Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10](N)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:23]1C(Cl)=NC(Cl)=N[C:24]=1Cl.O.C(OCC)(=O)C>CN(C=O)C>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([C:24]#[N:23])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: N#CC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 139.7 %

Procedure:
Cbz-Phe-NH2 (4.86 g, 16.29 mmoles) was dissolved in DMF under nitrogen and cooled on ice bath. Cyanuric chloride (1.95 g, 10.59 mmoles) was added with stirring, and the mixture was allowed to warm to rt overnight. Water (100 ml) and ethyl acetate (250 ml) were added to the mixture. The organic phase was separated and washed three times with water (100 ml) and then dried over magnesium sulfate. The material was filtered and concentrated in vacuo to afford Cbz-Phe-CN as a white solid (4.56 g, 99%) HPLC analysis: >99% purity; Retention time 10.1 min.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]21[CH2:14][CH2:13][C:12](=NO)[CH2:11][CH2:10]2.C(OC(=O)C)(=[O:19])C>N1C=CC=CC=1>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]21[CH2:14][CH2:13][C:12](=[O:19])[CH2:11][CH2:10]2
Reactant: CC(=O)OC(C)=O
Reactant: ON=C1CCC2(CC1)Cc1ccccc1C2
Solvent: c1ccncc1
Product: O=C1CCC2(CC1)Cc1ccccc1C2
Reaction time: 6 h
Yield: 88 %

Procedure:
A solution of 3.1 g. spiro(cyclohexane-1,2'-indan)-4-one oxime [12] (prepared in Example 24B) and 6 ml. of acetic anhydride in 25 ml. of pyridine is allowed to stand at room temperature for about 6 hours. The reaction mixture is then poured into ice: water and the solid collected on a filter. The solid is recrystallized from Skellysolve B to give 2.94 g. (88% yield) of spiro(cyclohexane-1,2'-indan)-4-one, oxime acetate [13] having a melting point of 91° to 94° C.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][C@H:8]3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=1.[CH3:17][NH:18][C:19](=[O:32])[C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC.CS(C)=O>[CH3:17][NH:18][C:19](=[O:32])[C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:31][CH2:30][N:29]([CH2:2][C:3]3[CH:12]=[N:11][C:10]4[N:9]5[CH2:13][CH2:14][CH2:15][C@H:8]5[C:7](=[O:16])[NH:6][C:5]=4[CH:4]=3)[CH2:28][CH2:27]2)=[CH:24][CH:25]=1
Reactant: O=C1Nc2cc(CO)cnc2N2CCC[C@@H]12
Reactant: CNC(=O)c1ccc(N2CCNCC2)cc1
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)cc1
Temperature: 90 °C

Procedure:
(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (1.500 g, 6.84 mmol), N-methyl-4-(piperazin-1-yl)benzamide (1.500 g, 6.84 mmol), (cyanomethyl)trimethylphosphonium iodide (2.494 g, 10.26 mmol) and N,N-diisopropylethylamine (5.97 ml, 34.2 mmol) were suspended in propiononitrile (Volume: 27.4 ml) and heated in a closed vial at 90° C. The crude reaction was cooled to RT, DMSO (1 ml) was added, and the mixture was purified via HPLC (55-90, basic) to give the product as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:46])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][NH:22][C@@H:23]([CH3:45])[C@@H:24]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[C:28]([NH:40][S:41]([CH3:44])(=[O:43])=[O:42])[CH:27]=3)[OH:25])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)C.[OH-].[Na+].Cl>O1CCCC1>[CH2:33]([O:32][C:29]1[CH:30]=[CH:31][C:26]([C@@H:24]([OH:25])[C@@H:23]([NH:22][CH2:21][CH2:20][O:19][C:16]2[CH:17]=[CH:18][C:13]([C:10]3[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:46])=[O:3])=[CH:8][CH:9]=3)=[CH:14][CH:15]=2)[CH3:45])=[CH:27][C:28]=1[NH:40][S:41]([CH3:44])(=[O:42])=[O:43])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CCOC(=O)COc1ccc(-c2ccc(OCCN[C@@H](C)[C@H](O)c3ccc(OCc4ccccc4)c(NS(C)(=O)=O)c3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@H](NCCOc1ccc(-c2ccc(OCC(=O)O)cc2)cc1)[C@H](O)c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Yield: 94.1 %

Procedure:
A mixture of ethyl(4′-{2-[(1S,2R)-2-(4-benzyloxy-3-methanesulfonylaminophenyl)-2-hydroxy-1-methylethylamino]-ethoxy}biphenyl-4-yloxy)acetate (60 mg) and a 2 mol/L aqueous solution of sodium hydroxide (0.138 mL) in tetrahydrofuran (5 mL) was stirred at room temperature for 30 minutes. To the mixture was added 2 mol/L hydrochloric acid (0.138 mL), and the solvent was evaporated under reduced pressure. The residue was washed with water to afford the title compound (0.054 g).
Reaction SMILES: [NH:1]([C:3]1[N:8]=[N:7][C:6]2[CH2:9][CH2:10][N:11]([C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:12][C:5]=2[CH:4]=1)[NH2:2]>C(C(CC)=O)C>[CH3:3][CH2:4][C:5](=[N:2][NH:1][C:3]1[N:8]=[N:7][C:6]2[CH2:9][CH2:10][N:11]([C:13](=[O:18])[C:14]([CH3:15])([CH3:17])[CH3:16])[CH2:12][C:5]=2[CH:4]=1)[CH2:6][CH3:9]
Reactant: CC(C)(C)C(=O)N1CCc2nnc(NN)cc2C1
Solvent: CCC(=O)CC
Product: CCC(CC)=NNc1cc2c(nn1)CCN(C(=O)C(C)(C)C)C2
Reaction time: 1 h

Procedure:
1 g of 3-hydrazino-5,6,7,8-tetrahydro-6-pivaloylpyrido[4,3-c]pyridazine is suspended in 10 cc of diethylketone, and heating on a water bath is effected for 1 hour. The title compound has a M.P. of 183°-185° (decomp., from absolute ethanol).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([Cl:20])[C:7]([CH3:19])=[C:8]([C:17]#[N:18])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)(=[O:3])[CH3:2].[N:21]([Si](C)(C)C)=[N+:22]=[N-:23].C([Sn](CCCC)=O)CCC>C1(C)C=CC=CC=1>[Cl:20][C:6]1[C:7]([CH3:19])=[C:8]([C:17]2[NH:23][N:22]=[N:21][N:18]=2)[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=1
Reactant: CC(=O)c1cc(Cl)c(C)c(C#N)c1-c1cccc(F)c1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: CC(=O)c1cc(Cl)c(C)c(-c2nnn[nH]2)c1-c1cccc(F)c1
Yield: 85.7 %

Procedure:
A mixture of 6-acetyl-4-chloro-3′-fluoro-3-methylbiphenyl-2-carbonitrile (100 mg, 0.3 mmol), azidotrimethylsilane (0.092 mL, 0.69 mmol), and dibutyloxostannane (13 mg, 0.052 mmol) in toluene (2.9 mL) was heated at reflux overnight. The mixture was evaporated to dryness and purified on silica gel, eluting with 0 to 50% ethyl acetate in hexane, to give the desired product (85 mg, 70%). LCMS calculated for C16H13ClFN4O (M+H)+: m/z=331.1. found: 331.0.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([OH:25])[CH:6]=[C:7]([CH2:23][CH3:24])[C:8]=1[O:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH2:15][CH:16]([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])[CH3:2].[Cl:26][C:27]([Cl:31])=[CH:28][CH2:29]Cl.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:23]([C:7]1[CH:6]=[C:5]([O:25][CH2:29][CH:28]=[C:27]([Cl:31])[Cl:26])[CH:4]=[C:3]([CH2:1][CH3:2])[C:8]=1[O:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH2:15][CH:16]([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])[CH3:24]
Reactant: CCOC(COCCCCOc1c(CC)cc(O)cc1CC)OCC
Reactant: ClCC=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(COCCCCOc1c(CC)cc(OCC=C(Cl)Cl)cc1CC)OCC
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.6 %

Procedure:
Then, 19.9 g of 3,5-diethyl-4-(4-(2,2-diethoxyethoxy)butyloxy)phenol, 9.20 g of 1,1,3-trichloro-1-propene, 9.15 g of potassium carbonate, and 200 ml of N,N-dimethylformamide were placed in a reaction vessel. After stirring at room temperature for 24 hours, the reaction mixture was poured into water, and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over anhydrous magnesium, and concentrated to give a residue. This residue was subjected to silica gel chromatography, which afforded 25.4 g (yield, 91%) of 3,5-diethyl-1-(3,3-dichloro-2-propenyloxy)-4-(4-(2,2-diethoxyethoxy)butyloxy)benzene, nD26.0 1.4991.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:10]2[CH:14]=[C:13]([CH2:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:12]=[N:11]2)[S:5][C:6]=1[C:7]([OH:9])=O.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.[N:54]1[CH:59]=[CH:58][CH:57]=[C:56]([CH2:60][NH2:61])[CH:55]=1>CN(C)C=O.ClCCl>[CH3:1][C:2]1[N:3]=[C:4]([N:10]2[CH:14]=[C:13]([CH2:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:12]=[N:11]2)[S:5][C:6]=1[C:7]([NH:61][CH2:60][C:56]1[CH:55]=[N:54][CH:59]=[CH:58][CH:57]=1)=[O:9]
Reactant: Cc1nc(-n2cc(CCCc3ccccc3)nn2)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-n2cc(CCCc3ccccc3)nn2)sc1C(=O)NCc1cccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51 %

Procedure:
To a solution of 4-methyl-2-(4-(3-phenylpropyl)-1H-1,2,3-triazol-1-yl)thiazole-5-carboxylic acid (4.62 g, 14.07) in anhydrous N,N-dimethylformamide (50 mL) was added 1-hydroxybenzotriazole (2.28 g, 16.88 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (3.24 g, 16.88 mmol), N,N-diisopropylethylamine (7.35 mL, 42.20 mmol) and pyridin-3-ylmethanamine (1.72 mL, 16.88 mmol). The reaction mixture was stirred at ambient temperature for 18 hours, diluted with dichloromethane (150 mL) and washed with saturated aqueous sodium bicarbonate (50 mL) and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography to afford the title compound as a white solid in 51% yield (3.00 g): mp 108-110° C. (dichloromethane/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 9.00 (t, J=6.0 Hz, 1H), 8.72 (s, 1H), 8.57 (s, 1H), 8.48 (d, J=6.0 Hz, 1H), 7.77-7.73 (m, 1H), 7.40-7.36 (m, 1H), 7.31-7.18 (m, 5H), 4.47 (d, J=6.0 Hz, 2H), 2.76-2.61 (m, 7H), 2.03-1.95 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ 160.4, 155.1, 152.6, 148.8, 148.7, 148.2, 141.5, 135.2, 134.5, 128.3, 128.2, 125.7, 123.9, 123.5, 119.7, 40.6, 34.4, 30.1, 24.3, 17.1; MS (ES+) m/z 419.4 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][CH:17]=[C:18](Br)[CH:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[CH:34]([C:37]1[CH:42]=[CH:41][C:40]([S:43]([NH2:46])(=[O:45])=[O:44])=[CH:39][CH:38]=1)([CH3:36])[CH3:35].[H-].[Na+]>FC(C1C=CC=CC=1)(F)F.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]>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([NH:46][S:43]([C:40]3[CH:41]=[CH:42][C:37]([CH:34]([CH3:36])[CH3:35])=[CH:38][CH:39]=3)(=[O:44])=[O:45])[CH:17]=[N:16][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1ccc(S(N)(=O)=O)cc1
Reactant: Brc1cncc(N2CCN(Cc3ccccc3)CC2)c1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: FC(F)(F)c1ccccc1
Product: CC(C)c1ccc(S(=O)(=O)Nc2cncc(N3CCN(Cc4ccccc4)CC3)c2)cc1
Temperature: 25 °C
Yield: 25.2 %

Procedure:
To a solution of 1-benzyl-4-(5-bromo-pyridin-3-yl)-piperazine (320 mg, 0.88 mmol) in 5 ml trifluoromethylbenzene under an argon atmosphere was added Pd2(dba)3 (40 mg, 0.04 mmol), and tri-tert-butyl-phosphane (27 mg, 0.13 mmol). To a solution of 4-isopropylbenzene sulfonamide (175 mg, 0.88 mol) in 10 ml trifluoromethyl benzene in a separate flask was added sodium hydride (50%, 42 mg, 0.88 mmol) at 50° C. This second solution was added after cooling to room temperature to the first solution. The mixture was heated in a microwave instrument (CEM) at 150° C. for 1 h. After evaporation of the solvent under reduced pressure the mixture was diluted with 50 ml of water and was extracted with 25 ml of ethyl acetate. The combined organic layers were extracted with aqueous HCl solution. The pH of the aqueous solution was adjusted to pH 9 with aqueous NaOH. After extraction with ethyl acetate, the combined organic phases were dried with magnesium sulfate, filtered and the solvent was evaporated under reduced pressure. The so obtained oil was purified via silica gel chromatography with cyclohexane/ethyl acetate (3:7) as eluent, yielding 100 mg of the product.
Reaction SMILES: [F:1][P-:2]([F:7])([F:6])([F:5])([F:4])[F:3].F[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:28]=2[S:27][C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[SH+:20]3)=[CH:11][CH:10]=1.[OH:29][CH2:30][CH:31]([CH2:33][OH:34])[OH:32].[OH-].[K+].O>ClCCl>[F:1][P-:2]([F:7])([F:6])([F:5])([F:4])[F:3].[OH:32][CH:31]([CH2:33][OH:34])[CH2:30][O:29][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:28]=2[S:27][C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[SH+:20]3)=[CH:11][CH:10]=1
Reactant: OCC(O)CO
Reactant: Fc1ccc(-c2cccc3c2Sc2ccccc2[SH+]3)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: OCC(O)COc1ccc(-c2cccc3c2Sc2ccccc2[SH+]3)cc1
Temperature: 120 °C
Yield: 0.3 %

Procedure:
To a 3 necked round bottom flask 0.2 g (438.6 mmol) of 9-(4-fluoro-phenyl)-thianthrenium hexafluorophosphate and 10 g of glycerol were added. The suspension was stirred at 120° C. until complete dissolution. Then 50 mg of potassium hydroxide were added and stirred for 10 minutes and the mixture was poured into water. Dichloromethane was added and the organic layer was washed and dried (Na2SO4). Removal of the solvent under vacuum gave a white solid (0.17 g, 73.4%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10](O)=[O:11].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(O)C.Cl>O1CCCC1>[OH:11][CH2:10][CH:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1]1
Reactant: O=C(O)C1Cc2ccccc2N1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCO
Solvent: C1CCOC1
Product: OCC1Cc2ccccc2N1
Temperature: 60 °C
Reaction time: 18 h
Yield: 64.3 %

Procedure:
To a solution of (RS)-indoline-2-carboxylic acid (8.16 g, 50 mmol) in tetrahydrofuran (50 ml) was added under ice-cooling lithium aluminum hydride (5.7 g, 150 mmol) and the mixture was stirred at 60° C. for 18 h. The reaction mixture was stirred under ice-cooling and ethanol and 1N hydrochloric acid were added. The precipitate was filtered off and the mother liquor was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was applied to silica gel column chromatography and eluted with ethyl acetate-hexane (1:4-1:1) to give the title compound (4.8 g, 64%).
Reaction SMILES: [CH2:1]([N:8]1[C@H:12]([C:13]([OH:15])=[O:14])[C@H:11]([C:16]([OH:18])=[O:17])[N:10]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:9]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:27]1[CH:32]=[CH:31][CH:30]=CC=1.S(=O)(=O)(O)O>C(O)CCC>[CH2:19]([N:10]1[C@H:11]([C:16]([O:18][CH2:1][CH2:2][CH2:3][CH3:4])=[O:17])[C@H:12]([C:13]([O:15][CH2:27][CH2:32][CH2:31][CH3:30])=[O:14])[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]1=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: c1ccccc1
Reactant: O=C(O)[C@@H]1[C@H](C(=O)O)N(Cc2ccccc2)C(=O)N1Cc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CCCCO
Product: CCCCOC(=O)[C@@H]1[C@H](C(=O)OCCCC)N(Cc2ccccc2)C(=O)N1Cc1ccccc1

Procedure:
A mixture of cis-1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylic acid (35.4 g), benzene (500 ml), n-butanol (45 ml) and conc. sulfuric acid (5.0 g) was refluxed for 16 hours, cooled, washed successively with water, 5% aqueous sodium hydroxide and water, and then concentrated under reduced pressure to give oily product of di-n-butyl cis-1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylate (39.5 g). IR (neat, cm-1): 2950, 1750, 1710, 1445, 1420, 1350, 1200, 1060, 1020, 960, 745, 695.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:31]=[C:30]([F:32])[C:7]([O:8][C:9]([C:12]2[N:13]([CH:27]([CH3:29])[CH3:28])[C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[C:22](=[O:26])[NH:21][CH2:20]4)=[N:15][N:16]=2)([CH3:11])[CH3:10])=[C:6]([F:33])[CH:5]=1.I[CH3:35]>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([F:33])[C:7]([O:8][C:9]([C:12]2[N:13]([CH:27]([CH3:29])[CH3:28])[C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[C:22](=[O:26])[N:21]([CH3:35])[CH2:20]4)=[N:15][N:16]=2)([CH3:10])[CH3:11])=[C:30]([F:32])[CH:31]=1
Reactant: CC(C)n1c(-c2ccc3c(c2)CNC3=O)nnc1C(C)(C)Oc1c(F)cc(Cl)cc1F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1c(-c2ccc3c(c2)CN(C)C3=O)nnc1C(C)(C)Oc1c(F)cc(Cl)cc1F
Reaction time: 1 h

Procedure:
Sodium hydride (55% mineral oil, 30 mg) was added to a mixture of 5-{5-[1-(4-chloro-2,6-difluorophenoxy)-1-methylethyl]-4-isopropyl-4H-1,2,4-triazol-3-yl}isoindolin-1-one (200 mg) and DMF (5 ml) under ice cooling, followed by stirring for one hour, iodomethane (0.084 ml) was added thereto, followed by stirring for one hour, while slowly elevating to room temperature. The reaction solution was concentrated, water was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate and the solvent was then evaporated. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:0 to 90:10) and then was solidified from ethyl acetate-diisopropylether, and the solid was collected by filtration, washed with diisopropylether and then dried under reduced pressure to obtain 5-{5-[1-(4-chloro-2,6-difluorophenoxy)-1-methylethyl]-4-isopropyl-4H-1,2,4-triazol-3-yl}-2-methylisoindolin-1-one (111 mg) as a light yellow solid.
Reaction SMILES: C(OC([NH:11][C:12]1[CH:30]=[CH:29][C:15]2[C:16]3[C:24]([O:25][CH:26]([F:28])[F:27])=[CH:23][CH:22]=[CH:21][C:17]=3[O:18][CH:19]([OH:20])[C:14]=2[C:13]=1Br)=O)C1C=CC=CC=1>[Pd].CO>[NH2:11][C:12]1[CH:30]=[CH:29][C:15]2[C:16]3[C:24]([O:25][CH:26]([F:28])[F:27])=[CH:23][CH:22]=[CH:21][C:17]=3[O:18][CH:19]([OH:20])[C:14]=2[CH:13]=1
Reactant: O=C(Nc1ccc2c(c1Br)C(O)Oc1cccc(OC(F)F)c1-2)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1)C(O)Oc1cccc(OC(F)F)c1-2

Procedure:
A mixture of Example 27E (0.5 g, 1.04 mmol) and 10% palladium on carbon (50 mg) in methanol (50 mL) was shaken under hydrogen gas (balloon) for 6 hours, filtered through diatomaceous earth (Celite®), and concentrated to provide the desired product. MS (ESI(−)Q1MS) m/z 278 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:24][C:25]2[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=2)=[N:4][C:5]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH:16]3[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]3)=[C:11]([CH3:23])[CH:10]=2)=[N:6][CH:7]=1.CC([O-])=O.[Na+].[NH2:36][OH:37].Cl>CO>[Cl:1][C:2]1[C:3]([NH:24][C:25]2[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=2)=[N:4][C:5]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH:16]3[CH2:21][CH2:20][C:19](=[N:36][OH:37])[CH2:18][CH2:17]3)=[C:11]([CH3:23])[CH:10]=2)=[N:6][CH:7]=1
Reactant: NO
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCC(=O)CC4)cc3C)ncc2Cl)n[nH]1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCC(=NO)CC4)cc3C)ncc2Cl)n[nH]1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5-dimethylphenyl)cyclohexanone (15 mg, 0.033 mmol) in MeOH (0.5 mL) was added NaOAc (6 mg, 0.073 mmol) and NH2OH HCl (5 mg, 0.073 mmol). The resulting mixture was stirred at 70° C. for 2 h. and then cooled down to room temperature. The mixture was purified directly by preparative RP-HPLC to provide 4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5-dimethylphenyl)-cyclohexanone oxime; ESMS m/z 440.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[O:9][CH2:10][CH2:11][CH3:12].[C:13](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:13])=[CH:4][C:3]=1[O:9][CH2:10][CH2:11][CH3:12]
Reactant: O=C([O-])[O-]
Reactant: CCCOc1cc(O)ccc1Br
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCCOc1cc(OC)ccc1Br
Yield: 97.1 %

Procedure:
To a solution of 4-bromo-3-propoxy-phenol (500 mg, 2.164 mmol) in acetone (10 mL) were added potassium carbonate (299 mg, 2.164 mmol) and methyl iodide (674 μL, 10.82 mmol). The reaction mixture was heated at gentle reflux for 12 h. The solvent was removed and the residue was taken in diethyl ether (50 mL). The white solid was filtered off, and the filtrated was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 5-10% ethyl acetate in hexanes yielded 1-bromo-4-methoxy-2-propoxy-benzene as a clear oil (515 mg, 97%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C@H:6]1[C@H:15]2[CH2:16][CH2:17][N:18]([C:19]([C@H:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]3[NH:27][C:28](=[O:35])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:20])[C@H:14]2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:7]1.[H-].[Na+].[CH3:38]I.O>CN(C=O)C>[CH3:38][N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C@H:6]1[C@H:15]2[CH2:16][CH2:17][N:18]([C:19]([C@H:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]3[NH:27][C:28](=[O:35])[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[O:20])[C@H:14]2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:7]1
Reactant: O=C(N[C@@H]1CCCC[C@@H]1C(=O)N1CC[C@@H]2[C@H](c3ncc[nH]3)Nc3ccccc3[C@@H]21)c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ccnc1[C@@H]1Nc2ccccc2[C@H]2[C@@H]1CCN2C(=O)[C@H]1CCCC[C@H]1NC(=O)c1ccccc1
Reaction time: 1 h
Yield: 62.8 %

Procedure:
To a solution of the compound (119 mg, 0.252 mmol) synthesized in Example 81 in DMF (1 ml) was added sodium hydride (60% in oil, 12.1 mg, 0.30 mmol) under ice-cooling, and the mixture was stirred for 1 hr. Methyl iodide (0.0187 ml, 0.30 mmol) was added dropwise and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous MgSO4, and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography using silica gel and eluted with hexane-ethyl acetate (5:95, v/v) to give the title compound (76.5 mg, 63%) as an amorphous form.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[S:4][CH2:3]1.[CH2:22]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([CH2:38][CH2:39][CH:40](Cl)[C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:34][CH2:33]1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.[I-].[K+]>C(#N)C>[CH2:22]([O:29][C:30]([N:32]1[CH2:33][CH2:34][CH:35]([CH2:38][CH2:39][C@@H:40]([NH:1][C@@H:2]2[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[C:6]3[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=3[S:4][CH2:3]2)[C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:36][CH2:37]1)=[O:31])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)CSc2ccccc21
Reactant: CCOC(=O)C(Cl)CCC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [I-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)[C@@H](CCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@H]1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Yield: 18.1 %

Procedure:
A mixture of 0.4 g of tert-butyl 3(R)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate, 1 g of ethyl 4-(1-benzyloxycarbonyl-4-piperidyl)-2-chlorobutyrate, 0.2 g of triethylamine, 0.9 g of potassium iodide and 50 ml of acetonitrile is heated under reflux for 2 days. After cooling, the reaction solution is concentrated under reduced pressure, and the residue is purified by silicagel column chromatography (hexane:ethyl acetate=2:1) to give 0.15 g of tert-butyl 3(R)-[3-(1-benzyloxycarbonyl-4-piperidyl)-1(R)-ethoxycarbonylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate and 0.25 g of tert-butyl 3(R)-[3-(1-benzyloxycarbonyl-4-piperidyl)-1(S)-ethoxycarbonylpropyl]amino-4-oxy-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate as a colorless oily material, respectively.