Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:20])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1.[C:21]1([CH:27]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:28]2[CH2:31][C:30](=O)[CH2:29]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.COC(OC)OC>CO>[CH:27]([N:28]1[CH2:31][C:30](=[N:1][CH2:2][C@H:3]([OH:20])[CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:8][CH:7]=2)[CH2:29]1)([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: NC[C@H](O)COc1ccc(OCc2ccccc2)cc1
Solvent: CO
Solvent: COC(OC)OC
Product: O[C@@H](CN=C1CN(C(c2ccccc2)c2ccccc2)C1)COc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 79.6 %

Procedure:
A mixture of (2S)1-Amino-3-(4-benzyloxy-phenoxy)-propan-2-ol (1.64 g, 6 mmol) and 1-(diphenylmethyl)-3-azetidinone (1.19 g, 5 mmol) in methanol (20 ml) was treated with trimethylorthoformate (1.59 g, 15 mmol), and stirred at room temperature for 2 days. The resulting suspension was filtered, and the precipitate washed with 3×5 ml of methanol, and dried in vacuo to give 1.96 g of a white solid. The methanol filtrate was evaporated, and the residue was dissolved in ethyl acetate. The ethyl acetate solution was filtered through a pad of silica gel, and eluted with 2×30 ml of ethyl acetate. The combined filtrate was evaporated, and the residue triturated with a mixture of ether and hexanes to give an additional 0.30 g of product; m.p. 141-142° C.; MS (ES) m/z 748 (MH+); HRMS (El) Calcd. for C32H32N2O3 (M+): 492.2413, Found: 492.2397.
Reaction SMILES: [OH:1][C:2]1[C:14]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:13][C:5]([CH2:6][NH:7][N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:4][C:3]=1[C:19]([CH3:22])([CH3:21])[CH3:20].[O:23]1CCC[CH2:24]1>>[CH:24]([N:7]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)[CH2:6][C:5]1[CH:13]=[C:14]([C:15]([CH3:16])([CH3:18])[CH3:17])[C:2]([OH:1])=[C:3]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:4]=1)=[O:23]
Reactant: C1CCOC1
Reactant: CC(C)(C)c1cc(CNn2ccnc2)cc(C(C)(C)C)c1O
Product: CC(C)(C)c1cc(CN(C=O)n2ccnc2)cc(C(C)(C)C)c1O
Reaction time: 1 h

Procedure:
15 ml of acetic anhydride and 7.5 ml of formic acid (98-100%) are mixed carefully at 0° and subsequently heated to 50° on a water-bath for 1 hour. The mixed anhydride formed is diluted with 25 ml of abs. tetrahydrofuran and 4.52 g of 1-(4-hydroxy-3,5-di-tert.-butylbenzylamino)imidazole are introduced in small portions into the solution obtained. The reaction mixture is left to stand at room temperature for 1 hour and evaporated under reduced pressure on a rotary evaporator. The residue is treated with a small amount of ice-cold water and saturated sodium bicarbonate is added up to a weakly alkaline reaction. After three-fold extraction with methylene chloride, the combined organic extracts are washed once with water and once with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue is recrystallized from ethyl acetate/n-hexane and there is obtained 1-[N-formyl-N-(4-hydroxy-3,5-di-tert.-butylbenzyl)amino]imidazole of m.p. 167°.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[C:16]([NH:17][C:18](=[O:26])[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)=[CH:15][C:14]([Cl:27])=[CH:13][N:12]=2)[CH2:7][CH2:6]1)=[O:4].O.[OH-].[Na+]>CO>[Cl:27][C:14]1[CH:15]=[C:16]([NH:17][C:18](=[O:26])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[C:11]([N:8]2[CH2:9][CH2:10][CH:5]([C:3]([OH:4])=[O:2])[CH2:6][CH2:7]2)=[N:12][CH:13]=1
Reactant: COC(=O)C1CCN(c2ncc(Cl)cc2NC(=O)c2cccc(Cl)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(Nc1cc(Cl)cnc1N1CCC(C(=O)O)CC1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
To a suspension of 0.480 g (1.18 mmol) of 5′-chloro-3′-(3-chloro-benzoylamino)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid methyl ester in a 1:1 mixture of water:methanol (10 mL) is added 1.0 mL (2.5 mmol) of sodium hydroxide as a 10% aqueous solution. The mixture is stirred at room temperature overnight then concentrated under reduced pressure to remove volatile organics. The pH is adjusted to approximately pH 5 by the addition of a 2N solution of hydrochloric acid causing a solid to precipitate from solution. The material is collected by filtration, washed with water, and dried on the filter pad to provide 0.35 g (75%) of 5′-chloro-3′-(3-chloro-benzoylamino)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid as a light yellow solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]([CH3:11])[CH3:10])=[N:7][CH:8]=1.Br[C:13]1[C:14]2[CH2:22][N:21]([C:23]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:24]=3[C:25]#[N:26])[CH2:20][CH2:19][C:15]=2[N:16]=[CH:17][N:18]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:31][C:28]1[CH:29]=[CH:30][C:23]([N:21]2[CH2:20][CH2:19][C:15]3[N:16]=[CH:17][N:18]=[C:13]([NH:1][CH2:2][C:3]4[CH:8]=[N:7][C:6]([N:9]([CH3:11])[CH3:10])=[CH:5][CH:4]=4)[C:14]=3[CH2:22]2)=[C:24]([CH:27]=1)[C:25]#[N:26]
Reactant: N#Cc1cc(Cl)ccc1N1CCc2ncnc(Br)c2C1
Reactant: CN(C)c1ccc(CN)cn1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)c1ccc(CNc2ncnc3c2CN(c2ccc(Cl)cc2C#N)CC3)cn1

Procedure:
A mixture of 5-(aminomethyl)-N,N-dimethylpyridin-2-amine (24 mg, 0.16 mmol), 2-(4-bromo-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-chlorobenzonitrile (50 mg, 0.14 mmol), and N,N-diisopropylethylamine (62 μL, 0.36 mmol) in acetonitrile (1.9 mL) was subjected to microwave irradiation at 180° C. for 6 hrs. The reaction mixture was concentrated to an oil which was purified by silica gel column (0-15% MeOH/CH2Cl2) to obtain a light yellow solid.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:7][OH:8])[C@H:3]([OH:6])[CH2:4][OH:5].[CH3:10][S:11](Cl)(=[O:13])=[O:12].Cl>N1C=CC=CC=1.ClCCl>[CH3:10][S:11]([O:5][CH2:4][C@@H:3]([OH:6])[C:2]([CH3:9])([CH3:1])[CH2:7][O:8][S:11]([CH3:10])(=[O:13])=[O:12])(=[O:13])=[O:12]
Reactant: CC(C)(CO)[C@H](O)CO
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(COS(C)(=O)=O)[C@H](O)COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 39.6 %

Procedure:
To a 0° C. solution of 25.3 g (189 mmol) of (2S)-3,3-dimethyl-1,2,4-butanetriol in 170 mL of pyridine was added dropwise 29.1 mL (378 mmol) of methanesulfonyl chloride. The reaction mixture was allowed to warm slowly to room temperature, and was stirred for 18 h. It was then diluted with dichloromethane. To the resulting solution was added 200 mL of 1 N hydrochloric acid, followed by enough concentrated hydrochloric acid to acidify the aqueous phase (pH=2). The mixture was extracted with dichloromethane, and the combined extracts were washed with brine and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with acetone:dichloromethane (1:9) to afford 21.75 g (52%) of (2S)-2-hydroxy-3,3-dimethyl-4-[(methylsulfonyl)oxy]butyl methanesulfonate. 1H-NMR (300 MHz, DMSO-d6): δ 5.48 (d, J=6 Hz, 1H), 4.30 (dd, J=3 Hz, J=10 Hz, 1H), 4.05–3.91 (m, 3H), 3.16 (d, J=4 Hz, 6H), 0.90 (d, J=13 Hz, 6H).
Reaction SMILES: C(NC(C)C)(C)C.[C:8]1([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:20]([O:23][CH:24](C)[CH2:25][CH2:26][CH2:27]I)(=[O:22])[CH3:21].Cl>O1CCCC1>[C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:14]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:22])[CH3:21]
Reactant: CCOC(=O)Cc1ccccc1
Reactant: CC(=O)OC(C)CCCI
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(CCCCOC(C)=O)c1ccccc1
Temperature: -70 °C
Reaction time: 0.17 h
Yield: 89.8 %

Procedure:
Diisopropylamine (2.4 g, 23.8 mmole) was dissolved in anhydrous tetrahydrofuran (50 ml) under argon, and the solution was cooled at -70° C. 1.6M n-butyllithium-hexane solution (14.8 ml, 23.7 mmole) was added dropwise to the solution, followed by stirring at -70° C. for 10 minutes. Tetrahydrofuran (10 ml) solution containing ethyl phenylacetate (3.24 g, 20 mmole) was added, while maintaining the reaction solution at not higher than -60° C. After stirring was continued for 30 minutes under the same conditions, a solution of 4-acetoxypentyl iodide (4.8 g, 20 mmole) in hexamethylphosphortriamide (4 ml) was added dropwise to the reaction solution. Following the dropwise addition, stirring was continued at -70° C. for another 1 hour, and the reaction temperature was allowed to rise to room temperature. 2N hydrochloric acid (30 ml) was added, and the product was extracted with isopropyl ether. The organic layer was washed with water, dried and concentrated under reduced pressure. The residue was chromatographed on silica gel, and development was effected with isopropyl ether:hexane (1:1) to yield ethyl 6-acetoxy-2-phenylhexanoate (5 g, 90%).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.I[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][C:34](I)=[CH:33][CH:32]=3)=[CH:27][CH:26]=2)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu].CCCCCCCCCCCC>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]([C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=3)[C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][C:28]([C:31]5[CH:36]=[CH:35][C:34]([N:10]([C:6]6[CH:5]=[C:4]7[C:9](=[CH:8][CH:7]=6)[CH2:1][CH2:2][CH2:3]7)[C:11]6[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=6)=[CH:33][CH:32]=5)=[CH:27][CH:26]=4)=[CH:21][CH:20]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Ic1ccc(-c2ccc(-c3ccc(I)cc3)cc2)cc1
Reactant: Cc1ccc(Nc2ccc3c(c2)CCC3)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCCCCCCCC
Product: Cc1ccc(N(c2ccc(-c3ccc(-c4ccc(N(c5ccc(C)cc5)c5ccc6c(c5)CCC6)cc4)cc3)cc2)c2ccc3c(c2)CCC3)cc1
Temperature: 205 °C
Reaction time: 30 h
Yield: 75.8 %

Procedure:
Indane-5-yl-p-tolylamine (18.1 g (0.081 mol)), 18.9 g (0.039 mol) of 4,4″-diiodo-p-terphenyl, 7.2 g (0.052 mol) of anhydrous potassium carbonate, 0.76 g (0.012 mol) of copper powder and 30 ml of n-dodecane were mixed, and heated up to 200 to 210° C. while introducing nitrogen gas, followed by stirring for 30 hours. After the termination of the reaction, the reaction product was extracted with 400 ml of toluene, and insoluble matter was removed by filtration. Then, the filtrate was concentrated to dryness. The resulting solid matter was purified by column chromatography (carrier: silica gel, eluent: toluene:hexane=1:4) to obtain 19.9 g of N,N′-bisindane-5-yl-N,N′-di-p-tolyl-4,4″-diamino-p-terphenyl (compound No. 1) (yield: 75.7%, melting point: 207.4 to 208.1° C.).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:15]4[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N:16]=4)=[CH:10]3)[C:6]=2[CH:22]=1.[CH:23]([N:26]1[CH2:31][CH2:30][CH:29]([SH:32])[CH2:28][CH2:27]1)([CH3:25])[CH3:24].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:23]([N:26]1[CH2:31][CH2:30][CH:29]([S:32][C:2]2[CH:3]=[CH:4][C:5]3[O:14][CH2:13][CH2:12][N:11]4[C:7](=[N:8][C:9]([C:15]5[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N:16]=5)=[CH:10]4)[C:6]=3[CH:22]=2)[CH2:28][CH2:27]1)([CH3:25])[CH3:24]
Reactant: Cc1cccnc1-c1cn2c(n1)-c1cc(Br)ccc1OCC2
Reactant: CC(C)N1CCC(S)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccnc1-c1cn2c(n1)-c1cc(SC3CCN(C(C)C)CC3)ccc1OCC2
Temperature: 120 °C
Yield: 53.7 %

Procedure:
A mixture of 9-bromo-2-(3-methylpyridin-2-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (107 mg, 0.30 mmol), 1-isopropylpiperidine-4-thiol (72 mg, 0.45 mmol), Pd2(dba)3 (14 mg, 0.015 mmol, 5 mol %), XantPhos (17 mg, 0.030 mmol, 10 mol %) and DIPEA (210 μl, 1.20 mmol) in dioxane (4 mL) was purged with nitrogen and then heated at 120° C. for 1 h using microwave irradiation. The reaction mixture was diluted with DCM (75 mL) and purified by column chromatography (Si-PCC, gradient 0-10% 2M NH3/MeOH in DCM followed by C18, gradient 5-45% MeOH in 0.5% TFA/H2O). The product containing fractions were combined and concentrated in vacuo and the resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 0.5M NH3/MeOH. The basic fractions were concentrated under reduced pressure affording 9-(1-Isopropylpiperidin-4-ylsulfanyl)-2-(3-methylpyridin-2-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene as a colorless gum (70 mg, 54%). LCMS: RT1.83 min [M+H]+ 435.1
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[C:16](Cl)(=[O:20])[CH2:17][CH2:18][CH3:19].Cl>N1C=CC=CC=1>[C:16]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)(=[O:20])[CH2:17][CH2:18][CH3:19]
Reactant: CCCC(=O)Cl
Reactant: CC1CC(=O)NN=C1c1ccc(O)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCCC(=O)Oc1ccc(C2=NNC(=O)CC2C)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
A 100 ml round-bottomed flash was charged with pyridine (30 ml) and 7.10 g (34.8 mmol) of (±)-4,5-dihydro-6-(4'-hydroxyphenyl)-5-methyl-3(2H)-pyridazinone from Example I, then cooled to 0° C. under an atmosphere of nitrogen. Butanoyl chloride (4.10 g, 38.3 mmol) was added dropwise to the solution via syringe. The reaction mixture was stirred for 30 min at 0° C., warmed to 23° C. over 15 min then poured into 1N aqueous hydrochloric acid (400 ml). The aqueous solution was extracted with EtOAc (2×200 ml). The combined EtOAc extracts were successively washed with 5% aqueous sodium bicarbonate solution (300 ml), saturated aqueous sodium chloride (200 ml), dried over anhydrous magnesium sulfate (5 g), filtered and concentrated in vacuo to provide 9.8 g of crude product as a solid. Recrystallization from ethyl acetae/hexanes (2:1, 35 ml) yielded 7.61 g (80%) of pure (±)-6-(4'-butanoyloxyphenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone as colorless needles, m.p. 112°-113° C.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([CH2:22][C:23]([OH:25])=O)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:26]=2)=[N:7][C:6]([CH3:27])=[N:5]1)([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.C[N+:36](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[Cl-].[NH4+].C(N(CC)CC)C>CN(C)C=O>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([CH2:22][C:23]([NH2:36])=[O:25])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:26]=2)=[N:7][C:6]([CH3:27])=[N:5]1)([CH3:2])[CH3:3]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(CC(=O)O)cc2OCC3)n(C(C)C)n1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(-c2cn3c(n2)-c2ccc(CC(N)=O)cc2OCC3)n(C(C)C)n1
Reaction time: 0.67 h

Procedure:
A mixture of 58 mg (0.158 mmol) of 2-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)acetic acid, 76 mg (0.20 mmol) of N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate, (HATU, 16 mg, 0.30 mmol) of ammonium chloride and 28 uL (0.200 mmol) of Triethylamine in N,N-3.0 ml of Dimethylformamide was stirred for 40 min. The mixture was concentrated in vacuum and triturated with 10 ml of water. The solid was collected and purified by RP HPLC (acetonitrile gradient) to give 300. Yield 8.1 mg. M/z 367.2, calc. 366.18. 1H NMR (500 MHz, DMSO) δ 8.30 (d, J=8.2, 1H), 7.86 (s, 1H), 7.44 (s, 1H), 7.04 (d, J=8.3, 1H), 6.96 (s, 1H), 6.88 (s, 1H), 5.80 (dt, J=13.1, 6.5, 1H), 4.49 (q, J=6.2, 4H), 3.38 (s, 2H), 2.25 (s, 3H), 1.45 (d, J=6.6, 6H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([NH2:8])=[S:7].[C:16]([CH:19](Cl)[C:20]([CH3:22])=O)(=[O:18])[CH3:17]>C1C=CC=CC=1>[CH3:15][O:14][C:10]1[CH:9]=[C:5]([C:6]2[S:7][C:19]([C:16](=[O:18])[CH3:17])=[C:20]([CH3:22])[N:8]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:11]=1[O:12][CH3:13]
Reactant: CC(=O)C(Cl)C(C)=O
Reactant: COc1cc(C(N)=S)cc(OC)c1OC
Solvent: c1ccccc1
Product: COc1cc(-c2nc(C)c(C(C)=O)s2)cc(OC)c1OC
Yield: 79.7 %

Procedure:
Into 200 ml of benzene, 22.7 g (0.1 mol) of 3,4,5-trimethoxythiobenzamide and 16.0 g (0.12 mol) of 1-acetyl-1-chloroacetone were dissolved, and the solution was heated under a reflux condenser for 3 hours. The crystals, which separated out after cooling the reaction mixture, were recrystallized from methanol to obtain 24.5 g of pale yellow needle-like crystals of the product melting at 128° to 129° C. The yield was 79.8%. The method belongs to the above-mentioned method (a).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][OH:14])=[C:11]([CH3:15])[S:10][N:9]=2)=[CH:4][CH:3]=1.[F:16][C:17]1[C:22]([F:23])=[C:21](O)[CH:20]=[CH:19][C:18]=1[CH2:25][CH2:26][C:27]([O:29]CC)=[O:28]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:21]3[CH:20]=[CH:19][C:18]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[C:17]([F:16])[C:22]=3[F:23])=[C:11]([CH3:15])[S:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1snc(-c2ccc(Cl)cc2)c1CO
Reactant: CCOC(=O)CCc1ccc(O)c(F)c1F
Product: Cc1snc(-c2ccc(Cl)cc2)c1COc1ccc(CCC(=O)O)c(F)c1F

Procedure:
The title compound was prepared according to the procedure described in Example 91 following Step 5 and 6 by coupling ((3-(4-chlorophenyl)-5-methylisothiazol-4-yl)methanol and ethyl 3-(2,3-difluoro-4-hydroxyphenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J=7.1 Hz, 2H), 7.42 (d, J=7.0 Hz, 2H), 6.90 (m, J=5.6 Hz, 1H), 6.72 (m, J=5.6 Hz, 1H), 4.98 (s, 2H), 2.96 (m, 2H), 2.68 (m, 2H), 2.62 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]1([NH:8][C:9]2[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11]([S:17][CH3:18])[N:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1)[CH3:2].[OH:19]O.[OH-].[Na+]>CS(C)=O.O>[CH2:1]([C:3]1([NH:8][C:9]2[C:14]([C:15]([NH2:16])=[O:19])=[CH:13][N:12]=[C:11]([S:17][CH3:18])[N:10]=2)[CH2:4][CH2:5][CH2:6][CH2:7]1)[CH3:2]
Reactant: CCC1(Nc2nc(SC)ncc2C#N)CCCC1
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCC1(Nc2nc(SC)ncc2C(N)=O)CCCC1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 90.6 %

Procedure:
To a stirred solution of 4-(1-ethylcyclopentylamino)-2-(methylthio)-pyrimidine-5-carbonitrile (830 mg, 3.2 mmol) in DMSO (10 mL) was added aqueous hydrogen peroxide (1.8 g, 30%, 16 mmol), and aqueous sodium hydroxide solution (2.7 mL, 6 mol/L, 16 mmol) at 0° C. The mixture was stirred at 50° C. for 15 min and diluted with water. The mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. Concentration under reduced pressure gave the crude product, which was purified by silica gel column chromatography (5% methanol in DCM) to afford the desired product as a white solid (800 mg, 2.9 mmol, 90% yield). MS (ESI) m/z=281.2 [M+1]
Reaction SMILES: C(N1CCC(=O)CC1)(=[O:8])C1C=CC=CC=1.COC(C=[P:21]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=O>C1(C)C=CC=CC=1>[C:34]1([P:21](=[O:8])([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCN(C(=O)c2ccccc2)CC1
Solvent: Cc1ccccc1
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
Under N2, a mixture of 1-benzoyl-4-piperidone (10.2 g, 0.05 mol), methyl (triphenylphosphoranylidene) acetate (25 g. 0.074 mol) in toluene (100 ml) was heated at reflux for 7 hours. After stirring at room temperature overnight, the solid was filtered off to yield 13.9 g (100%) of triphenylphosphine oxide. The mother liquor was concentrated to dryness and the residue was treated with acetic acid (42 ml), H2O, (6 ml) and 12N HCl (6 ml). The mixture was heated at 80°-85° C. with stirring for 15 hours. The reaction was then concentrated to dryness and the residue was partitioned between saturated Na2CO3 and ethyl acetate. The aqueous layer was further extracted with ethyl acetate (1×), neutralized to pH 3 with 6N HCl and extracted with ethylacetate (4×). The organic layer was dried, filtered and concentrated to dryness to yield 7.2 g (59%) of title compound.
Reaction SMILES: [NH2:1][C@H:2]([C@@H:10]([OH:28])[CH2:11][C@@H:12]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O-])(=O)CCC([O-])=O.C([O-])(O)=O.[Na+].[CH3:42][C:43]1[CH:53]=[CH:52][CH:51]=[C:50]([CH3:54])[C:44]=1[O:45][CH2:46][C:47](Cl)=[O:48]>CCOC(C)=O.O>[CH3:42][C:43]1[CH:53]=[CH:52][CH:51]=[C:50]([CH3:54])[C:44]=1[O:45][CH2:46][C:47]([NH:1][C@H:2]([C@@H:10]([OH:28])[CH2:11][C@@H:12]([NH:20][C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:48]
Reactant: Cc1cccc(C)c1OCC(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Agent: O=C([O-])CCC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cccc(C)c1OCC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
Oxallyl chloride (36.3 ml, 0.42 mol) was added to a slurry of 2-6 dimethylphenoxyacetic acid (50 g, 0.28 mol) in 500 ml toluene followed by addition of 5 drops of DMF and stirred at room temperature for 30 min, then at 55° C. for 1.5 hours. The toluene was removed on a rotary evaporator and remaining volatiles were removed in vacuo to afford 2,6-dimethylphenoxyacetyl chloride as an amber oil, 55 grams, 100%. [2S,3S,5S]-2-Amino-3-hydroxy-5-t-butyloxycarbonylamino-1,6-diphenylhexane×0.5 succinate (111.9 g, 0.25 mol) was charged to a 2 L, 3-necked round-bottomed flask with mechanical stirring. NaHCO3 (106 9, 1.26 mol), 600 ml H2O and 600 ml EtOAc were added and stirred vigorously until all solids were dissolved (15 minutes). Stirring was slowed and a solution of the 2,6-dimethyl-phenoxyacetyl chloride and EtOAc (100 ml) was added in a narrow stream via addition funnel. After 30 min of stirring, starting materials were consumed (HPLC analysis) and the layers were separated. The aqueous layer was extracted with EtOAc, the organic layers were combined and washed with 200 ml of 1 M NaOH, 200 ml of 10% HCl, 200 ml of brine, dried over MgSO4, filtered and concentrated to provide the desired product as a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:15][C:16]1[CH:35]=[CH:34][C:33]([CH:36]2[CH2:41][CH2:40][N:39](C(OC(C)(C)C)=O)[CH2:38][CH2:37]2)=[CH:32][C:17]=1[C:18]([NH:20][C:21]1[CH:30]=[C:29]([Br:31])[CH:28]=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24])=[O:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:8]([O:15][C:16]1[CH:35]=[CH:34][C:33]([CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[CH:32][C:17]=1[C:18]([NH:20][C:21]1[CH:30]=[C:29]([Br:31])[CH:28]=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24])=[O:19])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COC(=O)c1ccc(Br)cc1NC(=O)c1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(Br)cc1NC(=O)c1cc(C2CCNCC2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
Under ice-cooling, trifluoroacetic acid (1.3 mL) was added to a methylene chloride (6.5 mL) solution of methyl 2-(2-(benzyloxy)-5-(1-(tert-butoxycarbonyl)piperidin-4-yl)benzamido)-4-bromobenzoate (0.65 g), followed by stirring at room temperature for 30 minutes. The reaction mixture was added to a saturated aqueous solution of sodium bicarbonate under ice-cooling. The organic layer was separated, washed with a saturated aqueous solution of sodium bicarbonate, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 0.54 g of methyl 2-(2-(benzyloxy)-5-(piperidin-4-yl)benzamido)-4-bromobenzoate as a white solid.