Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH:7]([CH3:13])[C:8]([O:10]CC)=O)[C:3]1=[O:14].[CH3:15][C@H:16]1[CH2:21][CH2:20][CH2:19][C@@H:18]([CH3:22])[N:17]1[CH2:23][CH2:24][NH2:25]>>[CH3:15][C@H:16]1[CH2:21][CH2:20][CH2:19][C@@H:18]([CH3:22])[N:17]1[CH2:23][CH2:24][NH:25][C:8](=[O:10])[CH:7]([N:4]1[CH2:5][CH2:6][CH:2]([OH:1])[C:3]1=[O:14])[CH3:13]
Reactant: CCOC(=O)C(C)N1CCC(O)C1=O
Reactant: C[C@@H]1CCC[C@H](C)N1CCN
Product: CC(C(=O)NCCN1[C@H](C)CCC[C@@H]1C)N1CCC(O)C1=O

Procedure:
1.5 g of ethyl (R/S)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)propionate are left to stand at room temperature for 24 hours with 2.45 g of cis-2-(2,6-dimethyl-1-piperidinyl)ethylamine. Thereafter, the excess cis-2-(2,6-dimethyl-1-piperidinyl)ethylamine is distilled off in a high vacuum and the residue (3.5 g) is chromatographed on 30 g of silica gel (granular size 0.2-0.5 mm). The (R/S)-cis-N-[2-(2,6-dimethyl-1-piperidinyl)ethyl]-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)propionamide which is eluted with methanol has a melting point of 129°-130° after recrystallization from ethyl acetate.
Reaction SMILES: I[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[O:11][CH2:12][CH2:13][C:3]=12.[F:14][C:15]([F:31])([F:30])[C@H:16]1[CH2:21][NH:20][CH2:19][C@@H:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:17]1.CCN(C(C)C)C(C)C>CCO>[N+:8]([C:7]1[C:2]([N:20]2[CH2:21][C@H:16]([C:15]([F:31])([F:30])[F:14])[CH2:17][C@H:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:19]2)=[C:3]2[CH2:13][CH2:12][O:11][C:4]2=[N:5][CH:6]=1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNC[C@H](C(F)(F)F)C1
Reactant: O=[N+]([O-])c1cnc2c(c1I)CCO2
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](C(F)(F)F)CN(c2c([N+](=O)[O-])cnc3c2CCO3)C1
Temperature: 120 °C
Reaction time: 18 h
Yield: 69.1 %

Procedure:
To a mixture of 4-iodo-5-nitro-2,3-dihydrofuro[2,3-b]pyridine (238.2 mg, 0.8157 mmol) and tert-butyl [(3S,5R)-5-(trifluoromethyl)piperidin-3-yl]carbamate (from MolBridge, 203.9 mg, 0.7600 mmol) was added EtOH (3.0 mL), followed by DIPEA (539.5 mg, 4.174 mmol). The mixture was stirred at 120° C. for 18 h. After cooling to room temperature, the reaction was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0-50% EtOAc in hexanes) to afford the sub-title compound as a yellow solid (227.1 mg, 69%). LCMS calc. for C18H24F3N4O5 (M+H)+: m/z=433.2. found 433.2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][C:16]([C:20]([O:22]CC)=[O:21])=[CH:17][CH:18]=2)[CH:13]=[N:12]1.[OH-].[Na+]>C(O)C.O>[N:3]1[CH:4]=[CH:5][CH:6]=[N:1][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH:18]=2)[CH:13]=[N:12]1
Reactant: CCOC(=O)c1ccc2c(cnn2CCCNc2ncccn2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc2c(cnn2CCCNc2ncccn2)c1
Yield: 89.3 %

Procedure:
The product of step A (510 mg, 1.16 mmol) was dissolved in ethanol (50 mL) and sodium hydroxide (6.5 mL of a 1N solution, 6.5 mmol) added. The solution was heated at reflux for 1.5 hours, diluted with water (45 mL), and the ethanol removed under vacuum. The solution was acidified to pH=3 with 1N HCl (˜7 mL) with stirring. The resulting solids were filtered, washed with water, and dried under vacuum to afford the product (308 mg, 89%).
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5](=[O:18])[N:6]([CH2:8][CH2:9][O:10][Si](C(C)(C)C)(C)C)[CH:7]=1.Cl>CO>[Br:1][C:2]1[N:3]=[CH:4][C:5](=[O:18])[N:6]([CH2:8][CH2:9][OH:10])[CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OCCn1cc(Br)ncc1=O
Agent: Cl
Solvent: CO
Product: O=c1cnc(Br)cn1CCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
The crude 5-bromo-1-(2-(tert-butyldimethylsilyloxy)ethyl)pyrazin-2(1H)-one was dissolved in MeOH (30 mL) and concentrated HCl (0.15 mL) was added, and the reaction was stirred at room temperature. After 1 hour, the reaction was quenched with saturated sodium bicarbonate (3 mL) and then concentrated. The concentrate was treated with 5:1 CH2Cl2/MeOH and filtered. The filtrate was concentrated, and put on high vacuum in water bath (50° C.). This solid was washed with hexanes (50 mL) in portions, and then put on high vacuum again to afford the desired product (870.8 mg, 3.98 mmol, 90% purity, 52% yield over two steps). MS (ESI pos. ion) m/z (MH+): 219 (79Br), 221 (81Br). Calc'd exact mass for C18H13BrFN3O2: 218 (79Br), 220 (81Br). 1H NMR (400 MHz, CDCl3): 8.01 (s, 1H), 7.49 (s, 1H), 5.33 (br s, 1H), 4.08 (t, J=4.5 Hz, 2H), 3.96 (t, J=4.5 Hz, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[O:12][CH2:11][C:10]1[N:5]2[CH:6]([CH3:17])[C:7](=[O:16])[NH:8][N:9]=1.[C:18]([O:22][C:23]([N:25]1[CH2:28][C:27](=[CH2:29])[CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.C(N(CC)CC)C>CC#N.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:18]([O:22][C:23]([N:25]1[CH2:28][C:27](=[CH:29][C:2]2[CH:3]=[C:4]3[C:13](=[CH:14][CH:15]=2)[O:12][CH2:11][C:10]2[N:5]3[CH:6]([CH3:17])[C:7](=[O:16])[NH:8][N:9]=2)[CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: C=C1CN(C(=O)OC(C)(C)C)C1
Reactant: CC1C(=O)NN=C2COc3ccc(Br)cc3N21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC1C(=O)NN=C2COc3ccc(C=C4CN(C(=O)OC(C)(C)C)C4)cc3N21
Temperature: 25 °C
Yield: 51.6 %

Procedure:
A solution of 6-bromo-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (Preparation #1, Step D, 0.30 g, 1.013 mmol), 3-methylene-azetidine-1-carboxylic acid tert-butyl ester (0.343 g, 2.026 mmol), Pd(OAc)2 (0.023 g, 0.101 mmol), tri-O-tolylphosphine (0.0617 g, 0.203 mmol) and triethylamine (0.308 mg, 3.04 mmol) in CH3CN (10 mL) was heated at 110° C. for 14 h. The mixture was cooled to ambient temperature and the solvent was removed in vacuo. The residue was purified by preparative TLC (eluting with 50% EtOAc in petroleum ether) to give 3-(4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylmethylene)-azetidine-1-carboxylic acid tert-butyl ester as yellow solid (0.201 g, 52%), which was used directly in the next step. LC/MS (Table 1, Method 2) Rt=1.264 min; MS m/z: 385 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][O:11][CH2:12][C:13]([NH:15][C:16]([C:18]2[C:23](Cl)=[N:22][CH:21]=[CH:20][N:19]=2)=[O:17])=[NH:14])[CH:5]=[CH:6][C:7]=1[F:8].C([O-])([O-])=O.[K+].[K+].O.Cl>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][O:11][CH2:12][C:13]2[NH:15][C:16](=[O:17])[C:18]3[C:23](=[N:22][CH:21]=[CH:20][N:19]=3)[N:14]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N=C(COCCc1ccc(F)c(Cl)c1)NC(=O)c1nccnc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]c(COCCc2ccc(F)c(Cl)c2)nc2nccnc12
Temperature: 100 °C
Yield: 45.1 %

Procedure:
A mixture of crude 3-chloro-pyrazine-2-carboxylic acid{2-[2-(3-chloro-4-fluoro-phenyl)-ethoxy]-1-imino-ethyl}-amide (300 mg) and K2CO3 (223 mg, 1.616 mmol) in DMF (3 ml) was heated to 100° C. for 2 h. Then water was added and the pH was adjusted to 5 by addition of 0.1 N HCl. The brown precipitate that formed was filtered off, washed with water and dried. The resulting solid was triturated with Et2O. The remaining solid was filtered off, washed with a small amount of Et2O and dried to give the title compound as a light brown solid (122 mg, 45%). MS: m/e=335.2 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[CH:5]2
Reactant: O=C1NCCc2cc(F)ccc21
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: O=c1[nH]ccc2cc(F)ccc12
Temperature: 100 °C
Yield: 36.5 %

Procedure:
6-Fluoro-3,4-dihydro-2H-isoquinolin-1-one (149 mg, 0.903 mmol) was dissolved in 3 mL 1,4-dioxane. Argon was bubbled through this solution for 1 minute and 2,3-dichloro-5,6-dicyano-p-benzoquinone (205 mg, 0.903 mmol) was added. This was heated at 100° C. for 24 hours. The resulting mixture was partitioned between ethyl acetate and 1M aq. sodium hydroxide. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by flash chromatography (50% ethyl acetate/hexanes) to yield 6-Fluoro-2H-isoquinolin-1-one (54 mg, 0.33 mmol). MS (ESI) 164.1 (M+H)−.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[CH2:3][S:4][C:5]1[N:10]=[C:9]([N:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1.ClC1C=C(C=CC=1)C(OO)=[O:29]>C(Cl)(Cl)Cl>[F:23][C:2]([F:1])([F:22])[CH2:3][S:4]([C:5]1[N:10]=[C:9]([N:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)=[O:29]
Reactant: O=c1c2ccccc2ncn1-c1ccnc(SCC(F)(F)F)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: O=c1c2ccccc2ncn1-c1ccnc(S(=O)CC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 30.4 %

Procedure:
3-[2-(2,2,2-Trifluoro-ethylsulfanyl)-pyrimidin-4-yl]-3H-quinazolin-4-one (1.1 g, 3.25 mmol) was dissolved in 20 mL chloroform, and m-chloroperoxybenzoic acid (m-CPBA) (0.7 g, 3.57 mmol, 85% of purity) was added at room temperature. The reaction mixture was stirred for 3 hours at room temperature. Washing with sodium-thiosulfate solution and sodium-hydrogencarbonate, drying with Na2SO4 and the crude product was purified by prep-TLC and then prep-HPLC to give 3-[2-(2,2,2-trifluoro-ethylsulfinyl)pyrimidin-4-yl]-3H-quinazolin-4-one (0.35 g, 30.5%) as an off-white solid.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5].[Cl:26][C:27]1[CH:32]=[CH:31][C:30](I)=[CH:29][N:28]=1.C([Mg]Cl)(C)C>C1COCC1>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4]([C:30]3[CH:29]=[N:28][C:27]([Cl:26])=[CH:32][CH:31]=3)=[O:5])=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Reactant: Clc1ccc(I)cn1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=C(c1ccc(Cl)nc1)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 275 mg (0.68 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 3 mL THF and 360 mg (1.51 mmol) of 2-chloro-5-iodo-pyridine in 2 mL THF with 0.79 mL 2M isopropylmagnesium chloride. Yield: 187 mg of a white powder. LC-MSD, m/z for C21H13BrClN3O2 [M+H]+=454.0, 456.0; HPLC retention time: 2.2 min.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][C:5]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:3])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:49][CH2:50][C:51]1[C:52]([OH:59])=[N:53][C:54]([CH3:58])=[CH:55][C:56]=1[CH3:57]>ClCCl>[OH:59][C:52]1[C:51]([CH2:50][NH:49][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][C:4]([CH:1]([CH3:2])[CH3:3])=[C:5]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:6]=2)=[C:56]([CH3:57])[CH:55]=[C:54]([CH3:58])[N:53]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: CC(C)c1ccc(C(=O)O)cc1Oc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)C)c(Oc3ccccc3)c2)c(O)n1
Reaction time: 0.5 h
Yield: 32.8 %

Procedure:
To a solution of 4-isopropyl-3-phenoxybenzoic acid (100 mg, 0.39 mmol) in dichloromethane (20 mL) were added N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (96 mg, 0.50 mmol), N-hydroxy benzotriazole (68 mg, 0.50 mmol) and triethylamine (175 mg, 1.73 mmol). The resultant reaction mixture was stirred for 30 minutes. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (61 mg, 0.40 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified through pre-HPLC and the obtained solution was freeze-dried to afford N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-isopropyl-3-phenoxy benzamide (50 mg, 32.8%) as a white solid. LRMS (M+H+) m/z: calcd 391.19. found 391 HPLC purity (214 nm): 90.4%. 1H NMR (300 MHz, DMSO) δ 7.58 (m, 1H), 7.55 (m, 1H), 7.33 (m, 3H), 7.07 (m, 1H), 6.89 (m, 2H), 6.07 (s, 1H), 4.44 (s, 2H), 3.31 (m, 1H), 2.32 (s, 3H), 2.22 (s, 3H), 1.24 (d, J=9 Hz, 6H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH2:12][CH3:13])[N:8]=[C:7]2[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.C(COC)OC.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.CC(C)([O-])C.[Na+]>O>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:7]2[C:6]3[C:10](=[C:2]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[CH:3]=[CH:4][CH:5]=3)[N:9]([CH2:11][CH2:12][CH3:13])[N:8]=2)=[CH:15][CH:16]=1
Reactant: CCCn1nc(-c2ccc(OC)cc2)c2cccc(Cl)c21
Reactant: C1COCCN1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCCn1nc(-c2ccc(OC)cc2)c2cccc(N3CCOCC3)c21
Temperature: 25 °C
Yield: 61.6 %

Procedure:
To a stirred solution of 7-chloro-3-(4-methoxyphenyl)-1-propyl-1H-indazole (0.218 g, 0.73 mmol) in anhydrous degassed dimethoxyethane (3 mL) was added morpholine (0.076 mL, 0.84 mmol) and sodium t-butoxide (0.098 g, 1.02 mmol). Tris(dibenzylidene-acetone)dipalladium(0) (0.010 g, 0.011 mmol) and 2-dicyclohexyl phosphino-2′-(N,N-dimethylamino)biphenyl (0.09 g, 0.23 mmol) were added and the reaction refluxed for 90 minutes. The reaction was cooled to room temperature and water added. The mixture was extracted with ethyl acetate and the organic layer washed with water and saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the organic phase was filtered and the filtrate evaporated in vacuo to yield crude title compound. The oil was purified by silica gel column chromatography eluting with hexane/ethyl acetate (5/1 to 3/1) to provide the title compound as a white solid (0.157 g, 0.45 mmol, 63%). An analytical sample was crystallized from hexane.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:22])[C:6]=1[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1.C(OC([NH:30][C:31]1[S:35][C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[F:42])=[N:33][C:32]=1[C:43](O)=[O:44])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[NH2:30][C:31]1[S:35][C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[F:42])=[N:33][C:32]=1[C:43]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:22])[C:6]=1[NH:7][CH2:8][CH:9]1[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]1)=[O:44]
Reactant: Cn1ncc(N)c1NCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2ccccc2F)nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cn1ncc(NC(=O)c2nc(-c3ccccc3F)sc2N)c1NCC1CCNCC1
Yield: 10 %

Procedure:
Following the procedures as described in Example 113, tert-butyl 4-((4-amino-1-methyl-1H-pyrazol-5-ylamino)methyl)piperidine-1-carboxylate and 5-(tert-butoxycarbonylamino)-2-(2-fluorophenyl)thiazole-4-carboxylic acid, and HATU were reacted to give 104 as a white solid (5.4 mg, 10%) over two steps. 1H NMR (400 MHz, DMSO) δ 9.06 (s, 1H), 8.32 (dd, J=15.5, 6.0, 2H), 7.52-7.24 (m, 6H), 4.95 (t, J=6.7, 1H), 3.61 (s, 4H), 2.96 (t, J=22.0, 3H), 2.82 (t, J=6.5, 2H), 1.77 (d, J=12.5, 2H), 1.58 (s, 1H), 1.25-1.04 (m, 2H). ESIMS m/z=430.1 (M+1)
Reaction SMILES: [CH2:1]([SnH:5]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[Li+].CC([N-]C(C)C)C.Cl[C:23]1[N:28]=[C:27]([NH:29][C@@H:30]2[CH2:35][CH2:34][CH2:33][N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:31]2)[CH:26]=[N:25][CH:24]=1>C1COCC1>[CH2:10]([Sn:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:6][CH2:7][CH2:8][CH3:9])[C:23]1[N:28]=[C:27]([NH:29][C@@H:30]2[CH2:35][CH2:34][CH2:33][N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:31]2)[CH:26]=[N:25][CH:24]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2cncc(Cl)n2)C1
Reactant: CCCC[SnH](CCCC)CCCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cncc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 40.1 %

Procedure:
To a solution of (R)-tert-butyl 3-aminopiperidine-1-carboxylate (1.53 g, 7.6 mmol) in DMF (76 mL) was added Et3N (22 mmol) stirred for 15 min. 2-6-Dichloro pyrazine (1.14 g, 76 mmol) was added at RT and the reaction mixture was stirred at 100° C. overnight. The resulting reaction mixture was quenched with ice cold water and precipitate was formed. The precipitate was collected by filtration, washed with ice cold water and dried to obtain (R)-tert-butyl 3-(6-chloropyrazin-2-ylamino)piperidine-1-carboxylate (1.1 g, 43%). MS (ESI, pos. ion) m/z: 313 (M+1). To a solution of tributyltin hydride (1.39 g, 4.8 mmol) in THF (25 mL) at 0° C. was added LDA (1.8 M; 0.5 mL, 4.8 mmol) and stirred at the same temperature for 10 min. (R)-tert-butyl 3-(6-chloropyrazin-2-ylamino)piperidine-1-carboxylate (1.1 g) was added at 0° C. and the reaction mixture was stirred at RT for an additional 3 h. The resulting mixture was quenched with 10% KF aqueous solution and extracted with EtOAc. The organic layer was separated, dried over Na2SO4 and concentrated to dryness. The crude product was purified by column chromatography, using basic alumina, and eluting with 10% EtOAc/hexane to obtain pure (R)-tert-butyl 3-(6-(tributylstannyl)pyrazin-2-ylamino)piperidine-1-carboxylate (0.8 g, 48%). MS (ESI, pos. ion) m/z: 569.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([NH:12][NH:13][C:14](=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>C1COCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[S:30][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:13][N:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(=O)NNC(=O)CNC(=O)OC(C)(C)C
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1nnc(CNC(=O)OC(C)(C)C)s1
Yield: 261.8 %

Procedure:
To the solution of ethyl 2-(2-(2-(tert-butoxycarbonylamino)acetyl) hydrazinyl)-2-oxoacetate (9-4) (228 mg, 0.6913 mmol) in THF (10 mL) was added lawesson's reagent (354 mg, 0.8669 mmol). The solution was heated to reflux for 3 h. Then solvent was evaporated under reduced pressure and the residue was purified by chromatography on silica gel with the eluant (PE/EA/NEt3=10/1/1%; 5/1/1%; 2/1/1%). The yellow solid was obtained as the product (520 mg, 69%). 1H NMR (500 MHz, CDCl3) δ 5.31 (br, 1H), 4.76 (d, J=6.1 Hz, 2H), 4.51 (d, J=14, 7.1 Hz, 2H), 1.60-1.39 (m, 12H); LRMS (ESI) calculated M+H for C11H18N3O4S: 288.3; Found: 288.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[CH:11]1([C:14]2[CH:15]=[C:16]([CH3:26])[C:17]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[N:18][CH:19]=2)[CH2:13][CH2:12]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:23]2[CH2:24][CH2:25][N:20]([C:17]3[C:16]([CH3:26])=[CH:15][C:14]([CH:11]4[CH2:12][CH2:13]4)=[CH:19][N:18]=3)[CH2:21][CH2:22]2)=[O:10])=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cn2)CC1
Yield: 47 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 60 and using 5-bromo-2-picolinic acid (1.5 g) and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (1.8 g) described in Preparation Example 96, the title compound (1.4 g) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1)O.P(Br)(Br)[Br:16]>>[Br:16][CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1)[C:3]([O:2][CH3:1])=[O:14]
Reactant: COC(=O)C(O)c1cccc(OC)c1
Reactant: BrP(Br)Br
Product: COC(=O)C(Br)c1cccc(OC)c1

Procedure:
Methyl-m-methoxymandelate is reacted with phosphorous tribromide by the method of I. P. Beletskaya, Zh. Obshch. Khim., 34, 321 (1964) to give methyl bromo-(m-methoxyphenyl)acetate as a pale yellow liquid, and used below (without further purification).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1.[Cl:23][C:24]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[C:26]([F:39])[C:25]=1[OH:40]>>[Cl:23][C:24]1[CH:29]=[C:28]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[CH:27]=[C:26]([F:39])[C:25]=1[OH:40]
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1NC1CCN(C)CC1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)nc2c1NC1CCN(C)CC1
Yield: 46.6 %

Procedure:
Following general procedure II, 1-{6-chloro-4-[(1-methylpiperidin-4-yl)amino]-1,5-naphthyridin-3-yl}ethanone (69 mg, 0.22 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (88 mg, 0.32 mmol) to afford the desired product (44 mg, 47%) as a yellow solid: 1H NMR (500 MHz, CD3OD+D2O) δ 8.94 (s, 1H), 8.15 (s, 2H), 7.92 (s, 1H), 7.74 (dd, J=12.0, 2.2 Hz, 1H), 5.70-5.62 (m, 1H), 3.17-3.12 (m, 2H), 2.71 (s, 3H), 2.69-2.64 (m, 2H), 2.53 (s, 3H), 2.37-2.35 (m, 2H), 1.85-1.82 (m, 2H); ESI MS m/z 429 [M+H]+; HPLC>99% (AUC), tR=8.80 min.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:27]=[CH:28][CH:29]=3)[CH2:19][S:20][CH2:21][CH2:22][C:23]([O:25]C)=[O:24])=[O:15])=[C:9]([C:30]([C:32]3[NH:33][C:34]4[C:39]([CH:40]=3)=[CH:38][CH:37]=[C:36]([C:41]([F:44])([F:43])[F:42])[CH:35]=4)=[O:31])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[Li+]>O1CCCC1.O>[N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:27]=[CH:28][CH:29]=3)[CH2:19][S:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:15])=[C:9]([C:30]([C:32]3[NH:33][C:34]4[C:39]([CH:40]=3)=[CH:38][CH:37]=[C:36]([C:41]([F:43])([F:44])[F:42])[CH:35]=4)=[O:31])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)c2cc3ccc(C(F)(F)F)cc3[nH]2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)c2cc3ccc(C(F)(F)F)cc3[nH]2)c1
Temperature: 15 °C
Reaction time: 8 h

Procedure:
Into a 50 mL round bottom flask, was placed a solution of methyl 3-(3-((4-(piperidin-1-yl)-2-(6-(trifluoromethyl)-1H-indole-2-carbonyl)phenyl)carbamoyl)benzylthio)-propanoate (60 mg, 0.10 mmol, 1.00 equiv) in tetrahydrofuran (5 mL), and a solution of lithium hydroxide hydrate (100 mg, 2.50 mmol, 26.00 equiv) in water (2 mL). The solution was stirred overnight at 15° C. The solution was then diluted with 30 mL of water. The mixture was washed with 1×20 mL of ethyl acetate. The pH value of the solution was adjusted to 5 with 1N hydrochloric acid. The resulting solution was extracted with 2×30 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was dissolved in 2 mL of ether. The product was precipitated by the addition of hexane. The solids were collected by filtration. This resulted in 20 mg (34%) of 3-(3-((4-(piperidin-1-yl)-2-(6-(trifluoromethyl)-1H-indole-2-carbonyl)phenyl)-carbamoyl)-benzylthio)-propanoic acid as a orange solid. 1H-NMR (300 MHz, DMSO, ppm): δ 12.30 (1H, s), 10.36 (s, 1H), 7.94-7.91 (d, 1H), 7.76 (s, 1H), 7.68-7.58 (m, 2H), 7.65 (s, 1H), 7.47-7.44 (d, 1H), 7.40-7.32 (m, 2H), 7.25-7.24 (d, 2H), 7.12 (s, 1H), 3.74 (s, 2H), 3.19 (s, 4H), 2.5 (m, 4H), 1.56-1.64 (m, 6H), MS (ES, m/z): 610 [M+H]+.