Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:3]([C:5]1[CH:10]=[C:9]([N:11]([CH3:17])[CH2:12][C@@H:13]2[CH2:15][C@H:14]2[CH3:16])[N:8]=[C:7]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])[CH:6]=1)=[O:4])[NH2:2].[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH2:34][C@H:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C@@H:32]1[C:43](O)=[O:44])=[O:30])([CH3:27])([CH3:26])[CH3:25].ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.C(=O)([O-])[O-]>ClCCCl>[CH3:17][N:11]([CH2:12][C@@H:13]1[CH2:15][C@H:14]1[CH3:16])[C:9]1[CH:10]=[C:5]([CH:6]=[C:7]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])[N:8]=1)[C:3]([NH:1][NH:2][C:43]([C@H:32]1[C@@H:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:34][CH2:35][CH2:36][N:31]1[C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])=[O:44])=[O:4]
Reactant: C[C@@H]1C[C@H]1CN(C)c1cc(C(=O)NN)cc(N(C)S(C)(=O)=O)n1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](c2ccccc2)[C@@H]1C(=O)O
Agent: O=C([O-])[O-]
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1C[C@H]1CN(C)c1cc(C(=O)NNC(=O)[C@H]2[C@@H](c3ccccc3)CCCN2C(=O)OC(C)(C)C)cc(N(C)S(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of N-[4-(hydrazinocarbonyl)-6-(methyl[(trans-2-methylcyclopropyl)methyl]amino)pyridin-2-yl]-N-methylmethanesulfonamide (3A.3b-1, 59.0 mg, 0.17 mmol) in 1,2-dichloroethane (2 ml) were added cis-1-(tert-butoxycarbonyl)-3-phenylpiperidine-2-carboxylic acid (Intermediate 1A.5, 45.9 mg, 0.15 mmol), 1-hydroxybenzotriazole (23.2 mg, 0.16 mmol), diisopropylethylamine (0.090 ml, 0.52 mmol), and polystyrene bound carbodiimide (246 mg, 0.34 mmol, 1.31 mmol/g). The reaction mixture was allowed to stir gently at room temperature for 18 h. Macroporous carbonate resin (360 mg, 0.68 mmol, 2.74 mmol/g) was added to the reaction, and the mixture was again allowed to stir gently for 18 h. The reaction mixture was filtered and concentrated in vacuo to yield tert-butyl cis-2-[(2-{2-(methyl[(trans-2-methylcyclopropyl)methyl]amino)-6-[methyl(methylsulfonyl)amino]isonicotinoyl}hydrazino)carbonyl]-3-phenylpiperidine-1-carboxylate.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)[C:3]([NH:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[N:20]1([C:27]([NH:29][C@@H:30]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:31](O)=[O:32])=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(Cl)Cl>[C:6]([NH:5][C:3]([CH:2]([NH:1][C:31]([CH:30]([NH:29][C:27]([N:20]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:28])[CH2:34][CH:35]([CH3:37])[CH3:36])=[O:32])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=1)=[O:4])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)NC(=O)[C@@H](N)Cc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)CC(NC(=O)N1CCCCCC1)C(=O)NC(Cc1ccc([N+](=O)[O-])cc1)C(=O)NC(C)(C)C
Reaction time: 1 h

Procedure:
The crude product from Example AK ((S)-2-Amino-3-(4-nitrophenyl)-N-tert-butylpropionamide) (1.34 g, 5.25 mmol) and the product from Example Z (1.35 g, 5.25 mmol) were dissolved in DMF (40 mL), then HBTU (1.99 g, 5.25 mmol) and diisopropylethylamine (4.3 g, 33 mol) were added and stirred for 1 hour. The mixture was poured into CH2Cl2 (100 mL); the CH2Cl2 solution was washed with aqueous sodium bicarbonate (3×) and dried over sodium bicarbonate. The crude reaction mixture was further purified by column chromatography (SiO2, EtOAc) to yield the title compound (2.5 g), mp 194-195° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:12][NH:11]1)([O-])=O.[C:23](N1C=CN=C1)(N1C=CN=C1)=[S:24]>COCCOC.C(Cl)(Cl)Cl>[C:17]1([N:14]2[CH2:15][CH2:16][N:10]3[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[NH:1][C:23](=[S:24])[N:11]3[CH2:12][CH2:13]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: O=[N+]([O-])c1ccccc1N1CCN(c2ccccc2)CCN1
Solvent: ClC(Cl)Cl
Solvent: COCCOC
Product: S=C1Nc2ccccc2N2CCN(c3ccccc3)CCN12

Procedure:
Hexahydro-1-(2-nitrophenyl)-5-phenyl-1H-1,2,5-triazepine (22.4 g) was hydrogenated in 1,2-dimethoxyethane (800 ml) as in Example 11 and the volume reduced to 250 ml. 1,1'-Thiocarbonyldiimidazole (27 g) was added and the mixture, protected from moisture, was heated under reflux on a steam bath overnight. The solution was evaporated to dryness. The residue was dissolved in toluene and applied to a column (63×8.0 cm) of dry column grade neutral alumina prepacked in toluene. Elution with toluene (several liters) removed a faster moving yellow component from the column. The eluting solvent was changed to toluene-chloroform (4:1, 2 l) and then to chloroform. Monitoring of fractions was by t.l.c. on Alox-25 uv254 plates (Brinkmann) with chloroform as developer and on silica gel GF (Analtech) plates with chloroform as developer. A slightly faster moving minor purple component was eluted in the earlier fractions containing the major component. In later fractions a slower moving yellow component contaminated the major component. The first fractions (having none of the slower yellow minor component) were evaporated to smaller volume. Coevaporation with toluene caused crystallization. Addition of heptane completed the process; wt. 12.46 g (crop 1), mp=206°-208°. The later yellow fractions similarly gave 5.33 g (crop 2), mp=203°-208° of crude titled product. Recrystallization of crop 2 (from chloroform-toluene-heptane) gave material which was combined with crop 1. This material was dissolved in chloroform and the solution was decolorized. Evaporation to smaller volume followed by coevaporation with toluene and addition of heptane gave 17.6 g (76%) of crude titled product, mp=205°-209°. Recrystallization from the same solvent system gave titled product, mp=205°-208°.
Reaction SMILES: [CH:1]([C:4]1[C:13]2[CH:12]3[CH2:14][CH2:15][CH:9]([CH2:10][CH2:11]3)[C:8]=2[C:7](=[O:16])[NH:6][N:5]=1)([CH3:3])[CH3:2].CC([O-])(C)C.[K+].C1(P(O[NH2:38])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1.CN(C=O)C.CCOC(C)=O>[NH2:38][N:6]1[N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:13]2[CH:12]3[CH2:14][CH2:15][CH:9]([CH2:10][CH2:11]3)[C:8]=2[C:7]1=[O:16]
Reactant: NOP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(C)c1n[nH]c(=O)c2c1C1CCC2CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)c1nn(N)c(=O)c2c1C1CCC2CC1
Reaction time: 4 h
Yield: 54.5 %

Procedure:
A mixture of Example 8B (31.5 mg, 0.144 mmol) and KOtBu (1 M in THF, 0.16 mL, 0.16 mmol) in THF (0.3 mL) and DMF (0.2 mL) was stirred for 30 minutes, and O-(diphenylphosphoryl)hydroxylamine (37.0 mg, 0.159 mmol) was added and stirred 4 h. The mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine, dried (Na2SO4), and filtered. The residue was chromatographed on SiO2 (2.5% MeOH/CH2Cl2) to give the title compound as a white solid (18.3 mg) which was used without further purification. LC/MS (APCI) M/Z 234.2 (M+H)+.
Reaction SMILES: CCN(C(C)C)C(C)C.[I:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1.Cl.[CH3:21][NH:22][C:23](=[O:31])[C@H:24]([C:27](=[O:30])[O:28][CH3:29])[NH:25][CH3:26]>C(Cl)(Cl)Cl>[I:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](=[O:16])[N:25]([CH:24]([C:23]([NH:22][CH3:21])=[O:31])[C:27]([O:28][CH3:29])=[O:30])[CH3:26])=[CH:13][CH:12]=1
Reactant: CNC(=O)[C@@H](NC)C(=O)OC
Reactant: O=C(Cl)c1ccc(I)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CNC(=O)C(C(=O)OC)N(C)C(=O)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.5 %

Procedure:
DIPEA (27 mL) was added to a chloroform (0.20 L) suspension of 4-iodobenzoyl chloride (13 g) and N,N2,O-trimethyl-3-oxoserinamide hydrochloride (Intermediate 5-2, 10 g) under ice cooling, and the mixture was stirred for 4 hours at room temperature, whereafter the reaction mixture was concentrated. The resulting residue was purified by OH type silica gel column chromatography (gradient elution with hexane/ethyl acetate=70/30→0/100) to obtain 1-iodo-4-{[1-methoxy-3-(methylamino)-1,3-dioxopropan-2-yl](methyl)carbamoyl}benzene (Intermediate 6-2, white solid) (14 g, 68%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.Cl.Cl[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+].CC(C)=O>CN(C=O)C>[O:26]1[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH:8]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=2)[CH2:24][CH2:25]1
Reactant: COC(=O)C(c1ccccc1)c1ccc(O)cc1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: COC(=O)C(c1ccccc1)c1ccc(OCCN2CCOCC2)cc1
Yield: 41.8 %

Procedure:
A stirring solution of compound 71 (1.5 g, 6.19 mmol), 4-(2-chloroethyl)morpholine hydrochloride (1.152 g, 6.19 mmol) and potassium carbonate (1.709 g, 12.38 mmol) in (1:1) DMF: acetone (60 mL) was heated to 60° C. for 16 h then concentrated. The crude residue was diluted with ethyl acetate and washed with water, dried over Na2SO4, filtered and concentrated to afford compound 73 (0.92 g, 42%) after purification by ISCO-HPLC (20 to 100% ethyl acetate in hexanes).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1([CH2:12][CH:13]([CH3:15])[CH3:14])[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(Cl)Cl.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>N1C=CC=CC=1>[CH2:12]([C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][CH:2]1[O:1][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:13]([CH3:14])[CH3:15]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)C1(CC(C)C)CCCC1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C1(CC(C)C)CCCC1OC(=O)c1ccccc1
Reaction time: 12 h

Procedure:
Ethyl 2-hydroxy-1-iso-butyl-cyclopentane carboxylate (5.00 g) was diluted using 60 ml of methylene chloride. At room temperature and with magnetic stirring, pyridine (2.85 ml) was slowly added, then benzoyl chloride (4.15 ml,) was dropwise added. Upon the completion of the addition, the reaction was continued for 12 hours. Then solvent was removed, and the residue was extracted using ethyl acetate and water. Organic layer was washed, in turn, using 10% hydrochloric acid aqueous solution to pH of about 2, using saline solution to neutrality, using 10% aqueous solution of sodium carbonate for three times, and then using saline solution to neutrality. The organic layer was dried, and removing solvent gave 7.70 g of brown liquid. MS: m/e 319(M+′+1), 318(M+′), 273, 244, 213, 196, 105(base), 77.
Reaction SMILES: [CH:1]1([C:5]2[C:26]([C:27]3[NH:31][C:30]([CH3:32])=[N:29][N:28]=3)=[CH:25][C:8]([C:9]([N:11]3[CH2:16][CH2:15][CH:14]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=4)[CH2:13][CH2:12]3)=[O:10])=[C:7]([CH3:33])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[O:34]1C[CH2:37][CH2:36][C@@H:35]1C(NN)=O>>[CH:1]1([C:5]2[C:26]([C:27]3[NH:31][C:30]([C@H:32]4[CH2:37][CH2:36][CH2:35][O:34]4)=[N:29][N:28]=3)=[CH:25][C:8]([C:9]([N:11]3[CH2:12][CH2:13][CH:14]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=4)[CH2:15][CH2:16]3)=[O:10])=[C:7]([CH3:33])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: NNC(=O)[C@H]1CCCO1
Reactant: Cc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2C2CCC2)[nH]1
Product: Cc1cc(C2CCC2)c(-c2nnc([C@H]3CCCO3)[nH]2)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of 4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 152), using (R)-tetrahydrofuran-2-carbohydrazide (compound 174.1) in place of acetohydrazide. m/z (ES+) 496 (M+H)+. 1H NMR (300 MHz, CD3OD) δ 7.70 (d, 2H), 7.49-7.41 (m, 4H), 5.15 (t, 1H), 4.89-4.80 (m, 1H), 4.14-3.92 (m, 3H), 3.65-3.51 (m, 1H), 3.33-3.27 (m, 1H), 3.03-2.95 (m, 2H), 2.47-2.37 (m, 4H), 2.24-1.91 (m, 9H), 1.83-1.71 (m, 4H).
Reaction SMILES: C[O:2][C:3](=[O:21])[C@@H:4]([O:19][CH3:20])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]([C:16]([OH:18])=O)([CH3:15])[CH3:14])[CH:7]=1.[CH2:22]([NH2:29])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH2:22]([NH:29][C:16]([C:13]([CH3:14])([O:12][C:8]1[CH:7]=[C:6]([CH2:5][C@H:4]([O:19][CH3:20])[C:3]([OH:2])=[O:21])[CH:11]=[CH:10][CH:9]=1)[CH3:15])=[O:18])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCN
Reactant: COC(=O)[C@H](Cc1cccc(OC(C)(C)C(=O)O)c1)OC
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CCCCCCCNC(=O)C(C)(C)Oc1cccc(C[C@H](OC)C(=O)O)c1

Procedure:
The title compound was prepared from (2S)-3-[3-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-methoxy-propionic acid methyl ester (EXAMPLE 56, step 2) and heptylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C21H33NO5 [M+H]+: 480.
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]12[CH2:15][CH:11]3[CH2:12][CH:13]([CH2:14]1)[C:9]([NH2:16])([CH2:10]3)[CH2:8]2.C([O-])([O-])=O.[K+].[K+].Cl[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C:33]#[N:34])=[O:27]>CS(C)=O.CCOC(C)=O>[O:1]=[S:2]1(=[O:17])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]12[CH2:15][CH:11]3[CH2:10][C:9]([NH:16][CH2:25][C:26]([N:28]4[CH2:32][CH2:31][CH2:30][C@H:29]4[C:33]#[N:34])=[O:27])([CH2:8]1)[CH:13]([CH2:12]3)[CH2:14]2
Reactant: NC12CC3CC1CC(N1CCCS1(=O)=O)(C3)C2
Reactant: N#C[C@@H]1CCCN1C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#C[C@@H]1CCCN1C(=O)CNC12CC3CC1CC(N1CCCS1(=O)=O)(C3)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
To a stirred mixture of 1-(1,1-dioxidoisothiazolidin-2-yl)tricyclo[3.3.1.03,7]nonan-3-amine prepared as in preparation 10 (0.17 g, 0.66 mmol), and K2CO3 (0.28 g, 2.0 mmol) in DMSO (2.6 mL) at ice bath temperature was added (S)-1-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (0.13 g, 0.66 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 3 h. Upon completion of the reaction (by TLC), the reaction mixture was diluted with EtOAc and washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain (2S)-1-{N-[2-(1,1-dioxidoisothiazolidin-2-yl) hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrile as a viscous liquid (0.1 g) in 40% yield. m/z (M+1) 393; 1H NMR (CDCl3) 300 MHz δ 4.80-4.75 (m, 1H), 3.70-3.37 (m, 4H), 3.36 (t, J=6.6 Hz, 2H), 3.16 (t, J=7.4 Hz, 2H), 2.43-2.37 (m, 1H), 2.35-2.13 (m, 9H), 2.05-1.99 (m, 1H), 1.95-1.75 (m, 5H), 1.70-1.63 (m, 1H), 1.54-1.47 (m, 1H).
Reaction SMILES: C[O:2][C:3](=[O:32])[C@H:4]([NH:12][C:13]([O:15][CH2:16][C:17]1[NH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][C:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[CH:21][CH:20]=2)=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O.[OH-].[Li+]>CO.O>[C:26]1([C:22]2[CH:23]=[C:24]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17]([CH2:16][O:15][C:13]([NH:12][C@H:4]([CH2:5][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:3]([OH:32])=[O:2])=[O:14])=[CH:25]3)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COC(=O)[C@@H](Cc1ccccc1)NC(=O)OCc1cc2cc(-c3ccccc3)ccc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(N[C@H](Cc1ccccc1)C(=O)O)OCc1cc2cc(-c3ccccc3)ccc2[nH]1
Temperature: 50 °C
Yield: 24.4 %

Procedure:
A solution of (R)-2-(5-phenyl-indol-2-ylmethoxycarbonylamino)-3-phenyl-propionic acid methyl ester 46 (0.195 g, 0.455 mmole) in methanol (20 ml) was treated with a solution of lithium hydroxide monohydrate (23 mg, 0.55 mmole) in water (1 ml) and heated to 50° C. for 7 hrs, cooled to room temperature, acidified, evaporated, extracted with EtOAc, washed, dried, and evaporated. The residue was purified by chromatography to give about 46 mg of (R)-2-(5-phenyl-indol-2-ylmethoxycarbonylamino)-3-phenyl-propionic acid 47, mp. 168 -1740.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[C:9]([O:18]C)(=O)[C:10]([CH2:12][C:13](OC)=[O:14])=[CH2:11].O(C(C)C)C(C)C.[NH4+:27].[OH-]>CCOC(C)=O>[OH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:9]([CH:10]1[CH2:11][NH:27][C:13](=[O:14])[CH2:12]1)=[O:18]
Reactant: [NH4+]
Reactant: C=C(CC(=O)OC)C(=O)OC
Reactant: Nc1ccccc1O
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(C)OC(C)C
Product: O=C1CC(C(=O)Nc2ccccc2O)CN1

Procedure:
A mixture of 21.8 g. (0.2 mole) of o-aminophenol and 31.6 g. (0.2 mole) of dimethyl itaconate in a 500 ml. round bottomed flask was heated to 190° for 1 hr. and volatile by-products were allowed to escape. The residue was taken up in 150 ml. of boiling EtOAc and diluted with 300 ml. of (i-Pr)2O. After the solution had cooled, it was clarified by filtration, evaported to a volume of 100 ml., and chilled at 5°. The tan crystalline solid was collected on a filter, and dried in air to give 22 g. of crude hydroxy ester, m.p. 120°-124°. Conversion of 5.0 g. (0.0212 mole) of the foregoing hydroxy ester was accomplished by stirring with 50 ml. of concentrated NH4OH at 25° for 24 hrs. Volatile material was removed by distillation at 95°/50 mm and the red glassy residue was taken up in a small amount of EtOAc-MeOH and allowed to stand. Crystals were deposited on standing. They were collected, and recrystallized from i-PrOH-EtOAc to give 3.12 g. of the desired product, m.p. 133°-135°, which was further purified by recrystallization from CH3CN using activated carbon, yield 1.9 g. m.p. 135°-138°. This material was used without further purification as starting material for Procedure 6.
Reaction SMILES: C([O-])CC[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Na+].[CH2:13]([OH:23])CCCCCCCCC.C(OCCOCCOCCOCCO)CCC>>[CH2:9]([CH:8]([CH2:7][CH2:6][CH2:5][CH3:4])[CH2:13][OH:23])[CH3:10]
Reactant: CCCCCCCCCC[O-]
Reactant: CCCCCCCCCCO
Agent: CCCCOCCOCCOCCOCCO
Agent: [Na+]
Product: CCCCC(CC)CO
Temperature: 25 °C

Procedure:
250.4 g of sodium decanolate (sodium salt of decanol) and 27.7 g of 1-decanol are treated at 200° C. with 113 g of tetraethylene glycol monobutyl ether. A clear solution has formed within 10 minutes. 142 g of high-naphthene neutral oil is added at 140° C., and the mixture is cooled to room temperature with stirring. The mixture which can be poured easily at 25° C. has the composition:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:13]([CH:14]=[N:15][NH:16]S(C2C=CC(C)=CC=2)(=O)=O)=[C:12]([Cl:27])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7].[CH3:28][C:29](=[O:32])[C:30]#[CH:31].C(O)[CH2:34][OH:35]>>[Cl:3][C:4]1[C:13]([C:14]2[NH:15][N:16]=[C:30]([C:29]([CH3:28])=[O:32])[CH:31]=2)=[C:12]([Cl:27])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH2:9][CH2:34][OH:35])=[O:7]
Reactant: OCCO
Reactant: C#CC(C)=O
Reactant: COC(=O)c1ccc(Cl)c(C=NNS(=O)(=O)c2ccc(C)cc2)c1Cl
Agent: [H-]
Agent: [Na+]
Product: CC(=O)c1cc(-c2c(Cl)ccc(C(=O)OCCO)c2Cl)[nH]n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 54 %

Procedure:
At -10° C. and under an atmosphere of protective gas, 250 ml of ethylene glycol were added to 1.5 g (62.3 mmol) of sodium hydride. The mixture was warmed to room temperature, 12.5 g (31.2 mmol) of methyl 2,4-dichloro-3-[N-(4-methylphenylsulfonylamino)iminomethyl]benzoate were added and the mixture was heated at 85° C. for 15 minutes. After cooling, the diazo compound was extracted with diethyl ether or ethyl acetate, the combined organic phases were washed with 10% strength aqueous sodium hydroxide solution and water and dried and a large part of the solvent was removed. 4.7 g (68.6 mmol) of 3-butyn-2-one were subsequently added and the mixture was heated at 80° C. for 2.5 hours. The mixture was stirred at room temperature for 48 hours and then washed with water, dried and concentrated. The residue was chromatographed over silica gel (eluent: cyclohexane/ethyl acetate=1/1). 5.75 g (54% of theory) of 2-hydroxyethyl 2,4-dichloro-3-(3-methylcarbonyl-1H-pyrazol-5-yl)benzoate were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH:15]([NH:18][C:19]2[CH:29]=[CH:28][C:22](C(OCC)=O)=[CH:21][CH:20]=2)[CH2:16][CH3:17])=[N:13][CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][OH:31].[OH-:32].[Na+]>C1COCC1>[CH2:1]([O:8][C:9]1[C:14]([CH:15]([NH:18][C:19]2[CH:29]=[CH:28][CH:22]=[CH:21][C:20]=2[C:30]([OH:32])=[O:31])[CH2:16][CH3:17])=[N:13][CH:12]=[CH:11][N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(NC(CC)c2nccnc2OCc2ccccc2)cc1
Reactant: CO
Reactant: [OH-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(Nc1ccccc1C(=O)O)c1nccnc1OCc1ccccc1
Temperature: 25 °C

Procedure:
Ethyl 4-(1-(2-benzyloxypyrazin-3-yl)prop-1-ylamino)benzoate (229 mg) was dissolved in THF (7 mL) and methanol (7 mL) and sodium hydroxide solution added (1.5 mL, 2M). The mixture was stirred for seventeen hours at ambient temperature, then heated at reflux for 2 hours, allowed to cool to ambient temperature and then the solvents evaporated off. The resulting foam was dissolved in water (25 mL) and extracted with ethyl acetate (2×20 mL) the aqueous phase was then adjusted to pH 4-5 with glacial acetic acid and re-extracted with ethyl acetate (2×20 mL). The combined organic phases were dried over magnesium sulphate. After removal of solvents, the residue was purified by MPLC (1% acetic acid, 24% ethyl acetate in hexane, silica)to give a yellow gum which was further purified by crystallisation from the above eluent system to give 4-(1-(2-benzyloxypyrazin-3-yl)prop-1-ylamino benzoic acid (138 mg, mp 141.5° C.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:14])([CH3:13])[CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][C:3]=1[CH2:15][CH:16]([CH3:24])[CH2:17][N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.[CH3:25]Br>CC#N>[Br-:1].[Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:13])([CH3:14])[CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][C:3]=1[CH2:15][CH:16]([CH3:24])[CH2:17][N+:18]1([CH3:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CCCCC(C)(C)c1ccc(CC(C)CN2CCCCC2)c(Br)c1
Reactant: CBr
Solvent: CC#N
Product: CCCCC(C)(C)c1ccc(CC(C)C[N+]2(C)CCCCC2)c(Br)c1
Product: [Br-]
Reaction time: 14 h

Procedure:
17 g of (XIV) in 100 ml of CH3CN were added to a solution of 16.4 g of CH3Br in 200 ml of CH3CN. After 14 hours at room temperature, the mixture was concentrated. The crystalline residue was triturated with ether, filtered off under suction and dried under reduced pressure. Yield: 15 g; melting point: 178° C. (compound No. 78).