Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][CH:14]=[CH:15][N:16]=2)=[CH:8][C:7]=1[C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1.C(Cl)CCl.CCOC(C)=O>C(Cl)Cl>[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][CH:14]=[CH:15][N:16]=2)=[CH:8][C:7]=1[C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:1](=[O:4])[CH3:2])=[CH:19][CH:18]=1
Reactant: CC(=O)O
Reactant: Cc1ccc(-c2ncco2)cc1-c1ccc(N)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CC(=O)Nc1ccc(-c2cc(-c3ncco3)ccc2C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into an 8 ml sealed tube, was placed acetic acid (48 mg, 0.80 mmol). This was followed by the addition of a solution of 2′-Methyl-5′-oxazol-2-yl-biphenyl-4-ylamine (100 mg, 0.40 mmol) in CH2Cl2 (2 g) with stirring for 10 mins in a bath of H2O/ice. This was followed by the addition of a solution of EDC (90 mg, 0.47 mmol) in CH2Cl2 (2 g). The resulting solution was allowed to react, with stirring, overnight while the temperature was maintained at room temperature. The reaction progress was monitored by TLC (EtOAc/PE=1:1). The resulting mixture washed 3 times with 10 ml of HCl(10%), 3 times with 10 ml of sat.NaHCO3 and 3 times with 10 ml of H2O. The organic layer was dried over Na2SO4. Removal of the solvents under reduced pressure afforded the title compound, N-(2′-Methyl-5′-oxazol-2-yl-biphenyl-4-yl)-acetamide, as a yellow solid (82 mg, 70%).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[C:15](=[O:21])[CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:22]([OH:24])=[O:23])[CH2:3]1.C(N(CC)CC)C.[CH2:32](I)[CH2:33][CH2:34][CH3:35]>CC(C)=O>[CH2:32]([O:23][C:22]([C@H:11]1[CH2:10][CH2:9][C@H:8]2[C@H:7]3[C@H:16]([C:15](=[O:21])[CH2:14][C@:12]12[CH3:13])[C@:17]1([CH3:20])[C@H:4]([CH2:3][C@H:2]([OH:1])[CH2:19][CH2:18]1)[CH2:5][CH2:6]3)=[O:24])[CH2:33][CH2:34][CH3:35]
Reactant: CCCCI
Reactant: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)O)[C@@]3(C)CC(=O)[C@@H]12
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCCCOC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C

Procedure:
A solution of 3α-hydroxy-11-oxo-5α-androstane-17β-carboxylic acid (521 mg.) in dry acetone (50 ml.) was refluxed with triethylamine (1.04 ml.) and n-butyl iodide (0.87 ml.) for 16 hours. The mixture was evaporated to a residue which was dissolved in chloroform, washed with water, dried (Na2SO4) and evaporated to a foam (534 mg.). A solution of the foam in ether was washed with saturated sodium bicarbonate solution and with water, dried (Na2SO4) and evaporated to give title compound (443 mg.) as a white foam, [α]D + 51°.
Reaction SMILES: [CH:1]([C@H:14]1[O:19][CH2:18][C@@H:17]([NH2:20])[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH:25]=O.C(O)(=O)C.[BH3-]C#N.[Na+]>ClCCCl.CO>[CH:1]([C@H:14]1[O:19][CH2:18][C@@H:17]([NH:20][CH2:25][C:24]2[CH:27]=[CH:28][C:29]([Cl:30])=[C:22]([Cl:21])[CH:23]=2)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: N[C@H]1CC[C@@H](C(c2ccccc2)c2ccccc2)OC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: CO
Product: Clc1ccc(CN[C@H]2CC[C@@H](C(c3ccccc3)c3ccccc3)OC2)cc1Cl
Yield: 74.1 %

Procedure:
Trans-5-amino-2-diphenylmethyl-tetrahydropyran 15 (0.1 g, 0.38 mmol) was reacted with 3,4-dichlorobenzaldehyde (0.066 g, 0.38 mmol) in the presence of glacial acetic acid (0.023 g, 0.38 mmol) in 1,2-dichloroethane (20 ml), and NaCNBH3 (0.03 g, 0.45 mmol) in methanol (5 ml) (Procedure D) to give compound 16i (0.12 g, 75%) as an oil.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([Cl:7])[CH3:6])=[O:3].[CH2:8]([OH:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].N1C=CC=CC=1>C(Cl)(Cl)Cl>[C:2](=[O:3])([O:26][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[O:4][CH:5]([Cl:7])[CH3:6]
Reactant: CC(Cl)OC(=O)Cl
Reactant: CCCCCCCCCCCCCCCCCCO
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCOC(=O)OC(C)Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1-Chloroethyl chloroformate (7.15 g, 50 mmol) and 1-octadecanol (13.53 g, 50 mmol) were suspended in chloroform (100 ml) at 0° C. Pyridine (3.96 g, 50 mmol) was added dropwise during 20 minutes, maintaining the temperature below 10° C. After stirring at room temperature for 24 hours the reaction mixture was washed four times with 1N hydrochloric acid, once with a saturated sodium bicarbonate solution and finally twice with water. The organic solution was dried with magnesium sulphate and the solvent was removed at reduced pressure. Yield: 19 g.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]1[CH:33]=[CH:32][C:31](OB(O)O)=[CH:30][CH:29]=1.O>O1CCCC1.C(=O)([O-])O.[Na+].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:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:31]3[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=3)=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(Br)cn2)cs1
Reactant: OB(O)Oc1ccc(F)cc1
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: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(-c3ccc(F)cc3)cn2)cs1
Yield: 60.5 %

Procedure:
Under nitrogen atmosphere, 2-[(4-{2-[(5-bromopyridin-2-yl)oxy]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (486 mg) synthesized in Example 100-1 and 4-fluorophenylboric acid (297 mg) were dissolved in tetrahydrofuran (10 mL) and sodium hydrogen carbonate (1 mol/l, 10 mL), tetrakis(triphenylphosphine)palladium (245 mg) was added, and the mixture was refluxed for 4.5 hr. The reaction mixture was cooled, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=10:1 to 5:1) to give the title compound (304 mg) as a pale-yellow oil.
Reaction SMILES: [CH2:1]1[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[S:4][S:3][CH2:2]1.ClC(OCC)=O.[CH:19]([NH2:22])([CH3:21])[CH3:20].[Zn:23]>C(#N)C.C(N(CC)CC)C>[Zn:23].[SH:4][CH:5]([CH2:1][CH2:2][SH:3])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:22][CH:19]([CH3:21])[CH3:20])=[O:12]
Reactant: CC(C)N
Reactant: O=C(O)CCCCC1CCSS1
Agent: CCOC(=O)Cl
Agent: [Zn]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)NC(=O)CCCCC(S)CCS
Temperature: -65 °C
Reaction time: 1 h

Procedure:
4.2 g of DL-α-lipoic acid and 2.4 g of triethylamine were dissolved in 50 ml of acetonitrile and cooled down to −65° C. with stirring. To this was gradually added 2.4 g of ethyl chloroformate dropwise. Twenty minutes after the completion of the dropwise addition, 1.5 g of isopropylamine dissolved in 30 ml of acetonitrile was quickly added, and stirring was continued for 30 minutes and, further one hour at room temperature. The solvent was evaporated under reduced pressure, and water was added to the residue and the mixture then was cooled down. Precipitated pale yellow crystals were collected by filtration, dissolved in 60 ml of tetrahydrofuran (THF). To this were added 20 ml of 50% acetic acid aqueous solution and 2.0 g of zinc powder and reaction was allowed for two hours at 50° C. with stirring. Unreacted zinc was separated out by filtration, and the filtrate was concentrated. After addition of water to the residue, precipitated white crystals were collected by filtration. Recrystallized from THF/acetic acid/water gave 5.0 g of the aimed compound. mp. 271-273° C. TLC, Rf=0.89 (n-butanol/acetic acid/water=4/1/2).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[C:16]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:15]=2[CH2:29][NH2:30])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:39](Cl)([O:41]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[C:16]3[C:15]=2[CH2:29][NH:30][C:39](=[O:41])[N:21]3[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(F)ccc(NCc3ccccc3)c2CN)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2c(F)ccc3c2CNC(=O)N3Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
The crude 4-(2-aminomethyl-3-benzylamino-6-fluoro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester of step 3 was dissolved in 10 mL dichloromethane and cooled to 0° C. Triethylamine (293 μL, 3 eq., 2.1 mmol) and 69 mg (1 eq., 0.233 mmol) triphosgene were added. The reaction mixture was stirred for 10 minutes. The mixture partitioned between ethyl acetate and water, dried over magnesium sulfate and concentrated. Column chromatography, eluting with acetone/dichloromethane provided 141 mg of 4-(1-benzyl-6-fluoro-2-oxo-1,2,3,4-tetrahydro-quinazolin-5-yl)-piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22](O)=[O:23])=[CH:17][CH:16]=3)[CH:11]=[C:10]([C:25]([F:28])([F:27])[F:26])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.[NH3:35].CO>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([NH2:35])=[O:23])=[CH:17][CH:16]=3)[CH:11]=[C:10]([C:25]([F:27])([F:26])[F:28])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N
Reactant: O=C(O)Cc1ccc(Cc2cc(-c3cccc(Cl)c3)nc(C(F)(F)F)c2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: NC(=O)Cc1ccc(Cc2cc(-c3cccc(Cl)c3)nc(C(F)(F)F)c2)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 21 %

Procedure:
An 100-mL round bottom flask was charged with 2-(4-((2-(3-chlorophenyl)-6-(trifluoromethyl)pyridin-4-yl)methyl)phenyl)acetic acid (0.17 g, 0.42 mmol) in dichloromethane (10 ml). To this solution at 0° C. was added oxalyl chloride (0.18 mL, 2.10 mmol) followed by DMF (1 drop). After stirring for 5 h the volatile material was removed under reduced pressure to afford crude acid chloride. The residue was dissolved in dichloromethane (10 mL), cooled to 0° C., and 7N ammonia in methanol (10.0 mL, 70 mmol) was added. After stirring for 0.5 h, the volatile material was removed under reduced pressure. The residue was purified by chromatography on silica using hexanes/ethyl acetate (10:0 to 0:10) as eluent followed by chromatography on silica using dichloromethane/methanol (10:0 to 9:1) as eluent to afford the title compound (0.079 g, 21%) as an off-white solid. MW=404.81. M.p. 148-160° C. 1H NMR (DMSO-d6, 500 MHz) δ 8.33 (s, 1H), 8.17-8.15 (m, 1H), 8.11-8.05 (m, 1H), 7.76 (d, J=0.5 Hz, 1H), 7.60-7.55 (m, 2H), 7.41 (br s, 1H), 7.31 (d, J=8.0 Hz, 2H), 7.21 (d, J=8.0 Hz, 2H), 6.82 (br s, 1H), 4.11 (s, 2H), 3.32 (s, 2H); APCI MS m/z 405 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]([CH2:10][CH3:11])=[CH:5][O:6][CH2:7][CH2:8][Cl:9].[H][H]>CO.[C].[Pd]>[CH3:1][O:2][C:3](=[O:12])[CH:4]([CH2:10][CH3:11])[CH2:5][O:6][CH2:7][CH2:8][Cl:9]
Reactant: CCC(=COCCCl)C(=O)OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCC(COCCCl)C(=O)OC
Yield: 87 %

Procedure:
346.8 g 3-(2-Chloroethoxy)-2-ethyl-acrylic acid methyl ester was hydrogenated in 1200 ml methanol in the presence of 27 g 5% palladium-carbon catalyst at atmospheric pressure. The amount of hydrogen required to saturate the double bond was absorbed within approximately 90-120 minutes, whereupon the catalyst was filtered off, and the filtrate was partly evaporated. The residue was distilled in a vacuum to produce 305 g 3-(2-chloroethoxy)-2-ethyl-propionic acid methyl ester (87% yield) boiling at 110°-112° C./14 torr.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[N:22]([CH3:23])[CH2:21][CH:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]2[OH:30])[C:12]3=[O:31])=[CH:4][CH:3]=1.CN[C@@H]1CCCC[C@H]1NC>CO.[Cu]I>[OH:30][C@H:25]1[CH2:26][CH2:27][CH2:28][CH2:29][C@@H:24]1[N:13]1[C:12](=[O:31])[C:11]2[C:16](=[C:17]3[N:22]([CH3:23])[CH2:21][CH:20]=[CH:19][C:18]3=[C:9]([CH2:8][C:5]3[CH:6]=[N:7][CH:2]=[CH:3][CH:4]=3)[CH:10]=2)[N:15]=[CH:14]1
Reactant: CN1CC=Cc2c(Cc3ccc(Cl)nc3)cc3c(=O)n([C@H]4CCCC[C@@H]4O)cnc3c21
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Solvent: CO
Product: CN1CC=Cc2c(Cc3cccnc3)cc3c(=O)n([C@H]4CCCC[C@@H]4O)cnc3c21
Temperature: 160 °C

Procedure:
To a solution of 6-[(6-chloropyridin-3-yl)methyl]-3-[(1S,2S)-2-hydroxycyclohexyl]-10-methyl-9,10-dihydropyrido[3,2-h]quinazolin-4(3H)-one (Example 1, 0.050 g, 0.11 mmol) in 1 mL of methanol under an atmosphere of nitrogen was added trans-N,N′-dimethylcyclohexane-1,2-diamine (1.6 mg, 0.011 mmol) and copper(I) iodide (2.2 mg, 0.011 mmol). The mixture was heated at 160° C. for 2 h in a sealed pressure vessel, cooled to rt, and concentrated in vacuo. The residue was purified via preparative reverse phase HPLC to provide the title compounds.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[N:9]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21]C)=[O:20])=[CH:14][CH:13]=1)=[C:10]=[O:11]>>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:10](=[O:11])[NH:9][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:16][CH:17]=1
Reactant: COC(=O)Cc1ccc(N=C=O)cc1
Reactant: Nc1ccccc1F
Product: O=C(O)Cc1ccc(NC(=O)Nc2ccccc2F)cc1

Procedure:
4-(2-Fluorophenyl)ureidophenylacetic acid was prepared using procedure C with 2-fluoroaniline and KCl: 1H NMR (CD3SOCD3, 300 MHz, ppm) 9.00 (s, 1H), 8.51 (d, 2.4 Hz, 1H), 8.14 (dd, 8.3 Hz, 1.5 Hz, 1H), 7.37 (d, 8.5 Hz, 2H), 7.07-7.25 (m, 4H), 6.99 (m, 1H), 3.48 (s, 2H).
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)C=C[CH:4]=[CH:3][CH:2]=1.NC1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.C(N)CCC>C(O)(=O)C>[CH2:1]([N:7]1[C:12](=[O:13])[C:11]2[S:14][CH:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:10]=2[N:9]=[CH:8]1)[CH2:2][CH2:3][CH3:4]
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Agent: COC(=O)c1scc(-c2ccccc2)c1N
Solvent: CCCCN
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: CCCCn1cnc2c(-c3ccccc3)csc2c1=O
Yield: 75.2 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (100 mg, 0.43 mmol), triethyl orthoformate (1.0 ml), n-butylamine (0.097 ml, 0.99 mmol), and acetic acid (0.1 ml) were used to give 92 mg (0.32 mmol, 75.2% yield) of the title compound.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][N:12]=2)[CH2:6]1)=[N+]=[N-].O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[NH2:1][CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][N:12]=2)[CH2:6]1
Reactant: [N-]=[N+]=NC[C@H]1CN(c2ccc(Br)cn2)C(=O)O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Product: NC[C@H]1CN(c2ccc(Br)cn2)C(=O)O1
Temperature: 25 °C
Reaction time: 48 h
Yield: 88.8 %

Procedure:
(5R)-5-(Azidomethyl)-3-(5-bromopyrid-2-yl)-1,3-oxazolidin-2-one (5.60 g, 18.7 mM) was dissolved in acetonitrile:water (100:10 ml). Triphenylphosphine (5.42 g, 20.7 mM) was added. The reaction mixture was degassed and stirred at room temperature for 48 hours. The light yellow liquid was concentrated and the residue was purified by flash chromatography eluting with ethyl acetate then 6% methanol in ethyl acetate. Relevant fractions were combined to give the desired product as a light yellow solid (4.54 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]([O:11][CH2:12][C:13]([F:24])([F:23])[C:14]([F:22])([F:21])[C:15]([F:20])([F:19])[CH:16]([F:18])[F:17])(=[O:10])[CH:8]=[CH2:9]>>[O:4]1[CH2:5][CH2:6][N:1]([CH2:9][CH2:8][C:7]([O:11][CH2:12][C:13]([F:23])([F:24])[C:14]([F:21])([F:22])[C:15]([F:20])([F:19])[CH:16]([F:17])[F:18])=[O:10])[CH2:2][CH2:3]1
Reactant: C=CC(=O)OCC(F)(F)C(F)(F)C(F)(F)C(F)F
Reactant: C1COCCN1
Product: O=C(CCN1CCOCC1)OCC(F)(F)C(F)(F)C(F)(F)C(F)F
Yield: 97 %

Procedure:
With ice cooling and stirring, 9.6 g of morpholine was added dropwise to 28.6 g of 2,2,3,3,4,4,5,5-octafluoropentyl acrylate. The mixture was stirred for one hour at room temperature, after which it was directly distilled for purification. There was obtained 36.2 g of 2,2,3,3,4,4,5,5-octafluoropentyl 3-morpholinopropionate (boiling point 84° C./13 Pa, yield 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[NH:4][C:5]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:6][C:7](=[O:18])[CH:8]([CH3:17])[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[N:4]1[C:5]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:6][C:7](=[O:18])[C:8]([CH3:17])=[C:9]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C(=O)C=C(Nc1ccccc1Cl)c1ccccc1)C(=O)c1ccccc1
Solvent: Cc1ccccc1C
Product: Cc1c(-c2ccccc2)n(-c2ccccc2Cl)c(-c2ccccc2)cc1=O
Reaction time: 2 h
Yield: 15.1 %

Procedure:
To 17.8 g (0.050 mole) of 5-(2-chloroanilino)-2-methyl-1,5-diphenyl-4-pentene-1,3-dione, 200 ml of xylene and 100 g of polyphosphoric acid were added. The resultant mixture was heated under reflux for 30 minutes. After cooling the reaction mixture, the solvent was removed by decantation and the remaining solid matter was added with 200 ml of chloroform and 200 ml of water. The resultant mixture was then stirred vigorously for 2 hours. Thereafter, the organic layer was washed with water and then dried over anhydrous sodium sulfate. After removal of the sodium sulfate, the solvent was distilled off and the residue was recrystallized from acetone, thereby affording 2.8 g of 1-(2-chlorophenyl)-3-methyl-2,6-diphenyl-4(1H)-pyridinone having a melting point of 228°-231° C.
Reaction SMILES: [N:1]1([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH2:6][CH2:5][CH:4]([N:7]2[C@@H:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C@H:10]3[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.[CH:23]1([C:28](O)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH:23]1([C:28]([N:20]2[CH2:21][CH2:22][CH:17]([N:1]3[CH2:2][CH2:3][CH:4]([N:7]4[C@@H:11]5[CH2:12][CH2:13][CH2:14][CH2:15][C@H:10]5[NH:9][C:8]4=[O:16])[CH2:5][CH2:6]3)[CH2:18][CH2:19]2)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C(O)C1CCCC1
Reactant: O=C1N[C@@H]2CCCC[C@H]2N1C1CCN(C2CCNCC2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(C1CCCC1)N1CCC(N2CCC(N3C(=O)N[C@@H]4CCCC[C@H]43)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
To the solution of (3aR,7aR)-1-(1,4′-bipiperidin-4-yl)octahydro-2H-benzimidazol-2-one, 0.25 mmol) in dry DMF (3 mL) was added cyclopentanecarboxylic acid (34 mg, 0.3 mmol) followed by HATU (114 mg, 0.3 mmol) and diisopropylethylamine (0.10 mL, 0.5 mmol) and the mixture was stirred at room temperature for 1 h. The reaction was quenched with water (5 mL) and the solvent was removed in vacuo. Dichloromethane (15 mL) was added and washed with saturated NaHCO3 (10 mL) and brine (10 mL) and dried over Na2SO4. The crude product was purified with high pH prep-LCMS to yield (3aR,7aR)-1-[1′-(cyclopentylcarbonyl)-1,4′-bipiperidin-4-yl]octahydro-2H-benzimidazol-2-one (64 mg, 63%) as white powder. 1H NMR (400 MHz, METHANOL-D4): δ ppm 1.25-1.49 (m, 6H), 1.53-1.73 (m, 8H), 1.76-2.03 (m, 9H), 2.18-2.36 (m, 3H), 2.51-2.62 (m, 2H), 2.91-3.11 (m, 6H), 3.56-3.68 (m, 1H), 4.13 (d, J=13.28 Hz, 1H), 4.58 (d, J=13.28 Hz, 1H). MS (M+1): 403.3
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]2=[C:7](C(O)=O)[N:8]=[CH:9][N:4]2[CH:3]=1.Br.[OH-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.C(O)(=O)C.O>[Br:1][C:2]1[S:6][C:5]2=[CH:7][N:8]=[CH:9][N:4]2[CH:3]=1
Reactant: O=C(O)c1ncn2cc(Br)sc12
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: Brc1cn2cncc2s1
Temperature: 105 °C
Reaction time: 22 h
Yield: 93.8 %

Procedure:
2-Bromoimidazo[5,1-b]thiazole-7-carboxylic acid (0.52 g, 2.10 mmol) was suspended in a mixed solvent composed of water (4.0 ml) and acetic acid (6.0 ml). 48 wt % hydrobromic acid (0.75 g, 4.42 mmol) was added to the suspension at room temperature, and the mixture was stirred at 105° C. for about 22 hr. After the completion of the reaction, ethyl acetate (5 ml), a 25 wt % aqueous solution of sodium hydroxide (10 ml), and sodium carbonate (1.63 g, 15.38 mmol) were added to the reaction solution. The mixture was adjusted to pH 6, followed by separation. After the separation, the aqueous layer was extracted twice with 5 ml of ethyl acetate. Thereafter, the organic layers were combined, were washed with 15 wt % brine (5 ml), were then dehydrated over magnesium sulfate, and were evaporated to dryness. The residue was further dried under the reduced pressure with an oil pump to give 2-bromoimidazo[5.1-b]thiazole (0.40 g, yield 93.8%) as a white solid.
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=2)[C:7]([CH3:19])=[N:6][C:5]=1[CH3:20])(=[O:3])[NH2:2].[F:21][C:22]1[CH:23]=[C:24]([CH:37]([CH3:42])[C:38]([O:40][CH3:41])=[O:39])[CH:25]=[C:26]([F:36])[C:27]=1OS(C(F)(F)F)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Li+]>COCCOC.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:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:27]3[C:26]([F:36])=[CH:25][C:24]([CH:37]([CH3:42])[C:38]([O:40][CH3:41])=[O:39])=[CH:23][C:22]=3[F:21])=[CH:12][CH:11]=2)[C:7]([CH3:19])=[N:6][C:5]=1[CH3:20])(=[O:3])[NH2:2]
Reactant: Cc1nc(C)c(-c2ccc(B(O)O)cc2)nc1C(N)=O
Reactant: COC(=O)C(C)c1cc(F)c(OS(=O)(=O)C(F)(F)F)c(F)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: [Cl-]
Solvent: COCCOC
Product: COC(=O)C(C)c1cc(F)c(-c2ccc(-c3nc(C(N)=O)c(C)nc3C)cc2)c(F)c1
Temperature: 85 °C
Reaction time: 17 h
Yield: 67.6 %

Procedure:
A solution of 4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)phenylboronic acid (175 mg, 0.65 mmol) and methyl 2-(3,5-difluoro-4-(trifluoromethylsulfonyloxy)phenyl)propanoate (Intermediate 21-2; 200 mg, 0.57 mmol) and Sodium carbonate (0.467 mL, 0.93 mmol), tetrakis(triphenylphosphine)palladium(0) (41.1 mg, 0.04 mmol) and lithium chloride (42.6 mg, 1.01 mmol) in DME (14.300 mL) was degassed and then stirred at 85° C. for 17 hours. The reaction mixture was partitioned between EtOAc (10 mL) and saturated brine (15 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford methyl 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2,6-difluorobiphenyl-4-yl)propanoate (164 mg, 67.1%) as a white solid.