Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[N+]([CH:26]=[CH:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1)([O-])=O>CCO>[CH2:15]([N:22]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:13][C:12]=2[C:27]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=2)=[CH:26]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=[N+]([O-])C=Cc1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: NCc1ccccc1
Solvent: CCO
Product: Fc1cccc(-c2cn(Cc3ccccc3)c3c2CNCC3)c1

Procedure:
The title compound (282.6 mg) was prepared from 0.61 g of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 330 μL of benzylamine, and 0.50 g of (2-nitro-vinyl)-3-fluorobenzene, using EtOH as the solvent and without SiO2. MS (ESI): exact mass calculated for C20H19FN2, 306.15; found, m/z 307.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.38-7.32 (m, 3H), 7.30-7.26 (m, 1H), 7.20-7.14 (m, 4H), 7.10-7.06 (m, 1H), 6.95-6.90 (m, 1H), 5.15 (s, 2H), 4.36 (s, 2H), 3.50 (t, J=6.3 Hz, 2H), 2.86 (t, J=6.3 Hz, 2H).
Reaction SMILES: [OH:1][N:2]([CH3:21])[C:3](=[O:20])[CH:4]([NH:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:10]([CH3:16])=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18])[CH3:5].[C:22](N1C=CN(C)C1)(=[O:24])[CH3:23].O>C(Cl)Cl>[C:22]([O:1][N:2]([CH3:21])[C:3](=[O:20])[CH:4]([NH:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:10]([CH3:16])=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18])[CH3:5])(=[O:24])[CH3:23]
Reactant: CC(=O)N1C=CN(C)C1
Reactant: Cc1cc([N+](=O)[O-])c(NC(C)C(=O)N(C)O)c([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: O
Product: CC(=O)ON(C)C(=O)C(C)Nc1c([N+](=O)[O-])cc(C)cc1[N+](=O)[O-]
Yield: 63.3 %

Procedure:
3 g of N-hydroxy-N-methyl-2-(4-methyl-2,6-dinitrophenylamino)propanamide and 0.82 g of N-acetyl-N'-methylimidazole were added to a stirred suspension in 0.8 g of methylene chloride for 3 hours. The resulting mixture was poured into water. The methylene chloride layer was washed, dried over MgSO4, and evaporated to give a yellow residue which was recrystallized from ethanol to yield 1.4 g (41% yield) of product; m.p. 137-138° C., (d,1) isomer form.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[C:8](=[O:11])([O-])[O-:9].[K+].[K+].Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)=O>CC(C)=O.C(OCC)(=O)C>[N:21]1[CH:22]=[CH:23][C:18]([C:16]2[N:1]=[C:2]3[CH2:7][N:6]([C:8]([O:9][C:18]([CH3:23])([CH3:19])[CH3:16])=[O:11])[CH2:5][CH2:4][N:3]3[CH:15]=2)=[CH:19][CH:20]=1
Reactant: O=C([O-])[O-]
Reactant: Nc1cnccn1
Reactant: O=C(CBr)c1ccncc1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCn2cc(-c3ccncc3)nc2C1
Temperature: 60 °C
Yield: 12 %

Procedure:
To a solution of 2-aminopyrazine (1.87 g) in dry acetone (30 ml) was added potassium carbonate (3 eqv), 4-bromoacetyl pyridine (2 eqv) and the resulting reaction mixture was heated at 60° C. for 20 hrs. Reaction mixture was filtered through a celite bed, residue washed with DCM and combined organic layer was evaporated completely to get a brown residue. It was again dissolved in ethyl acetate, washed with water and brine and finally dried over sodium sulfate. Evaporation of organic layer gave the crude product which was purified by column chromatography (1% methanol in dichloromethane). Yield: 12%, 30% Starting material recovered.
Reaction SMILES: [CH:1]([CH:4]1[CH2:9][C:8](=O)[CH2:7][CH2:6][N:5]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])([CH3:3])[CH3:2].ClC1C=CC(C2CC(=O)CC[N:29]2[C:35](OCC2C=CC=CC=2)=O)=CC=1.C([Mg]Cl)(C)C.O.NN.[NH:53]1CCC(=O)CC1>>[CH:1]([CH:4]1[N:5]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:6][C:7]2[CH:35]=[N:29][NH:53][C:8]=2[CH2:9]1)([CH3:3])[CH3:2]
Reactant: O=C1CCN(C(=O)OCc2ccccc2)C(c2ccc(Cl)cc2)C1
Reactant: O=C1CCNCC1
Reactant: CC(C)C1CC(=O)CCN1C(=O)OCc1ccccc1
Agent: CC(C)[Mg]Cl
Agent: NN
Solvent: O
Product: CC(C)C1Cc2[nH]ncc2CN1C(=O)OCc1ccccc1

Procedure:
Benzyl 2-isopropyl-4-oxopiperidine-1-carboxylate, prepared as described for compound 67 in Example 3 using isopropylmagnesium chloride, was formylated and treated with hydrazine hydrate as described for compound 50 in Example 1 to give benzyl 6-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate. This compound was then deprotected and treated with 4-chlorophenylsulfonyl chloride followed by NaOH as described for compound 52 in Example 1.
Reaction SMILES: S1CCCS[CH:2]1[CH:7]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:8]1.[N+]([O-])([O-])=[O:21].[NH4+]>C(#N)C.O>[F:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C@@H:9]2[CH2:10][CH2:11][C@H:7]([CH:2]=[O:21])[CH2:8]2)=[CH:14][CH:15]=1.[F:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C@H:9]2[CH2:10][CH2:11][C@H:7]([CH:2]=[O:21])[CH2:8]2)=[CH:14][CH:15]=1
Reactant: O=[N+]([O-])[O-]
Reactant: Fc1ccc(OC2CCC(C3SCCCS3)C2)cc1
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: O=C[C@H]1CC[C@@H](Oc2ccc(F)cc2)C1
Product: O=C[C@H]1CC[C@H](Oc2ccc(F)cc2)C1
Reaction time: 0.5 h
Yield: 37 %
Yield: 20 %

Procedure:
To a stirred solution of 1-(1,3-dithian-2-yl)-3-(4-fluorophenoxy)cyclopentane (10.0 g, 33.5 mmol) in 75% aqueous acetonitrile (300 ml) was added eerie ammonium nitrate (J. Chem Soc., Chem. Commun., 1977, 680) (74.0 g, 135 mmol) at room temperature. The reaction mixture was stirred for 0.5 h at the same temperature, diluted with water (500 ml) and then extracted with ether (500 ml). The ether phase was washed with brine (300 ml), dried (MgSO4) and concentrated in vacuo. Purification by flash column chromatography {SiO2, 250 g; hexane/ethyl acetate (10:1)} gave 1.28 g (20%) of cis-3-(4-fluorophenoxy)cyclopentanecarbaldehyde (Rf=0.2), 2.35 g (37%) of trans-3-(4-fluorophenoxy)cyclopentanecarbaldehyde (Rf=0.25) and 1.01 g (17%) of cis/trans mixture, respectively, as colorless oils: cis-3-(4-fluorophenoxy)cyclopentanecarbaldehyde; 1H NMR δ9.66 (s, 1H), 7.06-6.90 (m, 2H), 6.86-6.75 (m, 2H), 4.87-4.73 (m, 1H), 2.91-2.73 (m, 1H), 2.40-1.80 (m, 6H): trans-3-(4-fluorophenoxy)cyclopentanecarbaldehyde; 1H NMR δ9.71 (s, 1H), 7.05-6.91 (m, 2H), 6.90-6.75 (m, 2H), 4.87-4.72 (m, 1H), 3.25-3.01 (m, 1H), 2.32-1.79 (m, 6H).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Se](=O)=[O:22].O1CCOCC1>O>[CH2:1]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH:19]=[O:22])=[O:20])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=[Se]=O
Reactant: CCCCCCCCCCOc1ccc(C(C)=O)cc1
Solvent: O
Solvent: C1COCCO1
Product: CCCCCCCCCCOc1ccc(C(=O)C=O)cc1

Procedure:
A mixture of 11.56 g. of 4'-(decyloxy)acetophenone, 4.6 g. of selenium dioxide, 150 ml. of dioxane and 4 ml. of water was refluxed overnight, filtered through diatomaceous earth, washed with dioxane and the filtrate evaporated to dryness. The residue was triturated with water, dried and crystallized from 150 ml. of hot acetone giving the desired product as an off-white solid, m.p. 81°-83° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13].S(=O)(=O)(O)O.[C:24](=O)(O)[O-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([O:14][CH3:24])=[O:13]
Reactant: O=C([O-])O
Reactant: COc1ccccc1Sc1ccccc1C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccccc1Sc1ccccc1OC
Temperature: 25 °C

Procedure:
Dissolve 115 gm of the acid of Step A in 3.5 1. of methanol and add slowly 25 cc of sulfuric acid. Stir under reflux for 72 hours. Cool the reaction mixture to room temperature.and add 100 gm of sodium bicarbonate in portions. Stir for an additional hour, filter and strip the filtrate to dryness. Dissolve the residue in methylene chloride and wash the solution three times with water. Dry the solution and strip to an oil which solidifies. (m.p. 82°-84° C.).
Reaction SMILES: C(N[C@H:12]([C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:30]([CH3:36])[CH2:31][C:32](=[O:35])[NH:33][N:34]=2)=[CH:25][CH:24]=1)=[O:21])[CH2:13]C1C=CC=CC=1)(OCC1C=CC=CC=1)=O.N1NC(=[O:43])C=CC=1.CC1C=NNC(=O)C1.C(N[C@H](C(NC1C=CC(C2C(C)CC(=O)NN=2)=CC=1)=O)CC(=O)N)(OCC1C=CC=CC=1)=O>>[OH:43][CH:12]([CH3:13])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:30]([CH3:36])[CH2:31][C:32](=[O:35])[NH:33][N:34]=2)=[CH:25][CH:24]=1)=[O:21]
Reactant: CC1CC(=O)NN=C1c1ccc(NC(=O)[C@H](Cc2ccccc2)NC(=O)OCc2ccccc2)cc1
Reactant: O=c1cccn[nH]1
Agent: CC1C=NNC(=O)C1
Agent: CC1CC(=O)NN=C1c1ccc(NC(=O)[C@H](CC(N)=O)NC(=O)OCc2ccccc2)cc1
Product: CC(O)C(=O)Nc1ccc(C2=NNC(=O)CC2C)cc1

Procedure:
A composition which comprises an effective blood pressure depressing, platelet aggregation inhibiting, or myocardial-contraction reinforcing amount of a compound selected from the group consisting of 6-[4-(N-carbobenzoxy-L-phenylalanylamino)-phenyl]-5-methyl -4,5-dihydro-3(2H)-pyridazinone, 6-[4-(L-phenylalanylamino)-phenyl-5-methyl-4,5-dihydro-3(2H)=pyridazinone, 6-]4-(N-carbobenzoxy-L-tryptophylamino)-phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone, and 6-[4-(N-carbobenzoxy-L-asparaginylamino)-phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone; and a pharmaceutically acceptable carrier.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:15][C:16]2[CH:17]=[N:18][C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:10][CH2:9]1)=O)(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[CH3:28][CH:27]([CH3:29])[CH2:26][N:14]([CH2:15][C:16]1[CH:17]=[N:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)CN(Cc1cnc2ccccc2c1)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC(C)CN(Cc1cnc2ccccc2c1)C1CCNCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
4-{Isobutyl-[(quinolin-3-yl)methyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester is added to a stirred solution of dichloromethane (5 ml) and anisole (9.0 ml, 82.8 mmol). The reaction is cooled to 0° C. Trifluoroacetic acid (6.0 ml, 72.9 mmol) is then added. The reaction is stirred for 1 h at 0° C. and then for 2 h at room temperature. The reaction is loaded onto a pre-washed SCX-2 (10 g) column and washed with methanol (200 ml). The product is then eluted with 2M ammonia in methanol (100 ml) and concentrated on a rotary evaporator to yield (0.74 g, 99%) of N-(2-methylpropyl)-N-[(quinolin-3-yl)methyl]piperidin-4-amine: mass spectrum (ion spray): m/z=298.2 (M+1); 1H NMR (CDCl3): δ=8.93 (1H, d), 8.08 (1H, d), 8.02 (1H, d), 7.79-7.77 (1H, m), 7.68-7.64 (1H, m), 7.54-7.50 (1H, m), 3.79 (2H, s), 3.13-3.10 (2H, m), 2.59-2.46 (3H, m), 2.28 (2H, d), 2.06 (1H, br s), 1.80-1.77 (2H, m), 1.72-1.61 (1H, m), 1.55-1.44 (2H, m), 0.84 (6H, d).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[CH3:24][NH:25][C:26]1[CH2:30][S:29][C:28](=[O:31])[N:27]=1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:30]2/[C:26]([NH:25][CH3:24])=[N:27][C:28](=[O:31])[S:29]/2)[CH2:8][CH2:7]1
Reactant: CNC1=NC(=O)SC1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 53.4 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (1.00 g) in 2-propanol (15 mL) were added 4-(methylamino)-1,3-thiazol-2(5H)-one (0.77 g) and piperidinium acetate (0.44 g). The reaction mixture was stirred at 60° C. overnight and concentrated. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water, 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 (0.71 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C:14]([F:17])([F:16])[F:15])[N:8]([CH3:13])[C:9]=1[C:10]([OH:12])=O)=[O:4].Cl.Cl.[CH3:20][N:21]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:23]=[C:22]1[CH2:32][CH2:33][NH2:34]>>[CH3:13][N:8]1[C:9]([C:10](=[O:12])[NH:34][CH2:33][CH2:32][C:22]2[N:21]([CH3:20])[CH:25]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:23]=2)=[C:5]([C:3]([O:2][CH3:1])=[O:4])[N:6]=[C:7]1[C:14]([F:17])([F:16])[F:15]
Reactant: Cn1cc(-c2ccccc2)nc1CCN
Reactant: COC(=O)c1nc(C(F)(F)F)n(C)c1C(=O)O
Agent: Cl
Product: COC(=O)c1nc(C(F)(F)F)n(C)c1C(=O)NCCc1nc(-c2ccccc2)cn1C

Procedure:
The product was obtained starting from 4-(methoxycarbonyl)-1-methyl-2-(trifluoromethyl)-1H-imidazole-5-carboxylic acid (200 mg, 793 μmol) and 2-(1-methyl-4-phenyl-1H-imidazol-2-yl)ethanamine hydrochloride (226 mg, 952 μmol, example 7, step 4) according to the method described in example 7, step 5 after aqueous work-up and purification by flash chromatography (using silica gel and an ethyl acetate/heptane gradient) as white foam (128 mg, 294 μmol, 37.1%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[S:10](Cl)(=[O:12])=[O:11].[NH2:14][C:15]1[CH:16]=[C:17]([C:21]2[NH:25][N:24]=[N:23][N:22]=2)[CH:18]=[CH:19][CH:20]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[S:10]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[NH:25][N:24]=[N:23][N:22]=2)[CH:16]=1)(=[O:12])=[O:11]
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Reactant: O=S(=O)(Cl)c1cc(Cl)c(Cl)cc1Cl
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1cc(Cl)c(Cl)cc1Cl
Yield: 57 %

Procedure:
The product was prepared according to General Procedure 6, described in Example 65, with 2,4,5-trichlorobenzenesulfonyl chloride (15.4 mg, 0.055 mmol) and 5-(3-aminophenyl)tetrazole (8.0 mg, 0.050 mmol). The title compound was obtained in 57% yield (11.4 mg). MS (ESI+) calcd mass for C13H8Cl3N5O2S 402.946428, found 402.946388.
Reaction SMILES: [CH:1]([C:4]1[S:5][CH:6]=[CH:7][N:8]=1)([CH3:3])[CH3:2].[O:9]1[C:13]2([CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]2)[O:12][CH2:11][CH2:10]1>>[CH:1]([C:4]1[S:5][C:6]([C:16]2([OH:19])[CH2:17][CH2:18][C:13]3([O:12][CH2:11][CH2:10][O:9]3)[CH2:14][CH2:15]2)=[CH:7][N:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nccs1
Reactant: O=C1CCC2(CC1)OCCO2
Product: CC(C)c1ncc(C2(O)CCC3(CC2)OCCO3)s1

Procedure:
The title compound was prepared as a white solid from 2-iso-propyl-thiazole and 1,4-dioxa-spiro[4.5]decan-8-one using the procedure described in Step A of Example 33.
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][C@H:4]([N:8]([CH3:14])[CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])[C:5]([OH:7])=[O:6].[CH:16](=O)[CH2:17][CH:18]([CH3:20])[CH3:19].[C:22](O[BH-](OC(=O)C)OC(=O)C)(=O)[CH3:23].[Na+]>C(Cl)Cl>[CH2:19]([O:6][C:5](=[O:7])[C@@H:4]([N:8]([CH3:14])[CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:3][CH:2]([CH3:15])[CH3:1])[C:18]1[CH:20]=[CH:23][CH:22]=[CH:16][CH:17]=1
Reactant: CC(C)CC=O
Reactant: CC(C)CCN(C)[C@@H](CC(C)C)C(=O)O
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)CCN(C)[C@@H](CC(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
Step 1: Method A of the synthesis of (S)-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid (IIb) ##STR36## Step i: N-Methyl-O-benizyl-L-leucine p-tosylate salt (4.01 g, 9.84 mmol) was dissolved in CH2Cl2 (50 mL) and treated with isovaleraldehyde (1.06 mL, 9.84 mmol). The reaction was stirred at room temperature for 30 minutes and then cooled to 0° C. Sodium triacetoxyborohydride (3.13 g, 14.8 mmol) was added, and the reaction was allowed to warm to room temperature and stir overnight. The reaction was diluted with CH2Cl2 (400 mL). The organic layer was washed twice with saturated bicarbonate solution (2×400 mL), once with brine (400 mL), and then dried over Na2SO4. The solution was filtered, concentrated, and the crude material chromatographed on silica gel eluting with 10% EtOAc/hexanes to give 2.86 g (90%) of (S)-4-methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid benzyl ester as a pale oil.
Reaction SMILES: CO[C:3](=[O:20])[C:4]([C:16]([O:18][CH3:19])=[O:17])=[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:7][N:8]([CH3:10])C.[CH3:21][O:22][C:23]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:24]=1CN>CCO>[CH3:19][O:18][C:16]([C:4]1[C:3](=[O:20])[N:8]([CH2:10][C:28]2[CH:27]=[CH:24][C:23]([O:22][CH3:21])=[CH:30][C:29]=2[O:31][CH3:32])[CH:7]=[CH:6][C:5]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:17]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: CCOC(=O)C(C=CN(C)C)=C(C(=O)OC)C(=O)OC
Solvent: CCO
Product: CCOC(=O)c1ccn(Cc2ccc(OC)cc2OC)c(=O)c1C(=O)OC
Temperature: 25 °C
Yield: 94.8 %

Procedure:
A mixture of 5-dimethylamino-3-ethoxycarbonyl-2-methoxycarbonyl-penta-2,4-dienoic acid methyl ester (14.7 g, 51.7 mmol) and 2,4-dimethoxybenzylamine (8.2 mL, 54.3 mmol) in EtOH (90 mL) was refluxed for 5 h. The mixture was cooled to r.t., concentrated in vacuo, and the residual oil was partitioned between ether and 1 M HCl. The aqueous layer was extracted with additional ether, and the organic layers were combined, washed with water, and dried over MgSO4. Evaporation of the solvent in vacuo afforded 18.4 g of the title compound as a viscous orange oil. MS: (+) m/z 398.23 (M+Na).
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:12][CH2:11][O:10][C:9]([CH3:14])([CH3:13])[CH2:8]1)(=O)=O.[Br-:15].[Li+]>CC(C)=O>[Br:15][CH2:6][CH:7]1[CH2:12][CH2:11][O:10][C:9]([CH3:14])([CH3:13])[CH2:8]1
Reactant: [Br-]
Reactant: CC1(C)CC(COS(C)(=O)=O)CCO1
Agent: [Li+]
Solvent: CC(C)=O
Product: CC1(C)CC(CBr)CCO1
Yield: 88 %

Procedure:
A mixture of (2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl methanesulfonate (1.5 g) and anhydrous lithium bromide (2.72 g) in acetone (40 mL) was refluxed under nitrogen for 4 h. The reaction was allowed to cool and the solvent was evaporated. The residue was treated with saturated sodium bicarbonate solution and was extracted with DCM (×3). The combined organics were washed with dilute brine, dried by passing through a hydrophobic frit and evaporated to give the title compound as a brown oil (1.23 g).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>O1CCCC1.CN(C)C=O>[CH2:14]([O:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1c(O)cccc1C(=O)O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(OCc2ccccc2)cccc1C(=O)O
Temperature: 0 °C
Yield: 72.5 %

Procedure:
To a solution of 3-hydroxy-2-methyl-benzoic acid (55, 5.0 g, 0.033 mol) in tetrahydrofuran (100 mL) and N,N-dimethylformamide (50 mL), sodium hydride (4.4 g as 60% dispersion in mineral oil, 0.11 mol) was added slowly over 30 minutes and the reaction was stirred at 0° C. under an atmosphere of nitrogen. The reaction mixture was allowed to warm to room temperature, then stirred at room temperature for 1 hour. Benzyl bromide (9.0 mL, 0.076 mol) was added slowly into the reaction mixture, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into water, extracted with ethyl acetate, washed with a solution of ammonium chloride and ammonium hydroxide (4:1), brine, and dried over magnesium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as a white solid (56, 5.8 g, 73%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:15])[NH:13][C:12](=[O:14])[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.F[B-](F)(F)F.[CH3:21][O+](C)C>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:15])[N:13]=[C:12]([O:14][CH3:21])[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC1(c2cccc(Br)c2)COCC(=O)N1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC1=NC(C)(c2cccc(Br)c2)COC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 98.9 %

Procedure:
In a vacuum dried flask under an argon atmosphere, a solution of (RS)-5-(3-bromo-phenyl)-5-methyl-morpholin-3-one (3.0 g, 11.1 mmol) in dichloromethane (145 ml) was treated with trimethyloxonium tetrafluoroborate (2.594 g, 17 mmol). The reaction mixture was stirred at room temperature for 17 hours. For the workup, the incomplete reaction was extracted with a saturated solution of sodium hydrogen carbonate (70 ml). The organic layer was dried over sodium sulphate and evaporated. There were obtained 3.12 g of the title compound as a light yellow oil containing about 17% of the starting lactam. Mass (calculated) C12H14BrNO2 [284.16]; (found) [M+H]+=284 and [M+H]+=286.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[O:24][C:23]([CH3:26])([CH3:25])[CH:22]=[CH:21][C:5]2=C2[C:15]=1[C:14](=[O:16])[C:13]1[CH:12]=[C:11]3[CH:17]=[CH:18][CH:19]=[CH:20][C:10]3=[CH:9]C=1N2.[H-].[Na+].S(OC)(O[CH3:33])(=O)=O.[CH3:36][N:37]([CH3:40])[CH:38]=O>>[CH3:33][O:1][C:2]1[CH:3]=[C:4]2[O:24][C:23]([CH3:26])([CH3:25])[CH:22]=[CH:21][C:5]2=[C:36]2[C:15]=1[C:14](=[O:16])[C:13]1[CH:12]=[C:11]3[CH:17]=[CH:18][CH:19]=[CH:20][C:10]3=[CH:9][C:38]=1[N:37]2[CH3:40]
Reactant: CC1(C)C=Cc2c(cc(O)c3c(=O)c4cc5ccccc5cc4[nH]c23)O1
Reactant: COS(=O)(=O)OC
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: COc1cc2c(c3c1c(=O)c1cc4ccccc4cc1n3C)C=CC(C)(C)O2
Reaction time: 0.25 h

Procedure:
To a solution of 0.5 g of the product of Example 1 in 20 ml of anhydrous dimethylformamide there are slowly added at 0° C., under an inert atmosphere, 0.16 g of sodium hydride and then, after 15 minutes, 0.65 ml of dimethyl sulphate (6 equivalents). After one hour, the reaction mixture is poured onto ice and then extracted with ethyl acetate. The organic phase is washed with an aqueous sodium hydroxide solution and subsequently dried over sodium sulphate and then evaporated in vacuo. Chromatography on silica gel (cyclohexane/acetone: 98/2) allows 0.42 g of the expected product to be isolated.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:61]([CH3:64])[CH2:62][CH3:63])[C@H:26]([O:59][CH3:60])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:57][CH3:58])[C@@H:36]([CH3:56])[C:37]([NH:39][C@H:40](/[CH:48]=[CH:49]\[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:38])=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH:11]([CH3:13])[CH3:12].O=[CH:66][CH2:67][CH2:68][C:69]([OH:71])=[O:70].C([BH3-])#N.[Na+].O1CCOCC1>O1CCOCC1.O>[C:69]([CH2:68][CH2:67][CH2:66][N:9]([CH3:8])[C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:61]([CH3:64])[CH2:62][CH3:63])[C@H:26]([O:59][CH3:60])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:57][CH3:58])[C@@H:36]([CH3:56])[C:37]([NH:39][C@H:40](/[CH:48]=[CH:49]\[C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)[CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)=[O:38])=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:19])[CH3:20])=[O:15])[CH:11]([CH3:13])[CH3:12])([OH:71])=[O:70]
Reactant: O=CCCC(=O)O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](/C=C\c1ccccc1)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC)C(C)C)C(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](/C=C\c1ccccc1)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C

Procedure:
9 mg (10 μmol) N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S,3Z)-1,4-diphenylbut-3-en-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide trifluoroacetic acid salt (intermediate 18) was dissolved in 0.6 mL dioxane/water (1:1) and reacted with a 15% aqueous solution of 4-oxobutanoic acid in the presence of sodium cyanoborohydride in a process similar to the synthesis in Example 1. After lyophilization from dioxane, 5.6 mg (64% of the theoretical) of the title compound was obtained in the form of a white solid.