Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[NH:4][CH2:3][CH2:2]1.C=O.[C:23](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH3:23][N:4]1[CH:5]2[CH:10]([CH2:9][CH2:8][CH2:7][CH2:6]2)[N:1]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:2][CH2:3]1
Reactant: O=C(OCc1ccccc1)N1CCNC2CCCCC21
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCN(C(=O)OCc2ccccc2)C2CCCCC21
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
To a solution of phenylmethyl octahydro-1(2H)-quinoxalinecarboxylate (enantiomeric mixture) (2.32 g, 8.5 mmol) in dichloromethane (80 mL) at 0° C. was added formaldehyde (0.76 mL, 37% water solution, 10.2 mmol) followed by sodium triacetoxyborohydride (2.7 g, 12.75 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 1 h before being diluted with dichloromethane and washed with 1N NaOH solution. The organics were washed with brine, dried (Na2SO4) and evaporated to yield 2.3 g of phenylmethyl 4-methyloctahydro-1(2H)-quinoxalinecarboxylate (enantiomeric mixture, cis) (2.3 g), which was separated by chiral LC to afford phenylmethyl (4aS,8aR)-4-methyloctahydro-1(2H)-quinoxalinecarboxylate, and phenylmethyl (4aR,8aS)-4-methyloctahydro-1(2H)-quinoxalinecarboxylate. Absolute configuration was assigned using Ab Initio vibrational circular dichroism. LCMS: (M+H)+: 289.2.
Reaction SMILES: [F:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:9](Cl)=[O:10].[CH3:12][O:13][C:14]1[C:15]([CH2:22][NH:23][CH:24]2[CH2:26][CH2:25]2)=[N:16][CH:17]=[CH:18][C:19]=1[O:20][CH3:21].C(N(CC)CC)C.CCCCC.C(OCC)(=O)C>ClCCl>[CH:24]1([N:23]([CH2:22][C:15]2[C:14]([O:13][CH3:12])=[C:19]([O:20][CH3:21])[CH:18]=[CH:17][N:16]=2)[C:9]([C:3]2[C:4]([CH3:8])=[N:5][N:6]([CH3:7])[C:2]=2[F:1])=[O:10])[CH2:25][CH2:26]1
Reactant: COc1ccnc(CNC2CC2)c1OC
Reactant: Cc1nn(C)c(F)c1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ccnc(CN(C(=O)c2c(C)nn(C)c2F)C2CC2)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 0.1 %

Procedure:
At ambient temperature a solution of 0.14 g (0.8 mmol) of 5-fluoro-1,3-dimethyl-1H-pyrazole-4-carbonyl chloride in 2 ml of dichloromethane was added drop wise to a solution of 0.15 g (0.7 mmol) of N-[(3,4-dimethoxypyridin-2-yl)methyl]cyclopropylamine and 0.3 ml of triethylamine in 4 ml of dichloromethane. The reaction mixture was stirred for 16 hrs at ambient temperature and quenched with water. The watery layer was extracted three times with dichloromethane (3×10 ml), the combined organic layers were dried over magnesium sulphate and concentrated in vacuum. Column chromatography (gradient n-pentane/ethyl acetate) yielded 0.23 mg (92% yield) of N-cyclopropyl-N-[(3,4-dimethoxypyridin-2-yl)methyl]-5-fluoro-1,3-dimethyl-1H-pyrazole-4-carboxamide (M+H=349).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[CH:13](C(OC)=O)[C:14]([O:16][CH3:17])=[O:15].[Cl-].[Na+].O.CCOC(C)=O>CS(C)=O>[CH3:17][O:16][C:14](=[O:15])[CH2:13][C:3]1[CH:4]=[C:5]([O:11][CH3:12])[C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[Cl:1]
Reactant: COC(=O)C(C(=O)OC)c1cc(OC)c([N+](=O)[O-])cc1Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1cc(OC)c([N+](=O)[O-])cc1Cl
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 61.2 %

Procedure:
A mixture of dimethyl 2-(2-chloro-5-methoxy-4-nitrophenyl)malonate (3.0 g, 9.44 mmol) and sodium chloride (0.99 g, 16.99 mmol) in DMSO (50 mL) and water (0.17 mL, 9.44 mmol) was heated for 5 hours at 120° C. The reaction mass was allowed to cool to room temperature and water (400 mL) and EtOAc (50 mL) were added and stirring continued for 15 minutes. The separated aqueous layer was extracted with EtOAc (50 mL), and then the combined organic layers were washed with brine (50 mL), dried (Na2SO4) and concentrated under reduced pressure. The crude residue was purified by column chromatography on neutral silica gel using 15-25% EtOAc in hexane to give the desired material (1.5 g, 61%) as a solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([OH:24])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCC1C=C([F:39])C=CC=1OC>>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([OH:24])[CH2:15][C:16]2[CH:21]=[C:20]([F:39])[CH:19]=[CH:18][C:17]=2[O:22][CH3:23])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(F)cc1CCl
Reactant: COc1ccccc1CC(O)(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Product: COc1ccc(F)cc1CC(O)(c1ccccc1)C1CN(Cc2ccccc2)CCO1

Procedure:
The procedure for the synthesis of example 1a, 1-(4-Benzyl-morpholin-2-yl)-2-(2-methoxy-phenyl)-1-phenyl-ethanol, was followed using 2-chloromethyl-4-fluoro-1-methoxy-benzene (synthesized as described above) as starting material making non-critical variations, to yield the title compound which was taken without further purification in the next step. LCMS (6 minutes method) [M+H]+=422 @ Rt 2.85 min. major peak.
Reaction SMILES: C([O:3][C:4](=[O:22])[C@@H:5]([O:20][CH3:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([C:17]([OH:19])=O)([CH3:16])[CH3:15])=[CH:9][CH:8]=1)C.[F:23][C:24]([F:34])([F:33])[C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][NH2:29].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>>[CH3:21][O:20][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][C:14]([CH3:15])([C:17](=[O:19])[NH:29][CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[C:25]([C:24]([F:23])([F:33])[F:34])[CH:26]=2)[CH3:16])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:22]
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)[C@H](Cc1ccc(OC(C)(C)C(=O)O)cc1)OC
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OC(C)(C)C(=O)NCc2cccc(C(F)(F)F)c2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (PREPARATION 5, step 2) and 3-trifluoromethyl-benzylamine 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 C22H24F3NO5 [M−H]−: 438.
Reaction SMILES: [C:1]([CH2:3][C:4]([N:6]([CH:17]([CH3:19])[CH3:18])[C:7]1[CH:16]=[CH:15][C:10]2[N:11]=[C:12]([SH:14])[S:13][C:9]=2[CH:8]=1)=[O:5])#[N:2].[H-].[Na+].[F:22][C:23]([F:34])([F:33])[C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>C1COCC1>[C:1]([C:3](=[C:28]([OH:29])[C:27]1[CH:31]=[CH:32][C:24]([C:23]([F:22])([F:33])[F:34])=[CH:25][CH:26]=1)[C:4]([N:6]([CH:17]([CH3:19])[CH3:18])[C:7]1[CH:16]=[CH:15][C:10]2[N:11]=[C:12]([SH:14])[S:13][C:9]=2[CH:8]=1)=[O:5])#[N:2]
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)N(C(=O)CC#N)c1ccc2nc(S)sc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)N(C(=O)C(C#N)=C(O)c1ccc(C(F)(F)F)cc1)c1ccc2nc(S)sc2c1
Reaction time: 0.25 h

Procedure:
Cooled a 0.1 M solution of α-cyano-N-isopropyl-N-(2-mercaptobenzothiazol-6-yl)acetamide (50 mg, 0.172 mmol) in anhydrous THF to 0° C. Added 60% sodium hydride in mineral oil (69 mg, 1.720 mmol) and stirred 15 minutes. 4-(trifluoromethyl)benzoyl chloride (36 μl, 0.189 mmol) was added dropwise and the mixture stirred an additional 30 minutes. The reaction was quenched by addition of 0.1 M aqueous HCl. The mixture was extracted with ethyl acetate three times, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative TLC (5% methanol, 95% dichloromethane) to yield 27 mg (34%). 1H NMR (CDCl3) δ1.17 (d, 6H), 5.01 (m, 1H), 7.12 (d, 1H), 7.21 (dd, 1H), 7.31 (s, 1H), 7.64 (app q, 4H); ESIMS: m/z 462 (M-H).
Reaction SMILES: [CH2:1]([C:3]1([CH2:18][CH2:19][OH:20])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:16][CH3:17])[CH3:2].[H-].[Na+].[CH3:23]I>C1COCC1.[Cl-].[Na+].O>[CH2:1]([C:3]1([CH2:18][CH2:19][O:20][CH3:23])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:16][CH3:17])[CH3:2]
Reactant: CCc1cccc2c3c([nH]c12)C(CC)(CCO)OCC3
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCc1cccc2c3c([nH]c12)C(CC)(CCOC)OCC3
Yield: 62.5 %

Procedure:
To a solution of compound 1 (348 mg, 1.27 mmol) in dry THF (5 mL) under argon, 60% NaH in mineral oil (64 mg, 1.59 mmol, 1.25 eq) was added in a portion-wise manner. After stirring for thirty minutes, MeI (99 μL, 1.59 mmol, 1.25 eq) was added dropwise, and the reaction was stirred for 2 days at room temperature. The resulting mixture was diluted with brine and extracted three times with Et2O. The combined organic phases were dried with Na2SO4, concentrated, and purified by column chromatography using 20:80:EtOAc:Hexane to give a yellow-white solid (228 mg, 62%): mp 125-126° C. 1HNMR (CDCl3, δ TMS): 0.86 (t, 3H), 1.37 (t, 3H), 1.94 (m, 2H), 2.15 (m, 2H), 2.78 (t, 2H), 2.85 (q, 2H), 3.37 (s, 3H), 3.52 (m, 2H), 4.00 (m, 2H), 6.99-7.38 (m, 3H, Ar—H), 8.43 (br, 1H, NH). MS−: m/z 286 ([M−H]−). Anal. (C18H25NO2): C, H, N.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[Br:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][C:21](OC)=[O:22])[CH:15]=[CH:14]2.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+].CCOCC>C1COCC1>[Br:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][CH2:21][OH:22])[CH:15]=[CH:14]2
Reactant: COC(=O)Cn1ccc2cc(Br)ccc21
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCCn1ccc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
DIBAL-H (1 M in hexanes) (6.1 mL, 6.1 mmol) was added to a 0° C. solution of methyl (5-bromo-1H-indol-1-yl)acetate (660 mg, 2.46 mmol) in anhydrous THF (12 mL). The reaction was warmed to ambient temperature and maintained for 1 h. The reaction mixture was poured into saturated aqueous Rochelle's salt (25 mL) and Et2O (25 mL). The mixture was stirred vigorously for 30 min. The layers were separated and the aqueous phase was extracted with Et2O. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated to afford the desired product as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=O.[C:13]1([CH2:19][CH2:20][NH2:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[F:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH2:4][NH:21][CH2:20][CH2:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCCc1ccccc1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=[N+]([O-])c1ccc(F)c(CNCCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 24 h
Yield: 81.2 %

Procedure:
2-Fluoro-5-nitro-benzaldehyde (11.9 g, 70 mmol) and 2-phenylethylamine (13 mL, 0.1 mol) were dissolved in methanol (150 mL) and glacial acetic acid (15 mL). The solution was cooled to 0° C., and sodium cyanoborohydride (6.6 g, 0.1 mol) was added portionwise. The reaction was adjusted to pH 6 with acetic acid and stirred at room temperature for 24 h. The reaction mixture was quenched with ice and diluted with water. The pH was adjusted to 11 with sodium hydroxide and the mixture was extracted with EtOAc. The organic extracts were washed with cold dilute HCl solution and a solid precipitated. Filtration yielded the title compound (15.6 g, 82%). Mp 235-6° C.; MS m/e 275 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][NH:3]1.Cl.C(N=C=NCCCN(C)C)C.[CH3:20][O:21][C:22]1[C:23](=[O:49])[C:24]([CH3:48])=[C:25]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([O:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[C:36]([CH:40]=2)[C:37](O)=[O:38])[C:26](=[O:30])[C:27]=1[O:28][CH3:29]>C(Cl)Cl>[CH3:20][O:21][C:22]1[C:23](=[O:49])[C:24]([CH3:48])=[C:25]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([O:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[C:36]([CH:40]=2)[C:37]([N:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]2[CH3:1])=[O:38])[C:26](=[O:30])[C:27]=1[O:28][CH3:29]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(Oc3ccccc3)c(C(=O)O)c2)=C(C)C1=O
Reactant: CC1CCCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(Oc3ccccc3)c(C(=O)N3CCCCC3C)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 46.9 %

Procedure:
2-Methylpiperidine (0.039 g, 0.391 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.112 g, 0.587 mmol) were added to a methylene chloride solution (5 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-phenoxybenzoic acid (0.080 g, 0.196 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=9:1) to obtain the titled compound (0.045 g, 0.0919 mmol, 47%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](Br)[C:7]=1[CH2:8][CH2:9][CH2:10][OH:11].NC1C=CC=CN=1.C[O-].[Na+].C([O-])(O)=O.[Na+]>COCCOC.[Cu]Cl>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]2[O:11][CH2:10][CH2:9][CH2:8][C:7]=12
Reactant: OCCCc1c(Br)cncc1Br
Agent: Cl[Cu]
Agent: C[O-]
Agent: Nc1ccccn1
Solvent: COCCOC
Product: Brc1cncc2c1CCCO2

Procedure:
To a solution of 3-(3,5-dibromo-pyridin-4-yl)-propan-1-ol (1 eq, 4.41 mmol, 1.3 g) in DME (8 ml) is added copper (I) chloride (0.05 eq, 0.22 mmol, 22 mg), 2-aminopyridine (0.05 eq, 0.22 mmol, 21 mg), and NaOMe (5.4M in MeOH, 1.5 eq, 6.61 mmol, 1.22 ml). The resulting mixture is heated using microwave radiation at 70° C. for 20 h. Then sat. aqueous NaHCO3 solution is added, and the mixture is extracted with EtOAc. The organic layer is dried with MgSO4, filtered, and concentrated in vacuo. The crude product is purified using column chromatography (hexane/EtOAc) to give the title compound; [M+H]+=214/216.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH:50]=[O:51])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.[CH2:63]=[O:64]>CN(C)C=O>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:42]=[CH:43][C:44]([O:47][CH2:48][CH3:49])=[CH:45][CH:46]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@:10]1([CH2:63][OH:64])[CH:50]=[O:51])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](C=O)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Reactant: C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCOc1ccc(Cc2cc([C@]3(OC)O[C@](C=O)(CO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 65.1 %

Procedure:
To a solution of (2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde 1h (0.82 g, 1.16 mmol, obtained from the synthetic method described in step 7 of example 1) in N,N-dimethylformamide (20 mL) were added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.02 mL, 0.12 mmol) and formaldehyde (1.7 mL, 23.2 mmol, 37% in water) in turn. The mixture was stirred at room temperature for 5 hours and quenched with 10 mL of saturated aqueous sodium bicarbonate. The resulting mixture was filtered. The filtrate was extracted with ethyl acetate (20 mL×1 and 10 mL×3). The combined organic layers were washed with water (10 mL×3) and then saturated aqueous sodium chloride (10 mL×3), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=5/1 to give the title compound 8a as yellow oil (0.56 g, 65.1%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, DMSO-d6) δ(ppm): 9.99 (s, 1H), 7.55-7.49 (m, 2H), 7.43 (d, 1H), 7.34-7.24 (m, 13H), 7.07 (dd, 2H), 6.95 (d, 2H), 6.72 (d, 2H), 5.38 (dd, 1H), 4.84 (m, 3H), 4.72 (d, 1H), 4.56-4.43 (m, 2H), 4.16 (d, 1H), 4.01 (d, 1H), 3.92 (q, 2H), 3.81 (m, 3H), 3.57 (dd, 1H), 3.25 (d, 1H), 2.70 (s, 3H), 1.27 (t, 3H).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([I:17])=[C:7]([C:11]([I:16])=[C:12]([NH2:15])[C:13]=1[I:14])[C:8]([OH:10])=[O:9])(=[O:3])[CH3:2].[O-][CH2:19]C.[Na+].[Na].CI>>[NH2:15][C:12]1[C:11]([I:16])=[C:7]([C:6]([I:17])=[C:5]([N:4]([CH3:19])[C:1](=[O:3])[CH3:2])[C:13]=1[I:14])[C:8]([OH:10])=[O:9]
Reactant: CC(=O)Nc1c(I)c(N)c(I)c(C(=O)O)c1I
Reactant: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CI
Product: CC(=O)N(C)c1c(I)c(N)c(I)c(C(=O)O)c1I
Temperature: 22 °C
Reaction time: 0.17 h
Yield: 82.6 %

Procedure:
3-Acetamido-5-amino-2,4,6-triiodobenzoic acid (I; 228.76 g., 0.4 mole) was added to an anhydrous ethanolic solution of sodium ethoxide (prepared from 18.4 g. (0.8 g. atom) of sodium) at 45° C. After 10 minutes, the homogeneous solution was cooled to 22° C. and methyl iodide (62.48 g.; 0.44 mole) was added. The reaction mixture was heated at 50°-55° C. for 30 minutes, at 62° C. for 30 minutes and finally at 68°-70° C. for 15 minutes. The reaction mixture was now pH 8. Methyl iodide (1 ml.) was added and heating was continued at 70° C. for 15 minutes after which the solution was neutral. The ethanol was removed under reduced pressure and water (1300 ml.) was added to the residue. The solid which dropped out of solution was collected; the filtrate was basified (~pH 10) with 50% sodium hydroxide and was washed with a 3:1 chloroform-isopropyl alcohol mixture (800 ml.). The aqueous layer was acidified to pH 5 with acetic acid and treated with activated charcoal marketed under the trade designation "Darco G-60" (5 g.) for 1 hour. The filtered solution was added to 6 N hydrochloric acid (700 ml.) at room temperature to precipitate the product. The precipitate was digested for 10 minutes and was then collected, washed with water (500 ml.), and dried at 60° C. overnight to yield 193.5 g. of 3-amino-2,4,6-triiodo-5-(N-methylacetamido)benzoic acid (82.6% yield). The product was homogeneous by thin-layer chromatography (chloroform-ethyl acetateacetic acid, 30:20:1) and the structure of the product was confirmed by nuclear magnetic resonance spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10](/[CH:13]=[C:14](/[N+:16]([O-])=O)\[CH3:15])=[CH:11][CH:12]=2)=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].[O-]S([O-])(=O)=O.[Mg+2]>C(OCC)C.O.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH2:13][CH:14]([NH2:16])[CH3:15])=[CH:11][CH:12]=2)=[CH:4][C:3]=1[C:19]([F:22])([F:20])[F:21]
Reactant: C/C(=C\c1ccc(-c2ccc(Cl)c(C(F)(F)F)c2)o1)[N+](=O)[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: O
Product: CC(N)Cc1ccc(-c2ccc(Cl)c(C(F)(F)F)c2)o1
Temperature: 0 °C
Reaction time: 3 h
Yield: 47.8 %

Procedure:
(E)-2-(4-chloro-3-(trifluoromethyl)phenyl)-5-(2-nitroprop-1-enyl)furan (2.58 g, 7.78 mmol) was mixed with diethyl ether (54 ml) and toluene (25 ml) and added drop wise to a cooled (−20° C.) solution of lithium aluminium hydride (2.5 g, 65.9 mmol) in diethyl ether (11 ml). The mixture was allowed to warm up to 0° C. and stirred for 3 h and then at RT for additional 1 h stirring. Then the mixture was cooled again and 2.5 ml of water was added at −30° C. and then 2.5 ml of 15% aqueous NaOH solution. An additional 7.5 ml of water was added and the solution was allowed to warm to RT. MgSO4 was added and the mixture was stirred and filtered, precipitate was washed with toluene and diethyl ether and the filtrate was evaporated to dryness. After CombiFlash purification with DCM:MeOH as eluent system, the pooled fractions afforded 1.13 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.01 (d, 3H), 2.63 (m, 2H), 3.11-3.15 (m, 1H) 6.28 (d, 1H), 7.07 (d, 1H), 7.68 (d, 1H), 7.87 (m, 1H), 7.95 (m, 1H).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([C:23]4[O:24][C:25]([C:28]5[N:33]=[C:32]([C:34]([O:36]C)=[O:35])[CH:31]=[CH:30][CH:29]=5)=[CH:26][N:27]=4)=[O:22])=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[OH-].Cl>C1COCC1.O.C(Cl)Cl>[N:1]1([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([C:23]4[O:24][C:25]([C:28]5[N:33]=[C:32]([C:34]([OH:36])=[O:35])[CH:31]=[CH:30][CH:29]=5)=[CH:26][N:27]=4)=[O:22])=[CH:15][CH:14]=3)=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1cccc(-c2cnc(C(=O)CCc3ccc(-c4ccc(CN5CCCC5)cc4)cc3)o2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc(-c2cnc(C(=O)CCc3ccc(-c4ccc(CN5CCCC5)cc4)cc3)o2)n1
Yield: 55.9 %

Procedure:
Methyl 6-(2-(3-(4′-(pyrrolidin-1-ylmethyl)biphenyl-4-yl)propanoyl)oxazol-5-yl)pyridine-2-carboxylate (13 mg, 0.026 mmol) was dissolved in THF/H2O (3:2, 2 mL) and LiOH (1.8 mg, 0.079 mmol) was added. The reaction solution was stirred at room temperature under an atmosphere of Ar for 25 min before the addition of aqueous 1 N HCl to pH 4. The reaction solution was diluted with CH2Cl2 and the organic and aqueous layers were separated. The aqueous layer was made basic to pH 8 with the addition of saturated aqueous NaHCO3 and extracted with CH2Cl2. The organic phases were combined, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by tritration in ether to provide 6-(2-(3-(4′-(pyrrolidin-1-ylmethyl)biphenyl-4-yl)propanoyl)oxazol-5-yl)pyridine-2-carboxylic acid as a white solid (7 mg, 55%): 1H NMR (CDCl3, 600 MHz) δ 8.22 (d, 1H, J=6.5 Hz), 8.04-8.02 (m, 3H), 7.67 (d, 2H, J=7.9 Hz), 7.58 (d, 2H, J=7.9 Hz), 7.47 (d, 2H, J=8.1 Hz), 7.33 (d, 2H, J=8.0 Hz), 4.26 (s, 2H), 3.50 (t, 2H, J=7.5 Hz), 3.16 (t, 2H, J=7.5 Hz), 2.45-1.90 (m, 8H); 13C NMR (CDCl3, 150 MHz) δ 187.3, 164.8, 157.5, 151.8, 145.3, 142.3, 140.0, 139.2, 138.0, 131.0, 129.0, 128.6, 128.1, 127.7, 127.2, 124.3, 123.6, 58.0, 52.8, 40.6, 29.4, 23.1; HR ESI-TOF m/z 482.2071 (M+H+, C29H27N3O4, requires 482.2074.
Reaction SMILES: FC1C=CC=CC=1C1C2C=C(C(=NO)C)C=CC=2N(C)C(=O)C(C)N=1.F[B-](F)(F)F.[F:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]1[C:44]2[CH:45]=[C:46]([N+:49]#N)[CH:47]=[CH:48][C:43]=2[NH:42][C:41](=[O:51])[C:40]([CH3:53])([CH3:52])[N:39]=1>>[NH2:49][C:46]1[CH:47]=[CH:48][C:43]2[NH:42][C:41](=[O:51])[C:40]([CH3:53])([CH3:52])[N:39]=[C:38]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[F:31])[C:44]=2[CH:45]=1
Reactant: CC1(C)N=C(c2ccccc2F)c2cc([N+]#N)ccc2NC1=O
Agent: CC(=NO)c1ccc2c(c1)C(c1ccccc1F)=NC(C)C(=O)N2C
Agent: F[B-](F)(F)F
Product: CC1(C)N=C(c2ccccc2F)c2cc(N)ccc2NC1=O

Procedure:
From 56.62 g (0.19 mol) of 7-amino-5-(o-fluorophenyl)-1,3-dihydro-3,3-dimethyl-2H-1,4-benzodiazepin-2-one there is obtained in analogy to paragraph (e) of Example 1 5-(o-fluorophenyl)-2,3-dihydro-3,3-dimethyl-2-oxo-1H-1,4-benzodiazepine-7-diazonium tetrafluoroborate of melting point 203°.
Reaction SMILES: C1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]2C([O:12][C:13](=[O:14])[C:3]=2C=1)=O.C1OC1CO>>[C:13]([OH:14])(=[O:12])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Agent: OCC1CO1
Product: O=C(O)CCCCC(=O)O
Temperature: 120 °C

Procedure:
By addition of 274.5 g of trimellitic acid anhydride and further heating, condensation was continued to an acid number of 120. After cooling to 120° C., the product was reacted under stirring with 168 g of glycide to an acid number of 23.4.