Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:11]1[CH:31]=[CH:30][C:14]([CH2:15][NH:16][CH2:17][C:18]2[CH:29]=[CH:28][C:21]([O:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=2)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:32]1(/[CH:38]=[CH:39]/[C:40](Cl)=[O:41])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[C:1]([C:11]1[CH:31]=[CH:30][C:14]([CH2:15][N:16]([CH2:17][C:18]2[CH:29]=[CH:28][C:21]([O:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=2)[C:40](=[O:41])/[CH:39]=[CH:38]/[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCC#Cc1ccc(CNCc2ccc(OCC(=O)OC)cc2)cc1
Reactant: O=C(Cl)/C=C/c1ccccc1
Product: CCCCCCCCC#Cc1ccc(CN(Cc2ccc(OCC(=O)OC)cc2)C(=O)/C=C/c2ccccc2)cc1

Procedure:
The title compound was prepared following the procedure E using methyl (4-{[(4-dec-1-ynylbenzyl)amino]methyl}phenoxy)acetate and (2E)-3-phenylacryloyl chloride (purification by flash chromatography on SiO2-c-Hex/EtOAc 9:1) as a colorless oil (64%). M+ (ESI): 552.1. HPLC, Rt: 6.1 min (purity: 99.5%). 1H NMR (CDCl3) δ: 7.85 (m, 1H), 7.47-7.12 (m, 11H), 6.90 (m, 3H), 4.65-4.52 (m, 6H), 3.82 (s, 3H), 2.41 (t, J=7.0 Hz, 2H), 1.61 (m, 2H), 1.45 (m, 2H), 1.30 (m, 8H), 0.89 (t, J=6.8 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][CH3:10])[C:3]=1[OH:11].C(C1C=C(C=C(C)C=1O)[C:17]([NH:19][OH:20])=[NH:18])C>>[OH:11][C:3]1[C:4]([CH2:8][CH2:9][CH3:10])=[CH:5][C:6]([C:17]([NH:19][OH:20])=[NH:18])=[CH:7][C:2]=1[CH3:1]
Reactant: CCc1cc(C(=N)NO)cc(C)c1O
Reactant: CCCc1cccc(C)c1O
Product: CCCc1cc(C(=N)NO)cc(C)c1O

Procedure:
The title compound is prepared from commercially available 2-methyl-6-propyl-phenol in analogy to literature procedures (e.g. B. Roth et al., J. Med. Chem. (1988), 31, 122-129; and literature cited for 3-ethyl-4,N-dihydroxy-5-methyl-benzamidine). LC-MS: tR=0.54 min; [M+1]+=209.43; 1H NMR (D6-DMSO): δ 0.90 (t, J=7.3 Hz, 3H), 1.48-1.59 (m, 3H), 2.19 (s, 3H), 2.56 (t, J=7.3 Hz, 2H), 7.37 (s, 1H), 7.40 (s, 1H), 9.34 (s, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[CH:23]=[C:22]([CH3:32])[C:10]=1[O:11][C:12]1[C:13]2[NH:21][N:20]=[N:19][C:14]=2[N:15]=[C:16](Cl)[N:17]=1.[NH2:33][C:34]1[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][CH:35]=1.FC(F)(F)CO>>[CH3:8][C:9]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[CH:23]=[C:22]([CH3:32])[C:10]=1[O:11][C:12]1[C:13]2[NH:21][N:20]=[N:19][C:14]=2[N:15]=[C:16]([NH:33][C:34]2[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][CH:35]=2)[N:17]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: Cc1cc(-c2ccncc2)cc(C)c1Oc1nc(Cl)nc2nn[nH]c12
Solvent: O=C(O)C(F)(F)F
Solvent: OCC(F)(F)F
Product: Cc1cc(-c2ccncc2)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc2nn[nH]c12
Temperature: 90 °C

Procedure:
Trifluoroacetic acid (8 eq) is added to a suspension of 7-(2,6-dimethyl-4-(pyridin-4-yl)phenoxy)-5-chloro-1H-[1,2,3]triazolo[4,5-d]pyrimidine (1 eq) and 4-aminobenzonitrile (4 eq) in 2,2,2-trifluoroethanol (1 ml/0.1 mmol) in a sealed tube. The resulting mixture is heated at 90° C. for 3 days. The reaction is cooled to room temperature, concentrated to dryness and purified by silica gel chromatography.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:13][CH3:14])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:27][CH2:28][C:29]1([OH:37])[CH:34]2[CH2:35][CH2:36][N:31]([CH2:32][CH2:33]2)[CH2:30]1.CN(C)C=O>O1CCCC1>[Cl:1][C:2]1[C:3]([NH:13][CH3:14])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([NH:27][CH2:28][C:29]1([OH:37])[CH:34]2[CH2:33][CH2:32][N:31]([CH2:36][CH2:35]2)[CH2:30]1)=[O:9]
Reactant: CNc1cc(OC)c(C(=O)O)cc1Cl
Reactant: NCC1(O)CN2CCC1CC2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CNc1cc(OC)c(C(=O)NCC2(O)CN3CCC2CC3)cc1Cl
Reaction time: 1 h
Yield: 53.9 %

Procedure:
A solution of 5-chloro-2-methoxy-4-(methylamino)benzoic acid (3.02 g, 0.014 mole) in anhydrous tetrahydrofuran (15 ml) under nitrogen was treated with 1,1'-carbonyldiimidazole (2.35 g, 0.0145 mole) and stirred for one hour. A solution/suspension of 3-aminomethyl-1-azabicyclo[2.2.2]octan-3-ol (2.34 g, 15 mole) in tetrahydrofuran (15 ml) containing a little N,N-dimethylformamide for solubility was added slowly over a few minutes, and the mixture was stirred overnight (18 hours) at room temperature and for one hour at 60° C., then concentrated in vacuo. The white solid was partitioned between 1.0N sodium carbonate (100 ml) and methylene chloride (200 ml) containing a little methanol, and the organic layer was separated. The aqueous solution was extracted with methylene chloride (2×50 ml) containing a little methanol, and the combined organic solution was dried (sodium sulfate) and passed through a short column of alumina (eluted with 10% methanol/methylene chloride). The filtrate was concentrated in vacuo, triturated from ether, and triturated from acetonitrile to afford 2.67 g (54%) of the title compound as a colorless solid; mp 236°-237° C. (dec).
Reaction SMILES: O.[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([OH:14])[C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1.Cl.[CH2:16](OCC)[CH3:17]>C(O)C>[OH:14][CH:10]([CH2:9][C:6]1[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=1)[C:11]([O:13][CH2:16][CH3:17])=[O:12]
Reactant: O=C(O)C(O)Cc1ccc(O)cc1
Reactant: CCOCC
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(O)Cc1ccc(O)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of 0.5 g (2.74 mmol) of D,L 3-(4-hydroxyphenyl) lactic acid hydrate in 10 mL of ethanol was added a catalytic amount of concentrated hydrochloric acid. The mixture was heated at reflux for 2 hours then cooled to room temperature and concentrated under vacuum. The residue was dissolved in 50 mL of ether and washed with saturated aqueous sodium bicarbonate (1×50 mL) and brine (1×50 mL). The organic layer was removed, dried over magnesium sulfate, filtered and evaporated under vacuum to afford 0.54 g (2.57 mmol,94%) of the ethyl ether. 1H NMR (200 MHz,CDCl3): 1.26 (t,7 Hz,3H), 2.86 (dd;7,14 Hz;1H); 3.03 (dd;4,14 Hz; 1H), 4.19 (q,7 Hz,2H), 4.38 (dd;4,7 Hz;1H), 5.60 (br s,1H), 6.66 (d,8 Hz,2H), 7.03 (d,8 Hz,2H).
Reaction SMILES: [CH:1]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[C:10]([C:16]([OH:18])=O)[NH:11]3)[CH2:4][CH2:3][CH2:2]1.Cl.Cl.Cl.[NH2:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][C@H:34]([OH:37])[C@@H:33]([CH3:38])[CH2:32]2)[CH2:25][CH2:24]1>>[OH:37][C@H:34]1[CH2:35][CH2:36][N:31]([CH2:30][CH2:29][N:26]2[CH2:25][CH2:24][CH:23]([NH:22][C:16]([C:10]3[NH:11][C:12]4[C:8]([CH:9]=3)=[C:7]([O:6][CH2:5][CH:1]3[CH2:2][CH2:3][CH2:4]3)[CH:15]=[CH:14][CH:13]=4)=[O:18])[CH2:28][CH2:27]2)[CH2:32][C@@H:33]1[CH3:38]
Reactant: O=C(O)c1cc2c(OCC3CCC3)cccc2[nH]1
Reactant: C[C@H]1CN(CCN2CCC(N)CC2)CC[C@@H]1O
Agent: Cl
Product: C[C@H]1CN(CCN2CCC(NC(=O)c3cc4c(OCC5CCC5)cccc4[nH]3)CC2)CC[C@@H]1O

Procedure:
This compound is synthesized analogously to example 1 from 4-cyclobutylmethoxy-1H-indole-2-carboxylic acid, 82 (see example 22) and amine 14.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:19])[NH:6][C:7]1[CH:8]=[N:9][N:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:11]=1.[CH:22]([C:25]1[N:29]2[CH:30]=[C:31]([O:34][C@@H:35]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[C@@H:38]([NH2:45])[CH2:37][CH2:36]3)[CH:32]=[CH:33][C:28]2=[N:27][N:26]=1)([CH3:24])[CH3:23].CCN(C(C)C)C(C)C>CN(C=O)C>[CH:22]([C:25]1[N:29]2[CH:30]=[C:31]([O:34][C@@H:35]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[C@@H:38]([NH:45][C:5]([NH:6][C:7]4[CH:8]=[N:9][N:10]([C:12]5[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=5)[CH:11]=4)=[O:19])[CH2:37][CH2:36]3)[CH:32]=[CH:33][C:28]2=[N:27][N:26]=1)([CH3:24])[CH3:23]
Reactant: CC(C)c1nnc2ccc(O[C@H]3CC[C@H](N)c4ccccc43)cn12
Reactant: Cc1ccc(-n2cc(NC(=O)OCC(Cl)(Cl)Cl)cn2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-n2cc(NC(=O)N[C@H]3CC[C@H](Oc4ccc5nnc(C(C)C)n5c4)c4ccccc43)cn2)cc1
Yield: 77.9 %

Procedure:
A solution of Intermediate 6c (65.0 mg, 0.19 mmol), Intermediate 5c (50.0 mg, 0.155 mmol), and DIPEA (0.127 mL, 0.8 mmol) in DMF (1 mL) was heated at 110° C. for 75 min and 50° C. for 64 h. After cooling, the mixture was concentrated to dryness and the residue purified by FCC, eluting with 0-10% MeOH in DCM, to give the impure product (63 mg). Further purification by HPLC (Method 6) gave the title compound as a white solid (45 mg, 56%). LCMS (Method 5): Rt 4.06 min, m/z 522.1 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.36-1.41 (6H, m), 1.76-1.85 (1H, m), 1.98-2.08 (1H, m), 2.13-2.28 (2H, m), 2.33 (3H, s), 3.59 (1H, quintet, J 6.8), 4.96-5.03 (1H, m), 5.62 (1H, t, J 4.6), 6.74 (1H, d, J 8.5), 7.24 (1H, dd, J 9.9, 2.1), 7.26-7.46 (6H, m), 7.62-7.66 (2H, m), 7.68 (1H, s), 7.70 (1H, dd, J 9.9, 0.8), 8.24 (1H, br d), 8.26 (1H, s), 8.31 (1H, s).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]([F:41])([F:40])[O:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH:34]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:34][C:33]3[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=3[O:31][C:30]([F:29])([F:40])[F:41])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1ccccc1OC(F)(F)F
Product: FC(F)(F)Oc1ccccc1CNc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 2-trifluoromethoxy benzaldehyde. MS (ESI) m/z 553.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:31]2[CH2:35][CH2:34][C@@H:33]([NH:36]C(=O)OC(C)(C)C)[CH2:32]2)=[N:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[N:10](COCC[Si](C)(C)C)[N:9]=2)=[CH:6][CH:7]=1.Cl>CO.O1CCOCC1>[CH3:1][C:2]1[C:3]([N:31]2[CH2:35][CH2:34][C@@H:33]([NH2:36])[CH2:32]2)=[N:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2nn(COCC[Si](C)(C)C)c3cnc(-c4cccnc4)cc23)nc1N1CC[C@@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1ccc(-c2n[nH]c3cnc(-c4cccnc4)cc23)nc1N1CC[C@@H](N)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.9 %

Procedure:
To (R)-tert-butyl 1-(3-methyl-6-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)pyrrolidin-3-ylcarbamate in MeOH (4 mL) was added 4.0 M of Hydrogen chloride in 1,4-Dioxane (6 mL). The resulting mixture was stirred overnight at room temperature. The mixture was then concentrated, and the residue was purified by reverse phase HPLC to afford 316 as an off-white solid (15.4 mg, 56.9%). 1H NMR (400 MHz, DMSO) δ 9.27 (d, J=1.7 Hz, 1H), 9.19 (s, 1H), 9.12 (s, 1H), 8.59 (d, J=3.8 Hz, 1H), 8.41 (d, J=8.0 Hz, 1H), 7.53 (dd, J=7.9, 4.8 Hz, 1H), 7.51-7.43 (m, 2H), 3.85 (dd, J=9.5, 5.6 Hz, 2H), 3.77 (dd, J=16.6, 7.1 Hz, 1H), 3.63-3.57 (m, 1H), 3.43 (dd, J=9.6, 5.6 Hz, 1H), 2.37 (s, 3H), 2.11 (td, J=12.2, 5.9 Hz, 1H), 1.74 (dq, J=13.8, 7.1 Hz, 1H); ESI MS m/z=372.2 (M+1)
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH:7]1([C:10]([OH:12])=[O:11])[CH2:9][CH2:8]1.Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=1)=[O:16]>CN(C=O)C>[CH:7]1([C:10]([O:12][CH2:14][C:15]([C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=2)=[O:16])=[O:11])[CH2:9][CH2:8]1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: O=C(O)C1CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(COC(=O)C1CC1)c1ccc(Br)cc1
Reaction time: 0.25 h
Yield: 98.8 %

Procedure:
To a slurry of sodium carbonate (9.00 g, 84.91 mmol) in DMF (100 ml) was added dropwise cyclopropane carboxylic acid (4.5 ml, 56.50 mmol). The mixture was stirred for 15 min and then treated with 2,4′-dibromoacetophenone (15.71 g, 56.52 mmol). After 3 h, the mixture was partitioned between Et2O and water. The aqueous phase was extracted with Et2O (4×125 ml). The combined organic phases were dried over MgSO4 and concentrated in vacuo to yield 2-(4-bromophenyl)-2-oxoethyl cyclopropane carboxylate as a yellow solid (15.81 g, 98%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:10]([C:15]#[N:16])=[CH:11][CH:12]=[CH:13][CH:14]=1.[B:17](OC)([O:20]C)[O:18]C>>[C:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:3]1[C:2]([F:1])=[CH:7][CH:6]=[C:5]([B:17]([OH:20])[OH:18])[C:4]=1[F:8])#[N:16]
Reactant: N#Cc1ccccc1-c1c(F)cccc1F
Reactant: COB(OC)OC
Product: N#Cc1ccccc1-c1c(F)ccc(B(O)O)c1F

Procedure:
2′,6′-Difluorobiphenyl-2-carbonitrile was lithiated and reacted with trimethyl borate as described in Example 31 to give 2′-cyano-2,6-difluorobiphenyl-3-boronic acid as a white crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].C1COCC1.[Br:17][C:18]([CH3:23])([CH3:22])[C:19](Br)=[O:20]>CCN(CC)CC>[Br:17][C:18]([CH3:23])([CH3:22])[C:19]([NH:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11])=[O:20]
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: CC(C)(Br)C(=O)Br
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(Br)C(=O)Nc1cc([N+](=O)[O-])ccc1O
Reaction time: 0.75 h

Procedure:
2-Amino-4-nitro-phenol (3.08 g, Aldrich) was stirred with THF (30 ml, Aldrich) in an ice bath. 2-Bromo-2-methyl-propionyl bromide (2.47 ml, Aldrich) and Et3N (2.0 g, Aldrich) was slowly added via syringe. The mixture was stirred for 45 min then poured into ice. The aqueous phase was extracted by EtOAc (50 mL×4). The organic layer was dried and concentrated. The desired product was crystallized from EtOAc. (Chem. Pharm. Bull 1996, 44(1) 103-114).
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>O>[CH3:18][O:17][C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:8]([C:5]3[CH:6]=[N:7][C:2]([N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:3][CH:4]=3)[S:9][C:10]=2[CH:16]=1
Reactant: COc1ccc2nc(-c3ccc(F)nc3)sc2c1
Reactant: C1CCNC1
Solvent: O
Product: COc1ccc2nc(-c3ccc(N4CCCC4)nc3)sc2c1
Temperature: 100 °C

Procedure:
In a microwave vial were added 2-(6-fluoropyridin-3-yl)-6-methoxy-1,3-benzothiazole (75 mg, 0.29 mmol), water (2.5 mL) and pyrrolidine (0.50 mL) and the reaction was heated in a microwave oven at 100° C. for 5 min. The precipitated product was filtered off, washed with water and methanol and dried in a desicator over P2O5 to give the title compound (76 mg) as a white solid. 1H NMR (CHLOROFORM-d) δ 8.77 (d, 1H) 8.13 (dd, 1H) 7.87 (d, 1H) 7.33 (d, 1H) 7.05 (dd, 1H) 6.44 (d, 1H) 3.89 (s, 3H) 3.63-3.46 (m, 4H) 2.11-1.98 (m, 4H); MS m/z (M+H) 312.
Reaction SMILES: C([O:3][C:4](=[O:45])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][CH:15]=[C:16]([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=3)=[CH:31][CH:30]=2)[C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[CH:19][CH:18]=2)=[CH:9][C:8]=1[C:41]([F:44])([F:43])[F:42])C>C(O)C.[OH-].[Na+]>[N:25]1[CH:26]=[CH:27][CH:28]=[C:23]([C:20]2[CH:19]=[CH:18][C:17]([C:16]([C:29]3[CH:30]=[CH:31][C:32]([C:35]4[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=4)=[CH:33][CH:34]=3)=[CH:15][CH2:14][S:13][C:10]3[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:45])=[O:3])=[C:8]([C:41]([F:44])([F:42])[F:43])[CH:9]=3)=[CH:22][CH:21]=2)[CH:24]=1
Reactant: CCOC(=O)COc1ccc(SCC=C(c2ccc(-c3cccnc3)cc2)c2ccc(-c3cccnc3)cc2)cc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)COc1ccc(SCC=C(c2ccc(-c3cccnc3)cc2)c2ccc(-c3cccnc3)cc2)cc1C(F)(F)F

Procedure:
A solution of {4-[3,3-bis-(4-pyridin-3-yl-phenyl)-allylsulfanyl]-2-trifluoromethyl-phenoxy}-acetic acid ethyl ester (70 mg, 0.1 mmol) in ethanol (10 ml) and 1N NaOH (0.5 ml) was stirred at 75° C. for 1 h. The reaction mixture was evaporated and the residue was treated with 1N HCl (0.7 ml) and extracted with methylene chloride (2×25 ml). The organic phases were dried and evaporated to give the title compound in 23 mg (34%) yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:11][O:12][C:13](=[O:16])[CH2:14]Br.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:11][O:12][C:13](=[O:16])[CH2:14][O:10][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(Cl)cc1C=O
Temperature: 80 °C

Procedure:
5-Chloro-2-hydroxy-benzaldehyde (30 g, 192 mmol), bromo-acetic acid methyl ester (29.4 g, 192 mmol), K2CO3 (53 g, 384 mmol) and KI (9.6 g, 57 mmol) were mixed in acetone (100 mL). Then the mixture was heated at 80° C. for 30 min. The mixture was filtered and the filtrate was concentrated. The residue was dissolve in ethyl acetate and washed with base aqueous solution (1N NaOH). The organic layer was separated, dried and concentrated to give (4-chloro-2-formyl-phenoxy)-acetic acid methyl ester yellow solid. (44 g)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[CH:6]=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1.[Cl:22][C:23]1[S:27][C:26]([C:28]([C:30]2[N:31]([CH3:35])[CH:32]=[N:33][CH:34]=2)=[O:29])=[CH:25][CH:24]=1>>[Cl:22][C:23]1[S:27][C:26]([C:28]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([O:12][CH3:13])[CH:6]=[C:5]3[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)([C:30]2[N:31]([CH3:35])[CH:32]=[N:33][CH:34]=2)[OH:29])=[CH:25][CH:24]=1
Reactant: COc1cccc(-c2cc(OC)nc3ccc(Br)cc23)c1
Reactant: Cn1cncc1C(=O)c1ccc(Cl)s1
Product: COc1cccc(-c2cc(OC)nc3ccc(C(O)(c4ccc(Cl)s4)c4cncn4C)cc23)c1
Yield: 80.1 %

Procedure:
Following the same procedure as that described in example 1E, 6-bromo-4-(3-methoxy-phenyl)-2-methoxy-quinoline (1 g, 2.91 mmol) and (5-chloro-thiophen-2-yl)-(3-methyl-3H-imidazol-4-yl)-methanone (0.78 g, 3.49 mmol) generated the title compound of 31A (1.147 g, 80.2% yield).
Reaction SMILES: [H-].[Na+].[C:3](#[N:5])[CH3:4].C([O:8][C:9](=O)[CH:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:14]([F:24])[CH:13]=1)[CH3:11])C.C(O)(C)C>O1CCCC1>[F:24][C:14]1[CH:13]=[C:12]([CH:10]([CH3:11])[C:9](=[O:8])[CH2:4][C:3]#[N:5])[CH:17]=[CH:16][C:15]=1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)C(C)c1ccc(-c2ccccc2)c(F)c1
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CC(C(=O)CC#N)c1ccc(-c2ccccc2)c(F)c1
Temperature: 25 °C
Yield: 55 %

Procedure:
After 60% sodium hydride (6.5 g, 0.163 mmol) was suspended in tetrahydrofuran under nitrogen atmosphere, the mixture was refluxed for 0.5 h, then added dropwise acetonitrile (7.6 g, 0.185 mol) and ethyl-2-(2-fluoro-4-biphenylyl)-propionate described above in tetrahydrofuran (100 ml). After refluxed for 2 h, the mixture was cooled at room temperature and added isopropylalcohol. After stirring for a while, the mixture was evaporated under reduced pressure to a residue, which was made acid with 2N hydrochloric acid and extracted with chloroform. The extracts were washed with water, dried over, and evaporated under reduced pressure to a residue, which was chromatographed and recrystallized with ethanol to afford 4-(2-fluoro-4-biphenylyl)-3-oxo-pentanenitril (18.0 g, 55% yiled) as pale yellow crystalline material: mp 84°-85° C.
Reaction SMILES: Br[C:2]1[N:11]=[C:10]([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[O:13])[C:9]([OH:23])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.CN.C[CH2:27][N:28](C(C)C)C(C)C>CS(C)=O.C1COCC1>[F:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][NH:14][C:12]([C:10]2[C:9]([OH:23])=[C:8]3[C:3]([CH:4]=[CH:5][CH:6]=[N:7]3)=[C:2]([NH:28][CH3:27])[N:11]=2)=[O:13])=[CH:17][CH:18]=1
Reactant: O=C(NCc1ccc(F)cc1)c1nc(Br)c2cccnc2c1O
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CNc1nc(C(=O)NCc2ccc(F)cc2)c(O)c2ncccc12
Reaction time: 72 h

Procedure:
A suspension of 5-bromo-N-(4-fluorobenzyl)-8-hydroxy-1,6-naphthyridine-7-carboxamide (12.0 g, 32 mmol) in DMSO (48 mL) was treated with methyl amine (48 mL of a 2M solution in THF, 96 mmol) and Hunig's base (11.1 mL, 86 mmol). The vessel was purged with argon, sealed and stirred at 135C for 3 days. The reaction was cooled, quenched with water (280 mL) and the pH adjusted to 5 by the addition of acetic acid. The reaction was stirred at room temperature for 1 hr and filtered. The solids were washed with water (100 mL) and then EtOAc (50 mL), and dried in vacuo to afford the title compound as a white solid.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[Br:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>C(Cl)Cl>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][C:27]([Br:26])=[CH:28][CH:29]=2)[CH2:11][CH2:10]3)[CH2:13][CH2:14]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(Br)cc2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (130 mg, 0.53 mmol) and triethylamine (110 μL, 0.79 mmol) in methylene chloride (25 mL) was added dropwise 4bromobenzoyl chloride (122 mg, 0.56 mmol) in methylene chloride (5 mL). After the addition, the reaction was allowed to stir at ambient temperature for 15 min and was then washed with dilute aqueous sodium hydrogen carbonate. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:4) as the eluent. Yield: 120 mg (51%) of the title compound as white crystals: mp 200-201° C.; [α]21D -32° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 427 and 429 (3, M+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([N:19]2[CH2:23][CH2:22][CH2:21][C@@H:20]2[CH2:24][OH:25])[CH:18]=1)[C:5]([NH:7][CH2:8][C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1)=[O:6].[CH3:26][C:27]1[CH:28]=[CH:29][C:30]([Sn](CCCC)(CCCC)CCCC)=[N:31][CH:32]=1.C1(C)C=CC=CC=1>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>[OH:25][CH2:24][C@H:20]1[CH2:21][CH2:22][CH2:23][N:19]1[C:17]1[CH:16]=[C:4]([CH:3]=[C:2]([C:30]2[CH:29]=[CH:28][C:27]([CH3:26])=[CH:32][N:31]=2)[CH:18]=1)[C:5]([NH:7][CH2:8][C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1)=[O:6]
Reactant: Cc1ccc(CNC(=O)c2cc(Br)cc(N3CCC[C@@H]3CO)c2)cn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc(C)nc3)cc(N3CCC[C@@H]3CO)c2)nc1
Temperature: 25 °C

Procedure:
A mixture of (R)-3-bromo-5-(2-(hydroxymethyl)pyrrolidin-1-yl)-N-((6-methylpyridin-3-yl)methyl)benzamide (55 mg, 0.14 mmol), 5-methyl-2-(tributylstannyl)pyridine (65 mg, 0.16 mmol), Tetrakis(triphenylphosphine)palladium(0) (7.8 mg, 0.0068 mmol) and Toluene (1.5 mL, 14 mmol) under argon was subjected to microwave irradiation at 160° C. for 1 hour. The mixture was cooled to room temperature. Solvent was removed in vacuo and the residue was rinsed with hexane and then dissolved in MeOH and filtered. The filtrate was purified by preparative HPLC (100×21.2 mm C18 column, 20-70% CH3CN/water [10 mM Et2NH]) to afford a white foam. LC-MS: 1.64 min, 417.3 [M+1]+; HPLC: 6.76 min.