Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15](=[O:19])[N:16]([CH3:18])[CH3:17])[C@H:9]2[CH3:20])[CH:5]=[N:4][C:3]=1[C:21]#[N:22].[CH:23]1([N:26]2[CH2:31][CH2:30][CH:29]([C:32]3[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=3)[CH2:28][CH2:27]2)[CH2:25][CH2:24]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:21]([C:3]1[N:4]=[CH:5][C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15](=[O:19])[N:16]([CH3:18])[CH3:17])[C@H:9]2[CH3:20])=[N:7][C:2]=1[NH:36][C:35]1[CH:37]=[CH:38][C:32]([CH:29]2[CH2:30][CH2:31][N:26]([CH:23]3[CH2:25][CH2:24]3)[CH2:27][CH2:28]2)=[CH:33][CH:34]=1)#[N:22]
Reactant: C[C@@H]1[C@H](NC(=O)N(C)C)CCCN1c1cnc(C#N)c(Cl)n1
Reactant: Nc1ccc(C2CCN(C3CC3)CC2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: C[C@@H]1[C@H](NC(=O)N(C)C)CCCN1c1cnc(C#N)c(Nc2ccc(C3CCN(C4CC4)CC3)cc2)n1
Temperature: 115 °C
Reaction time: 3 h

Procedure:
The mixture of 3-((2R,3R)-1-(6-chloro-5-cyanopyrazin-2-yl)-2-methylpiperidin-3-yl)-1,1-dimethylurea (326) (80 mg, 0.25 mmol), 4-(1-cyclopropylpiperidin-4-yl)aniline (322, HCl salt, 76 mg, 0.30 mmol), fine-powder cesium carbonate (326 mg, 1.00 mmol), Pd(OAc)2 (18 mg, 0.08 mmol), BINAP (50 mg, 0.08 mmol) in 15 mL dioxane was degassed with nitrogen stream for 3 min. It was then stirred in 115° C. bath in nitrogen atmosphere for 3 hours. The mixture was cooled to RT, diluted with 100 mL EtOAc, and filtered using ChemGlass OP-6602-12 disposable funnel. The filtrate was concentrated in vacuo and subjected to silica flash column using 0 to 5% MeOH in DCM to isolate 3-((2R,3R)-1-(5-cyano-6-(4-(1-cyclopropylpiperidin-4-yl)phenylamino)pyrazin-2-yl)-2-methylpiperidin-3-yl)-1,1-dimethylurea (327). It was dissolved in 10 mL MeOH and 2 mL DMSO. To it were added 100 μL Et3N, 100 mg powder cesium carbonate, and then 0.5 mL 30% H2O2. The mixture was stirred at RT for 1.5 hour, diluted with 10 mL MeCN, stirred for 5 mM, concentrated on rotavap. The residue was treated with 0.3 mL TFA, and directly subjected to reverse phase prep HPLC using 5 mM HCl (aq) and neat MeCN as mobile phases to isolate 3-(4-(1-cyclopropylpiperidin-4-yl)phenylamino)-5-((2R,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)pyrazine-2-carboxamide (328) as HCl salt (76 mg, 58% yield). LC-MS (ESI): m/z (M+1) 521.8. UV: λ=268, 277, 306, 336, 372 nm. Proton NMR (CD3OD): δ 7.64 (1H, s), 7.61 (2H, d, J=8.5 Hz), 7.20 (2H, d, J=8.5 Hz), 4.98 (1H, m), 4.34 (1H, m), 3.87 (1H, m), 3.77 (1H, s), 3.74 (1H, s), 3.34 (2H, m), 3.02 (1H, m), 2.95 (6H, s), 2.90 (1H, m), 2.85 (1H, m), 2.15 (2H, m), 1.95-1.65 (6H, m), 1.17 (3H, d, J=7.0 Hz), 1.02 (4H, m) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]2[C:18](=[O:19])[CH:17]=[CH:16][C:15]([C:20](=[S:22])[NH2:21])=[N:14]2)[CH:7]=1)[CH3:2].[CH2:24]1[CH2:28][N:27]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([CH2:37]Br)=O)=[CH:31][CH:30]=2)[CH2:26][CH2:25]1>CCO>[CH2:1]([O:3][C:4](=[O:23])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]2[C:18](=[O:19])[CH:17]=[CH:16][C:15]([C:20]3[S:22][CH:37]=[C:35]([C:32]4[CH:33]=[CH:34][C:29]([N:27]5[CH2:28][CH2:24][CH2:25][CH2:26]5)=[CH:30][CH:31]=4)[N:21]=3)=[N:14]2)[CH:7]=1)[CH3:2]
Reactant: O=C(CBr)c1ccc(N2CCCC2)cc1
Reactant: CCOC(=O)Nc1cccc(Cn2nc(C(N)=S)ccc2=O)c1
Solvent: CCO
Product: CCOC(=O)Nc1cccc(Cn2nc(-c3nc(-c4ccc(N5CCCC5)cc4)cs3)ccc2=O)c1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
104 mg (0.31 mmol) of ethyl[3-(6-oxo-3-thiocarbamoyl-6H-pyridazin-1-yl-methyl)phenyl]carbamate are suspended in 2 ml of EtOH, and 100 mg (0.37 mmol) of α-bromo-4-(1-pyrrolidino)acetophenone are added. The reaction mixture is stirred at 80° C. for 15 h. The precipitate formed is filtered off with suction and washed with ethanol and dried in vacuo.
Reaction SMILES: [C:1]1([NH:7][NH:8][C:9]([C@H:11]2[CH2:13][C@H:12]2[C:14]([OH:16])=[O:15])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:18](Cl)([O:20]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCCC1>[O:20]=[C:18]1[O:10][C:9]([C@H:11]2[CH2:13][C@H:12]2[C:14]([OH:16])=[O:15])=[N:8][N:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(NNc1ccccc1)[C@H]1C[C@H]1C(=O)O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1C[C@@H]1c1nn(-c2ccccc2)c(=O)o1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.85 g (8.4 mmol) of cis-2-(N′-phenyl-hydrazinocarbonyl)-cyclopropanecarboxylic acid were dissolved in 20 ml of tetrahydrofuran and 0.823 g (2.8 mmol) of triphosgene were added. The reaction mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure, and the residue dissolved in acetonitrile/DMF. The product was purified by preparative RP HPLC eluting with a gradient of 0 to 100% acetonitrile in water (+0.01% TFA). After lyophilization, the product was obtained as a white solid. Yield: 980 mg.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][C:13]([OH:15])=O.[N:16]1([C:21]2[N:26]=[C:25]([N:27]3[CH2:33][CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[CH:24]=[C:23]([N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[N:22]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1>O1CCCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][C:13]([N:30]1[CH2:31][CH2:32][CH2:33][N:27]([C:25]2[CH:24]=[C:23]([N:34]3[CH2:35][CH2:36][CH2:37][CH2:38]3)[N:22]=[C:21]([N:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)[N:26]=2)[CH2:28][CH2:29]1)=[O:15]
Reactant: c1c(N2CCCC2)nc(N2CCCC2)nc1N1CCCNCC1
Reactant: O=C(O)COc1ccc2ccccc2c1
Solvent: C1CCOC1
Product: O=C(COc1ccc2ccccc2c1)N1CCCN(c2cc(N3CCCC3)nc(N3CCCC3)n2)CC1
Temperature: 25 °C
Yield: 28 %

Procedure:
To a solution of 2-(2-naphthyloxy)acetic acid (1.1 g, 5.0 mmol) in anhydrous tetrahydrofuran (25 ml) carbonyl-diimidazole (0.80 g, 5.0 mmol) was added in portions, under stirring at room temperature. After 15 minutes a solution of 1-[2,6-di(1-pyrrolidinyl)-4-pyrimidinyl]homopiperazine (1.58 g, 5.0 mmol) in anhydrous tetrahydrofuran (15 ml) was added dropwise. The mixture was stirred at room temperature for 8 hours and the solvent was distilled off under reduced pressure. The residue was dissolved in methylene chloride, the solution was washed three times with water, dried over MgSO4 and concentrated. The obtained crude product was chromatographed over a silica gel column eluting with a 1:2 mixture of benzene and ethyl acetate to afford 0.7 g of the title compound, yield: 28%, mp. 103°-110° C.
Reaction SMILES: C(OC)(=O)[CH2:2][C:3]([CH3:5])=[O:4].[OH-].[Na+].Cl.C([O-])(=O)C.[Na+].[F:17][C:18]([F:31])([F:30])[C:19]1[CH:24]=[CH:23][C:22]([S:25][CH2:26][CH2:27][CH:28]=[O:29])=[CH:21][CH:20]=1>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[OH:29][CH:28]([CH2:27][CH2:26][S:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]([F:30])([F:17])[F:31])=[CH:20][CH:21]=1)[CH2:2][C:3](=[O:4])[CH3:5]
Reactant: COC(=O)CC(C)=O
Reactant: O=CCCSc1ccc(C(F)(F)F)cc1
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)CC(O)CCSc1ccc(C(F)(F)F)cc1
Reaction time: 3 h
Yield: 92 %

Procedure:
15.1 Grams of methyl acetoacetate were dissolved in 20 ml of water, and 18.2 g of a 30% aqueous sodium hydroxide solution were added thereto by drops while cooling the mixture to 35° C. or less. After having been stirred at 30°-35°C. for 3 hours, the mixture was adjusted to pH 7.5 with a concentrated aqueous hydrochloric acid solution. Thereafter, 0.82 g of sodium acetate and 3.22 g of tetrabutylammonium bromide were added thereto and then 54.85 g of a toluene solution containing 36.6% of 3-(4-trifluoromethylphenylthio)propanal were added thereto. The mixture was stirred at 45°-50° C. for 6 hours. After the mixture has been neutralized with a concentrated aqueous hydrochloric acid solution, the organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. Removing the solvent from the layer under reduced pressure gave 27.08 g of crude 4-hydroxy-6-(4-trifluoromethylphenylthio)-2-hexanone (purity: 87.8 %, yield: 92.0%).
Reaction SMILES: [O:1]=[C:2]1[NH:7][N:6]=[C:5]([C:8]([NH2:10])=O)[CH:4]=[CH:3]1.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl.O>[O:1]=[C:2]1[NH:7][N:6]=[C:5]([C:8]#[N:10])[CH:4]=[CH:3]1
Reactant: NC(=O)c1ccc(=O)[nH]n1
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: N#Cc1ccc(=O)[nH]n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.6 %

Procedure:
6-Oxo-1,6-dihydropyridazine-3-carboxamide (J. Chem. Soc. 1948, 2195) (1.1 g, 8.0 mmol) was suspended in dichloromethane (20 mL), cooled to 0° C. then pyridine (1.3 mL, 16 mmol) and trifluoroacetic anhydride (1.2 mL, 8.4 mmol) were added and the reaction was stirred at room temperature for 1 hour. A further 5 mL of pyridine was added to aid solubility and then the reaction was warmed to room temperature and stirred overnight. The mixture was diluted with water (100 mL) and then extracted with dichloromethane (3×100 mL). The combined organic extracts were dried (Na2SO4), the solvent was removed in vacuo, with residual pyridine removed by azeotroping with toluene. The residue was purified by flash chromatography on silica gel (dichloromethane/methanol 95:5 as eluant) to give the title compound as an off-white solid (0.8 g).
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:8]([CH2:9][OH:10])[O:7][C@@H:6]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:5]1)=[N+]=[N-].[H][H]>C(O)C.[Pd]>[NH2:1][C@@H:4]1[C@@H:8]([CH2:9][OH:10])[O:7][C@@H:6]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:5]1
Reactant: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1cn([C@H]2C[C@H](N)[C@@H](CO)O2)c(=O)[nH]c1=O
Yield: 87.8 %

Procedure:
A slurry of 2.17 g of 3'-azido-3'-deoxythymidine (Aldrich, Milwaukee, Wis.) and 0.91 g of 10% Pd/C in 25 ml of ethanol were vigorously stirred under 1 atm. of hydrogen for 4 hr. The mixture was filtered through celite, washed with methanol, and the filtrate was evap. Purification by chromatography on silica (2 to 40% methanol/DCM) gave 1.72 g of 3'-amino-3'-deoxythymidine as a light yellow solid: NMR (300 MHz,d6-DMSO) δ7.76 (s,1H), 6.07 (t,1H,J=6 Hz), 4.97 (m,1H), 3.5-3.7 (m,3H), 3.39 (q,1H,J=7 Hz), 3.33 (br,2H), 1.9-2.15 (m,2H), 1.77 (s,3H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([C:8]([F:11])([F:10])[F:9])([OH:7])C([O-])=[O:5].[Na+].C(=O)([O-])[O-].[Na+].[Na+].ClCl>O>[OH2:5].[F:1][C:2]([F:13])([F:12])[C:3]([C:8]([F:11])([F:10])[F:9])=[O:7]
Reactant: O=C([O-])C(O)(C(F)(F)F)C(F)(F)F
Agent: ClCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(C(F)(F)F)C(F)(F)F
Temperature: 40 °C

Procedure:
In a 50-ml three-necked flask were placed 20 mmol of the aqueous sodium 3,3,3-trifluoro-2-trifluoromethyl-2-hydroxypropionate solution prepared in Reference Example 2 and 2.12 g (20 mmol) of sodium carbonate. 20 g of water was added to dissolve the mixture. The pH was 9.8. A reaction was performed by blowing chlorine gas at 20 ml/min for 29 minutes (24.1 mmol, 1.2 eq.) while stirring the solution under heat at 40° C. in a water bath. The pH during this treatment was 6.9. To this solution, 1.06 g (10 mmol) of sodium carbonate was further added, followed by dissolving. The pH was 9.1. The reaction was further performed by blowing chlorine gas at 10 ml/min for 22 minutes (9.2 mmol, 0.46 eq.) while stirring the solution under heat at 40° C. The pH when the reaction was complete was 6.8. Hexafluoroacetone hydrate was obtained at a starting material conversion of 82% with a selectivity of at least 99%.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][CH:4]=1.Br[C:11]1[CH:20]=[CH:19][C:14]([CH2:15][N:16]([CH3:18])[CH3:17])=[CH:13][CH:12]=1>O1CCCC1.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>[Br:9][C:6]1[CH:7]=[CH:8][C:3]([C:13]2[C:14]([CH2:15][N:16]([CH3:18])[CH3:17])=[CH:19][CH:20]=[CH:11][CH:12]=2)=[CH:4][CH:5]=1
Reactant: CN(C)Cc1ccc(Br)cc1
Reactant: Brc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: CN(C)Cc1ccccc1-c1ccc(Br)cc1
Reaction time: 5 h

Procedure:
A solution of the Grignard reagent prepared from 344 mg of magnesium and 2.27 g of 1,4-dibromobenzene in 15 ml of THF (tetrahydrofuran) is added dropwise to a suspension of 2 g of 4-bromo-N,N-dimethylbenzylamine and 158 mg of tetrakistriphenylphosphinepalladium in 10 ml of THF. The addition is carried out at room temperature and under an argon atmosphere. After completion of the addition, the mixture is heated to boiling for an additional 5 hours and then evaporated under reduced pressure. The residue is then treated with ether and saturated ammonium chloride solution and the aqueous phase is separated. This is extracted with ether. The organic extracts are washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated. The residue is purified by chromatography on silica gel while eluting with methylene chloride/methanol 9:1. 4'-Bromo-N,N-dimethylbiphenylmethanamine, m.p. 60°-62° C., is obtained.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1[CH:14]=[C:13]([F:15])[C:12](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:11]([F:23])[CH:10]=1)C1C=CC=CC=1>C(O)(=O)C.[C].[Pd]>[NH2:8][C:9]1[CH:10]=[C:11]([F:23])[C:12]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:13]([F:15])[CH:14]=1
Reactant: CCOC(=O)/C=C/c1c(F)cc(N(Cc2ccccc2)Cc2ccccc2)cc1F
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)CCc1c(F)cc(N)cc1F
Temperature: 50 °C
Reaction time: 16 h
Yield: 93.3 %

Procedure:
To a solution of ethyl(2E)-3-[4-(dibenzylamino)-2,6-difluorophenyl]acrylate (5.00 g, 12.3 mmol) in acetic acid (100 mL) was added 10% palladium-carbon (50% water-containing product, 0.50 g), and the mixture was stirred under a hydrogen atmosphere at 50° C. for 16 hr. The catalyst was filtered off, and the obtained filtrate was concentrated. The residue was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5-hexane/ethyl acetate=50/50) to give the title compound (2.63 g, yield 93%) as a yellow oil.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([OH:15])=O)=[CH:5][CH:4]=1)#[N:2].C(Cl)[Cl:17].C(Cl)(=O)C(Cl)=O>CN(C=O)C>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([Cl:17])=[O:15])=[CH:5][CH:4]=1)#[N:2]
Reactant: ClCCl
Reactant: N#Cc1ccc(C(=O)O)c2ccccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: N#Cc1ccc(C(=O)Cl)c2ccccc12
Reaction time: 3 h

Procedure:
A mixture containing 4-cyano-1-naphthoic acid (0.090 g, 0.45 mmol), DCM (3 mL), oxalyl chloride (0.063 g, 0.50 mmol) and DMF (approximately 5 μL) was stirred for 3 h and concentrated to provide 4-cyano-1-naphthoyl chloride as an off-white solid which was used directly. Using standard acylation conditions 4-cyano-1-naphthoyl chloride (0.090 g) was reacted with N-[(S)-2-(3,4-dichlorophenyl)-4-[4-[(S)-2-methylsulfinylphenyl]-1-piperidinyl]butyl]-N-methylamine to afford the free base (0.215 g) which was converted to the citrate salt.
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]([CH2:6][CH:7]2[O:11][CH2:10][CH2:9][O:8]2)=[CH:4][CH:3]=1.B(O)(O)[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=[O:22])[CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].[BH4-].[Na+]>O1CCOCC1.O.CO>[O:8]1[CH2:9][CH2:10][O:11][CH:7]1[CH2:6][C:5]1[CH:12]=[CH:13][C:2]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][OH:22])[CH:16]=2)=[CH:3][CH:4]=1
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: Brc1ccc(CC2OCCO2)cc1
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: OCc1cccc(-c2ccc(CC3OCCO3)cc2)c1
Temperature: 125 °C
Reaction time: 0.5 h
Yield: 52.3 %

Procedure:
A mixture of 2-(4-bromobenzyl)-1,3-dioxolane (2.0 g, 8.2 mmol), 3-formylboronic acid (2.45 g, 16.4 mmol), tetrakis-(triphenylphosphine)palladium (0) (0.763 g, 0.66 mmol), and sodium carbonate (1.74 g, 16.4 mmol) in dioxan/water (15 mL/3 mL) in a microwave vessel was degassed in a stream of nitrogen for 10 minutes. The vessel was sealed and heated in the microwave at 125° C. for 30 minutes. The solvent was decanted off, and the solid residues washed with ethyl acetate. The organic phases were combined, and the solvent evaporated at reduced pressure. The crude material was purified by silica gel chromatography eluting with 100% iso-hexane to 50% ethyl acetate in iso-hexane to afford an oil. The oil was dissolved in methanol (25 mL) and cooled to 0° C. Sodium borohydride (0.393 g, 10.4 mmol) was added portion-wise, and the reaction mixture was stirred at 0° C. for 30 minutes followed by 1 hour at ambient temperature. The reaction mixture was quenched with water and extracted twice with ethyl acetate. The combined organic extracts were dried with anhydrous magnesium sulfate, and the solvent evaporated at reduced pressure. The crude material was purified by silica gel chromatography eluting with 100% iso-hexane to 100% ethyl acetate in iso-hexane to afford the title compound (1.16 g, 52%).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][N:4]=1)[NH2:2].[F:10][C:11]([F:21])([F:20])[C:12](=O)[CH2:13][C:14](OCC)=[O:15]>C(O)(=O)C>[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([N:1]2[C:14]([OH:15])=[CH:13][C:12]([C:11]([F:21])([F:20])[F:10])=[N:2]2)=[N:4][CH:5]=1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: NNc1ccc(Cl)cn1
Solvent: CC(=O)O
Product: Oc1cc(C(F)(F)F)nn1-c1ccc(Cl)cn1
Yield: 53.9 %

Procedure:
A mixture of 1.445 g (10 mmol) of 2-hydrazino-5-chloropyridine and ethyl trifluoroacetoacetate (1.5 ml; 10 mmol) in 5 ml of acetic acid was refluxed overnight with stirring under nitrogen and then cooled. The mixture was concentrated in vacuo, the residue was diluted with ethyl acetate, and the solid mixture was filtered. The filtrate was washed with saturated sodium bicarbonate solution, the aqueous layer was extracted with ethyl acetate, and the combined organic layer was dried over magnesium sulfate. The organic layer was concentrated in vacuo, the residue was purified by flash chromatography (ethyl acetate) and crystallized (from ethyl acetate/hexane followed by hexane) to afford 1.42 g of 1-(5-chloro-2-pyridyl)-3-trifluoromethyl-5-hydroxy-pyrazole as a white solid, m.p. 58°-59° C.
Reaction SMILES: [ClH:1].[NH2:2][C@@H:3]([CH2:9][CH:10]([CH3:12])[CH3:11])[CH:4]([OH:8])[C:5]([OH:7])=[O:6].[CH:13]1[CH:18]=CC=C[CH:14]=1>C(O)(C)C>[ClH:1].[NH2:2][C@@H:3]([CH2:9][CH:10]([CH3:12])[CH3:11])[CH:4]([OH:8])[C:5]([O:7][CH:13]([CH3:18])[CH3:14])=[O:6]
Reactant: CC(C)C[C@H](N)C(O)C(=O)O
Reactant: c1ccccc1
Agent: Cl
Solvent: CC(C)O
Product: CC(C)C[C@H](N)C(O)C(=O)OC(C)C

Procedure:
Hydrogen chloride was passed into a solution of 4.0 g of (2RS,3S)-3-amino-2-hydroxy-5-methylhexanoic acid in 50 ml of isopropanol was stirring under ice-cooling, and to the reaction mixture was 100 ml of dry benzene. The mixture was heated under reflux for 10 minutes while removing water formed during the reaction. The reaction mixture was concentrated under reduced pressure to obtain 5.7 g of isopropyl (2RS,3S)-3-amino-2-hydroxy-5-methylhexanoate hydrochloride as a white powder.
Reaction SMILES: [C:1]1([C:6](Cl)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.[Cl:9][C:10]1[C:11]([OH:17])=[CH:12][C:13](=[O:16])[NH:14][CH:15]=1>N1C=CC=CC=1>[Cl:9][C:10]1[C:11]([O:17][C:6](=[O:7])[C:1]2[S:5][CH:4]=[CH:3][CH:2]=2)=[CH:12][C:13](=[O:16])[NH:14][CH:15]=1
Reactant: O=C(Cl)c1cccs1
Reactant: O=c1cc(O)c(Cl)c[nH]1
Solvent: c1ccncc1
Product: O=C(Oc1cc(=O)[nH]cc1Cl)c1cccs1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 23 %

Procedure:
A 2.42 g quantity of 2-thenoyl chloride was added to a suspension of 2.00 g of 5-chloro-4-hydroxy-2-pyridone in 100 ml of pyridine, and the mixture was stirred at room temperature for 4.5 hours. The reaction mixture was concentrated and the concentrate was washed with ethyl acetate and water, thereby producing 0.82 g of the title compound in a yield of 23%.
Reaction SMILES: O[CH:2]1[CH2:7][N:6]([C:8]([C:10]2[S:14][C:13]([CH3:15])=[N:12][C:11]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:9])[CH:5]([CH2:22][NH:23][C:24]([C:26]2[CH:27]=[CH:28][CH:29]=[C:30]3[C:35]=2[N:34]=[CH:33][CH:32]=[CH:31]3)=[O:25])[CH2:4][CH2:3]1.COCCN(S(F)(F)[F:46])CCOC>C(Cl)Cl>[F:46][CH:2]1[CH2:7][N:6]([C:8]([C:10]2[S:14][C:13]([CH3:15])=[N:12][C:11]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:9])[CH:5]([CH2:22][NH:23][C:24]([C:26]2[CH:27]=[CH:28][CH:29]=[C:30]3[C:35]=2[N:34]=[CH:33][CH:32]=[CH:31]3)=[O:25])[CH2:4][CH2:3]1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: Cc1nc(-c2ccccc2)c(C(=O)N2CC(O)CCC2CNC(=O)c2cccc3cccnc23)s1
Solvent: ClCCl
Product: Cc1nc(-c2ccccc2)c(C(=O)N2CC(F)CCC2CNC(=O)c2cccc3cccnc23)s1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
A solution of N-((5-hydroxy-1-(2-methyl-4-phenylthiazole-5-carbonyl)piperidin-2-yl)methyl)quinoline-8-carboxamide (0.07 mmol, 0.036 g) in DCM (0.3 mL) was added to a mixture of bis(2-methoxyethyl)aminosulfur trifluoride (0.14 mmol, 0.027 mL) in DCM (0.2 mL) at −78° C. under argon. The resulting mixture was stirred at −78° C. for 1 h and at rt for another 1.5 h. The desired product was purified by preparative TLC to give N-((5-fluoro-1-(2-methyl-4-phenylthiazole-5-carbonyl)piperidin-2-yl)methyl)quinoline-8-carboxamide with unidentified stereochemistry (Y: 16%). MS (ESI) 489 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[N:6][CH:7]=1.C1C=CC2N(O)N=[N:17][C:15]=2C=1.C(Cl)CCl.Cl.CN.C(N(C(C)C)C(C)C)C>CN(C=O)C>[Br:1][C:2]1[C:3]([C:8]([NH:17][CH3:15])=[O:10])=[N:4][CH:5]=[N:6][CH:7]=1
Reactant: O=C(O)c1ncncc1Br
Reactant: On1nnc2ccccc21
Agent: CN
Agent: Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1ncncc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.5 %

Procedure:
To a mixture of 5-bromopyrimidine-4-carboxylic acid (0.3 g, 1.478 mmol) in DMF (3 mL) were added HOBt (0.260 g, 1.921 mmol), EDC (0.397 g, 2.069 mmol), methanamine HCl (0.200 g, 2.96 mmol), followed by N-ethyl-N-isopropylpropan-2-amine (0.772 mL, 4.43 mmol). The reaction mixture was stirred for 18 hours at room temperature. The crude residue was purified by preparative HPLC (Waters SunFire C18, 5 μm, 30 mm ID×75 mm column) eluting with 5% ACN (containing 0.035% TFA) in water (containing 0.05% TFA) to give the title compound as a light brown solid (0.11 g, 35%). ESI-MS m/z [M+H]+ calc'd for C6H7BrN3O, 216.0. found 216.0.
Reaction SMILES: [C:1]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:13](OCC)=[O:14].[Na].O>C(OCC)C>[CH:13]([CH:2]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:1]([O:10][CH2:11][CH3:12])=[O:9])=[O:14]
Reactant: CCOC(=O)CCC(=O)OCC
Reactant: CCOC=O
Agent: [Na]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)CC(C=O)C(=O)OCC
Reaction time: 17 h

Procedure:
A mixture of diethyl succinate (26.1 g, 25.0 mL, 0.150 mol) and ethyl formate (11.1 g, 12.1 mL, 0.150 mol) was added drop wise over 1.5 hours to a stirred suspension of sodium (3.40 g, 0.150 mol) in diethyl ether (120 mL) at 0° C. under nitrogen. On completion of addition, stirring was continued at room temperature for 17 hours. Water (120 mL) was cautiously added to the resulting suspension and stirring continued until all the solids were dissolved. The layers were separated and the aqueous layer was washed with diethyl ether (100 mL). The aqueous layer was then acidified to pH 5 using 11 N HCl and extracted with diethyl ether (3×100 mL), the ethereal extracts of the acidified layer were combined, dried (Na2SO4) then evaporated to dryness under reduced pressure to give the title compound (I105) (16.5 g) as a yellow mobile liquid. The crude product was not purified further and was used directly in the following step.