Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:15][C:16]1[C:21]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[C:20](Cl)[N:19]2[N:28]=[CH:29][N:30]=[C:18]2[N:17]=1>ClCCl>[CH3:15][C:16]1[C:21]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[C:20]([N:5]2[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]2)[N:19]2[N:28]=[CH:29][N:30]=[C:18]2[N:17]=1
Reactant: Cc1nc2ncnn2c(Cl)c1C1CCCC1
Reactant: CC1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc2ncnn2c(N2CCC(C)CC2)c1C1CCCC1

Procedure:
With stirring, a solution of 4-methylpiperidine (1.5 mmol) and triethylamine (1.5 mmol) in 10 ml of dichloromethane was added to a solution of 5-methyl-6-cyclopentyl-7-chloro[1,2,4]triazolo[1,5-a]pyrimidine (1.5 mmol, Ex. 3) in 20 ml of dichloromethane. The reaction mixture was stirred at 20-25° C. for about 16 hours and then washed with a 5% strength solution of HCl. The organic phase was separated off and dried. Following distillative removal of the solvent and chromatography on silica gel, this gave 0.26 g of the title compound of m.p. 145° C.
Reaction SMILES: [NH2:1][CH:2]([CH2:5][CH3:6])[CH2:3][CH3:4].Cl[C:8]1[N:13]2[N:14]=[C:15]([CH3:26])[C:16]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[CH3:25])=[C:12]2[N:11]=[C:10]([CH3:27])[C:9]=1[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].O>C(#N)C>[CH2:3]([CH:2]([NH:1][C:8]1[N:13]2[N:14]=[C:15]([CH3:26])[C:16]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[CH3:25])=[C:12]2[N:11]=[C:10]([CH3:27])[C:9]=1[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:5][CH3:6])[CH3:4]
Reactant: CCC(N)CC
Reactant: CCOC(=O)Cc1c(C)nc2c(-c3c(C)cc(C)cc3C)c(C)nn2c1Cl
Solvent: O
Solvent: CC#N
Product: CCOC(=O)Cc1c(C)nc2c(-c3c(C)cc(C)cc3C)c(C)nn2c1NC(CC)CC

Procedure:
3-Aminopentane (0.6 mL) was added to a solution of ethyl 2-(7-chloro-3-mesityl-2,5-dimethylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (130 mg) in acetonitrile (5 mL), followed by heating under reflux overnight. After cooling the reaction solution, water was added thereto. The mixture was extracted twice with ethylacetate, and the organic layer was washed with an aqueous saturated solution of sodium bicarbonate, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography, to give the title compound (84 mg) as a green oil.
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([CH3:16])=[C:9]([C:11](=[O:15])[CH:12]([CH3:14])[CH3:13])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>O1CCCC1.CO>[F:1][C:2]1[C:7]2[C:8]([CH3:16])=[C:9]([CH:11]([OH:15])[CH:12]([CH3:13])[CH3:14])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(C(=O)C(C)C)oc2cccc(F)c12
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(C(O)C(C)C)oc2cccc(F)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
1-(4-Fluoro-3-methyl-1-benzofuran-2-yl)-2-methylpropan-1-one (1.4 g) synthesized in the above-mentioned (1) was dissolved in tetrahydrofuran (20 mL) and methanol (2 mL), and sodium borohydride (90%, 0.53 g) was added to the solution under ice-cooling. The ice bath was removed, and the reaction mixture was stirred at room temperature for 1 hr then ice-cooled again, and water (2 mL) and 1N hydrochloric acid (5 mL) were carefully added to the mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a crude product (1.4 g, quantitative) of the title object compound as a pale-yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:21])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:20])=[CH:17]/[CH2:18][OH:19].[CH3:22][C:23]([C:25]([O:27]C)=O)=C>O.C(OCC)(=O)C>[CH3:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:3][CH2:2][CH2:7][CH2:6][CH2:22][CH2:23][C:25]([O:19][CH2:18]/[CH:17]=[C:16](/[CH:15]=[CH:14]/[CH:13]=[C:12](/[CH:11]=[CH:10]/[C:3]1[C:4]([CH3:8])([CH3:9])[CH2:5][CH2:6][CH2:7][C:2]=1[CH3:1])\[CH3:21])\[CH3:20])=[O:27]
Reactant: C=C(C)C(=O)OC
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/CO)C(C)(C)CCC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCCCCCCCCCCCCC(=O)OC/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCCC1(C)C

Procedure:
An aqueous phase was prepared by dissolving 0.5 g of poly(vinyl alcohol) in 50 ml water saturated by 6 ml of ethyl acetate. An organic phase was prepared by dissolving 0.075 g retinol palmitate, 0.1 g mineral oil, 0.01 g of an antioxidant (chosen from BHA, BHT, tocopherol or their mixture) and 0.815 g PMMA in 5 ml of ethyl acetate. The organic phase was poured into the aqueous phase while stirring and then 100 ml of fresh water were added. The microcapsules formed were filtered, washed by water and dried at the temperature no higher 20° C. An average diameter of the microcapsules was 40 μm.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)=[CH:6][C:3]=1[CH:4]=O.[NH2:17][C:18]1[C:25]([F:26])=[CH:24][CH:23]=[C:22]([O:27][CH3:28])[C:19]=1[C:20]#[N:21].[BH4-].[Na+]>C1(C)C=CC=CC=1.CO>[F:26][C:25]1[C:18]([NH:17][CH2:4][C:3]2[CH:6]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=3)[CH:8]=[CH:9][C:2]=2[F:1])=[C:19]([C:22]([O:27][CH3:28])=[CH:23][CH:24]=1)[C:20]#[N:21]
Reactant: O=Cc1cc(-c2cccc(F)c2)ccc1F
Reactant: COc1ccc(F)c(N)c1C#N
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
To a solution of 2-fluoro-5-(3-fluorophenyl)benzaldehyde (505 mg, 2.32 mmol, 1.2 eq) and 2-amino-3-fluoro-6-methoxy-benzonitrile (320 mg, 1.93 mmol, 1 eq) in toluene (30 mL) was added 4 Å molecular sieves (10 g). The mixture was heated at reflux for 4 h, then filtered to remove the molecular sieves. The filtrate was concentrated and the residue obtained was dissolved in methanol (30 mL). NaBH4 (109.6 mg, 2.9 mmol, 1.5 eq) was added and the reaction stirred for 2 h at room temperature. The reaction was quenched by addition of water, and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum ether:EtOAc, 50:1) to give the title compound as an off-white solid (610 mg, 72%).
Reaction SMILES: [CH2:1]1[NH:6][CH2:5][CH2:4][N:3]2[CH2:7][CH2:8][C@H:9]([OH:10])[CH:2]12.[F:11][C:12]([F:46])([F:45])[C:13]1[CH:14]=[C:15]([C:23]([CH3:44])([CH3:43])[C:24]([N:26]([C:28]2[CH:29]=[N:30][C:31](Cl)=[CH:32][C:33]=2[C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=2[CH3:41])[CH3:27])=[O:25])[CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[F:22][C:19]([F:20])([F:21])[C:17]1[CH:16]=[C:15]([C:23]([CH3:44])([CH3:43])[C:24]([N:26]([C:28]2[CH:29]=[N:30][C:31]([N:6]3[CH2:5][CH2:4][N:3]4[CH2:7][CH2:8][C@H:9]([OH:10])[CH:2]4[CH2:1]3)=[CH:32][C:33]=2[C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=2[CH3:41])[CH3:27])=[O:25])[CH:14]=[C:13]([C:12]([F:46])([F:11])[F:45])[CH:18]=1
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O[C@H]1CCN2CCNCC12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(F)ccc1-c1cc(N2CCN3CC[C@H](O)C3C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 150 °C
Yield: 26.1 %

Procedure:
To a solution of (8S)-octahydropyrrolo[1,2-a]pyrazin-8-ol (D71, 32 mg) in methyl sulfoxide (1.2 mL), 2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(4-fluoro-2-methylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide [WO 2005/002577] (60 mg) and potassium carbonate (63 mg) were added. The resulting mixture was heated at 150° C. for 24 hours. The mixture was allowed to cool down to r.t. and diluted with water (2 mL). The aqueous phase was extracted with ethyl acetate (3×2.5 mL). The combined organic extracts were dried and concentrated in vacuo to a residue which was purified by flash chromatography (DCM/MeOH from 100:0 to 95:5) to give the desired compound (18.8 mg) as yellow foam.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[O:9])=[CH:6][N:5]=[C:4](S(CC)(=O)=O)[N:3]=1.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH2:33][CH:32]([NH2:36])[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH2:33][CH:32]([NH:36][C:4]2[N:3]=[C:2]([NH2:1])[C:7]([C:8](=[O:9])[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[O:16][CH3:17])=[CH:6][N:5]=2)[CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Reactant: CCS(=O)(=O)c1ncc(C(=O)c2ccccc2OC)c(N)n1
Product: COc1ccccc1C(=O)c1cnc(NC2CCCN(C(=O)OC(C)(C)C)C2)nc1N

Procedure:
The same procedure was used as described in Example 9 starting from (4-amino-2-ethanesulfonylpyrimidin-5-yl)-(2-methoxyphenyl)-methanone, Example 6, and 3-amino-piperidine-1-carboxylic acid tert-butyl ester (Astatech) to give 3-[4-amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid tert-butyl ester. MS (M+H)+, 428.
Reaction SMILES: [I-].[Na+].Cl[CH2:4][CH2:5][CH2:6][O:7][C:8]12[CH:22]=[CH:21][CH:20]=[CH:19][CH:9]1[CH2:10][CH:11]2[CH2:12][N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[N-:23]=[N+:24]=[N-:25].[Na+].O>CN(C=O)C>[N:23]([CH2:4][CH2:5][CH2:6][O:7][C:8]12[CH:22]=[CH:21][CH:20]=[CH:19][CH:9]1[CH2:10][CH:11]2[CH2:12][N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=[N-]
Reactant: ClCCCOC12C=CC=CC1CC2CN1CCCCC1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCCCOC12C=CC=CC1CC2CN1CCCCC1
Temperature: 75 °C
Reaction time: 12 h

Procedure:
Sodium iodide (3 g) is added to a stirred solution of 3-(3-chloropropoxy)-1-(1-piperidinylmethyl)benzocyclobutene (0.87 g) in 12 ml of DMF. The reaction mixture is stirred under nitrogen for 12 hours, sodium azide (1.17 g) is added to this solution followed by water (1.2 ml). The resulting suspension is heated at 75° C. for 5 hours. The reaction mixture is partitioned between water and methylene chloride and the organic layer is separated, washed, dried, filtered and evaporated in vacuo yielding the azide product as an oil.
Reaction SMILES: [C:1]([NH2:8])(=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].I[C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:20]/[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27])/[C:13](=[O:19])[NH:14]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C.CCN(CC)CC>[CH3:27][O:26][C:25]1[CH:24]=[CH:23][NH:22][C:21]=1/[CH:20]=[C:12]1\[C:13](=[O:19])[NH:14][C:15]2[C:11]\1=[C:10]([C:6]#[C:5][CH2:4][CH2:3][CH2:2][C:1]([NH2:8])=[O:7])[CH:18]=[CH:17][CH:16]=2
Reactant: C#CCCCC(N)=O
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CCCCC(N)=O)c21

Procedure:
Using Method C above, 5-hexynamide (46 mg, 0.4 mmol) (prepared from 5-hexynoic acid by Method G above) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (Starting Material 2 supra) (113 mg, 0.31 mmol) using (Ph3P)2PdCl2 (12 mg) and Cul (6 mg) as catalyst in DMF (1 mL) and Et3N (1 mL) as solvent at 70° C. for 22 h yielding (Z)-6-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-5-hexynamide. (Yield 52 mg, 48%).
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5]([S:14]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)(=[O:16])=[O:15])([CH3:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C>CO.[OH-].[Na+]>[CH3:25][O:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][S:14]([C:5]([CH3:13])([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([OH:26])=[O:3])(=[O:15])=[O:16])=[CH:23][CH:22]=1
Reactant: CCOC(=O)C(C)(Cc1ccccc1)S(=O)(=O)Cc1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(CS(=O)(=O)C(C)(Cc2ccccc2)C(=O)O)cc1

Procedure:
2-(4-Methoxy-phenylmethanesulfonyl)-2-methyl-3-phenyl-propionic acid was prepared starting from 2-(4-Methoxy-phenylmethanesulfonyl)-2-methyl-3-phenyl-propionic acid ethyl ester (3.5 g, 9.0 mmol) dissolved in methanol (50 ml) and 10 N NaOH (30 ml). The resulting reaction mixture was worked up as outlined in Example 9. Yield 930 mg, 31%. Colorless solid, mp: 106-108 C;. MS: 347 (M−H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]=[C:12]=[O:13])(=[O:10])=[O:9].[NH2:14][C:15]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=O>>[Cl:24][C:22]1[CH:23]=[C:15]2[C:16]([C:17](=[O:19])[N:11]([S:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])(=[O:9])=[O:10])[C:12](=[O:13])[NH:14]2)=[CH:20][CH:21]=1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: O=C=NS(=O)(=O)c1ccccc1Cl
Product: O=c1[nH]c2cc(Cl)ccc2c(=O)n1S(=O)(=O)c1ccccc1Cl
Yield: 51.6 %

Procedure:
1.14 g (5.22 mmol) of 2-chlorobenzenesulfonylisocyanate and 896 mg (5.22 mmol) of 2-amino-4-chlorobenzoic acid were treated in the same way as in Example 1 to obtain 1.00 g of the above-identified compound (yield 51.6%). Properties: colorless crystal, Melting point: 275°-276° C., PMR (δppm, DMSO-d6):7.16 (1H,s), 7.23 (1H,d), 7.63-7.76 (4H,m), 7.86 (1H,d), 8.20 (1H,d), 11.79 (1H,br).
Reaction SMILES: Cl[CH2:2][C@H:3]([CH3:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12].[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[F:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[O:5][CH2:4][C@@H:3]([CH3:13])[CH2:2][N:28]1[CH2:29][CH2:30][CH:25]([C:21]2[CH:20]=[C:19]([NH:18][C:16](=[O:17])[CH:15]([CH3:14])[CH3:31])[CH:24]=[CH:23][CH:22]=2)[CH2:26][CH2:27]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: C[C@@H](CCl)COc1ccccc1F
Product: CC(C)C(=O)Nc1cccc(C2CCN(C[C@H](C)COc3ccccc3F)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 1-{[(2R)-3-chloro-2-methylpropyl]oxy}-2-fluorobenzene and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 413.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]([CH3:25])[C:11]3[C:20]4[C:19](=[O:21])[NH:18][C:17]([CH3:22])=[C:16]([CH3:23])[C:15]=4[CH:14]=[CH:13][C:12]=3[N:24]=2)=[C:4]([CH3:26])[CH:3]=1.[O:27]1CCOCC1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]([CH3:25])[C:11]3[C:20]4[C:19](=[O:21])[NH:18][C:17]([CH:22]=[O:27])=[C:16]([CH3:23])[C:15]=4[CH:14]=[CH:13][C:12]=3[N:24]=2)=[C:4]([CH3:26])[CH:3]=1
Reactant: C1COCCO1
Reactant: Cc1cc(F)ccc1Nc1nc2ccc3c(C)c(C)[nH]c(=O)c3c2n1C
Product: Cc1cc(F)ccc1Nc1nc2ccc3c(C)c(C=O)[nH]c(=O)c3c2n1C
Temperature: 100 °C
Yield: 82 %

Procedure:
To a 200 mL round-bottom flask equipped with a magnetic stir bar was added 2-(4-fluoro-2-methyl-phenylamino)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (1.3 g, 3.7 mmol) selenium dioxide (1.23 g, 11.0 mmol) and dioxane (100 mL). The flask was fitted with a reflux condenser and heated to 100° C. in an oil bath for 5 h. The flask was then cooled to room temperature and the mixture filtered through a plug of celite, washing with 10% MeOH/DCM. The filtrate was concentrated to dryness and the resulting brown solid further purified by trituration with cold DCM to give 2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline-7-carbaldehyde (1.11 g, 82%) as a red-yellow solid. 1H NMR (400 MHz, DMSO-d6+TFA) δ 10.80 (br s, 1H), 10.70 (br s, 1H), 10.25 (s, 1H), 8.02 (d, 1H, J=8.8 Hz), 7.80 (d, 1H, J=8.8 Hz), 7.57 (dd, 1H, J1=5.5 Hz, J2=8.6 Hz), 7.35 (dd, 1H, J1=3.1 Hz, J2=9.8 Hz), 7.26 (td, 1H, J1=3.1 Hz, J2=8.6 Hz), 4.14 (s, 3H), 2.69 (s, 3H), 2.31 (s, 3H); ESMS (m/z): found, 365.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[NH:6][CH:7]([CH3:9])[CH3:8])([O-])=O.C([O-])=O.[NH4+]>C(O)C.[Pd]>[CH3:9][CH:7]([NH:6][C:5]1[C:4]([NH2:1])=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8]
Reactant: CC(C)Nc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)Nc1ccccc1N
Reaction time: 16 h
Yield: 79.9 %

Procedure:
To a solution of 2-nitro-N-(propan-2-yl)aniline (828 mg, 4.6 mmol) in ethanol (10 mL) under a nitrogen atmosphere is carefully added 20% palladium on carbon (50 mg, Degussa type) followed by ammonium formate (1.4 g, 23 mmol) and the reaction is stirred for 16 h. The suspension is carefully filtered through a bed of Celite and the filter cake is rinsed with additional ethanol (10 mL). The filtrate is concentrated and the residue is partitioned between H2O and ethyl acetate. The organic layer is dried (Na2SO4) and concentrated and the residue is purified by chromatography through a short bed of silica gel using 5% methanol/CH2Cl2 affords the title compound (552 mg, 80%) as an oil.
Reaction SMILES: O.C(O)(=O)C=[O:4].[CH2:7]1[CH2:12][CH2:11][CH:10]([N:13]=[C:14]=[N:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:9][CH2:8]1>CN(C=O)C>[C:14]([NH:13][CH:10]1[CH2:9][CH2:8][CH2:7][CH2:12][CH2:11]1)([NH:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:4]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
To a stirred solution of glyoxylic acid monohydrate (431 mg, 4.56 mmol) in anhydrous DMF (5 mL) were added NHS (563 mg, 4.89 mmol) and DCC (1.00 g, 4.85 mmol). A white solid (dicyclohexylurea) formed immediately. As the reaction was exothermic, the flask was cooled in an ice-bath for a while (approximately 5 minutes). The reaction mixture was then stirred under nitrogen at room temperature for approximately 1 hour. The solid was filtered off and washed with DMF. The filtrate (containing glyoxylic acid NHS ester) was then added to the reaction mixture obtained above. After stirring the mixture for approximately 5 minutes, a clear solution was obtained. TLC revealed completion of the reaction. The solvent was removed under reduced pressure. Flash chromatography (20:1 and 15:1 CH2Cl2—CH3OH followed by 20:1, 15:1 and 12:1 CH2Cl2—CH3OH containing 1% acetic acid) provided the desired Pro4-de novo-CHO (132 mg, 55%). The mass spectrum was in agreement with the assigned structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5][CH:4]=1
Reactant: COc1ccc(CO)cc1
Reactant: CCOC(=O)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)CCOCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.1 %

Procedure:
To a solution of (4-methoxyphenyl)methanol (76.3 g, 552.4 mmol) in anhydrous toluene (1 L) at 0° C. was added portionwise NaH (27.6 g, 630.5 mmol) over a period of 30 min, followed by ethyl 3-bromopropanoate (100 g, 552.4 mmol). The mixture was stirred at RT for 3 h and then quenched with 20% aqueous NH4Cl (500 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (2×500 mL). The combined organic layers were washed with brine, dried (Na2SO4) and then concentrated in vacuo to give ethyl 3-((4-methoxybenzyl)oxy)propanoate (112 g, 85%) as colorless oil.
Reaction SMILES: [O:1]1[C@H:7]2[C@@H:2]1[CH2:3][C@H:4]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:5][CH2:6]2.[Cl-].[NH4+].[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C)C=O>[N:20]([C@H:7]1[CH2:6][CH2:5][C@@H:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:3][C@@H:2]1[OH:1])=[N+:21]=[N-:22]
Reactant: O=C(OCc1ccccc1)[C@@H]1CC[C@H]2O[C@H]2C1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@H]1CC[C@@H](C(=O)OCc2ccccc2)C[C@@H]1O
Temperature: 70 °C
Reaction time: 24 h
Yield: 99.7 %

Procedure:
Benzyl (1R*,3S*,4R*)-3,4-epoxycyclohexane-1-carboxylate (52.3 g) was dissolved in N,N-dimethyl-formamide (1000 ml), ammonium chloride (21.9 g) and sodium azide (18.1 g) were added, and the mixture was heated to 70° C. and stirred for 24 hours. The solvent was distilled off under reduced pressure, and water was added to conduct extraction with ethyl acetate. The resultant organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (61.8 g) as a colorless oil.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH:19]1([CH2:25][C:26](Cl)=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C1COCC1>[CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:26](=[O:27])[CH2:25][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: O=C(Cl)CC1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(CC1CCCCC1)N1C(=O)OCC1Cc1ccccc1
Reaction time: 0.5 h

Procedure:
Thionyl chloride (20.0 mL) was added dropwise to cyclohexyl acetic acid (10.0 g, 70 mmol). After cessation of gas evolution, the reaction mixture was heated to reflux overnight. The reaction mixture was then concentrated in vacuo to yield cyclohexyl acetyl chloride. To a solution of (S)-(−)-4-benzyl-2-oxazolidinone (11.6 g, 65 mmol) in THF (130 mL) at −60° C. was added 1.6 M n-butyl lithium (42 mL, 67 mmol), dropwise, and the reaction mixture was stirred for 0.5 h. To the resulting solution was then added the cyclohexylacetyl chloride, and the resulting mixture was stirred at 0° C. for 2 h. The reaction was quenched with aqueous saturated NaHCO3 solution and extracted with ethyl acetate. The organic layer was dried (MgSO4) and concentrated until a slurry was formed. The slurry was filtered and washed with cold diethyl ether. The filtrate was re-concentrated to yield a solid. The combined solid, 4-benzyl-3-(2-cyclohexyl-acetyl)-oxazolidin-2-one, was dried in vacuo.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[C:14]([C:15]2[CH2:19][CH:18]([CH3:20])[O:17][N:16]=2)=[C:13]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:12]=[CH:11][C:7]=1[C:8](O)=[O:9].CN(C)C=O>C1(C)C=CC=CC=1>[Cl:5][C:6]1[C:14]([C:15]2[CH2:19][CH:18]([CH3:20])[O:17][N:16]=2)=[C:13]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:12]=[CH:11][C:7]=1[C:8]([Cl:3])=[O:9]
Reactant: CC1CC(c2c(S(C)(=O)=O)ccc(C(=O)O)c2Cl)=NO1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC1CC(c2c(S(C)(=O)=O)ccc(C(=O)Cl)c2Cl)=NO1

Procedure:
5.7 g (51 mmol) of thionyl chloride were added dropwise at room temperature to a solution of 13.0 g (41 mmol) of 2-chloro-3-(5-methyl-4,5-dihydroisoxazol-3-yl)-4-methylsulfonylbenzoic acid, 1 ml of dimethylformamide and 250 ml of dry toluene. The mixture was subsequently refluxed until the reaction was complete. After cooling, the solvent was distilled off. This gave 14.2 g of 2-chloro-3-(5-methyl-4,5-dihydroisoxazol-3-yl)-4-methyl-benzoyl chloride in quantitative yield.
Reaction SMILES: C([O:3][C:4](=[O:27])[C@@H:5]([N:10]1[CH2:14][C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N:22]([CH3:24])[CH3:23])[C:17]=2[F:25])=[CH:12][C:11]1=[O:26])[CH2:6][CH:7]([CH3:9])[CH3:8])C.O.[OH-].[Li+:30]>O1CCCC1>[Li+:30].[CH3:24][N:22]([CH3:23])[C:18]1[C:17]([F:25])=[C:16]([CH:21]=[CH:20][CH:19]=1)[O:15][C:13]1[CH2:14][N:10]([C@@H:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4]([O-:27])=[O:3])[C:11](=[O:26])[CH:12]=1
Reactant: CCOC(=O)[C@H](CC(C)C)N1CC(Oc2cccc(N(C)C)c2F)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C[C@@H](C(=O)[O-])N1CC(Oc2cccc(N(C)C)c2F)=CC1=O
Temperature: 20 °C
Reaction time: 2 h
Yield: 72.1 %

Procedure:
To a solution containing (S)-2-[4-(3-dimethylamino-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid ethyl ester (0.261 g, 0.001 mol) in tetrahydrofuran (4 mL) was treated with an aqueous solution of lithium hydroxide monohydrate (0.5N, 2 mL, 0.001 mol). The mixture was stirred at 20° C. for 2 h, and the solvents evaporated. The residue was dried under high vacuum and rinsed with diethyl ether to afford (S)-2-[4-(3-dimethylamino-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid lithium salt (0.257 g, 100%) as a yellow solid.