Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH:14]C(OCC2C=CC=CC=2)=O)[C@@H:10]([C:25]([N:27]2[CH2:32][CH2:31][CH2:30][C@@H:29]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[CH2:28]2)=[O:26])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH2:14])[C@@H:10]([C:25]([N:27]2[CH2:32][CH2:31][CH2:30][C@@H:29]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[CH2:28]2)=[O:26])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)OCc2ccccc2)[C@@H](C(=O)N2CCC[C@@H](Cc3ccc(F)cc3)C2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@@H](C(=O)N2CCC[C@@H](Cc3ccc(F)cc3)C2)C1
Reaction time: 20.5 h
Yield: 12.7 %

Procedure:
In a dry 500-mL Paar flask charged with palladium (10 wt % Pd, dry basis, on carbon, 31 mg) was added methanol (10 mL) and (3S,4R)-4-benzyloxycarbonylamino-3-[(S)-3-(4-fluoro-benzyl)-piperidine-1-carbonyl]-piperidine-1-carboxylic acid t-butyl ester (150 mg, 2.08 mmol). The reaction mixture was hydrogenated at 45 psi for 20.5 hours with vigorous shaking. The reaction mixture was filtered through a plug of celite. The plug was washed with 20 mL of ethanol and the combined filtrates were concentrated in vacuo to give a colorless oil (111 mg, 98%). 1H NMR (300 MHz, CDCl3), δ: 8.75 (bs, 2H), 7.09 (m, 2H), 6.97 (m, 2H), 4.30 (m, 1H), 4.01 (m, 2H), 3.70 (m, 2H), 3.25 (m, 1H), 3.10 (m, 1H), 2.75 (m, 1H), 2.48 (m, 4H), 1.82 (m, 5H), 1.42 (s, 9H), 1.21 (m, 2H). MS (ESI), m+/z: (M+H)+=420.3.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[NH:4][C:3]1=[O:14].C(N(CC)CC)C.[C:22](Cl)(=[O:25])[CH2:23][CH3:24]>CN(C=O)C>[O:9]=[C:8]1[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[NH:4][C:3](=[O:14])[CH:2]1[NH:1][C:22](=[O:25])[CH2:23][CH3:24]
Reactant: NC1C(=O)Nc2ccccc2NC1=O
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(=O)NC1C(=O)Nc2ccccc2NC1=O
Reaction time: 8 h

Procedure:
Combine 3-amino-1H-1,5-benzodiazepine-2,4-(3H, 5H)-dione (5.7 g, 30.0 mmol) and triethyl amine(3.33 g, 33.0 mmol) in 120 mL DMF and add propionyl chloride dropwise at RT. After stirrng overnight, remove DMF under reduced pressure, suspend the residue in a mixed solvent (CHCl3/i-PrOH=3/1, 400 mL). Collect an off-white solid via suction filtration to give the title compound. Wash the filtrate with NaHCO3 (sat.2×100 mL) and dry with Na2SO4. Concentrate the organic solvent down to a residue, treat with ether, collect the solid: mass spectrum (APCI) (m/e): 248.1 (M+1). 1H NMR (400 MHz, DMSO-d6): δ 10.70 (s, 2H), 8.19 (d, 1H, J=7.2 Hz), 7.23-7.15 (m, 4H), 4.73 (d, 1H, J=8.0 Hz), 2.27 (q, 2H, J=8.0 Hz), 0.94 (t, 3H, J=8.0 Hz).
Reaction SMILES: [F:1][C:2]1([F:18])[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C@@H](C2C=CC=CC=2)C)[C@@H:3]1[OH:17]>CO.[OH-].[OH-].[Pd+2]>[NH2:8][C@H:4]1[C@H:3]([OH:17])[C:2]([F:18])([F:1])[CH2:7][CH2:6][CH2:5]1
Reactant: C[C@@H](N[C@@H]1CCCC(F)(F)[C@H]1O)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: N[C@@H]1CCCC(F)(F)[C@H]1O
Reaction time: 16 h

Procedure:
A solution of (1S,6R)-2,2-difluoro-6-{[(1R)-1-phenylethyl]amino}cyclohexanol (2.0 g, 7.8 mmol) in methanol (100 mL) was degassed with nitrogen, treated with Pd(OH)2/C (0.55 g) and then placed under an atmosphere of hydrogen and stirred vigorously for 16 hours. The reaction was filtered, washed with methanol, and the filtrate evaporated in vacuo to afford the title compound as a white solid: 1H NMR (500 MHz, CD3OD) δ 3.34 (m, 1H); 2.74 (m, 1H); 2.07 (m, 1H); 1.89 (m, 1H); 1.73 (m, 2H); 1.50 (m, 1H); 1.27 (m, 1H).
Reaction SMILES: [B-](F)(F)(F)F.[Na+].[O:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.[OH2:12]>S(=O)(=O)(O)O>[CH3:8][CH2:9][CH2:10][CH2:11][O:7][C@H:9]([CH2:8][OH:12])[CH2:10][CH3:11]
Reactant: O
Reactant: C1CCOC1
Agent: F[B-](F)(F)F
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCCCO[C@@H](CC)CO
Temperature: 20 °C
Reaction time: 2 h

Procedure:
In the same manner as in Example 17, a solution prepared by dissolving 1.5 g of sodium borofluoride in 55 g of 25% fuming sulfuric acid was dropped into 500 g of tetrahydrofuran at -10° C. over 30 minutes, and the mixture was subjected to reaction at -10° C. for one hour. The conversion at this point was 20%. Then the reaction mixture was heated to 20° C. and subjected to reaction at this temperature for 2 hours. The final conversion was 61%. Then, to the polymerization product was added 520 g of water and heated in an oil bath at 80° C. with stirring for 2 hours while distilling off and recovering the unreacted tetrahydrofuran. Then, the oil bath temperature was elevated to 100° C. and 50 g of a 48% by weight aqueous sodium hydroxide solution was added continuously over a period of one hour to accomplish the hydrolysis of the reaction mixture. Recovery of the unreacted tetrahydrofuran was continued during said addition, and upon completion of said addition, the mixture was allowed to stand at 100° C. to cause the separation of layers. The aqueous layer was withdrawn, and to the remaining PTMG layer was added 250 g of water and a part of the withdrawn aqueous layer, after which the sulfuric acid concentration in the aqueous layer was adjusted to about 1% by weight, and the mixture was again heated and stirred in an oil bath at 100° C. for 2 hours to complete the hydrolysis and then allowed to stand at 100° C. to cause separation of layers. A part of the separated PTMG layer was sampled and analyzed to determined the amount of residual sulfuric ester groups and acid number. They were 4 ppm and 0.27, respectively. Then, without withdrawing the aqueous layer, 9.7 g of a 20% by weight aqueous sodium hydroxide solution was added and the mixed system was heated and stirred in an oil bath at 80° C. for about 15 minutes and then, 1.3 g of a 15% by weight aqueous suspension of a basic magnesium carbonate to adjust the pH of the mixture about 8, followed by additional heating and washing with stirring in an oil bath at 80° C. for 2 hours. Then, the mixture was allowed to stand to cause separation of layers. The mixture showed no emulsification phenomenon throughout the treatment, the separation of layers was easy, and the separated PTMG layer was only slightly turbid. After removing the aqueous layer, the remaining PTMG layer was treated in the same manner as in Example 17 to obtain PTMG. Its analytical results are shown in Table 3.
Reaction SMILES: C(OC([O:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[CH:10]=[CH:11][CH2:12]Cl)=O)C.[CH2:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][NH:18]1>CO>[OH:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[CH:10]=[CH:11][CH2:12][N:18]1[CH2:19][C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:17]1
Reactant: CCOC(=O)Oc1cccc(C=CCCl)c1
Reactant: c1ccc2c(c1)CNC2
Solvent: CO
Product: Oc1cccc(C=CCN2Cc3ccccc3C2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.9 %

Procedure:
The process for the preparation of this compound and its physical properties will be given below. 4.8 grams of m-ethoxycarbonyloxycinnamyl chloride and 7.15 grams of isoindoline are dissolved in 70 milliliters of methanol, and the resulting solution is stirred for 2 hours at room temperature. After completion of the reaction, the methanol is distilled off, and the residue is extracted with benzene. The resulting extract is then purified by silica gel column chromatography and recrystallized from methanol to obtain 1.2 grams (yield 23.9%) of N-(m-hydroxycinnamyl)-isoindoline as crystals having a melting point of 164.5°-165.5° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7]2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:22][CH2:23][CH2:24][CH3:25]>CN(C=O)C>[CH2:22]([N:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7]2)[CH2:3][CH2:2]1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCCI
Reactant: C1=CC2(CCNCC2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCN1CCC2(C=Cc3ccccc32)CC1
Yield: 31.3 %

Procedure:
In the same way as that described in Example 1, step 5, the title compound was prepared, using spiro[1H-indene-1,4'-piperidine] (333 mg, 1.8 mmol), DMF (15 ml), potassium carbonate (0.26 g, 1.9 mmol) and iodobutane (267 μl, 2.4 mmol). The crude residue was chromatographed in dichloromethane:methanol 95:5, to give 1'-butylspiro[1H-indene-1,4'-piperidine] (136 mg, 31%) as a clear oil.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][C:3]=1[CH2:13][CH:14]([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+].[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1.O>CC(C)=O>[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][O:1][C:2]2[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[CH2:13][CH:14]([CH3:15])[CH3:16])=[CH:26][CH:25]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CCOC(=O)c1ccc(O)c(CC(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)Cc1cc(C(=O)O)ccc1OCc1ccc(F)cc1
Reaction time: 4 h
Yield: 88.5 %

Procedure:
Ethyl 4-hydroxy-3-isobutylbenzoate (25.6 g), potassium carbonate (31.8 g), and 4-fluorobenzyl bromide (26.1 g) were refluxed in acetone (150 ml) with stirring for 4 hours. The reaction mixture, with water added thereto, was extracted with ethyl acetate. The extract was concentrated under a vacuum. The resulting residue, with water (50 ml), potassium hydroxide (12.9 g), and ethanol (100 mnl) added thereto, was refluxed with stirring for 2 hours. The reaction mixture, with water added thereto, was neutralized with hydrochloric acid and then extracted with ethyl acetate. The extract was washed with 10% hydrochloric acid and water successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum. Thus obtained solid was recrystallized from n-hexane/ethanol, thereby yielding 30.8 g of the aimed compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:5][CH:4]=1.Cl[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N+:34]([O-:36])=[O:35]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:10][CH:11]2[CH2:12][CH2:13][N:14]([CH2:24][CH2:25][CH2:26][O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[N+:34]([O-:36])=[O:35])[CH2:15][CH2:16]2)=[CH:7][CH:8]=1
Reactant: O=[N+]([O-])c1ccccc1OCCCCl
Reactant: COc1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Product: COc1ccc(C(OC2CCN(CCCOc3ccccc3[N+](=O)[O-])CC2)c2ccccc2)cc1

Procedure:
The procedure of Example 24 (a) was repeated except for using 4-[(4-methoxyphenyl)-phenylmethoxy]piperidine and 1-chloro-3-(2-nitrophenoxy)propane instead of 4-[(2-chlorophenyl)-phenylmethoxy]piperidine and 1-chloro-3-(2-nitrophenoxy)propane to give oily 4-[(4-methoxyphenyl)-phenylmethoxy]-1-[3-(2-nitrophenoxy)propyl]piperidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([NH:20][CH2:21][CH2:22][NH:23][C:24]2[N:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=2)[C:12]2[N:13]([N:15]=[C:16]([CH2:18][OH:19])[CH:17]=2)[CH:14]=1.COCCOC.CN(C=O)C.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([NH:20][CH2:21][CH2:22][NH:23][C:24]2[N:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=2)[C:12]2[N:13]([N:15]=[C:16]([CH:18]=[O:19])[CH:17]=2)[CH:14]=1
Reactant: N#Cc1ccc(NCCNc2nc(-c3ccc(Cl)cc3Cl)cn3nc(CO)cc23)nc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CN(C)C=O
Solvent: COCCOC
Solvent: ClCCl
Product: N#Cc1ccc(NCCNc2nc(-c3ccc(Cl)cc3Cl)cn3nc(C=O)cc23)nc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1.2 g (2.64 mmol) of 6-[(2-{[6-(2,4-dichlorophenyl)-2-(hydroxymethyl)pyrazolo[1,5-a]pyrazin-4-yl]amino}ethyl)amino]pyridine-3-carbonitrile (Example 42) were suspended in 80 ml of dichloromethane (shaken with water beforehand). 80 ml of 1,2-dimethoxyethane and 40 ml of DMF were then added, and the mixture was cooled to 0° C. 2.46 g (5.81 mmol) of Dess-Martin periodinane were added, ice-bath cooling was removed and the mixture was stirred at RT for 2 h. Ethyl acetate was added, and the mixture was washed first with a 10% strength sodium thiosulfate solution and then with saturated aqueous sodium bicarbonate solution. Drying of the organic phase with sodium sulfate and removal of the solvent under reduced pressure gave 1.2 g (94% of theory) of the product as a solid which was reacted without further purification.
Reaction SMILES: [CH3:1][CH:2]([CH3:10])[C:3](=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].[CH2:11](O)[CH2:12][OH:13]>C1(C)C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>[CH:2]([C:3]1([CH2:4][C:5]([O:7][CH3:8])=[O:6])[O:13][CH2:12][CH2:11][O:9]1)([CH3:10])[CH3:1]
Reactant: OCCO
Reactant: COC(=O)CC(=O)C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)CC1(C(C)C)OCCO1
Yield: 71.2 %

Procedure:
To a solution of methyl 4-methyl-3-oxopentanoate (72 g, 0.5 mol), and ethylene glycol (56 g, 1 mol) in toluene (500 mL) was added 4-methylbenzenesulfonic acid (1.9 g, 0.01 mol). The mixture was stirred at reflux with a Dean-Stark trap to remove water. The reaction mixture was washed with a small amount of water and brine, dried over anhydrous Na2SO4, and concentrated in vacuum to give the crude methyl 2-(2-isopropyl-1,3-dioxolan-2-yl)-acetate (67 g 71% yield), which was used for the next step without further purification.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([CH3:7])([CH3:6])[CH3:5].[NH2:9][NH:10][C:11]([NH2:13])=[S:12]>C(O)C>[C:4]([C:3]1[N:13]=[C:11]([NH:10][NH2:9])[S:12][CH:2]=1)([CH3:7])([CH3:6])[CH3:5]
Reactant: NNC(N)=S
Reactant: CC(C)(C)C(=O)CBr
Solvent: CCO
Product: CC(C)(C)c1csc(NN)n1
Yield: 59 %

Procedure:
A mixture of 1-bromo-3,3-dimethyl-butan-2-one (1.35 mL, 10 mmol) and thio-semicarbazide (0.91 g, 10 mmol) in ethanol (35 mL) was refluxed for 1.5 h and evaporated. Purification by flash chromatography (SiO2) provided (4-tert-butyl-thiazol-2-yl)-hydrazine (1.01 g, 59% yield) as an orange solid. 1H-NMR (DMSO-d6, 500 MHz) 9.0 (br, 1H), 7.3 (br, 2H), 6.37 (s, 1H), 1.22 (s, 9H) ppm; MS (LC-MS) 172.1 (M+H); HPLC (method A) 2.520 min.
Reaction SMILES: [N:1]12[CH2:9][CH:5]([CH2:6][CH2:7][CH2:8]1)[CH:4]([OH:10])[CH2:3][CH2:2]2.[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[N:1]12[CH2:9][CH:5]([CH2:6][CH2:7][CH2:8]1)[CH:4]([O:10][C:11](=[O:13])[CH3:12])[CH2:3][CH2:2]2
Reactant: OC1CCN2CCCC1C2
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OC1CCN2CCCC1C2
Temperature: 120 °C
Yield: 87 %

Procedure:
To acetic anhydride (150 ml) (4SR,5RS)-(1-aza-bicyclo[3.3.1]nonan-4-ol (21.34 g, 151 mmol) is added portionwise under cooling. The reaction mixture is heated to 120° C. for 2.5 h, is evaporated and extracted with THF/sat. K2CO3 soln. The aq. layer is reextracted with THF. The combined organic layers are washed with brine, dried over Na2SO4, filtered and evaporated. The crude product is purified by bulb-to-bulb distillation (HV, 90° C.) to give 24.07 g (87%) of (4SR,5RS)-acetic acid 1-aza-bicyclo[3.3.1]non-4-yl ester.
Reaction SMILES: [CH2:1]([Si:3]([CH2:17][CH3:18])([CH2:15][CH3:16])[O:4][C@@H:5]1[C@H:8]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[NH:7][C:6]1=[O:14])[CH3:2].C(N(C(C)C)CC)(C)C.[CH:28]([O:31][C:32](Cl)=[O:33])([CH3:30])[CH3:29]>ClCCl.CN(C1C=CN=CC=1)C>[CH2:17]([Si:3]([CH2:15][CH3:16])([CH2:1][CH3:2])[O:4][C@@H:5]1[C@H:8]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[N:7]([C:32]([O:31][CH:28]([CH3:30])[CH3:29])=[O:33])[C:6]1=[O:14])[CH3:18]
Reactant: CC(C)OC(=O)Cl
Reactant: CC[Si](CC)(CC)O[C@H]1C(=O)N[C@H]1c1ccco1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[Si](CC)(CC)O[C@H]1C(=O)N(C(=O)OC(C)C)[C@H]1c1ccco1
Reaction time: 1 h
Yield: 96.1 %

Procedure:
(3R, 4R)-3-Triethylsilyloxy-4-(2-furyl)azetidin-2-one (0.51 g, 1.91 mmol) in 25 mL of dichloromethane was stirred with diisopropylethyl amine (0.78 mL, 4.4 mmol) and i-propylchloroformate (4.0 mL, 1.0M in toluene, 4.0 mmol) in addition to a catalytic amount of DMAP. The solution was stirred for 1 h and diluted with dichloromethane and washed with brine, dried over MgSO4 and concentrated. The residue was chromatographed over silica gel (eluted with 5:1 hexane/ethyl acetate) to give 649 mg of the title product (Y: 96%); IR(KBr) 1822, 1812, 1716, 1374, 1314, 1186, 1018, 1004, 746 cm-1 ; 1H-NMR (CDCl3, 300 MHz) δ 7.39 (m, 1H), 6.35 (m, 2H), 5.08 (ABq, J=15.6, 5.6 Hz, 2H), 4.96 (d, J=10.0 Hz, 1H), 1.25 (d, J=6.3 Hz, 3H), 1.17 (d, J=6.3 Hz, 3H)), 0.83 (t, J=7.8, 9H), 0.50 (m, 6H); 13C-NMR (CDCl3, 75.5 Hz) δ 165.5, 148.6, 147.8, 142.9, 110.5, 109.9, 77.6, 71.1, 55.9, 21.7, 21.6, 6.3, 4.4; DCIMS M+H calcd for C17H28NO5Si: 354, Found: 354.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6](/[CH:9]=[C:10]2/[C:11]([NH:16][CH2:17][C:18]#[CH:19])=[N:12][C:13](=[O:15])[S:14]/2)[CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=1.O>CN(C=O)C>[F:35][C:34]([F:36])([F:37])[C:32]1[CH:33]=[C:28]([CH:29]=[C:30]([C:38]([F:41])([F:39])[F:40])[CH:31]=1)[CH2:27][N:3]1[CH2:8][CH2:7][CH:6]([CH:9]=[C:10]2[S:14][C:13](=[O:15])[N:12]=[C:11]2[NH:16][CH2:17][C:18]#[CH:19])[CH2:5][CH2:4]1
Reactant: C#CCNC1=NC(=O)S/C1=C\C1CCNCC1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCNC1=NC(=O)SC1=CC1CCN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.6 %

Procedure:
To a solution of (5Z)-5-(piperidin-4-ylmethylidene)-4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one dihydrochloride (200 mg) in DMF (3 mL) were added potassium carbonate (345 mg) and 1-(bromomethyl)-3,5-bis(trifluoromethyl)benzene (198 mg). The reaction mixture was stirred at room temperature overnight, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (164 mg).
Reaction SMILES: [CH3:1][O-:2].[Na+].[NH2:4][CH:5]1[N:10]=[C:9]([Cl:11])[N:8]=[C:7](F)[N:6]1[O:13][CH:14]([F:16])[F:15]>CO>[NH2:4][CH:5]1[N:10]=[C:9]([Cl:11])[N:8]=[C:7]([O:2][CH3:1])[N:6]1[O:13][CH:14]([F:16])[F:15]
Reactant: NC1N=C(Cl)N=C(F)N1OC(F)F
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC1=NC(Cl)=NC(N)N1OC(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
8.4 g (0.0466 mol) of 30% strength sodium methylate were added over the course of 15 minutes to a stirred mixture of 10 g (0.0466 mol) of 2-amino-4-chlorodifluoromethoxy-6-fluoro-1,3,5-triazine and 100 ml of methanol at 0° C. The mixture was stirred at 0° C. for one hour and then concentrated under reduced pressure, taken up in methylene chloride and extracted with water. Drying and concentration yielded 10.4 g (98.5% of theory) of the title compound of melting point 109°-111° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[CH:14]=[C:13]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH:12]=[CH:11][C:10]=1[NH:24][C:25](=[O:36])[C@H:26]([NH:28]C(OC(C)(C)C)=O)[CH3:27]>C(Cl)Cl>[Cl:8][C:9]1[CH:14]=[C:13]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH:12]=[CH:11][C:10]=1[NH:24][C:25](=[O:36])[C@H:26]([NH2:28])[CH3:27]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(S(=O)(=O)c2ccccc2)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](N)C(=O)Nc1ccc(S(=O)(=O)c2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.4 %

Procedure:
TFA (0.5 ml) was added drop wise to a solution of (R)-N-[2-chloro-4-(phenylsulphonyl)phenyl]-2-(t-butoxycarbonylamino)propanamide (Method 2) (0.090 g) in dry DCM (5 ml). The resulting mixture was stirred at room temperature for 3 hours. Volatile material was removed by evaporation. The resulting residue was re-dissolved in DCM (10 ml), and volatile material was removed by evaporation. This was repeated, the resulting residue was dried for 30 minutes on a high vacuum line. The residue was then dissolved in DCM and passed through a Varian Isolute SPE column containing basic residues, with DCM as the eluent to give the title compound (0.067 g) as a gum. NMR (CDCl3): 1.32-1.40 (d, 3H), 1.52 (brs, 2H), 3.51-3.64 (q, 1H), 7.40-7.55 (m, 3H), 7.71-7.8(m, 1H), 7.81-7.95 (m, 3H), 8.58-8.65 (m, 1H), 10.46 (brs, 1H). MS: (ESP−) 339.3 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[NH2:46][C:47]1[CH:52]=[N:51][CH:50]=[CH:49][N:48]=1>C(Cl)Cl>[CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)[C:8]([NH:46][C:47]2[CH:52]=[N:51][CH:50]=[CH:49][N:48]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CSc1ccc([C@@H](CC2CCCC2)C(=O)O)cc1
Reactant: Nc1cnccn1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CSc1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnccn2)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 14.9 %

Procedure:
A solution of 3-cyclopentyl-2(R)-(4-methylsulfanyl-phenyl)-propionic acid (529 mg, 2.0 mmol) and triphenylphosphine (892 mg, 3.4 mmol) in methylene chloride (10 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (605 mg, 3.4 mmol) in small portions. The reaction mixture color changed from light yellow to a darker yellow then to brown. After the complete addition of the N-bromosuccinimide, the reaction mixture was allowed to warm to 25° C. over 30 min. The brown reaction mixture was then treated with 2-aminopyrazine (476 mg, 5.0 mmol). The resulting reaction mixture was stirred at 25° C. for 19 h. The reaction mixture was then concentrated in vacuo to remove methylene chloride. The remaining black residue was diluted with a 10% aqueous hydrochloric acid solution (40 mL) and then extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 65/35 hexanes/ethyl acetate) afforded 3-cyclopentyl-2(R)-(4-methylsulfanyl-phenyl)-N-pyrazin-2-yl-propionamide (102 mg, 15%) as a white solid: mp 128-130° C., [α]23589=−103.1° (c=0.032, chloroform); EI-HRMS m/e calcd for C19H23N3OS (M+) 341.1562, found 341.1563.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[C:7]([CH:10]=1)[C:8]#[N:9].[CH3:22][N:23]1[CH:27]=[C:26]([CH2:28][C:29]2[C:30](=[O:36])[NH:31][C:32](=[S:35])[NH:33][CH:34]=2)[CH:25]=[N:24]1.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[CH3:22][N:23]1[CH:27]=[C:26]([CH2:28][C:29]2[C:30](=[O:36])[N:31]=[C:32]([S:35][CH2:2][C:3]3[CH:4]=[CH:5][C:6]([O:11][C:12]4[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=4)=[C:7]([CH:10]=3)[C:8]#[N:9])[NH:33][CH:34]=2)[CH:25]=[N:24]1
Reactant: N#Cc1cc(CCl)ccc1Oc1ccc(C(F)(F)F)cn1
Reactant: Cn1cc(Cc2c[nH]c(=S)[nH]c2=O)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cn1cc(Cc2c[nH]c(SCc3ccc(Oc4ccc(C(F)(F)F)cn4)c(C#N)c3)nc2=O)cn1
Temperature: 60 °C
Yield: 42.1 %

Procedure:
To a solution of 5-(chloromethyl)-2-{[5-(trifluoromethyl)-2-pyridinyl]oxy}benzonitrile (97 mg, 0.310 mmol) and 5-[(1-methyl-1H-pyrazol-4-yl)methyl]-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone (76 mg, 0.341 mmol) in chloroform (2 mL) was added dropwise DIPEA (0.163 mL, 0.931 mmol) at 0° C. The mixture was heated at 60° C. for 2 h. Purification via reverse phase flash chromatography then afforded the title compound (65 mg, 42.0% yield). LCMS: rt=2.98 min, [M+H+]=499