Cc1c(C=O)c2c(c(C)c1NC(=O)NC(C)(C)C)[C@@H](c1ccc(C(C)C)cc1)CO2
Yield: 78 %

Procedure:
Using (+)-N-(tert-butyl)-N′-((3R)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)urea, the title compound was synthesized in the same manner as in Example 20. Yield: 78%. Melting point: 209-210° C. (ethyl acetate-hexane). [α]D20=−31.2° (c=0.48, chloroform).
Reaction SMILES: [C:1](=[O:18])(SCC)[O:2][O:3][CH:4]([O:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]([CH3:7])[CH3:6].S(Cl)([Cl:22])(=O)=O>C(Cl)Cl>[Cl:22][C:1]([O:2][O:3][CH:4]([O:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]([CH3:7])[CH3:6])=[O:18]
Reactant: CCSC(=O)OOC(OC(=O)C(C)(C)C)C(C)C
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CC(C)C(OOC(=O)Cl)OC(=O)C(C)(C)C

Procedure:
A solution of (45) (4.76 mmol) in CH2Cl2 at 0° C. was treated with sulfuryl chloride (1.1 mmol) under N2 for 10 min, then the reaction mixture was concentrated to dryness in vacuo to afford the crude chloroformate (46) in quantitative yield, which used in the next step without further purification. 1H NMR (CDCl3, 400 MHz): δ 1.00 (d, 6H), 1.20 (d, 9H), 2.143 (m, 1H), 6.54 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[O:5][C:6]1[N:11]=[C:10]2[S:12][C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])=[N:14][C:9]2=[CH:8][CH:7]=1.[F:25][C:26]([F:38])([F:37])[C:27]1[CH:28]=[C:29]([CH2:33][C:34](O)=[O:35])[CH:30]=[CH:31][CH:32]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C(=O)C.N1C=CC=CC=1.C(OCC)(=O)C>[F:24][C:23]1[CH:22]=[CH:21][C:4]([O:5][C:6]2[N:11]=[C:10]3[S:12][C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])=[N:14][C:9]3=[CH:8][CH:7]=2)=[CH:3][C:2]=1[NH:1][C:34](=[O:35])[CH2:33][C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([C:26]([F:37])([F:25])[F:38])[CH:28]=1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: O=C(Cc1cccc(C(F)(F)F)c1)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Temperature: 90 °C
Reaction time: 2 h
Yield: 33.4 %

Procedure:
N-[5-(3-Amino-4-fluorophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (150 mg, 0.44 mmol) produced in Example 16(vi) was dissolved in N,N-dimethylacetamide (3.0 mL)/pyridine (9.0 mL), [3-(trifluoromethyl)phenyl]acetic acid (110 mg, 0.52 mmol) and 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (330 mg, 0.65 mmol) were added, and the mixture was stirred at 90° C. for 2 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (27 mL), and washed successively with water (27 mL) and saturated brine (27 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/hexane=50/50→100/0), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/heptane to give the title compound (78 mg, 34%) as a colorless powder.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C(O[C:13](=O)[C:14]1[CH:19]=CC(Cl)=N[CH:15]=1)C.C([Mg]Cl)C(C)C>>[CH2:13]([C:5]1[CH:6]=[CH:7][C:2]([C:1]([OH:9])=[O:8])=[CH:3][N:4]=1)[CH:14]([CH3:19])[CH3:15]
Reactant: O=C(O)c1cccnc1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Agent: CC(C)C[Mg]Cl
Product: CC(C)Cc1ccc(C(=O)O)cn1

Procedure:
6-Isobutyl-nicotinic acid is prepared in analogy to Nicotinic acid 2 from commercially available 6-chloronicotinic acid ethyl ester and isobutylmagnesium chloride; LC-MS: tR=0.52 min, [M+1]+=180.30.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C:4](=[O:7])[NH:3]1.CCN(C(C)C)C(C)C.[C:17](Cl)([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>C(Cl)Cl>[O:7]=[C:4]1[CH2:5][CH2:6][N:2]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[NH:3]1
Reactant: O=C1CCNN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCN(C(=O)OCc2ccccc2)N1
Reaction time: 3 h

Procedure:
To a suspension of pyrazolidin-3-one hydrogen chloride (5.00 g, 40.8 mmol) in DCM (120 mL) at 0° C. was added DIEA (2.5 eq), followed by CbzCl (1.15 eq). The resulting clear solution was warmed to it and stirred 3 h. The reaction mixture was washed with brine. The aqueous layer was separated and back-extracted with DCM (×2). The combined organic layers were dried over Na2SO4, and concentrated. The crude product was purified by a SiO2 column (0-100% EtOAc/Hexanes, Rf=0.35 in 100% EtOAc) to afford the desired product as a white solid (5.31 g).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:18][C:19]3[CH2:23][CH2:22][CH2:21][C:20]=3[C:24]3[CH:25]=[C:26]([CH:34]=[CH:35][CH:36]=3)[O:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.[Pd]>[C:1]1([C:7]2[N:8]=[C:9]([CH2:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH:20]3[C:24]3[CH:25]=[C:26]([CH:34]=[CH:35][CH:36]=3)[O:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)COc1cccc(C2=C(Cc3nc(-c4ccccc4)c(-c4ccccc4)o3)CCC2)c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)COc1cccc(C2CCCC2Cc2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reaction time: 6 h
Yield: 79.7 %

Procedure:
To a solution of ethyl [3-[2-[(4,5-diphenyloxazol-2-yl)methyl]-1-cyclopenten-1-yl]phenoxy]acetate (0.5 g) in ethanol (20 ml) was added 10% palladium on carbon (100 mg). After being stirred for 6 hours under hydrogen atmosphere, the reaction mixture was filtered. The solvent was evaporated in vacuo to give ethyl [3-[2-[(4,5-diphenyloxazol-2-yl)methyl]cyclopentyl]phenoxy]acetate (400 mg).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]([OH:9])=O.S(Cl)(Cl)=O.CN(C=O)C.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](/[CH:28]=[CH:29]/[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[NH2:36])=[N:20]1.C(N(CC)CC)C>C1COCC1.ClCCl>[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](/[CH:28]=[CH:29]/[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[NH:36][C:7]([C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=2)=[O:9])=[N:20]1
Reactant: Nc1ccccc1/C=C/c1n[nH]c2ccccc12
Reactant: Cn1ccnc1C(=O)O
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cn1ccnc1C(=O)Nc1ccccc1/C=C/c1n[nH]c2ccccc12
Yield: 33.9 %

Procedure:
In a similar manner to Example 29, 1-methyl-1H-imidazole-2-carboxylic acid (59 mg, 0.47 mmol) was treated with thionyl chloride (53 μL, 0.72 mmol), DMF (5.0 μL, 0.085 mmol) and dichloromethane (2.0 mL), followed by reacting with Compound 2 (0.10 g, 0.43 mmol), triethylamine (60 μL, 1.1 mmol) and THF (2.0 mL) to obtain Compound 352 (50 mg, 34%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27]C)[N:16]=2)[CH:12]=[CH:11][CH:10]=1.Cl.N1C=CC=CC=1.C(Cl)(Cl)Cl>O>[OH:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:17]1[N:16]=[C:15]([C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[OH:2])[N:14]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: COc1ccccc1-c1cccc(-c2cccc(-c3ccccc3OC)n2)n1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Oc1ccccc1-c1cccc(-c2cccc(-c3ccccc3O)n2)n1
Temperature: 160 °C
Yield: 72.2 %

Procedure:
A mixture of a 6,6′-bis(2-methoxyphenyl)-2,2′-bipyridyl ligand (0.3 g) and pyridine hydrochloride (10 g) was heated for 4 hours at 160° C. under a nitrogen atmosphere. After cooling the reaction solution to a room temperature, chloroform (20 ml) and water (20 ml) were added to the reaction solution for separation. Thereafter, the organic layer was concentrated. Purification by silica gel chromatography (chloroform as a developing solvent) was carried out, to obtain 0.2 g of 6,6′-bis(2-hydroxyphenyl)-2,2′-bipyridyl.
Reaction SMILES: [Br:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]3[C:12]([CH2:15][CH2:16][C:17](O)=[O:18])=[N:13][N:14]=[C:6]3[N:5]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:4]=2[N:3]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[Br:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]3[C:12]([CH2:15][CH2:16][C:17]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:18])=[N:13][N:14]=[C:6]3[N:5]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:4]=2[N:3]=1
Reactant: C1COCCN1
Reactant: CCCCCn1c2nc(Br)[nH]c2c(=O)n2c(CCC(=O)O)nnc12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCn1c2nc(Br)[nH]c2c(=O)n2c(CCC(=O)N3CCOCC3)nnc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.3 %

Procedure:
The mixture of 3-(7-bromo-5-oxo-9-pentyl-6,9-dihydro-5H[1,2,4]triazolo[4,3-a]purin-3-yl]propanoic acid (50 mg, 0.126 mmol), morpholine (21.0 mg, 0.252 mmol), triethylamine (25.5 mg, 0.252 mmol) and BOP (61.5 mg, 0.139 mmol) in CH2Cl2 (10 ml) was stirred at room temperature for 2 hours. After evaporation of solvent, the residue was purified by preparative LC-MS to afford the desired product (37.2 mg, 60%) as white solid. LCMS calculated for C18H25BrN7O3 (M+H): 466.1. Found: 466.1.
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=2)[CH2:2][CH3:3].Cl[CH2:20][C:21]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[O:23][N:22]=1>>[F:32][C:29]1[CH:28]=[CH:27][C:26]([C:24]2[O:23][N:22]=[C:21]([CH2:20][N:5]3[C:6]4[C:11](=[C:10]([C:13]([F:15])([F:16])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=4)[CH:12]=[C:4]3[CH2:1][CH2:2][CH3:3])[CH:25]=2)=[CH:31][CH:30]=1
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: Fc1ccc(-c2cc(CCl)no2)cc1
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1cc(-c2ccc(F)cc2)on1

Procedure:
Synthesized in a manner similar to Example 23 using 2-propyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile and 3-(chloromethyl)-5-(4-fluorophenyl)isoxazole: MS (ES) m/z 428 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][N:8]2[CH2:21][C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[CH:4][C:3]=1[O:34][CH3:35].[CH2:36](I)[CH3:37]>>[CH2:36]([O:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][N:8]2[CH2:21][C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[CH:4][C:3]=1[O:34][CH3:35])[CH3:37]
Reactant: COc1cc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)ccc1O
Reactant: CCI
Product: CCOc1ccc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)cc1OC

Procedure:
prepared by reaction of 2-[1-(4-hydroxy-3-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide with ethyl iodide
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[C:12]2[CH:11]=[CH:10][S:9][C:8]=2[CH2:7][CH2:6][CH2:5]1.Cl.[C:14]1([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>CN(C=O)C>[C:14]1([CH:20]2[CH2:21][CH2:22][N:23]([CH2:2][CH2:3][CH:4]3[C:12]4[CH:11]=[CH:10][S:9][C:8]=4[CH2:7][CH2:6][CH2:5]3)[CH2:24][CH2:25]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: ClCCC1CCCc2sccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: c1ccc(C2CCN(CCC3CCCc4sccc43)CC2)cc1
Yield: 59.7 %

Procedure:
A mixture of 4-(2-chloroethyl)-4,5,6,7-tetrahydrobenzo[b]thiophene (0.25 g, 1.24 mmol), 4-phenylpiperidine hydrochloride (0.25 g, 1.25 mmol), K2CO3 (0.40 g, 2.89 mmol) and a catalytic amount of NaI in DMF (5 mL) is heated to 110° C. overnight. The solvent is removed at reduced pressure, diethyl ether is added to the residue and washed with water. The organic phase is dried and evaporated at reduced pressure and the resulting crude is purified by column chromatography, giving 4-phenyl-1-(2-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)ethyl)piperidine (0.24 g, 0.74 mmol, 59%, oil). 1H NMR (300 MHz, CDCl3): δ 1.54 (m, 1H), 1.70-2.18 (m, 11H), 2.51 (m, 3H), 2.76 (m, 3H), 3.12 (m, 2H), 6.88 (d, J=5.2 Hz, 1H), 7.04 (d, J=5.2 Hz, 1H), 7.18-7.32 (m, 5H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:14][O:13][C:12]2[CH:11]=[CH:10][C:9]3[CH2:8][NH:7][C:6](=[O:15])[C:5]=3[C:4]=2[CH2:3]1.[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH2:26][CH2:27][CH2:28][CH:29]=O.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH2:26][CH2:27][CH2:28][CH2:29][NH:1][CH:2]1[CH2:14][O:13][C:12]2[CH:11]=[CH:10][C:9]3[CH2:8][NH:7][C:6](=[O:15])[C:5]=3[C:4]=2[CH2:3]1
Reactant: NC1COc2ccc3c(c2C1)C(=O)NC3
Reactant: O=CCCCc1c[nH]c2ccc(F)cc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C1NCc2ccc3c(c21)CC(NCCCCc1c[nH]c2ccc(F)cc12)CO3
Reaction time: 1.5 h
Yield: 78 %

Procedure:
To a mixture of (1) (60 mg, 0.294 mmol), 4-(5-fluoro-1H-indol-3-yl)butanal (21), 63 mg, 0.294 mmol) in acetic acid (37 μl, 0.62 mmol) and methanol (4 ml) was added NaBH3CN (37 mg, 0.588 mmol) in portions. Resulting mixture was stirred for 1.5 hr. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 and washed with 1 N NaOH and saturated NaCl. The organic solution was dried over Na2SO4 and concentrated in vacuo. The compound was purified on silica gel eluting with 60% EtOAc/Hexane to give (25) as a solid (90 mg, 78%). MS (ES) m/z 394.2;
Reaction SMILES: C(OC(=O)[N:10]([C:14]1[N:43]=[C:17]2[N:18]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=3)[C:19]([CH3:32])=[C:20]([C:30]#[N:31])[C@@H:21]([C:22]3[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=3)[N:16]2[N:15]=1)[CH2:11][C:12]#[N:13])C1C=CC=CC=1>CO.[Pd]>[C:12]([CH2:11][NH:10][C:14]1[N:43]=[C:17]2[N:18]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:41])([F:40])[F:42])[CH:34]=3)[C:19]([CH3:32])=[C:20]([C:30]#[N:31])[C@@H:21]([C:22]3[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=3)[N:16]2[N:15]=1)#[N:13]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N(CC#N)C(=O)OCc3ccccc3)nc2N1c1cccc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NCC#N)nc2N1c1cccc(C(F)(F)F)c1

Procedure:
Under an atmosphere of argon protective gas, benzyl{(7R)-6-cyano-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}(cyanomethyl)-carbamate (10.0 mg, 17 μmol) was dissolved in degassed methanol (3 ml). After addition of palladium on activated carbon (10%; 2 mg), the mixture was hydrogenated under a hydrogen atmosphere (˜1 atm) at RT for 0.5 h. The reaction mixture was then filtered, the filtrate was concentrated under reduced pressure and the residue was purified by preparative HPLC (Kromasil C18 column, 50×20 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (7.4 mg, 96% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:20][CH2:19][C:13]3[N:14]=[CH:15][N:16]=[C:17](Cl)[C:12]=3[CH2:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[NH2:21][C@@H:22]([C:25]1[CH:26]=[N:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=1)[CH2:23][OH:24].C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:20][CH2:19][C:13]3[N:14]=[CH:15][N:16]=[C:17]([NH:21][C@@H:22]([C:25]4[CH:26]=[N:27][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:29][CH:30]=4)[CH2:23][OH:24])[C:12]=3[CH2:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N[C@H](CO)c1ccc(C(F)(F)F)nc1
Reactant: N#Cc1cc(Cl)ccc1N1CCc2ncnc(Cl)c2C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: N#Cc1cc(Cl)ccc1N1CCc2ncnc(N[C@H](CO)c3ccc(C(F)(F)F)nc3)c2C1
Yield: 18.9 %

Procedure:
A reaction mixture of 5-chloro-2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzonitrile (150 mg, 0.49 mmol) and (S)-2-amino-2-(6-(trifluoromethyl)pyridin-3-yl)ethanol (150 mg, 0.74 mmol) (prepared similarly according to the method for Intermediate 10) in acetonitrile (3 mL) and N,N-diisopropylethylamine (170 μL, 0.98 mmol) was subjected to microwave irradiation at 180° C. for 4 h. The reaction mixture was concentrated and the residue was purified by silica gel column (100% EtOAc and then 0-20% MeOH/CH2Cl2) followed by semi-preparative HPLC (100×20.2 mm, C18 column; 30-70% acetonitrile-water [10 mM Et2NH]) to yield a light yellow foam (44 mg).