Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([C:5]1[CH:26]=[CH:25][C:8]([CH2:9][NH:10][C:11](=[O:24])[CH:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2[F:23])[O:13][CH3:14])=[CH:7][CH:6]=1)(=[NH:4])[NH2:3].Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29].C(N(CC)CC)C.C(OCC)(=O)C>CN(C=O)C>[CH2:31]([O:30][C:28](=[O:29])[N:4]=[C:2]([NH2:3])[C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][C:11](=[O:24])[CH:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2[F:23])[O:13][CH3:14])=[CH:25][CH:26]=1)[CH3:32]
Reactant: CCOC(=O)Cl
Reactant: COc1ccc(C(OC)C(=O)NCc2ccc(C(=N)N)cc2)c(F)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)N=C(N)c1ccc(CNC(=O)C(OC)c2ccc(OC)cc2F)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 99.7 %

Procedure:
(RS)-N-(4-Carbamimidoyl-benzyl)-2-(2-fluoro-4-methoxy-phenyl)-2-methoxy-acetamide hydrochloride (example 15.3, 200 mg) was dissolved in DMF (2.2 ml). The flask was placed in an ice bath. Ethyl chloroformate (58 mg) and triethylamine (160 mg) were added dropwise. The reaction mixture was stirred for 1.5 h at 0° C. Ethyl acetate (30 ml) and ice water (40 ml) were added and the mixture was extracted with ethyl acetate. The organic phase was washed with water, dried, filtered and evaporated. The product was purified by chromatography (silicagel, ethylacetate) to give (RS)-[amino-(4-{[2-(2-fluoro-4-methoxy-phenyl)-2-methoxy-acetylamino]-methyl}-phenyl)-methylene]-carbamic acid ethyl ester (218 mg) as a colorless amorphous solid. MS 418.3 ([M+H]+)
Reaction SMILES: N[CH2:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)/[C:5](=[CH:13]\[C:14]2[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=2)/[C:4]=1[CH3:22].Cl[O:24]C(C)(C)C.CC(C)([O-])C.[K+].Cl>CCOCC.C(O)C>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)/[C:5](=[CH:13]\[C:14]1[CH:15]=[CH:16][C:17]([S:20][CH3:21])=[CH:18][CH:19]=1)/[C:4]([CH3:22])=[C:3]2[CH:2]=[O:24]
Reactant: CSc1ccc(/C=C2/C(C)=C(CN)c3cc(F)ccc32)cc1
Reactant: CC(C)(C)OCl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOCC
Solvent: CCO
Product: CSc1ccc(/C=C2/C(C)=C(C=O)c3cc(F)ccc32)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a suspension of freshly liberated amine from Step 1 (11.5 g, 37 mmol) in ether (220 mL) at 0° C. there was added a solution of t-butyl hypochlorite (4.0 g) in ether (10 mL); the mixture was stirred at 0° C. for 5 minutes as a yellow solid formed. The mixture was then allowed to warm up to room temperature and there was slowly added a solution of potassium tert-butoxide (15 g, 133 mmol) in ethanol (200 mL). The mixture was boiled on a steam bath for 10 minutes and then cooled down. There was added 1N aqueous HCl (200 mL) and after stirring for 20 minutes, the mixture was extracted with ether to afford the crude aldehyde which was purified by column chromatography on silica gel, eluting with a 1:5 mixture of ethyl acetate:hexane. The pure title compound was obtained as an oil.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[CH:15]=[C:14]([C:16]([CH3:18])=[CH2:17])[C@H:13](O)[CH2:12][N:11]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:27]([O:30][N:31]([C@H]1CN(C(OC(C)(C)C)=O)[C@H](CO[Si](C(C)(C)C)(C)C)C=C1C)[S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[N+:41]([O-:43])=[O:42])(=[O:34])=[O:33])[CH:28]=[CH2:29]>>[CH2:27]([O:30][N:31]([C@H:13]1[CH2:12][N:11]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[C@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3])[CH:15]=[C:14]1[C:16]([CH3:18])=[CH2:17])[S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[N+:41]([O-:43])=[O:42])(=[O:34])=[O:33])[CH:28]=[CH2:29]
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: C=C(C)C1=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)C[C@H]1O
Product: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)C=C1C(=C)C)S(=O)(=O)c1ccccc1[N+](=O)[O-]

Procedure:
The title compound was prepared from (2S,5S)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-5-hydroxy-4-(prop-1-en-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 53, 3.86 g, 10.06 mmol) following the procedure described for Intermediate 10. The desired product was obtained as light yellow foam (3.25 g, 52%).
Reaction SMILES: [OH-].[Li+].[CH2:3]([O:5][C@@H:6]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:24][CH:23]=2)=[CH:15][CH:14]=1)[C:7]([O:9]CC)=[O:8])[CH3:4].Cl>C1COCC1.O>[CH2:3]([O:5][C@@H:6]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:26][CH:27]=2)=[CH:17][CH:18]=1)[C:7]([OH:9])=[O:8])[CH3:4]
Reactant: CCOC(=O)[C@H](Cc1ccc(CCOc2ccc(OS(C)(=O)=O)cc2)cc1)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCO[C@@H](Cc1ccc(CCOc2ccc(OS(C)(=O)=O)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
Lithium hydroxide (27 mg, 1.15 mmol) was added to a solution of ethyl(2S)-2-ethoxy-3-[4-(2-{4-[(methylsulfonyl)oxy]phenoxy}ethyl)phenyl]propanoate (167 mg, 0.38 mmol) in THF/water 4:1 (5 mL). The reaction mixture was stirred at room temperature overnight and 1 M HCl (2 mL) was added. The THF was removed under reduced pressure. The aqueous phase was diluted with water and extracted three times with CH2Cl2 in a Phase Separator. The combined organic layers were evaporated. The residue was purified by preparative HPLC to give the product as a colorless oil (129 mg, 83%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9]([NH2:11])=[CH:8][C:6]=2[N:7]=1.[CH3:18][O:19][CH2:20][C:21](Cl)=[O:22]>>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9]([NH:11][C:21](=[O:22])[CH2:20][O:19][CH3:18])=[CH:8][C:6]=2[N:7]=1
Reactant: COCC(=O)Cl
Reactant: Nc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: COCC(=O)Nc1cc2nc(Cl)nc(N3CCOCC3)c2s1

Procedure:
55 mg of 2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-amine was reacted with 26 mg of methoxyacetyl chloride via General Procedure G to give N-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-2-methoxyacetamide.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[S:14][C:13]([C:15]3[N:16]=[C:17]4[C:23]([C:24]([C:26]5([CH3:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)=[O:25])=[CH:22][N:21](COCC[Si](C)(C)C)[C:18]4=[N:19][CH:20]=3)=[CH:12][CH:11]=2)=[O:9])[CH2:4][CH2:3]1.O.O.O.C([O-])(=O)C.[Na+]>ClCCl.FC(F)(F)C(O)=O>[OH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([C:10]2[S:14][C:13]([C:15]3[N:16]=[C:17]4[C:23]([C:24]([C:26]5([CH3:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)=[O:25])=[CH:22][NH:21][C:18]4=[N:19][CH:20]=3)=[CH:12][CH:11]=2)=[O:9])[CH2:6][CH2:7]1
Reactant: CC1(C(=O)c2cn(COCC[Si](C)(C)C)c3ncc(-c4ccc(C(=O)N5CCC(O)CC5)s4)nc23)CCCCC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C(=O)c2c[nH]c3ncc(-c4ccc(C(=O)N5CCC(O)CC5)s4)nc23)CCCCC1
Reaction time: 8 h
Yield: 75 %

Procedure:
A solution of [2-[5-(4-hydroxy-piperidine-1-carbonyl)-thiophen-2-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-(1-methyl-cyclohexyl)-methanone (0.032 g, 0.056 mmol) in 1 mL of dichloromethane and 1 mL of trifluoroacetic acid was stirred for 2 h, then concentrated. The residue was dissolved in 2 mL of ethanol and treated with sodium acetate trihydrate (0.076 g, 0.56 mmol). The mixture was stirred overnight, then concentrated to a residue. Column chromatography (0->50% EtOAc/hexanes) afforded 0.019 g (76%) of {2-[5-(4-hydroxy-piperidine-1-carbonyl)-thiophen-2-yl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-(1-methyl-cyclohexyl)-methanone as an off-white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:30])([CH3:29])[C@H:3]([NH:7][C:8]([N:10]1[C:18]2[CH2:17][CH2:16][N:15]([CH3:19])[CH2:14][C:13]=2[C:12]([C:20]2[CH:25]=[C:24]([F:26])[C:23](F)=[CH:22][C:21]=2[F:28])=[N:11]1)=[O:9])[C:4]([OH:6])=[O:5].FC1C=CC(F)=CC=1C(Cl)=O>>[F:28][C:21]1[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:20]=1[C:12]1[C:13]2[CH2:14][N:15]([CH3:19])[CH2:16][CH2:17][C:18]=2[N:10]([C:8]([NH:7][C@@H:3]([C:2]([CH3:30])([CH3:29])[CH3:1])[C:4]([OH:6])=[O:5])=[O:9])[N:11]=1
Reactant: CN1CCc2c(c(-c3cc(F)c(F)cc3F)nn2C(=O)N[C@H](C(=O)O)C(C)(C)C)C1
Agent: O=C(Cl)c1cc(F)ccc1F
Product: CN1CCc2c(c(-c3cc(F)ccc3F)nn2C(=O)N[C@H](C(=O)O)C(C)(C)C)C1

Procedure:
Compound 81 was prepared according to the procedure described for the synthesis of compound 71 by replacing 2,4,5-trifluorobenzoyl chloride with 2,5-difluoro-benzoyl chloride in the synthesis of intermediate 19. LCMS (+ESI) m/z=407.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH3:22])[N:17]=[CH:16]4)O)=[CH:9][N:10]=2)[N:7]=1.II.O[PH2]=O>CC(O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH3:22])[N:17]=[CH:16]4)=[CH:9][N:10]=2)[N:7]=1
Reactant: Cn1ncc2cc(C(O)c3cnc4ccc(Cl)nn34)ccc21
Agent: II
Agent: O=[PH2]O
Solvent: CC(=O)O
Product: Cn1ncc2cc(Cc3cnc4ccc(Cl)nn34)ccc21

Procedure:
A solution of (6-chloroimidazo[1,2-b]pyridazin-3-yl)(1-methyl-1H-indazol-5-yl)methanol (156.8 mg, 0.50 mmol), I2 (381 mg, 1.50 mmol) and H3PO2 (0.273 mL, 2.50 mmol) in AcOH (4 mL) was heated at 110° C. for 7 h. The solvent was removed under reduced pressure. The residue was diluted with water and extracted with DCM twice. The organic layers were combined, dried over Na2SO4 and concentrated. The crude product was purified by flash chromatography (DCM:MeOH=20:1) to give the title compound containing some iodine and used in the next step without further purification (180.0 mg, 36% purity, 44%). LCMS (method A): [MH]+=298, tR=5.37 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][N:11]=1)=[O:8].C([BH3-])#N.[Na+].[CH3:30][C:31]([CH3:33])=O>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:21][CH2:22][N:23]([CH:31]([CH3:33])[CH3:30])[CH2:24][CH2:25]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][N:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(F)cn1)c1cc(Cl)ccc1NCC1CCNCC1
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)N1CCC(CNc2ccc(Cl)cc2C(=O)Nc2ccc(F)cn2)CC1
Temperature: 50 °C
Reaction time: 24 h
Yield: 21 %

Procedure:
A solution of 5-chloro-N-(5-fluoropyridin-2-yl)-2-[(4-piperidinylmethyl)amino]benzamide from Example 218 (0.50 g, 1.37 mmol) in 10 mL of acetone and 6 mL of 95:5 methanol-acetic acid was treated with sodium cyanoborohydride (0.35 g, 5.5 mmol). After stirring at 50° C. for 24 h, the solution was concentrated in vacuo; and the residue was subjected to silica gel chromatography. Elution with 98:2 dichloromethane-methanol furnished the title compound (0.12 g, 21%) as a yellow solid.
Reaction SMILES: O=[C:2]1[NH:8][CH2:7][CH2:6][CH:5]([C:9](OCC)=[O:10])[CH2:4][CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[NH:8]1[CH2:2][CH2:3][CH2:4][CH:5]([CH2:9][OH:10])[CH2:6][CH2:7]1
Reactant: CCOC(=O)C1CCNC(=O)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCC1CCCNCC1

Procedure:
Ethyl 7-oxoazepane-4-carboxylate was reacted in the presence of lithium aluminum hydride to produce azepan-4-ylmethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][CH2:13][C:14]#CC)[CH2:9][N:8]=[C:7]([C:17]3[C:22](F)=[CH:21][CH:20]=[CH:19][C:18]=3F)[C:6]=2[CH:25]=1.[C:26]([OH:29])(=O)[CH3:27].[CH:30](O)=O.O>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:27]([CH:26]=[O:29])=[C:13]([CH3:14])[N:12]=[C:10]3[CH:9]([CH3:30])[N:8]=[C:7]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:6]=2[CH:25]=1
Reactant: CC#CCNC1=Nc2ccc(Cl)cc2C(c2c(F)cccc2F)=NC1
Reactant: CC(=O)O
Reactant: O=CO
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nc2n(c1C=O)-c1ccc(Cl)cc1C(c1ccccc1)=NC2C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A stirred solution of 0.02 mole of 7-chloro-3-methyl-5-phenyl-2-[(1-methyl-2-propynyl)amino]-3H-1,4benzodiazepine (IV), 20 ml. of acetic acid, 20 ml. of 88% formic acid and 1.5 ml of water at ambient temperature is treated, dropwise, with 160 ml. of a 5% aqueous solution of mercuric acetate. The mixture is then stirred at room temperature for about 3 hours, poured into ice water and then extracted with chloroform. The extract thus obtained is washed with water and then concentrated in vacuo. The residue thus obtained is suspended in hot ethyl acetate and filtered. The filtrate is concentrated and chromatographed on silica gel with 50% ethyl acetate-hexanes to give 8-chloro-6-phenyl-2,4-dimethyl-4H-imidazo[1,2-a][1,4]benzodiazepine-1-carboxaldehyde.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH2:16])=[N:14][CH:15]=2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[CH:17]([C:20]1[CH:25]=[CH:24][C:23]([S:26]([Cl:29])(=[O:28])=[O:27])=[CH:22][CH:21]=1)([CH3:19])[CH3:18].C(N(CC)CC)C>O1CCCC1>[ClH:29].[CH2:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][S:26]([C:23]3[CH:24]=[CH:25][C:20]([CH:17]([CH3:19])[CH3:18])=[CH:21][CH:22]=3)(=[O:28])=[O:27])=[N:14][CH:15]=2)[CH2:8][CH2:9]1)[CH:2]=[CH2:3]
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: C=CCN1CCN(c2ccc(N)nc2)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCN1CCN(c2ccc(NS(=O)(=O)c3ccc(C(C)C)cc3)nc2)CC1
Product: Cl
Temperature: 45 °C
Reaction time: 6 h

Procedure:
520 mg (2.38 mmol) of 5-(4-allylpiperazin-1-yl)pyridin-2-ylamine and 495 mg (2.26 mmol) of 4-isopropylbenzenesulfonyl chloride were dissolved in 5 ml of tetrahydrofuran at room temperature, after which 1.0 ml (7.15 mmol) of triethylamine was added dropwise and the mixture was stirred at 40-50° C. for 6 hours. After the solvent had been evaporated down to dryness, the resulting residue was treated with water and this mixture was made acid using 1N aqueous hydrochloric acid and extracted twice with diethyl ether. The aqueous phase was made alkaline, to pH 9-10, using a 1N aqueous solution of sodium hydroxide and then extracted twice with ethyl acetate. After the combined organic phases had been dried over sodium sulfate, the drying agent had been filtered off and the solvent had been evaporated down to dryness, the resulting residue was chromatographed on silica gel using ethyl acetate. After the solvent had been removed, the resulting residue was brought into solution using a little diethyl ether in dichloromethane and then converted into the hydrochloride using ethereal hydrochloric acid. 415 mg (44% of theory) of the title compound were obtained.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C.[CH3:49][N:50]1[CH2:54][C@H:53]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C@:52]2([CH2:65][CH2:64][CH2:63][NH:62][CH2:61]2)[C:51]1=[O:66].CN1C[C@@H](C2C=CC=CC=2)[C@@]2(CCCNC2)C1=O>CC#N.Cl>[CH2:1]([O:8][CH2:9][C@@H:10]([NH:14][C:15](=[O:16])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:11]([N:62]1[CH2:63][CH2:64][CH2:65][C:52]2([C:51](=[O:66])[N:50]([CH3:49])[CH2:54][CH:53]2[C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[CH2:61]1)=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1C[C@H](c2ccccc2)[C@]2(CCCNC2)C1=O
Reactant: CC(C)(C)OC(=O)N[C@H](COCc1ccccc1)C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN1C[C@@H](c2ccccc2)[C@@]2(CCCNC2)C1=O
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN1CC(c2ccccc2)C2(CCCN(C(=O)[C@@H](COCc3ccccc3)NC(=O)OC(C)(C)C)C2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture comprising (R)-3-(benzyloxy)-2-(tert-butoxycarbonylamino)propanoic acid (Sigma-Aldrich) (1.052 g, 3.56 mmol) and ®T3P (50% in EtOAc) (4.16 ml, 7.12 mmol) in MeCN (20 mL) was treated dropwise with DIPEA (2.488 ml, 14.25 mmol). The resulting solution was stirred at room temperature for 30 minutes, then a racemic mixture of (4R,5S)-2-Methyl-4-phenyl-2,7-diazaspiro[4.5]decan-1-one and (4S,5R)-2-Methyl-4-phenyl-2,7-diazaspiro[4.5]decan-1-one (Intermediate 1A) (1 g, 3.56 mmol) was added portionwise. The reaction mixture was stirred for 20 hours at room temperature. The reaction mixture was diluted with 0.1M HCl (20 mL) and extracted with DCM (20 mL). The aqueous phase was further extracted with DCM (3×20 mL). The combined organic portions were washed with a saturated solution of sodium bicarbonate (20 mL), water (20 mL), dried (MgSO4), and concentrated in vacuo to afford the title compound. No purification was performed on the title compound.
Reaction SMILES: [N+](C1C=CC(COC(NCCOCC(O)=O)=O)=CC=1)([O-])=O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[N+](C1C=CC(COC([N:58]2[CH2:62][C@@H:61]([S:63][C:64](=[O:71])[C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)[CH2:60][C@H:59]2[C:72](N2CCNCC2)=[O:73])=O)=CC=1)([O-])=O>O1CCCC1.C(N(CC)CC)C>[C:72](=[C:59]1[CH2:60][CH:61]([S:63][C:64](=[O:71])[C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[CH2:62][NH:58]1)=[O:73]
Reactant: O=C(S[C@H]1C[C@@H](C(=O)N2CCNCC2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(O)COCCNC(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C=C1CC(SC(=O)c2ccccc2)CN1
Reaction time: 1 h

Procedure:
In 10 ml of tetrahydrofuran was dissolved 209 mg of 2-(2-(p-nitrobenzyloxycarbonylamino)ethoxy)acetic acid, followed by stirring on an ice bath. To this were added 161 mg of 1-hydroxybenzotriazole and 433 mg of dicyclohexylcarbodiimide, followed, after 1 hour of stirring at the same temperature, by the addition of 523 mg of (2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-(piperazine-1-yl)carbonyl-4-benzoylthiopyrrolidine and 0.146 m of triethylamine and subsequent 1 hour of stirring. After removing insoluble material by filtration, the resulting filtrate was evaporated under a reduced pressure, and a residue was subjected to a silica gel column chromatography to yield 402 mg of (2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-(4-(2-(2) -(p-nitrobenzyloxycarbonylamino) ethoxy)acetyl)piperazine-1-yl)carbonyl-4-benzoylthiopyrrolidine as the compound of interest.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[F:11][C:12]([F:16])([F:15])[CH2:13][OH:14].[NH2:17][C:18]1[CH:25]=[C:24](F)[C:21]([C:22]#[N:23])=[CH:20][N:19]=1>C1COCC1>[NH2:17][C:18]1[CH:25]=[C:24]([O:14][CH2:13][C:12]([F:16])([F:15])[F:11])[C:21]([C:22]#[N:23])=[CH:20][N:19]=1
Reactant: N#Cc1cnc(N)cc1F
Reactant: OCC(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1cnc(N)cc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of KHMDS in THF (1 M, 16.1 ml, 16.04 mmol) was added drop wise to a solution of 2,2,2-trifluoroethanol (0.53 ml, 7.29 mmol) in THF (40 ml) at room temperature. After 2 min a solution of 6-amino-4-fluoronicotinonitrile (intermediate 21, 1.0 g, 7.29 mmol) in THF (10 ml) was added and the reaction mixture stirred for 2 h at room temperature. The reaction mixture was partitioned between saturated aqueous NH4Cl and EtOAc, extracted with EtOAc (2×), the combined organic layers were dried over Na2SO4 and evaporated. The residue was triturated with Et2O and heptane to give the title compound. (UPLC-MS 7) tR 0.70; ESI-MS 218.1 [M+H]+.
Reaction SMILES: OC[CH2:3][NH:4][C:5]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8].Cl>C1COCC1.O>[N+:15]([C:14]1[C:5]2[NH:4][CH2:3][CH2:10][O:9][C:7](=[O:8])[C:6]=2[CH:11]=[CH:12][CH:13]=1)([O-:17])=[O:16]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1NCCO
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: O=C1OCCNc2c1cccc2[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.1 %

Procedure:
To a solution of 2.00 g (8.32 mmol) of methyl 2-[(2-hydroxyethyl)amino]-3-nitrobenzoate in 150 mL of THF was added dropwise 6N HCl (100 mL) at 0° C. and the mixture was stirred for 30 min. The reaction mixture was refluxed for 16 h. After being cooled to room temperature, the mixture was diluted with water (150 ml), and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with aqueous sodium hydrogen sulfate and water. The organics was dried over magnesium sulfate, filtered, and concentrated in vacuo to give 1.03 g (5.00 mmol, 60%) of the title compound.
Reaction SMILES: [CH3:1][C:2]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])=[CH:3][CH:4]=[CH:5][C:6](=[O:8])[CH3:7].CC(C)=CCC/C(/C)=C/C=C/C(C)=O.CC(=CCCC(=CC=O)C)C.CC(C)=O>[Pd].C(O)C>[CH3:1][CH:2]([CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:3][CH2:4][CH2:5][C:6](=[O:8])[CH3:7]
Reactant: CC(=O)C=CC=C(C)CCC=C(C)C
Agent: [Pd]
Agent: CC(=O)/C=C/C=C(\C)CCC=C(C)C
Agent: CC(C)=CCCC(C)=CC=O
Solvent: CC(C)=O
Solvent: CCO
Product: CC(=O)CCCC(C)CCCC(C)C
Yield: 86.7 %

Procedure:
A mixture of 17.82 g (92.8 mmoles) of 6,10-dimethyl-3,5,9-undecatrien-2-one ("pseudoionone", prepared from citral and acetone as described by A. Russell, et al., Organic Syntheses, Collective Volume-3, pages 747-750) and 1.0 g of 5% palladium on activated carbon in 50 mL of absolute ethyl alcohol was shaken vigorously under a hydrogen atmosphere (approximately 2-3 atm. pressure) for 30 minutes. After removal of the catalyst by filtration through a small pad of Hyflo Super-Cel® filtering aid, the filtrate was diluted with 150 mL of hexane. The organic layer was subsequently washed with water (2×400 mL), then dried over anhydrous magnesium sulfate, and re-filtered. Removal of the hexane by evaporation at reduced pressure, followed by distillation, afforded 15.95 g (87% yield) of 6,10-dimethyl-2-undecanone: boiling point 68°-72° C. at 0.15 mm. A previous synthesis of the latter ketone has been reported by F. G. Fischer, et al., Ann., 475, 183 (1929).
Reaction SMILES: C[O:2][C:3](=[O:26])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14](=[O:25])[N:15]([CH3:24])[C:16]([CH3:23])=[CH:17][C:18]=2[C:19]([F:22])([F:21])[F:20])=[CH:9][CH:8]=1)[NH2:5].[CH3:27][CH:28]([C:30]1[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[C:31]=1[C:32](Cl)=[O:33])[CH3:29]>>[CH3:29][CH:28]([C:30]1[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[C:31]=1[C:32]([NH:5][C@H:4]([C:3]([OH:2])=[O:26])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14](=[O:25])[N:15]([CH3:24])[C:16]([CH3:23])=[CH:17][C:18]=2[C:19]([F:22])([F:20])[F:21])=[CH:9][CH:8]=1)=[O:33])[CH3:27]
Reactant: Cc1cccc(C(C)C)c1C(=O)Cl
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2c(C(F)(F)F)cc(C)n(C)c2=O)cc1
Product: Cc1cccc(C(C)C)c1C(=O)N[C@@H](Cc1ccc(-c2c(C(F)(F)F)cc(C)n(C)c2=O)cc1)C(=O)O

Procedure:
N-[[2-(1-methylethyl)-6-methylphenyl]carbonyl]-4-[1,6-dimethyl-4-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine was prepared from 4-[1,6-dimethyl-4-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine methyl ester and 2-(1-methylethyl)-6-methylbenzoyl chloride using the general procedures described in example 33. ES-HRMS m/e calcd for C28H29F3N2O4 (M+Na) 537.1972. found 537.1977.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[NH:10][C:9](=O)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:26])=O.[OH-].[Na+]>O>[Cl:26][C:9]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cc(-c2ccccc2)nc(-c2ccc(C(F)(F)F)cc2)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: FC(F)(F)c1ccc(-c2nc(Cl)cc(-c3ccccc3)n2)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 89.8 %

Procedure:
A mixture of 6-phenyl-2-(4-trifluoromethylphenyl)-4-(3H)-pyrimidinone (10 g) and phosphorus oxychloride (7.3 g) was stirred at 80° C. for 3 hours. To the reaction mixture is added water, and the mixture is neutralized with an aqueous sodium hydroxide solution (1 mol/L). The precipitates are collected by filtration, washed with water, and recrystallized from isopropyl alcohol to give the desired compound (9.5 g).