Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:16]2[C@@H:15]3[CH2:17][C@@H:14]3[CH2:13][C:12]=2[C:11]([C:18]([OH:20])=O)=[N:10]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[NH2:63][C:64]1[C:69]([OH:70])=[CH:68][CH:67]=[CH:66][N:65]=1>CN(C=O)C>[OH:70][C:69]1[C:64]([NH:63][C:18]([C:11]2[C:12]3[CH2:13][C@H:14]4[CH2:17][C@H:15]4[C:16]=3[N:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])[N:10]=2)=[O:20])=[N:65][CH:66]=[CH:67][CH:68]=1
Reactant: Nc1ncccc1O
Reactant: O=C(O)c1nn(-c2ccc(F)cc2F)c2c1C[C@H]1C[C@@H]21
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: O=C(Nc1ncccc1O)c1nn(-c2ccc(F)cc2F)c2c1C[C@H]1C[C@@H]21
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 30 %

Procedure:
Intermediate 1 (see Example 1.1, 50 mg, 0.181 mmol) was dissolved in DMF (1 mL). PyBOP (104 mg, 0.199 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.098 mL, 0.561 mmol) were added. The reaction mixture was stirred at room temperature for about 3 min. 2-aminopyridin-3-ol (19.93 mg, 0.181 mmol) was then added to the mixture to give an amber solution which was stirred overnight at room temperature. The mixture was purified by HPLC to provide the title compound (20 mg). LCMS m/z=369.2 [M+H]+; 1H NMR: (400 MHz, CD3CN) δ ppm 0.53 (td, J=4.8 and 3.5 Hz, 1H), 1.23 (td, J=7.9 and 4.8 Hz, 1H), 2.21-2.27 (m, 1H), 2.33-2.40 (m, 1H), 2.93 (d, J=16.5 Hz, 1H), 3.05 (dd, J=16.6 and 6.3 Hz, 1H), 7.16-7.23 (m, 1H), 7.23-7.32 (m, 2H), 7.73-7.83 (m, 3H), 9.80 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([CH:13]=[CH:14][C:15]([OH:17])=[O:16])=[CH:8]2.S(=O)(=O)(O)O.[CH2:23](O)[CH3:24]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([CH:13]=[CH:14][C:15]([O:17][CH2:23][CH3:24])=[O:16])=[CH:8]2
Reactant: CCO
Reactant: COc1cccc2cc(C=CC(=O)O)ccc12
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C=Cc1ccc2c(OC)cccc2c1

Procedure:
β-(5-methoxynaphth-2-yl)propenoic acid (0.075 moles) is allowed to reflux with 8-10 pieces of Orierite in absolute ethanol (20 ml) containing concentrated sulfuric acid (5 ml) for 21 hours. The cooled reaction mixture is diluted with chloroform and filtered hot. The filtrate is washed 3 times with water, once with 10% sodium bicarbonate and twice more with water. After drying over sodium sulfate, the solvent is removed to give ethyl β-(5-methoxynaphth-2-yl)propenoate.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][O:6][C:7]1[CH:20]=[C:19]2[C:10]([CH2:11][CH2:12][C:13]3[S:17][C:16]([SH:18])=[N:15][C:14]=32)=[CH:9][CH:8]=1)C.Br[CH:23]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:24]1([CH:23]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[S:18][C:16]2[S:17][C:13]3[CH2:12][CH2:11][C:10]4[C:19](=[CH:20][C:7]([O:6][CH2:5][C:4]([OH:3])=[O:21])=[CH:8][CH:9]=4)[C:14]=3[N:15]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)COc1ccc2c(c1)-c1nc(S)sc1CC2
Reactant: BrC(c1ccccc1)c1ccccc1
Product: O=C(O)COc1ccc2c(c1)-c1nc(SC(c3ccccc3)c3ccccc3)sc1CC2
Yield: 90 %

Procedure:
Using ethyl[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-8-yl)oxy]acetate and bromodiphenylmethane, the procedure of Example 1 was otherwise repeated to synthesize the title compound. Yield 90%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([C:28](O)=[O:29])=[CH:24][CH:23]=3)[CH:19]=[CH:20][CH:21]=1)[C:10]([CH3:32])([CH3:31])[CH2:9]2)=[O:5])[CH3:2].C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[C:73]([NH2:77])([CH3:76])([CH3:75])[CH3:74]>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[C:18]([C:22]3[CH:23]=[CH:24][C:25]([C:28](=[O:29])[NH:77][C:73]([CH3:76])([CH3:75])[CH3:74])=[CH:26][CH:27]=3)[CH:19]=[CH:20][CH:21]=1)[C:10]([CH3:31])([CH3:32])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CC(C)(C)N
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(-c3ccc(C(=O)O)cc3)c1)N2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(-c3ccc(C(=O)NC(C)(C)C)cc3)c1)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a stirred solution of 2-(4′-carboxy-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (860 mg, 2 mmol), 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (HATU) (1.2 g, 3 mmol) and triethyl amine (0.86 mL, 6 mmol) in dichloromethane was added tert-butylamine (0.86 mL, 8 mmol) at room temperature and stirred at room temperature for overnight. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(4′-tert-butylcarbamoyl-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (968 mg, quant.) as a light yellow solid which was used for next step without further purification: LC/MS m/e calcd for C31H36N2O3 (M+H)+: 485.62, observed: 485.2.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]1([CH:15]2[CH2:20][C:19](=O)[O:18][C:16]2=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1C=CC=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[C:19](=[O:18])[CH2:20][CH:15]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:16]2=[O:17])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: O=C1CC(c2ccccc2)C(=O)O1
Solvent: c1ccccc1
Product: O=C1CC(c2ccccc2)C(=O)N1c1ccc(Br)cc1
Temperature: 25 °C
Yield: 83 %

Procedure:
A solution of 4-bromoaniline (5.48 g, 0.0318 mol) and phenylsuccinic anhydride (5.89 g, 0.0334 mol) in anhydrous benzene (80 mL) was heated at reflux for one and a half hours. The mixture was cooled to ambient temperature and concentrated under reduced pressure. To the residue, acetyl chloride (60 mL) was added and the solution was heated at reflux for one and a half hours. The reaction mixture was cooled to ambient temperature and the precipitate collected by filtration, washed with diethyl ether and dried to yield 1-(4-bromophenyl)-3-phenyl-2,5-pyrrolidinedione (8.7 g, 0.0264 mol) as an off-white solid.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)[CH2:8]2.[C:27]([C:29]1([C:32](O)=[O:33])[CH2:31][CH2:30]1)#[N:28]>>[CH:3]12[CH2:9][CH:7]3[CH2:6][CH:5]([CH2:10][CH:1]([CH2:8]3)[CH:2]1[CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([NH:24][C:32]([C:29]3([C:27]#[N:28])[CH2:31][CH2:30]3)=[O:33])=[CH:25][CH:26]=1)[CH2:4]2
Reactant: Nc1ccc(CCCCCCCOCC2C3CC4CC(C3)CC2C4)cc1
Reactant: N#CC1(C(=O)O)CC1
Product: N#CC1(C(=O)Nc2ccc(CCCCCCCOCC3C4CC5CC(C4)CC3C5)cc2)CC1
Yield: 96.2 %

Procedure:
General procedure E was used to convert 1.30 mmol of 13d and 1.95 mmol of 1-cyanocyclopropanecarboxylic acid to 1.25 mmol (96%) of the title compound.
Reaction SMILES: [C:1]([C:4]([C@@:6]([C:21](=[O:23])[CH3:22])([C@@:8]([C:18](=[O:20])[CH3:19])([C@:10]([C:15](=[O:17])[CH3:16])([C@H:12]([CH3:14])[OH:13])[OH:11])[OH:9])[OH:7])=[O:5])(=[O:3])[CH3:2].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1>ClCCl>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C@@:15]2([CH3:16])[O:17][C@@:4]([C:1](=[O:3])[CH3:2])([OH:5])[C@:6]([C:21](=[O:23])[CH3:22])([OH:7])[C@:8]([C:18](=[O:20])[CH3:19])([OH:9])[C@@:10]2([C:12](=[O:13])[CH3:14])[OH:11])=[CH:28][CH:27]=1
Reactant: CC(=O)C(=O)[C@@](O)(C(C)=O)[C@@](O)(C(C)=O)[C@](O)(C(C)=O)[C@H](C)O
Reactant: COc1ccc(O)cc1
Solvent: ClCCl
Product: COc1ccc([C@@]2(C)O[C@](O)(C(C)=O)[C@@](O)(C(C)=O)[C@@](O)(C(C)=O)[C@]2(O)C(C)=O)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
1,2,3,4-Tetraacetyl-L-rhamnose (19.2 g, 57.8 mmol) and p-methoxyphenol (MPOH) (12.2 g, 98.3 mmol) were dissolved in 150 mL of dichloromethane and cooled to 0° C. BF3 OEt2 (23.0 g, 20.5 mL, 162.0 mmol) was added and the mixture stirred overnight while warming to room temperature. The reaction mixture was quenched by addition of saturated NaHCO3 solution, washed 2 times with water, dried over Na2SO4, concentrated and the residue was purified by column chromatography (3:1 hexane/EtOAc) yielding 18.3 g (80%) of 4-methoxyphenyl 1,2,3,4-tetraacetyl-α-L-rhamnose. 4-Methoxyphenyl 1,2,3,4-tetraacetyl-α-L-rhamnose (18.0 g, 45.4 mmol) was dissolved in 300 mL of methanol and 9 mL of 0.5 M NaOMe solution were added. The mixture was stirred for 12 h, the solvent was removed in vacuo. Column chromatography (4:1 dichloromethane/methanol) afforded 2.63 g (96%) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[OH:13].[S:14]([O-:18])([O-])(=O)=[O:15]>N1C=CC=CC=1>[F:10][C:9]([F:12])([F:11])[S:14]([O:13][C:3]1[CH:4]=[CH:5][C:6]([O:8][C:9]([F:11])([F:12])[F:10])=[CH:7][C:2]=1[Br:1])(=[O:18])=[O:15]
Reactant: O=S(=O)([O-])[O-]
Reactant: Oc1ccc(OC(F)(F)F)cc1Br
Solvent: c1ccncc1
Product: O=S(=O)(Oc1ccc(OC(F)(F)F)cc1Br)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a cooled (0° C.) solution of 2-bromo-4-(trifluoromethoxy)phenol (Description 11, 10 g, 40 mmol) in pyridine (20 ml), was added trifluooromethanesulphonic anhydride (7.2 ml, 44 mmol), and the reaction was stirred at ambient temperature for 2 h. The reaction was diluted with saturated cooper (II) sulphate (80 ml) and extracted into ethyl acetate (3×60 ml). The combined organic fractions were washed with water (80 ml), brine (80 ml), dried (MgSO4) and evaporated in vacuo. Purification on silica, eluting with hexane gave the title compound as a clear oil (13.1 g, 85%). 1H NMR (250 MHz, CDCl3) δ7.28 (1H, m), 7.40 (1H, d, J 9.1 Hz), and 7.58 (1H, d, J 2.8 Hz).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=O)=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH2:33]([C:35](=[CH:40][CH3:41])[CH:36]=[CH:37][CH2:38][NH2:39])[CH3:34]>CN(C)C=O.CN(C)C1C=CN=CC=1.C(=O)([O-])O.[Na+]>[CH2:40]([C:35](=[CH:33][CH3:34])[CH:36]=[CH:37][CH2:38][NH:39][C:8]([C:5]1[CH:6]=[N:7][C:2]([NH2:1])=[CH:3][CH:4]=1)=[O:10])[CH3:41]
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: CC=C(C=CCN)CC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CC=C(C=CCNC(=O)c1ccc(N)nc1)CC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 75.7 %

Procedure:
A mixture of 6-aminopyridine-3-carboxylic acid (4.24 g), N-hydroxybenzotriazole (5.13 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (6.44 g) in N,N-dimethylformamide (100 ml) was stirred at 0° C. for 10 minutes. A solution of 4-ethyl-2,4-hexadien-1-ylamine (4.24 g) in N,N-dimethylformamide (50 ml) was added dropwise to the mixture over a period of 10 minutes and 4-dimethylaminopyridine (4.0 g) was added to the mixture. The mixture was stirred at 0° C. for 2 hours and then at room temperature overnight. The reaction mixture was diluted with aqueous sodium hydrogen carbonate solution and extracted three times with ethyl acetate. The extract was washed with aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (4% methanol-chloroform) to give N-(4-ethyl-2,4-hexadien-1-yl)-6-amino-3-pyridinecarboxamide (5.7 g).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([N:6]1[CH:15]([C:16](OC)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:20])[CH3:5].[Li+].[BH4-].CO>C1COCC1.C(Cl)Cl>[OH:17][CH2:16][CH:15]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:20])[N:6]1[CH:4]([CH3:5])[CH2:3][OH:2]
Reactant: COC(=O)C(C)N1C(=O)c2ccccc2CC1C(=O)OC
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(CO)N1C(=O)c2ccccc2CC1CO
Temperature: 25 °C
Yield: 88.5 %

Procedure:
Isomer B of methyl 2-(1-methoxy-1-oxopropan-2-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (0.28 g, 0.96 mmol) in THF (9.8 ml) was added to a stirring solution of LiBH4 (2.0 M in THF, 0.58 ml, 1.2 mmol) in THF (1.5 ml). After refluxing for 1.5 h, the reaction was cooled to room temperature and quenched with 0.036 ml of water. Sodium hydroxide (1N, 0.072 ml) and then water (0.054 ml) were added. The reaction mixture was filtered through Celite, rinsing with THF. Evaporation of the filtrate afforded 0.32 g of crude product. Flash chromatography (SiO2, 0.5 to 10% MeOH in CH2Cl2) afforded pure product (0.20 g, 89% yield). MS (ESI) 236 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:13])[C:8](Br)=[N:9][C:10]=1[CH3:11])=[O:5])[CH3:2].[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22])#[CH:15]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:13])[C:8]([C:15]#[C:14][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])=[N:9][C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)nc(Br)n1C
Reactant: C#Cc1ccccc1F
Product: CCOC(=O)c1c(C)nc(C#Cc2ccccc2F)n1C

Procedure:
The title compound, MS: m/e=287.4 (M+H+) was prepared in accordance with the general method of example 1b from 2-bromo-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester and 1-ethynyl-2-fluorobenzene.
Reaction SMILES: [O:1]1[C:5]([C:6]2[S:10][C:9]([C:11]3[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH:51]1[CH2:55][CH2:54][CH2:53][C@H:52]1[CH2:56][N:57]1[CH2:61][CH2:60][CH2:59][CH2:58]1>CN(C=O)C.ClCCl>[O:1]1[C:5]([C:6]2[S:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:15]([N:51]4[CH2:55][CH2:54][CH2:53][C@H:52]4[CH2:56][N:57]4[CH2:61][CH2:60][CH2:59][CH2:58]4)=[O:17])=[CH:18][CH:19]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1
Reactant: O=C(O)c1ccc(-c2ccc(-c3cnco3)s2)cc1
Reactant: C1CN[C@H](CN2CCCC2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(-c2ccc(-c3cnco3)s2)cc1)N1CCC[C@H]1CN1CCCC1
Yield: 47.9 %

Procedure:
The title compound is prepared in a manner substantially analogous to General Procedure D in 9 mL 50% DMF/dichloromethane using 4-(5-oxazol-5-yl-thiophen-2-yl)-benzoic acid (133 mg, 0.49 mmol), EDC-HCl (143 mg, 0.75 mmol), HOBt (101 mg, 0.75 mmol), DIEA (0.22 mL, 1.5 mmol) and (S)(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (63 mg, 0.41 mmol) to give the title compound (80 mg, 48% yield). MS (ES+) 408.3 (M+H)+
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH:12]([OH:17])[C:13]([F:16])([F:15])[F:14])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:18][C:19]1[CH:20]=[CH:21][C:22](B2OC(C)(C)C(C)(C)O2)=[C:23]([CH:26]=1)[C:24]#[N:25]>CN(C)C=O.C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:24]([C:23]1[CH:26]=[C:19]([CH3:18])[CH:20]=[CH:21][C:22]=1[C:2]1[CH:11]=[C:10]([CH:12]([OH:17])[C:13]([F:16])([F:15])[F:14])[CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:3]=1)#[N:25]
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(C#N)c1
Reactant: COC(=O)c1cc(Br)cc(C(O)C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(-c2ccc(C)cc2C#N)cc(C(O)C(F)(F)F)c1

Procedure:
A mixture of methyl 3-bromo-5-(2,2,2-trifluoro-1-hydroxyethyl)benzoate (300 mg, 0.96 mmol), 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (280 mg, 1.1 mmol), tetrakis(triphenylphosphine)palladium(0) (60 mg, 0.052 mmol) in N,N-dimethylformamide (0.75 mL) and toluene (1.5 mL) under nitrogen was subjected to microwave irradiation at 110° C. for 1 h. After cooling, the mixture was diluted with water (15 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated. The residue was purified by flash chromatography to afford the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[C:12]([CH2:13][C:14]([O-:16])=O)=[CH:11][N:10]=[CH:9]2)=[CH:5][C:4]=1[F:19])#[N:2].[Li+].Cl.[NH2:22][C@@H:23]1[CH2:27][CH2:26][N:25]([C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[C:35]([OH:38])[CH:36]=3)[CH:31]=[CH:30][CH:29]=2)[C:24]1=[O:39].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:1]([C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[C:12]([CH2:13][C:14]([NH:22][C@@H:23]3[CH2:27][CH2:26][N:25]([C:28]4[C:37]5[C:32](=[CH:33][CH:34]=[C:35]([OH:38])[CH:36]=5)[CH:31]=[CH:30][CH:29]=4)[C:24]3=[O:39])=[O:16])=[CH:11][N:10]=[CH:9]2)=[CH:5][C:4]=1[F:19])#[N:2]
Reactant: N#Cc1ccc(Cn2cncc2CC(=O)[O-])cc1F
Reactant: N[C@@H]1CCN(c2cccc3ccc(O)cc23)C1=O
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: N#Cc1ccc(Cn2cncc2CC(=O)N[C@@H]2CCN(c3cccc4ccc(O)cc34)C2=O)cc1F

Procedure:
A mixture of lithium [1-(4-cyano-3-fluorobenzyl)-1H-imidazol-5-yl]acetate, as described above in Step D, (46 mg, 0.18 mmol), (R)-3-amino-1-(7-hydroxynaphthalen-1-yl)-2-oxopyrrolidine hydrochloride, as described in Example 10A (45 mg, 0.16 mmol), HOBT (24 mg, 0.18 mmol), EDC (35 mg, 0.18 mmol), and N,N-diisopropylethylamine (0.084 mL, 0.48 mmol) was stirred in DMF (1 mL) at ambient temperature for 18 hours. The solvent was removed under reduced pressure and the residue was partitioned between saturated aqueous NaHCO3 (1 mL) and CHCl3 (2 mL). The aqueous layer was extracted further with CHCl3 (2×2 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with a gradient of EtOAc—10% MeOH—1% NH4OH to EtOAc—15% MeOH—1.5% NH4OH to yield the titled product as a white solid.
Reaction SMILES: C(CCN[C:6](=[O:32])[C@@H:7]([NH:12][C:13]([N:15]1[C:19]2[CH2:20][CH2:21][O:22][CH2:23][C:18]=2[C:17]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[C:26]([F:31])[CH:25]=2)=[N:16]1)=[O:14])[C:8]([CH3:11])([CH3:10])[CH3:9])#N.[NH2:33][C:34]1[CH:38]=[C:37]([CH3:39])[NH:36][N:35]=1>>[F:31][C:26]1[CH:25]=[C:24]([C:17]2[C:18]3[CH2:23][O:22][CH2:21][CH2:20][C:19]=3[N:15]([C:13]([NH:12][C@@H:7]([C:8]([CH3:9])([CH3:10])[CH3:11])[C:6]([NH:33][C:34]3[CH:38]=[C:37]([CH3:39])[NH:36][N:35]=3)=[O:32])=[O:14])[N:16]=2)[CH:29]=[CH:28][C:27]=1[F:30]
Reactant: CC(C)(C)[C@H](NC(=O)n1nc(-c2ccc(F)c(F)c2)c2c1CCOC2)C(=O)NCCC#N
Reactant: Cc1cc(N)n[nH]1
Product: Cc1cc(NC(=O)[C@@H](NC(=O)n2nc(-c3ccc(F)c(F)c3)c3c2CCOC3)C(C)(C)C)n[nH]1

Procedure:
Compound 105 was prepared by the procedure described for the synthesis of compound 104 by replacing 2-cyanoethylamine with 3-amino-5-methylpyrazole. LCMS (+ESI) m/z=473.3 [M+H]+. 1H NMR (CDCl3) δ 8.15 (d, J=9.8 Hz, 1H), 7.50-7.56 (m, 1H), 7.28-7.30 (m, 1H), 7.22-7.27 (m, 1H), 5.84 (d, J=9.9 Hz, 1H), 5.48 (s, 2H), 4.82 (s, 2H), 3.93 (t, J=5.6 Hz, 2H), 3.18 (t, J=4.8 Hz, 2H), 2.17 (s, 3H), 1.11 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:17]([CH2:32][CH2:33][NH:34][CH2:35][CH:36]4[CH2:38][CH2:37]4)[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=4)[N:20]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1.[CH:39]1(N)CCCC1>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:17]([CH2:32][CH2:33][NH:34][CH:35]4[CH2:39][CH2:37][CH2:38][CH2:36]4)[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:31])([F:29])[F:30])[CH:22]=4)[N:20]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1
Reactant: NC1CCCC1
Reactant: N#Cc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCNCC2CC2)CC1
Product: N#Cc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCNC2CCCC2)CC1

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[1-[2-(cyclopropylmethyl-amino)-ethyl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile using cyclopentylamine instead of cyclopropylmethylamine. LC-MS: (M+1=543, obsd.=543).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([N+:21]([O-])=O)[CH:15]=2)=[CH:4][C:3]=1[N+:24]([O-])=O>C(OCC)(=O)C.CO.[Pd]>[NH2:21][C:16]1[CH:15]=[C:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([NH2:24])[CH:4]=2)[CH:19]=[CH:18][C:17]=1[OH:20]
Reactant: O=[N+]([O-])c1cc(CCCCCCc2ccc(O)c([N+](=O)[O-])c2)ccc1O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1cc(CCCCCCc2ccc(O)c(N)c2)ccc1O
Yield: 96 %

Procedure:
A solution of 7.0 g of 1,6-bis(4-hydroxy-3-nitrophenyl)hexane of Example 4 in ethyl acetate:methanol (3:1) and 400 mg of 5% palladium on carbon was hydrogenated on a Parr hydrogenation apparatus for 3 hours. After filtration and removal of solvent, 5.6 g of off-white solid was obtained.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[Mg].[CH3:8][N:9]([CH3:28])[CH:10]([CH3:27])[CH2:11][C:12]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:13]=[O:14].[Cl-].[NH4+]>C1COCC1>[CH3:28][N:9]([CH3:8])[CH:10]([CH2:11][C:12]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH:13]([OH:14])[CH2:6][CH2:5][CH2:4][CH:3]=[CH2:2])[CH3:27]
Reactant: C=CCCCBr
Reactant: CC(CC(C=O)(c1ccccc1)c1ccccc1)N(C)C
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCCCC(O)C(CC(C)N(C)C)(c1ccccc1)c1ccccc1
Temperature: 45 °C
Reaction time: 4 h
Yield: 40 %

Procedure:
A solution of 5-bromo-1-pentene (4.8 g) in anhydrous THF was added dropwise to magnesium turnings (1 g) in THF (15 ml), under nitrogen with vigorous stirring. After the initial exothermic reaction had subsided, the mixture was stirred at 45° C. for 4 hours. A solution of 4-dimethylamino-2,2-diphenylpentanal (1.2 g), as prepared above, dissolved in THF (5 ml) was then added. The resultant mixture was stirred for 18 hours. Saturated ammonium chloride solution was added and the aqueous mixture was partitioned between water and ethyl acetate (3×). The combined organic layers were washed with brine and water (once each), and dried (MgSO4). Rotary evaporation of the solution gave a crude material which was flash-chromatographed over silica gel. Elution with chloroform (CHCl3)/methanol (20:1) yielded 0.6 g of 2-dimethylamino-4,4-diphenyl-9-decene-5-ol, as a mixture of two isomers.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]3[C:21](=[O:32])[N:20]([CH2:33][CH2:34][CH3:35])[C:19](Cl)=[N:18][C:17]=3[N:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.O.C([O-])=O.[NH4+]>CN(C=O)C.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:31])[CH3:30])[C:22]3[C:21](=[O:32])[N:20]([CH2:33][CH2:34][CH3:35])[CH:19]=[N:18][C:17]=3[N:16]=2)=[CH:13][CH:14]=1
Reactant: CCCn1c(Cl)nc2nc(-c3ccc(OCc4ccccc4)cc3)n(COCC[Si](C)(C)C)c2c1=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1cnc2nc(-c3ccc(O)cc3)n(COCC[Si](C)(C)C)c2c1=O
Temperature: 80 °C
Yield: 79.6 %

Procedure:
To a solution of 8-(4-benzyloxy-phenyl)-2-chloro-1-propyl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (0.25 g, 0.00048 mol) in DMF:water nil), 10% Pd/C (0.130 g) and ammonium formate (0.66 g, 0.010 mol) were added and refluxed at 80° C. for 2 hours. The mixture was cooled and filtered through celite bed, solvent was removed and the residue was diluted with water (10 ml), acidified with citric acid and extracted with ethyl acetate (3×10 ml). The organic layer was washed with brine (2×15 ml). It was dried over Na2SO4 and the solvent was removed to obtain pale yellow solid of 8-(4-hydroxy-phenyl)-1-propyl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (0.153 g, 80%).