Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[C:3]=1[CH2:17][CH2:18][C:19]([NH:21][C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:29])=[O:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(=O)(O)[O-].[Na+].[Cu](I)I>[Br:8][C:6]1[CH:7]=[C:2]2[C:3]([CH2:17][CH2:18][C:19](=[O:20])[N:21]2[C:22]2[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:29])=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[N:5]=1
Reactant: O=C(CCc1c(Br)cc(Br)nc1-c1ccc(F)cc1F)Nc1c(Cl)cccc1Cl
Agent: I[Cu]I
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: O=C1CCc2c(cc(Br)nc2-c2ccc(F)cc2F)N1c1c(Cl)cccc1Cl
Temperature: 155 °C
Reaction time: 24 h

Procedure:
To a solution of 3-[4,6-dibromo-2-(2,4-difluorophenyl)pyridin-3-yl]-N-(2,6-dichlorophenyl)propanamide (1 g) in 30 mL of DMF was added potassium carbonate (0.489 g) and copper iodide (0.5 g). The reaction mixture was stirred for 24 h at 155° C., then cooled and diluted with 10 mL of saturated sodium bicarbonate. This solution was extracted twice with 10 mL of ethyl acetate, washed with 10 mL of brine, dried with sodium sulfate, then concentrated. The residue was purified by flash chromatography with 1% acetone in CH2Cl2. Mass spectrum m/z (ESI) 485.3 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:19])[C:8](=[O:18])[N:9]2[CH2:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:4][CH:3]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>C(O)(=O)C.CN(C1C=CN=CC=1)C>[C:20]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:19])[C:8](=[O:18])[N:9]2[CH2:12][CH:13]([CH2:14][CH3:15])[CH2:16][CH3:17])=[CH:4][CH:3]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: CCC(CC)Cn1c(=O)c(=O)[nH]c2ccc(N)cc21
Agent: CN(C)c1ccncc1
Solvent: CC(=O)O
Product: CCC(CC)Cn1c(=O)c(=O)[nH]c2ccc(NC(C)=O)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
29.0 g (0.111 mol) of 7-amino-1-(2-ethylbutyl)-2,3(1H,4H)-quinoxalinedione were dissolved in 200 ml of acetic acid. A spatula tip of 4-(N,N-dimethylamino)pyridine was added and then 11.4 g (0.111 mol) of acetic anhydride were added dropwise. The mixture was stirred at room temperature for 30 minutes and then poured into ice-water, and the precipitate was filtered off with suction and dried to yield 22.5 g (67%) of the product. Melting point 168°-170° C.
Reaction SMILES: [N:1]1([C:7]([NH2:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(OC([NH:17][CH:18]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:27]([OH:29])=[O:28])[CH:24]=2)[CH2:19]1)=O)(C)(C)C.[ClH:30].O1CCOCC1>C(O)(=O)C>[ClH:30].[N:1]1([C:7]([NH2:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:17][CH:18]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:27]([OH:29])=[O:28])[CH:24]=2)[CH2:19]1
Reactant: CC(C)(C)OC(=O)NC1Cc2ccc(C(=O)O)cc2C1
Agent: Cl
Agent: NC(=O)N1CCOCC1
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: NC1Cc2ccc(C(=O)O)cc2C1

Procedure:
Using 2-(tert-butoxycarbonylamino)indan-5-carboxylic acid morpholinamide (1.0 g, 2.7 mmol), 4N hydrochloric acid-dioxane (12 ml) and acetic acid (36 ml), a similar procedure to Example 24 was carried out to obtain 2-aminoindan-5-carboxylic acid morpholinamide hydrochloride (750 mg, 2.7 mmol) having the following physical properties:
Reaction SMILES: NC(N)=O.[NH2:5][C:6]1[C:7]([OH:17])=[C:8]([S:13]([NH2:16])(=[O:15])=[O:14])[C:9]([Cl:12])=[CH:10][CH:11]=1.[O:18]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]=[C:32]=[O:33])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:32]([NH:31][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:33])=[C:7]([OH:17])[C:8]=1[S:13]([NH2:16])(=[O:15])=[O:14]
Reactant: O=C=Nc1ccccc1Oc1ccccc1
Reactant: Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Agent: NC(N)=O
Product: NS(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2ccccc2Oc2ccccc2)c1O
Yield: 52.5 %

Procedure:
Following the general procedure for urea formation outlined in example 12, 3-amino-6-chloro-2-hydroxybenzenesulfonamide (40 mg, 0.18 mmol) and 2-phenoxyphenylisocyanate (46 mg, 0.22 mmol) were coupled to form the desired urea (41 mg, 52%). 1H NMR (DMSO-d4): δ 10.69 (s, 1H), 9.25 (2, 1H), 9.11 (s, 1H), 8.18 (m, 4H), 7.41 (m, 2H), 7.04 (m, 8H), 6.84 (d, 1H).
Reaction SMILES: [OH:1][C@H:2]([CH3:6])[C:3]([NH2:5])=O.F[B-](F)(F)F.C([O+](CC)CC)C.N[C:20]1[C:21]([NH:29][CH:30]2[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]2)=[C:22]2[S:28][CH:27]=[CH:26][C:23]2=[N:24][CH:25]=1>O1CCCC1.C(O)C>[OH:1][C@@H:2]([C:3]1[N:29]([CH:30]2[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]2)[C:21]2=[C:22]3[S:28][CH:27]=[CH:26][C:23]3=[N:24][CH:25]=[C:20]2[N:5]=1)[CH3:6]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2c(N)cnc3ccsc23)CC1
Reactant: C[C@@H](O)C(N)=O
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: C1CCOC1
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 13.2 %

Procedure:
A mixture of (2R)-2-hydroxypropanamide (0.468 g, 5.26 mmol) and triethyloxonium tetrafluoroborate (0.941 g, 4.95 mmol) in tetrahydrofuran (7.2 mL) was stirred at room temperature for 2 h. The solvent was removed and the residue dissolved in ethanol (3.0 mL) and added to a suspension of tert-butyl 4-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]piperidine-1-carboxylate (0.57 g, 1.6 mmol) in ethanol (11 mL). The mixture was stirred at 80° C. for 1 h. The solvent was removed and the residue was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (85 mg, 13%). LCMS calculated for C20H27N4O3S (M+H)+: m/z=403.2. Found: 403.2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:8][CH:9]=[C:10]([C:12]([OH:14])=[O:13])[N:11]=1.[Si](Cl)(C)(C)[CH3:16]>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:8][CH:9]=[C:10]([C:12]([O:14][CH3:16])=[O:13])[N:11]=1
Reactant: C[Si](C)(C)Cl
Reactant: O=C(O)c1csc(-c2ccccn2)n1
Solvent: CO
Product: COC(=O)c1csc(-c2ccccn2)n1
Temperature: 50 °C

Procedure:
To a solution of 2-(pyridin-2-yl)thiazole-4-carboxylic acid 7.4 (500 mg, 2.425 mmol) in commercial anhydrous methanol (10 mL) was added TMS-Cl (0.77 mL, 6.06 mmol) at once. The RM was heated to 50° C. overnight. The RM. was concentrated under reduced pressure and the residue was used crude in next step. Yield: 649 mg (quantitative). LCMS: P=94%, rt=4.07 nm, m/z=221.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][O:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][NH2:12].[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O.ClCCl.C1(C)C=CC=CC=1.CCCCCC.C(OCC)(=O)C>[C:17]([NH:12][CH2:11][C:10]1[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=1[O:8][CH3:7])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COc1ccccc1CN
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: ClCCl
Solvent: O
Product: COc1ccccc1CNC(=O)c1ccccc1
Temperature: 9 °C

Procedure:
To a solution of sodium carbonate (232 g, 2.19 mol) in water (750 mL) were added toluene (750 mL) and water (750 mL), the mixture was cooled to 9° C., and o-methoxybenzylamine (300 g, 2.19 mol) was added thereto. To the mixture was added dropwise benzoyl chloride (307 g, 2.19 mol) with stirring at 3-8° C. During addition dropwise, toluene (750 mL) was added thereto to stir the mixture. The reaction mixture was allowed to warm to room temperature, and stirred for 20 min. The reaction was monitored by TLC (eluent: hexane/ethyl acetate (1:1)). The reaction mixture was cooled to 3° C., and filtered. To the solid was added city water (800 mL), and the mixture was stirred for 7.5 hr, and filtered. The organic layer of the mother liquor was concentrated to dryness. The solid collected by filtration was suspended in toluene (600 mL), the suspension was filtered, and the filtrate was concentrated to dryness. The solid collected by filtration, the residue obtained by concentration to dryness of the organic layer of the above-mentioned mother liquor, the residue obtained by concentration to dryness of the filtrate of the toluene suspension, dichloromethane (1500 mL) and water (1500 mL) were mixed, and the organic layer was separated. The organic layer was washed successively with 1 mol/L hydrochloric acid (600 mL), water (600 mL) and 20% brine (600 mL), and dried over magnesium sulfate (60 g). The magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure in a bath at 50° C. or lower (about 830 g), and the bath temperature was decreased to 18° C. The solid was collected by filtration, washed with cold dichloromethane (85 mL), and dried under reduced pressure at 50° C. or lower to give N-benzoyl-2-methoxybenzylamine (the primary crystals 481 g, 91.2%) as white crystals. As a result of HPLC analysis, the area percentage was 99.3%, and the content was 97.8%.
Reaction SMILES: [CH3:1]/[C:2](/[CH2:8][CH2:9]/[CH:10]=[C:11](\[CH3:18])/[CH2:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])=[CH:3]\[CH2:4][C:5]([OH:7])=[O:6].[CH3:19][O:20][C:21](=[O:30])[C@H:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)O.CO.C1CCC(N=C=NC2CCCCC2)CC1>CC(OC)(C)C.CN(C1C=CN=CC=1)C>[CH3:19][O:20][C:21]([C@@H:22]([O:6][C:5](=[O:7])[CH2:4]/[CH:3]=[C:2](\[CH3:1])/[CH2:8][CH2:9]/[CH:10]=[C:11](\[CH3:18])/[CH2:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:30]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC(=O)O
Reactant: COC(=O)[C@@H](O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: COC(C)(C)C
Product: COC(=O)[C@@H](OC(=O)C/C=C(\C)CC/C=C(\C)CCC=C(C)C)c1ccccc1
Temperature: 35 °C
Reaction time: 0.25 h
Yield: 99.4 %

Procedure:
To a solution of 12.5 g (50 mmol) (E,E)4,8,12-trimethyl-trideca-3,7,11-trienoic acid (isomeric purity of 95%) [K. Ishihara et al., J. Am. Chem. Soc. 2002, 124, 3647-3655] in 100 ml MTBE were added at r.t. 8.4 g (50 mmol) (S)-(+)-mandelic acid methyl ester [α]D=+144.9 (c=1.04, MeOH) and 1.5 g DMAP. After stirring for 15 min, 10.5 g (51 mmol) DCC is added, during which the temperature raised to 35° C. The reaction mixture was stirred for 4 h at 35° C., cooled to room temperature and filtered. The resulting solution was concentrated in vacuo to a volume of ca. 50 ml and filtered over 100 g of silicagel. The product was eluted with ca. 600 ml hexane/MTBE 1:1. Concentration of the combined fractions in vacuo and drying of the product in high vacuo (50° C./0.08 Torr) afforded 19.8 g (98%) of (E,E)-4,8,12-Trimethyl-trideca-3,7,11-trienoic acid (S)-methoxycarbonyl-phenyl-methyl ester (2) in form of a colorless oil.
Reaction SMILES: [O:1]1[C@H:3]2[C@H:4]([OH:24])[CH:5]=[C:6]3[C@:20]([CH3:21])([C@@H:2]12)[C@@H:19]1[C@H:9]([C@H:10]2[C@:16]([CH3:22])([CH2:17][CH2:18]1)[C@@H:13]([CH2:14][CH3:15])[CH2:12][CH2:11]2)[C@H:8]([OH:23])[CH2:7]3.CCCCCC.C(OCC)C.C(Cl)Cl>[O-2].[O-2].[Mn+4].C(Cl)(Cl)Cl>[O:1]1[C@H:3]2[C:4](=[O:24])[CH:5]=[C:6]3[C@:20]([CH3:21])([C@@H:2]12)[C@@H:19]1[C@H:9]([C@H:10]2[C@:16]([CH3:22])([CH2:17][CH2:18]1)[C@@H:13]([CH2:14][CH3:15])[CH2:12][CH2:11]2)[C@H:8]([OH:23])[CH2:7]3
Reactant: CC[C@H]1CC[C@H]2[C@@H]3[C@H](O)CC4=C[C@@H](O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CC[C@H]1CC[C@H]2[C@@H]3[C@H](O)CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C

Procedure:
Thus, alcoholysis of compound (III) with a lower alcohol, such as methanol, ethanol, etc., in the presence of a basic compound, such as anhydrous potassium carbonate, anhydrous sodium carbonate, etc., at a temperature of about 0° to 30° C. yields an 1α,2α-epoxypregn-4-ene-3β,7α-diol derivative of general formula (IV). This 1α,2α-epoxypregn-4-ene- 3β,7α-diol derivative (IV) is oxidized with manganese dioxide in a solvent, such as hexane, diethyl ether, methylene chloride, chloroform, etc., at room temperature to give an 1α,2α-epoxy-7α-hydroxypregn-4-en-3-one derivative of general formula (V) and finally this 1α,2α-epoxy-7α-hydroxypregn-4-en-3-one derivative is subjected to dehydration reaction in t-butyl alcohol in the presence of potassium t-butoxide at room temperature to give the compound (I-2-2). The compound (I-2-2) thus obtained can be subjected to said 6α,7α-epoxidation to compound (I-2-3) and to the reduction to compound (I-6-1) which will be described hereinafter.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:11]2[CH2:16][CH2:15][N:14]([C:17]([NH:19][C:20]3[S:21][C:22]([CH2:25][C:26](OC)=[O:27])=[CH:23][N:24]=3)=[O:18])[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C.C(O)(=O)C(C(C(O)=O)O)O.[Na]>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:11]2[CH2:16][CH2:15][N:14]([C:17]([NH:19][C:20]3[S:21][C:22]([CH2:25][CH2:26][OH:27])=[CH:23][N:24]=3)=[O:18])[CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1cnc(NC(=O)N2CCC(N3CCc4ccc(F)cc43)CC2)s1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C(O)C(O)C(O)C(=O)O
Agent: [Na]
Solvent: ClCCl
Product: O=C(Nc1ncc(CCO)s1)N1CCC(N2CCc3ccc(F)cc32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of methyl 2-(2-(4-(6-fluoroindolin-1-yl)piperidine-1-carboxamido)thiazol-5-yl)acetate (83.6 mg, 0.2 mmol, 1 equiv) in dried CH2Cl2 (3 mL) under N2 at room temperature was then slowly added DIBAL-H (1M in CH2Cl2, 1.0 mL, 1.0 mmol, 5 equiv). The resulting mixture became a clear solution and was stirred at room temperature for 1 h. The resulting mixture was slowly poured into a vigorously stirred mixture of CH2Cl2/10 wt % sodium tartaric acid (aq.) (10 mL/10 mL). The resulting mixture was stirred for 1 h and the layers were separated. The aqueous layer was extracted with CH2Cl2 (20 mL×2). The combined organic layer was dried (Na2SO4) and filtered. The solvent was removed by roto-evaporator and the resulting residue purified by column using 90-100% EtOAc/hexane as the eluent to yield 4-(6-fluoroindolin-1-yl)-N-(5-(2-hydroxyethyl)thiazol-2-yl)piperidine-1-carboxamide.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]=[CH:16][C:17]1[C:30]2[C:31]3=[C:32]4[C:27](=[CH:28][CH:29]=2)[CH:26]=[CH:25][CH:24]=[C:23]4[CH:22]=[CH:21][C:20]3=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].C1C=CC=CC=1>CO>[CH2:1]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16][C:17]1[C:30]2[C:31]3=[C:32]4[C:27](=[CH:28][CH:29]=2)[CH:26]=[CH:25][CH:24]=[C:23]4[CH:22]=[CH:21][C:20]3=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C(=NCCCCCCNCc1ccccc1)c1ccc2ccc3cccc4ccc1c2c34
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: c1ccc(CNCCCCCCNCc2ccc3ccc4cccc5ccc2c3c45)cc1

Procedure:
A solution of N-benzyl-N′-pyren-1-ylmethylene-hexane-1,6-diamine (420 mg, 1.00 mmol) and sodium borohydride (190 mg, 5.00 mmol) in methanol (10.0 ml) was stirred at room temperature for 3 hours under a nitrogen atmosphere. The solvent was removed under vacuum, and the residue was dissolved in chloroform and washed with water, and dried over magnesium sulphate. The solvent was removed and the residue was dried under vacuum to give a yellow oil (386/mg, 92%). 1H NMR (CDCl3) δ/ ppm 1.32 (4H, m, (CH2)2), 1.45 (2H m, BnNCCH2), 1.55 (2H, m, PyCNCCH2), 2.55 (2H, t, BnNCH2), 2.75 (2H, t, PyCNCH2), 3.75 (2H, s, PhCH2), 4.50 (2H, s, PyCH2), 7.15-7.25 (5H, m, Ph-H), 7.95-8.10, 8.15-8.22, 8.37 (4H, 4H, 1H respectively, m, m, d, Py-H). 13C NMR (CDCl3)δ/ppm 27.35, 30.16, 49.46, 50.02, 51.94, 54.13, 54.13, 123.19, 124.72, 125.00, 125.09, 125.89, 126.89, 127.03, 127.50, 127.64, 128.14, 128.40, 129.06, 131.34, 134.15; m/z (EI) 420 ([M])+, 7%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)=[N:5][CH:4]=[N:3]1.Cl.[NH2:16][OH:17]>N1C=CC=CC=1>[OH:17]/[N:16]=[C:7](\[C:6]1[N:2]([CH3:1])[N:3]=[CH:4][N:5]=1)/[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cn1ncnc1C(=O)c1ccccc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: Cn1ncnc1/C(=N\O)c1ccccc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 88.9 %

Procedure:
To a solution of (1-methyl-1H-1,2,4-triazol-5-yl)(phenyl)methanone (5.5 g, 29.38 mmol, 1 eq.) in 100 ml of pyridine was added hydroxylamine hydrochloride (5.1 g, 73.45 mmol, 2.5 eq.). The temperature was raised to 50° C. and the reaction stirred overnight. The solvent was then evaporated and the residue dissolved in DCM and washed with H2O. The organic layer was washed with 0.1N HCl and dried over MgSO4. The solvent was evaporated to give ((Z)-N-hydroxy-1-(1-methyl-1H-1,2,4-triazol-5-yl)-1-phenylmethanimine (5.28 g, 89% yield) as a white solid.
Reaction SMILES: S([O-])([O-])(=O)=O.[NH4+].[NH4+].OP([O-])(O)=O.[K+].[O-]S([O-])(=O)=O.[Mg+2].CC1[N+](CC2C=NC(C)=NC=2N)=CSC=1CCO.[NH2:38][C@H:39]([C:44]([OH:46])=[O:45])[C@H:40](CC)[CH3:41].[C:47]([O-:50])([O-:49])=O.[Ca+2]>C(O)C>[NH2:38][C@H:39]([C:44]([OH:46])=[O:45])[CH2:40][CH2:41][C:47]([OH:50])=[O:49]
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Reactant: O=C([O-])[O-]
Agent: Cc1ncc(C[n+]2csc(CCO)c2C)c(N)n1
Agent: O=P([O-])(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: N[C@@H](CCC(=O)O)C(=O)O
Reaction time: 21 h

Procedure:
Both strains, VL334thrC+ Pl-tacadhE* and VL334thrC+ Pl-tacadhE* (pPLydbK3), can be grown for 18-24 hours at 37° C. on L-agar plates. Then, one loop of the cells can be transferred into test tubes containing 2 ml of fermentation medium. The fermentation medium contains ethanol (20 g/l), ammonium sulfate (25 g/l), KH2PO4 (2 g/l), MgSO4 (1 g/l), thiamine (0.1 mg/ml), L-isoleucine (70 μg/ml), and CaCO3 (25 g/l). The pH is adjusted to 7.2. CaCO3 is sterilized separately. Cultivation can be carried out at 30° C. for 3 days with shaking. After the cultivation, the amount of L-glutamic acid which is produced can be determined by paper chromatography (liquid phase composition of butanol-acetic acid-water=4:1:1) with subsequent staining by ninhydrin (1% solution in acetone) and further elution of the compounds in 50% ethanol with 0.5% CdCl2.
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]([CH3:11])=[CH:6][C:7]=1[C:8]([OH:10])=O)=[O:2].[CH3:12][C@H:13]1[CH2:18][NH:17][CH2:16][C@@H:15]([CH3:19])[NH:14]1>>[CH3:12][C@H:13]1[NH:14][C@@H:15]([CH3:19])[CH2:16][N:17]([C:8]([C:7]2[CH:6]=[C:5]([CH3:11])[NH:4][C:3]=2[CH:1]=[O:2])=[O:10])[CH2:18]1
Reactant: Cc1cc(C(=O)O)c(C=O)[nH]1
Reactant: C[C@@H]1CNC[C@H](C)N1
Product: Cc1cc(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c(C=O)[nH]1
Yield: 73.7 %

Procedure:
2-Formyl-5-methyl-1H-pyrrole-3-carboxylic acid (1.00 g, 6.53 mmol) reacted with cis-2,6-dimethylpiperazine (900 mg, 7.84 mmol) to give 1.2 g (74%) of 3-[(3R,5S)-3,5-dimethyl-piperazine-1-carbonyl]-5-methyl-1H-pyrrole-2-carbaldehyde.
Reaction SMILES: [CH2:1]([NH:4][C:5](=O)[CH2:6][O:7][C:8]1[C:13]([Cl:14])=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=1[Cl:16])[CH2:2][CH3:3].C1(C)C=CC=CC=1.CSC.B>CO>[Cl:14][C:13]1[CH:12]=[C:11]([Cl:15])[CH:10]=[C:9]([Cl:16])[C:8]=1[O:7][CH2:6][CH2:5][NH:4][CH2:1][CH2:2][CH3:3]
Reactant: CCCNC(=O)COc1c(Cl)cc(Cl)cc1Cl
Agent: B
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CSC
Product: CCCNCCOc1c(Cl)cc(Cl)cc1Cl
Temperature: 60 °C

Procedure:
N-(n-propyl)-2,4,6-trichlorophenoxyacetamide, 44.0 gm, was added to 250 ml of toluene. 28 ml of borane methyl sulfide [BH3.(CH3)2S] (2 equivalents) was then slowly added to the system. The system was heated at approximately 60° C. for 15 hours at which time reaction completion was checked by IR spectroscopy. 200 ml of methanol was then slowly added to the system. After addition of the methanol, the system was acidified by bubbling in HCl gas. Afterwards, the system was refluxed for 1 hour. The solvent was then removed by stripping. The resulting oil was dissolved in methanol which was then stripped. The oil was next dissolved in methylene chloride. The organic solution was washed with a sodium hydroxide solution and then with water. The methylene chloride was removed by stripping to give 36.3 gm of the N-(n-propyl) ethanolamine 2,4,6-trichlorophenylether, as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([C:15]([CH:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18](OCC)=[O:19])=[O:16])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.OS(O)(=O)=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[C:18]([OH:19])=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:15](=[O:16])[C:9]12[CH2:10][CH2:11][O:12][CH2:13][CH2:14]1
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)C1(c2cccc(OC)c2)CCOCC1
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1=C(O)c2c(OC)cccc2C2(CCOCC2)C1=O
Temperature: 0 °C
Yield: 2.7 %

Procedure:
Diethyl 2-(4-(3-methoxyphenyl)-tetrahydro-2H-pyran-4-carbonyl)malonate (2.1 g) was added to 5 mL H2SO4 stirred at 0° C. The mixture was stirred at room temperature for 1 hour, M+1=379. The mixture was then poured into 100 g crushed ice and extracted with EtOAc (3×50 mL). The combined organic layers were washed with H2O (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified by column chromatography eluting with 20% EtOAc/hexane to give 0.05 g of the title compound. MS (m/z)=379 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=1)[C@H:3]([OH:8])[CH2:4][N:5]=[N+:6]=[N-:7].[CH2:18]([N:21]([CH2:35][CH2:36][CH3:37])[C:22]([C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([CH2:33]C)[CH:32]=1)[C:27](O)=[O:28])=[O:23])[CH2:19][CH3:20].C(N(CC)CC)C.C(N=C=NCCCN(C)C)C>ClCCl.C(OCC)(=O)C.CCCCCC.CO.ClCCl>[N:5]([CH2:4][C@@H:3]([OH:8])[C@@H:2]([NH:1][C:27](=[O:28])[C:26]1[CH:30]=[C:31]([CH3:33])[CH:32]=[C:24]([C:22]([N:21]([CH2:18][CH2:19][CH3:20])[CH2:35][CH2:36][CH3:37])=[O:23])[CH:25]=1)[CH2:9][C:10]1[CH:11]=[C:12]([F:17])[CH:13]=[C:14]([F:16])[CH:15]=1)=[N+:6]=[N-:7]
Reactant: [N-]=[N+]=NC[C@@H](O)[C@@H](N)Cc1cc(F)cc(F)c1
Reactant: CCCN(CCC)C(=O)c1cc(CC)cc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: CCCN(CCC)C(=O)c1cc(C)cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CN=[N+]=[N-])c1
Reaction time: 16 h

Procedure:
To (2R, 3S)-3-amino-1-azido-4-(3,5-difluorophenyl)-2-buta (XIV, EXAMPLE 166, 0.34 g, 1.4 mmole) in dichloromethane (20 ml) is added N,N-dipropylamidoisophthalic acid (IX, 0.53 g, 2 mmole), L-butyl alcohol (0.27 g, 2 mmole) and triethylamine (0.84 ml, 6 mmole) and ethyl-1-(3-dimethylaminopropyl)carbodiimide (0.58 g, 3 mmole). The mixture is stirred at 20–25 degrees C. for 16 hours. The reaction is monitored by TLC (methanol/dichloromethane, 20/80+ethyl acetate/hexane, 50/50; Rf=0.76). When the reaction is complete as measured by TLC, the reaction mixture is partitioned between dichloromethane and water, washed with hydrochloric acid (0.5 N), bicarbonate, saline, dried over anhydrous sodium sulfate and the solvent is removed under reduced pressure with heat to produce a concentrate. The concentrate is column chouromatographed on silica gel to give the title compound; MS (MH+)=488.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:11](=[O:21])[N:10]([CH2:22][C:23](O)=[O:24])[N:9]=2)=[CH:4][CH:3]=1.[C:26](=[O:40])([O:28][CH2:29][CH:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[Cl:39])[CH2:31][NH2:32])[NH2:27]>>[C:26](=[O:40])([O:28][CH2:29][CH:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[Cl:39])[CH2:31][NH:32][C:23](=[O:24])[CH2:22][N:10]1[C:11](=[O:21])[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[N:9]1)[NH2:27]
Reactant: NCC(COC(N)=O)c1ccccc1Cl
Reactant: O=C(O)Cn1nc(-c2ccc(Cl)cc2)n(Cc2ccccc2F)c1=O
Product: NC(=O)OCC(CNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(Cc2ccccc2F)c1=O)c1ccccc1Cl

Procedure:
Analogously to the procedure of Example 63, 49 mg (135 μmol) of [3-(4-chlorophenyl)-4-(2-fluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetic acid [for the preparation see Example 156A in WO 2007/134862] were reacted with 34 mg (149 μmol) of the compound of Example 15A. This gave 27 mg (35% of theory) of the title compound.