Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9](Br)=[CH:8]2)=[O:4].[CH3:25][S:26]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)(=[O:28])=[O:27].[O-]P([O-])([O-])=O.[K+].[K+].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.Cl>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].CCOC(C)=O.O>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:32]1[CH:33]=[CH:34][C:29]([S:26]([CH3:25])(=[O:28])=[O:27])=[CH:30][CH:31]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ncc2c(cc(Br)c(=O)n2Cc2ccccc2)c1O
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ncc2c(cc(-c3ccc(S(C)(=O)=O)cc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 100 °C
Yield: 27.7 %

Procedure:
A mixture of 1-benzyl-3-bromo-5-hydroxy-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (80 mg, 0.21 mmol), 4-methanesulfonyl-phenylboronic acid (62 mg, 0.31 mmol), K3PO4 (87 mg, 0.41 mmol), H2O (7.4 mg, 0.41 mmol), SPhos (4.2 mg, 0.010 mmol) and Pd(OAc)2 (4.2 mg, 0.0062 mmol) in toluene (5 mL) was heated at 100° C. under nitrogen atmosphere for 16 h. After the mixture was cooled to r.t., water (10 mL) and EtOAc (15 mL) were added. 1 M HCl was added with stirring until pH was about 2-3, and the organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (10-100% EtOAc/hexanes+2% AcOH) to give 27 mg of the title compound. MS: (+) m/z 465.23 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].S([CH2:22][N+:23]#[C-:24])(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][CH:24]=[N:23][CH:22]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C=O)cc1Br
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1ccc(-c2cnco2)cc1Br
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 80.4 %

Procedure:
The mixed solution of 3-bromo-4-methoxybenzaldehyde (200 mg, 0.93 mmol) in methanol (4 mL) was added tosylmethyl isocyanide (200 mg, 1.02 mmol) and K2CO3 (260 mg, 1.88 mmol). The reaction was stirred at room temperature for 5 min before heated to 80° C. in the sealed tube. After 30 min, the solution was cooled to room temperature and concentrated. Column chromatography afforded 5-(3-bromo-4-methoxyphenyl)oxazole (o) (190 mg, 80%). Following the procedures analogous to the Suzuki and amide coupling reactions described for Compound 20, Compound 25 was prepared.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH:10]([O:19][CH3:20])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[CH:3]=[CH:4][CH:5]=[CH:6][C:7]([OH:9])=[O:8]>CO.[Pd]>[CH3:1][C:2]([CH3:21])([CH:10]([O:19][CH3:20])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: COc1ccc(C(OC)C(C)(C)C=CC=CC(=O)O)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(C(OC)C(C)(C)CCCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of carboxylic acid 25 (100 mg, 0.345 mmol) in MeOH (6 mL), at room temperature was added a solution of Pd/C 10% (50 mg, 1 mL in MeOH). The system was then purged with H2 several times to a final pressure of 50 psi. The reaction mixture was stirred for 3 h at room temperature, and then the solid was filtered through a Celite pad in a fritted glass funnel. The solvents were evaporated, and the crude material (100 mg, 99%) was pure enough for use in the next step: 1H NMR (300 MHz d6-acetone) δ 7.18 (d, J=8 Hz, 2H), 6.89 (d, J=8 Hz, 2H), 3.85 (s, 1H), 3.78 (s, 3H), 3.11 (s, 3H), 2.30 (br. t, J=7.5 Hz, 2H), 1.58-1.53 (m, 2H), 1.37-1.25 (m, 4H), 0.84 (s, 3H), 0.77 (s, 3H).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([NH:18][NH2:19])=[S:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:19][NH:18][C:16]([NH:15][CH2:14][CH2:13][CH2:12][O:11][C:10]2[CH:20]=[CH:21][CH:22]=[C:8]([CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:9]=2)=[S:17])=[O:32])=[CH:26][CH:25]=1
Reactant: NNC(=S)NCCCOc1cccc(CN2CCCCC2)c1
Reactant: O=C=Nc1ccc(Cl)cc1
Product: O=C(NNC(=S)NCCCOc1cccc(CN2CCCCC2)c1)Nc1ccc(Cl)cc1

Procedure:
The compound is prepared by a method analogous to that of Example 9 from N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-hydrazine carbothioamide and 4-chlorophenyl isocyanate. The analytical values are summarized in Table I.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4](Cl)[N:3]=1.Cl.[NH2:26][C@@H:27]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:28]([O:30][CH3:31])=[O:29].C(N(C)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4]([NH:26][C@H:27]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:28]([O:30][CH3:31])=[O:29])[N:3]=1
Reactant: COc1ccc(CN2Cc3c(F)c(Cl)nc(Cl)c3C2=O)c(OC)c1
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: CC(C)N(C)C(C)C
Agent: Cl
Solvent: CC#N
Product: COC(=O)[C@@H](CC(C)C)Nc1nc(Cl)c2c(c1F)CN(Cc1ccc(OC)cc1OC)C2=O
Temperature: 100 °C
Reaction time: 72 h

Procedure:
A mixture of 4,6-dichloro-2-(2,4-dimethoxybenzyl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one (3 g, 8.08 mmol), (S)-methyl 2-amino-4-methylpentanoate hydrochloride (2.94 g, 16.16 mmol), and N-isopropyl-N-methylpropan-2-amine (3.76 mL, 24.25 mmol) in ACN (50 mL) was stirred at 100° C. for 3 d. The solvent was removed and the resulting residue was used in the next step without further purification. [M+H] calc'd for C23H27ClFN3O5, 480; found, 480.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:13]([C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C.C1COCC1>[CH3:22][O:21][C:19](=[O:20])[C:18]1[CH:23]=[CH:24][C:15]([CH2:13][NH:1][C:2]2[S:3][C:4]3[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=3[N:6]=2)=[CH:16][CH:17]=1
Reactant: COc1ccc2nc(N)sc2c1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CNc2nc3ccc(OC)cc3s2)cc1
Reaction time: 48 h
Yield: 50.8 %

Procedure:
To a solution of 2-amino-6-methoxybenzothiazole (2.00 g, 11.1 mmol) in a mixture of dichloroethane (20 mL) and THF (20 mL), were successively added methyl 4-formylbenzoate (1.82 g, 11.1 mmol), sodium triacetoxyborohydride (3.53 g, 16.7 mmol) and acetic acid (1.27 mL, 22.2 mmol). The mixture was stirred over 2 days and was quenched by adding aqueous saturated solution of NaHCO3. The mixture was poured in a separating funnel containing water and was extracted with dichloromethane. The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo, The crude material was purified by flash chromatography using EtOAc/hexane (20:80 to 30:70) to afford the title compound 232 (1.85 g, 51% yield). 1H NMR: (Acetone-d6) δ (ppm): 8.04 (d, J=8.5 Hz, 2H), 7.65 (d, J=8.8 Hz, 2H), 7.41 (d, J=8.8 Hz, 1H), 7.34 (d, J=2.5 Hz, 1H), 6.94 (dd, J=8.5, 2.7 Hz, 1H), 4.50 (t, J=5.5 Hz, 2H), 3.86 (s, 3H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[CH3:14][NH:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:14][N:15]([CH3:16])[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1
Reactant: O=Cc1ccc(F)cc1C(F)(F)F
Reactant: CNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)c1ccc(C=O)c(C(F)(F)F)c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
A suspension of 4-fluoro-2-trifluoromethylbenzaldehyde (500 mg, 2.60 mmol), dimethylamine (5.5 mol/L in ethanol, 0.95 mL, 5.2 mmol), potassium carbonate (360 mg, 2.6 mmol) in 5.2 mL of N,N-dimethylformamide was stirred at 110° C. overnight in a sealed tube. After the reaction mixture was diluted with water, the solution was extracted with ether. The extract was washed with brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=85/15 to 75/25) to obtain the title compound as a pale yellow powder (393 mg, 70%).
Reaction SMILES: [C:1]1([CH:7]2[C:12](=[O:13])[CH2:11][CH2:10][O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14](Cl)([N:16]=[C:17]=[O:18])=[O:15]>CCOC(C)=O>[C:1]1([CH:7]2[C:12]3[O:13][C:17](=[O:18])[NH:16][C:14](=[O:15])[C:11]=3[CH2:10][O:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCOCC1c1ccccc1
Reactant: O=C=NC(=O)Cl
Solvent: CCOC(C)=O
Product: O=c1[nH]c(=O)c2c(o1)C(c1ccccc1)COC2
Temperature: 58 °C
Reaction time: 1 h
Yield: 61.8 %

Procedure:
A mixture of 3-phenyldihydro-2H-pyran-4(3H)-one (Intermediate I(2)) (3 g, 17.02 mmol) and carbonisocyanatidic chloride (10.48 g, 29.8 mmol) in a sealed tube was heated to 58° C. and stirred for 1 h. The mixture was then brought to 130° C. and stirred for an additional 2 h. The reaction turned black during this time. After cooling to RT, the tar was taken up in EtOAc (100 mL). The resulting solution was washed with saturated aqueous sodium bicarbonate (2×50 mL), brine (50 mL), dried over MgSO4, filtered and concentrated in vacuo. Purification by flash chromatography (Silica, EtOAc/Hexanes) gave 8-phenyl-7,8-dihydropyrano[3,4-e][1,3]oxazine-2,4(3H,5H)-dione (2.58 g, 10.52 mmol, 61.8% yield) as a brown solid. LC-MS (M+H)+=246.0. 1H NMR (500 MHz, MeOD) δ ppm 7.34-7.41 (4 H, m), 7.29-7.34 (1 H, m), 4.42-4.63 (2 H, m), 4.08-4.15 (1 H, m), 3.94 (1 H, dd, J=11.44, 4.12 Hz), 3.85 (1 H, ddd, J=4.20, 2.44, 2.21 Hz).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:27][N:28]2[CH2:31][CH:30]([C:32]([O:34]C)=[O:33])[CH2:29]2)[S:6][C:7]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[CH:15][CH:14]=2)[O:10][N:9]=1)[CH3:2].O.[OH-].[Li+].C(O)(=O)C>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH2:27][N:28]2[CH2:31][CH:30]([C:32]([OH:34])=[O:33])[CH2:29]2)[S:6][C:7]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:14]=[CH:15][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[CH:17][CH:18]=2)[O:10][N:9]=1)[CH3:2]
Reactant: CCc1cc(CN2CC(C(=O)OC)C2)sc1-c1noc(-c2ccc(Oc3cccc(F)c3)cc2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CCc1cc(CN2CC(C(=O)O)C2)sc1-c1noc(-c2ccc(Oc3cccc(F)c3)cc2)n1
Yield: 54.1 %

Procedure:
The title compound (83 mg) was synthesized in a yield of 54% as a white crystalline solid by conducting the reaction similar to that mentioned in Example 2 (2e) using methyl 1-[(4-ethyl-5-{5-[4-(3-fluorophenoxy)phenyl]-1,2,4-oxadiazol-3-yl}-2-thienyl)methyl]azetidine-3-carboxylate (0.16 mg, 0.32 mmol) that was obtained in Example 17 (17c), lithium hydroxide monohydrate (30 mg, 0.71 mmol), and acetic acid (39 μL, 0.71 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[CH:3]=1.[Br:11]NC(=O)CCC(N)=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH2:10][Br:11])[CH:3]=1
Reactant: NC(=O)CCC(=O)NBr
Reactant: Cc1cc(Cl)ccc1C#N
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(Cl)cc1CBr
Yield: 40 %

Procedure:
To a stirred solution 4-Chloro-2-methyl-benzonitrile 1(5.0 g, 33.0 mmol) in carbon tetrachloride (150 mL) was added N-bromosuccinamide (7.6 g, 42.9 mmol) and 2,2′-azobisisobutyronitrile (cat.). The reaction mixture was refluxed 6 hrs, filtered, concentrated, and partitioned between ether and water. The ether layer was dried, concentrated, and purified by silica gel chromatography (10% ether/hexanes) to yield a white solid (40%). 1H NMR (400 MHz, CDCl3) δ7.61 (d, J=8.3 Hz, 1 H, Ar), 7.57 (d, J=2.2 Hz, 1 H, Ar), 7.41 (dd, J=8.3, 2.0 Hz, 1 H, Ar), 4.59 (s, 2 H, CH2).
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][CH:17]([CH:22]=O)[CH2:16][CH2:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[NH:24]1[CH2:29][CH2:28][CH:27]([C:30]([OH:32])=[O:31])[CH2:26][CH2:25]1.C(O)C.C([BH3-])#N.[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>>[C:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][CH:17]([CH2:22][N:24]2[CH2:29][CH2:28][CH:27]([C:30]([OH:32])=[O:31])[CH2:26][CH2:25]2)[CH2:16][CH2:15]3)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)C1CCNCC1
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3c(c2)CCC(C=O)C3)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3c(c2)CCC(CN2CCC(C(=O)O)CC2)C3)CC1
Temperature: 25 °C

Procedure:
A solution of 6-(trans-4-tert-butyl-cyclohexyloxy)-1,2,3,4-tetrahydro-naphthalene-2-carbaldehyde (34.5 mg, 0.110 mmol) and piperidine-4-carboxylic acid (14.2 mg, 0.110 mmol) in ethanol (0.8 mL, 10 mmol) was heated to reflux for 2 h. The yellow solution was cooled to room temperature and sodium cyanoborohydride (8.27 mg, 0.132 mmol) was added and heated to reflux for 1 h. After cooled down to room temperature, citric acid was added and concentrated down. The solid was suspended in water and filtered and the collected solid was washed thoroughly with water. HPLC purification of the solid gave the product (1.6 mg (3.4%). LCMS Rt=1.76 min, m/z=428.42 [M+1]. 1H NMR (400 MHz, METHANOL-d4) δ ppm 0.91 (s, 9H), 1.02-1.48 (m, 10H), 1.80-2.47 (m, 11H), 2.47-3.01 (m, 3H), 3.66-3.96 (m, 3H), 4.07-4.26 (m, 1H), 6.67-6.83 (m, 2H), 6.99-7.15 (m, 1H).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:15]=[C:14]([C@@H:16]4[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]4)[N:13]([CH3:29])[N:12]=3)[CH:9]=2)[NH:4][N:3]=1.[N:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[CH3:29][N:13]1[C:14]([C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:17]2)=[N:15][C:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][N:3]=[C:2]3[C:33]2[CH:34]=[CH:35][N:30]=[CH:31][CH:32]=2)=[N:12]1
Reactant: Cn1nc(-c2ccc3[nH]nc(Br)c3c2)nc1[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: OB(O)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1nc(-c2ccc3[nH]nc(-c4ccncc4)c3c2)nc1[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Yield: 604.5 %

Procedure:
Stirred a mixture of (R)-tert-butyl 3-(3-(3-bromo-1H-indazol-5-yl)-1-methyl-1H-1,2,4-triazol-5-yl)piperidine-1-carboxylate (50 mg, 0.0108 mmol), 4-pyridyl boronic acid (50 mg, 0.409 mmol), PdCl2dppf (10 mg, 0.0136 mmol), cesium carbonate (60 mg, 0.1846 mmol) in dioxane/H2O (v/v 3/1, 4 ml) at 100° C. in a microwave oven for 2 hours. Reaction was cooled, extracted with DCM (50 ml), washed with H2O (20 ml). Dried (Na2SO4), filtered and solvent evaporated to yield (R)-tert-butyl 3-(1-methyl-3-(3-(pyridin-4-yl)-1H-indazol-5-yl)-1H-1,2,4-triazol-5-yl)piperidine-1-carboxylate as a white solid (30 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[CH:3]=1.[N:10]1[CH:15]=[CH:14][CH:13]=[C:12](B2OC(C)(C)C(C)(C)O2)[CH:11]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O.C(OCC)(=O)C.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>[Cl:9][C:4]1[CH:3]=[C:2]([C:12]2[CH:11]=[N:10][CH:15]=[CH:14][CH:13]=2)[CH:7]=[C:6]([Cl:8])[CH:5]=1
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
Reactant: Clc1cc(Cl)cc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: Clc1cc(Cl)cc(-c2cccnc2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 114.2 %

Procedure:
Synthesized according to General Procedure 36. A mixture of 1-bromo-3,5-dichloro-benzene (424 mg, 1.88 mmol), 3-pyridineboronic acid pinacol ester (500 mg, 2.44 mmol), aqueous 2M Na2CO3 (1.96 mL, 3.93 mmol) and Pd(PPh3)4 (89 mg, 4 mol %) in anhydrous toluene (18 mL) was stirred overnight at 80° C. under nitrogen. The reaction was cooled down to room temperature, diluted with water (5 ml) and ethyl acetate (10 ml). The organic phase was separated, dried (Na2SO4), filtered and concentrated under reduced pressure to give a pale yellow oil, which was purified by silica-gel column chromatography to give 3-(3,5-dichlorophenyl)pyridine (481 mg, 74%) as a white solid. 1H-NMR (400 MHz, CDCl3) δ 8.81 (d, J=2.1 Hz, 1H), 8.65 (dd, J=1.4, 4.8 Hz, 1H), 7.85-7.82 (m, 1H), 7.46 (d, J=1.8 Hz, 2H), 7.41-7.38 (m, 2H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=224.3; tR=1.21 min.
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH2:6]([N:13](/[CH:17]=[CH:18]/[CH2:19][CH3:20])C(=O)C)[C:7]1[CH:12]=CC=CC=1.[ClH:21]>CN(C=O)C>[Cl:21][C:6]1[CH:7]=[CH:12][C:18]([CH2:19][CH3:20])=[CH:17][N:13]=1
Reactant: Cl
Reactant: CC/C=C/N(Cc1ccccc1)C(C)=O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1ccc(Cl)nc1
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 19 %

Procedure:
To DMF (3.8 mL) at 5° C., was added POCl3 (1.4 mL) dropwise. After 5 minutes, 62b (1 g, 4.9 mmol) was added dropwise in 2 mL of DMF. The mixture was heated to 100° C. overnight. The mixture was allowed to cool to room temperature and was added dropwise to 50 mL of 1N HCl. The solution was extracted 3 times with ethyl acetate. The combined organic layer was dried, evaporated, then purified by column chromatography (eluent: 0 to 30% EtOAc in hexane) to give 0.13 g of 62c (19% yield).
Reaction SMILES: [SH:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[CH3:13][N:14]([CH3:18])[C:15](Cl)=[O:16]>N1C=CC=CC=1>[CH3:13][N:14]([CH3:18])[C:15]([S:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1)=[O:16]
Reactant: Sc1nc(-c2ccccc2)c[nH]1
Reactant: CN(C)C(=O)Cl
Solvent: c1ccncc1
Product: CN(C)C(=O)Sc1nc(-c2ccccc2)c[nH]1
Temperature: 70 °C
Yield: 34.2 %

Procedure:
In 50 ml of pyridine was dissolved 5.0 g (28.4 millimoles) of 2-mercapto-4-phenylimidazole, and 3.13 ml (34.1 millimoles) of N,N-dimethylcarbamoyl chloride was added to the solution and the mixture was heated at 70° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, and 200 ml of water and 200 ml of chloroform were added to the concentrate to effect extraction. The chloroform layer was concentrated and the concentrate was recrystallized from ethanol to obtain 2.4 g (yield=34%) of intended 2-(N,N-dimethylcarbamoylthio)-4-phenylimidazole (compound No. 21) in the form of a colorless crystal.
Reaction SMILES: C1COCC1.[CH:6]1([C:9]2[CH:14]=[C:13]([C:15](OC)=[O:16])[C:12]([O:19][CH2:20][CH3:21])=[CH:11][C:10]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:8][CH2:7]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O>[CH:6]1([C:9]2[CH:14]=[C:13]([CH:15]=[O:16])[C:12]([O:19][CH2:20][CH3:21])=[CH:11][C:10]=2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:8][CH2:7]1
Reactant: CCOc1cc(-c2ccccc2)c(C2CC2)cc1C(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc(-c2ccccc2)c(C2CC2)cc1C=O
Reaction time: 0.08 h
Yield: 69.9 %

Procedure:
A THF (10 mL) solution of methyl 2-cyclopropyl-5-ethoxybiphenyl-4-carboxylate (1.80 g) was added to a THF (20 mL) suspension of lithium aluminum hydride (500 mg) under ice cooling in a nitrogen atmosphere. After stirring at the same temperature as above for 30 minutes, water (0.5 mL) and a 15% aqueous sodium hydroxide solution (0.5 mL) were added thereto, and the mixture was stirred for 5 minutes. Water (1.5 mL) was further added to the reaction mixture, and the mixture was stirred for 30 minutes and then filtered. The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate). Manganese dioxide (4.73 g) was added to a toluene (80 mL) solution of the obtained purified product, and the mixture was stirred at 60° C. for 1 hour in a nitrogen atmosphere. The reaction mixture was filtered, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (1.13 g).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23](I)[CH:22]=1.C([Sn](CCCC)(CCCC)[C:34]1[CH:39]=[N:38][CH:37]=[CH:36][N:35]=1)CCC>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:34]2[CH:39]=[N:38][CH:37]=[CH:36][N:35]=2)[CH:22]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(I)c2)c1N
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(-c3cnccn3)c2)c1N
Temperature: 160 °C
Yield: 5.2 %

Procedure:
To a stirred solution of 3-[5-amino-4-(3-iodo-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide (130 mg, 0.27 mmol) and 2-tributylstannylpyrazine (119 mg, 0.32 mmol) in DMF (2 mL) was added tetrakis(triphenylphosphine) palladium (catalytic) and the mixture was heated in microwave at 160° C. for 15 min. The solvent was removed and the residue was dissolved in EtOAc. The organics were washed by water, brine and concentrated. The crude material was purified by preparatory HPLC to provide the desired product as beige solid (6.2 mg, 5%). HPLC (4 minute 10-90 gradient) tR 2.12 min; MS m/z 439.19 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]3=[O:20])[CH:11]=[C:10]([C:21](O)=[O:22])[CH:9]=2)=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[CH3:47][C:48]1[N:53]=[CH:52][C:51]([C@H:54]([NH2:56])[CH3:55])=[CH:50][N:49]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]3=[O:20])[CH:11]=[C:10]([C:21]([NH:56][C@@H:54]([C:51]3[CH:50]=[N:49][C:48]([CH3:47])=[N:53][CH:52]=3)[CH3:55])=[O:22])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ncc([C@@H](C)N)cn1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(N3CCCCC3=O)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)N[C@H](C)c3cnc(C)nc3)cc(N3CCCCC3=O)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4′-methyl-5-(2-oxopiperidin-1-yl)biphenyl-3-carboxylic acid (45 mg, 0.14 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (56 mg, 0.29 mmol), 1-hydroxybenzotriazole hydrate (22 mg, 0.15 mmol), and CH2Cl2 (3 mL) were added (R)-1-(2-methylpyrimidin-5-yl)ethanamine (30 mg, 0.22 mmol) and N,N-diisopropylethylamine (51 μL, 0.29 mmol). The mixture was stirred at room temperature overnight and then concentrated. The residue was purified by preparative HPLC (100×20.2 mm, C18 column; 30-80% CH3CN-water [10 mM Et2NH]) to afford a white foam.