Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)[CH2:3][C:4](O)=[O:5].CO>C1COCC1>[NH2:1][C@H:2]([C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=1)[CH2:3][CH2:4][OH:5]
Reactant: N[C@@H](CC(=O)O)c1ccc(Cl)cc1
Solvent: CO
Solvent: C1CCOC1
Product: N[C@@H](CCO)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.9 %

Procedure:
Borane-tetrahydrofuran complex (376 mL, 375.69 mmol) was added dropwise to a stirred suspension of (S)-3-amino-3-(4-chlorophenyl)propanoic acid (10 g, 50.09 mmol) in THF (500 mL) at 0° C. over a period of 45 minutes under nitrogen. The resulting suspension was stirred at 0° C. for 30 minutes then at 22° C. for 5 hours. The reaction mixture was added portionwise to methanol (500 mL). The solution was stirred at room temperature for three days. The mixture was concentrated, redissolved in methanol (250 mL) and reconcentrated (this process was repeated three times). The residue was dissolved in DCM (75 mL) and washed with 1N NaOH (50 mL). The aqueous layer was extracted with DCM (3×100 mL) and the extracts combined with the organic layer. The combined organics were washed with saturated brine (50 mL), dried over MgSO4 and concentrated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 2 to 6% MeOH/ammonia in DCM. Pure fractions were evaporated to dryness to afford (S)-3-amino-3-(4-chlorophenyl)propan-1-ol (5.76 g, 61.9%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]([CH2:13][CH2:14][OH:15])[C:9]2=[O:12])=[CH:4][CH:3]=1.[N:16]1([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.CC([O-])(C)C.[K+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:25]([O:24][C:22]([N:16]1[CH2:21][CH2:20][N:19]([C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][N:8]([CH2:13][CH2:14][OH:15])[C:9]3=[O:12])=[CH:4][CH:3]=2)[CH2:18][CH2:17]1)=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: O=c1c2cc(Br)ccc2ccn1CCO
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3ccn(CCO)c(=O)c3c2)CC1
Temperature: 25 °C
Yield: 64.3 %

Procedure:
A solution of compound 6 (6.8 g, 25.4 mmol), tert-butyl piperazine-1-carboxylate (5.68 g, 30.5 mmol), Pd2(dba)3 (775 mg, 0.85 mmol), S-Phos (1.16 g) and t-BuOK (5.7 g, 50.8 mmol) in toluene (100 mL) was heated to 90° C. under nitrogen overnight. Then the mixture was cooled to room temperature and filtered. The filtrate was concentrated, the residue was dissolved in methylene chloride, washed with water, dried (sodium sulfate), concentrated and purified by flash column chromatography (silica gel) to give 7 (6.1 g, 64%)
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([O:8][CH:9]([CH3:13])[C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].O[CH2:17][CH2:18][O:19][C:20](=[O:33])[CH:21]([O:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)[CH3:22].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH:9]([CH3:13])[C:10]([O:12][CH2:17][CH2:18][O:19][C:20](=[O:33])[CH:21]([O:23][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)[CH3:22])=[O:11])=[CH:14][CH:15]=1)([O-:3])=[O:2]
Reactant: CC(Oc1ccc([N+](=O)[O-])cc1)C(=O)OCCO
Reactant: CC(Oc1ccc([N+](=O)[O-])cc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(Oc1ccc([N+](=O)[O-])cc1)C(=O)OCCOC(=O)C(C)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.1 %

Procedure:
To a mixture of 2-(4-nitrophenoxy)-propionic acid 29 (25 g, 118.5 mmol) and 2-(4-nitrophenoxy)propionic acid 2-hydroxyethyl ester 30 (25 g, 108 mmol) in anhydrous dichloromethane (625 ml) under nitrogen atmosphere was added dropwise a solution of 1,3-dicyclohexyl carbodiimide (40 g, 194 mmol) in anhydrous dichloromethane (250 ml). The reaction mixture was stirred at room temperature for 8 hours. The solids were filtered off and dichloromethane distilled off to get crude 31. The crude 31 was purified by column chromatography on silica gel using hexane as eluant to get pure 31 (17 g, 35.1%) as a white powder with an m.p. between 117.5-120.5° C.
Reaction SMILES: [CH:1]1([C@@H:7]([NH:31]C(=O)OC(C)(C)C)[C:8](=[O:30])[NH:9][C:10]2[CH:11]=[C:12]3[C:28](=[O:29])[NH:27][N:26]=[CH:25][C:14]4=[C:15]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)[NH:16][C:17]([CH:18]=2)=[C:13]34)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40].C(Cl)Cl>CO.C(OCC)C>[F:42][C:41]([F:44])([F:43])[C:39]([OH:45])=[O:40].[NH2:31][C@H:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:8]([NH:9][C:10]1[CH:11]=[C:12]2[C:28](=[O:29])[NH:27][N:26]=[CH:25][C:14]3=[C:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[NH:16][C:17]([CH:18]=1)=[C:13]23)=[O:30]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O)C1CCCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: N[C@@H](C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O)C1CCCCC1
Yield: 78 %

Procedure:
Preparation of example 60 from the title compound of Example 59 (90 mg, 0.17 mmol), and 1:1 TFA/CH2Cl2 (5 mL) was carried out analogously to Example 20. Isolation, also in an analogous manner, included a further trituration with methanol/diethyl ether and afforded the title compound (70 mg, 0.013 mmol) as an orange/yellow powder in 78% yield.
Reaction SMILES: F[C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:9][C:10]([F:13])([F:12])[F:11])=[O:7])=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].[CH:24]1([CH2:30][NH2:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.CCN(CC)CC>CCO>[CH:24]1([CH2:30][NH:31][C:2]2[CH:20]=[CH:19][C:5]([C:6]([N:8]([CH2:14][C:15]([F:17])([F:16])[F:18])[CH2:9][C:10]([F:12])([F:13])[F:11])=[O:7])=[CH:4][C:3]=2[N+:21]([O-:23])=[O:22])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: NCC1CCCCC1
Reactant: O=C(c1ccc(F)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(c1ccc(NCC2CCCCC2)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F

Procedure:
Following the general procedure for Intermediate 2 using 4-fluoro-3-nitro-N,N-bis(2,2,2-trifluoroethyl)benzamide (100 mg, 0.287 mmol) and cyclohexylmethyl amine (0.041 mL, 0.315 mmol) in 3 mL of EtOH containing Et3N (0.080 mL, 0.574 mmol). The product was purified by flash chromatography on silica gel using 4:1/hexanes:EtOAc as eluent. Yield: 107 mg (85%); 1H NMR (CDCl3) 1.05 (m, 2H), 1.24 (m, 4H), 1.69 (m, 2H), 1.75 (m, 2H), 1.83 (m, 1H), 3.17 (t, J=6.64 Hz, 2H), 4.23 (q, J=8.53 Hz, 4H), 6.91 (d, J=8.98 Hz, 1H), 7.51 (d, J=8.89 Hz, 1H), 8.28 (s, 1H), 8.39 (s, 1H); MS (ESI) 442.29 (MH+).
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][C:4]1[N:5]=[C:6]([CH:9]=O)[S:7][CH:8]=1.[BH4-].[Na+]>>[CH3:1][NH:2][CH2:9][C:6]1[S:7][CH:8]=[C:4]([CH3:3])[N:5]=1
Reactant: CN
Reactant: Cc1csc(C=O)n1
Agent: [BH4-]
Agent: [Na+]
Product: CNCc1nc(C)cs1
Reaction time: 0.25 h
Yield: 80 %

Procedure:
Ti(OiPR)4 (1.3 eq) was added with stirring to MeNH2 (2.0 M in MeOH, 3 eq) at 0° C. under Ar. After 15 min. 4-methylthiazole-2-carbaldehyde (1 eq) was added, and the solution was stirred for 2-3 h. NaBH4 (1.4 eq, in batches if large scale) was added and stirred at 0° C. to RT overnight, followed by solvent removal in vacuo. The residue was diluted with water/CH2Cl2, and a white ppt formed. The mixture was then filtered through Celite to remove the white ppt and the layers were separated. The aqueous layer was extracted with CH2Cl2 (×3) and the combined organics were dried over Na2SO4. The inorganics were filtered off, and the solvent was removed in vacuo to give the crude product. Purification via column chromatography yielded the pure product in 80-90% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12](=[O:15])[NH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-])=O>CN1C(=O)N(C)CC1.[Ni]>[NH2:1][C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12](=[O:15])[NH:11][CH:10]=2)=[CH:6][CH:5]=1
Reactant: O=c1ccc(Oc2ccc([N+](=O)[O-])cc2)c[nH]1
Agent: [Ni]
Solvent: CN1CCN(C)C1=O
Product: Nc1ccc(Oc2ccc(=O)[nH]c2)cc1

Procedure:
Hydrogenation of 3-(4-nitro-phenoxy)-1H-pyridin-6-one (Stage 93.2; 464 mg, 2.0 mmol) in DMEU (10 ml) in the presence of Raney Nickel (100 mg) affords after filtration and concentration of the filtrate the title compound: 1H-NMR (DMSO-d6): 11.2 (s, HN), 7.25 (dd, 1H), 7.11 (d, 1H), 6.68 (d, 2H), 6.51 (d, 2H), 6.35 (d, 1H), 4.87 (s, H2N).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][C:15]=2[F:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>C(OCC)(=O)C.CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([N:13]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])=[CH:16][C:15]=2[F:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Nc2ccc([N+](=O)[O-])cc2F)C1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@@H](N(C(=O)OCc2ccccc2)c2ccc(NC(=O)OCc3ccccc3)cc2F)C1

Procedure:
To a solution of 4 g of (3R)-3-(2-fluoro-4-nitro-phenyl-amino)-pyrrolidine-1-carboxylic acid tert-butyl ester (12.29 mmol) in 100 ml ethyl acetate and 50 ml methanol were added 1 g of Pd/C 10%. The suspension was stirred under hydrogen. The reaction was monitored by TLC. The catalyst was filtered, the filtrate evaporated to dryness, and the residue was dissolved in 100 ml of acetone. 25 ml of a saturated solution of sodium bicarbonate was added, than a 0° C. 3.63 ml of benzyl chloroformate (25.8 mmol). The reaction was stirred over night at rt and monitored by TLC. The acetone was evaporated, the water layer extracted twice with ethyl acetate, the org layer washed with water and brine, dried over Mg sulfate, filtered and the filtrate evaporated to dryness. The residue was purified by chromatography, using a 1/1 ethyl acetate/hexane mixture as eluent.
Reaction SMILES: [OH:1][C:2]1C=CC(C=O)=C(OC)C=1.Cl[C:13]1[CH:14]=[C:15]([CH:20]=[C:21](OC)[C:22]=1[OH:23])[C:16]([NH:18][OH:19])=[NH:17]>>[OH:23][C:22]1[CH:13]=[CH:14][C:15]([C:16]([NH:18][OH:19])=[NH:17])=[C:20]([O:1][CH3:2])[CH:21]=1
Reactant: COc1cc(C(=N)NO)cc(Cl)c1O
Reactant: COc1cc(O)ccc1C=O
Product: COc1cc(O)ccc1C(=N)NO

Procedure:
The title compound is prepared form commercially available 4-hydroxy-2-methoxy-benzaldehyde in analogy to 3-chloro-4,N-dihydroxy-5-methoxy-benzamidine; LC-MS: tR=0.42 min; [M+1]+=183.04.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:28])[C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[N:16]2[C:20]([CH2:21]O)=[C:19]([CH3:23])[N:18]=[C:17]2[CH2:24][N:25]([CH3:27])[CH3:26])[CH:5]=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:48]1(=[O:58])[NH:52][C:51](=[O:53])[C:50]2=[CH:54][CH:55]=[CH:56][CH:57]=[C:49]12.N(C(OCC)=O)=NC(OCC)=O>>[F:15][C:13]1[CH:12]=[CH:11][C:10]([N:16]2[C:20]([CH2:21][N:52]3[C:48](=[O:58])[C:49]4=[CH:57][CH:56]=[CH:55][CH:54]=[C:50]4[C:51]3=[O:53])=[C:19]([CH3:23])[N:18]=[C:17]2[CH2:24][N:25]([CH3:26])[CH3:27])=[C:9]([C:8](=[O:28])[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH:14]=1
Reactant: Cc1nc(CN(C)C)n(-c2ccc(F)cc2C(=O)c2cccc(Cl)c2)c1CO
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1nc(CN(C)C)n(-c2ccc(F)cc2C(=O)c2cccc(Cl)c2)c1CN1C(=O)c2ccccc2C1=O

Procedure:
In the manner given in Example 3, 3'-chloro-5-fluoro-2-[2-[(dimethylamino)methyl]-4-methyl-5-hydroxymethylimidazol-1-yl]benzophenone, triphenylphosphine, phthalimide and thereafter diethyl azodicarboxylate are reacted together to give N-[[1-[4-fluoro-2-(m-chlorobenzoyl)phenyl]-2-[(dimethylamino)methyl]-4-methylimidazol-5-yl]methyl]phthalimide.
Reaction SMILES: Cl.[C:2]([C:4]1[C:5]([CH2:30][CH3:31])=[CH:6][C:7]([NH:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([CH:28]=[O:29])=[C:20]([CH:23](OC)[O:24]C)[N:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[N:8][CH:9]=1)#[N:3].C([O-])(O)=O.[Na+]>C1COCC1.O>[C:2]([C:4]1[C:5]([CH2:30][CH3:31])=[CH:6][C:7]([NH:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([CH:28]=[O:29])=[C:20]([CH:23]=[O:24])[N:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[N:8][CH:9]=1)#[N:3]
Reactant: CCc1cc(NC(=O)N2CCCc3cc(C=O)c(C(OC)OC)nc32)ncc1C#N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCc1cc(NC(=O)N2CCCc3cc(C=O)c(C=O)nc32)ncc1C#N
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Concentrated hydrochloric acid (0.10 ml) was added to a solution of N-(5-cyano-4-ethylpyridin-2-yl)-7-(dimethoxymethyl)-6-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 110, 50 mg, 0.122 mmol) in THF (4 ml) and water (0.5 ml) at room temperature. After stirring for 3 h additional concentrated hydrochloric acid (0.10 ml) was added and the reaction mixture stirred for a further 48 h at room temperature. Saturated aqueous NaHCO3 was added, the mixture extracted with DCM (2×), the organic layers dried over Na2SO4 and evaporated to give the title compound as a beige solid. (UPLC-MS 6) tR 1.13 min, ESI-MS 364.2, [M+H]+.
Reaction SMILES: [CH:1]([NH:4][C:5]([CH2:7][N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH2:20][C@@H:21]([CH3:28])[CH2:22]OS(C)(=O)=O)[CH:15]=2)[N:10]=[C:9]1[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=1)=[O:6])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:43]([NH:45][CH2:46][CH3:47])[CH3:44].CCCCCC>C(#N)C>[CH2:43]([N:45]([CH2:46][CH3:47])[CH2:22][C@H:21]([CH3:28])[CH2:20][O:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=1)[N:8]([CH2:7][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])[C:17]2=[O:18])[CH3:44]
Reactant: CCNCC
Reactant: COc1cccc(-c2nc3ccc(OC[C@@H](C)COS(C)(=O)=O)cc3c(=O)n2CC(=O)NC(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CC#N
Product: CCN(CC)C[C@H](C)COc1ccc2nc(-c3cccc(OC)c3)n(CC(=O)NC(C)C)c(=O)c2c1
Temperature: 80 °C
Yield: 64.2 %

Procedure:
To a solution of (R)-(−)-methanesulfonic acid 3-[3-(isopropylcarbamoylmethyl)-2-(3-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-6-yloxy]-2-methylpropyl ester (1.13 g, 2.18 mmol) in anhydrous acetonitrile (40 mL) was added potassium carbonate (1.51 g, 10.95 mmol) followed by diethyl amine (3.20 g, 4.53 mL, 43.80 mmol) and the reaction mixture was heated at 80° C. in a pressure tube. After 2 days (reaction complete by HPLC), the reaction mixture was concentrated in vacuo to dryness and the residue was partitioned between water (100 mL) and ethyl acetate (150 mL). The aqueous layer was extracted with ethyl acetate (5×150 mL) and with dichloromethane (5×100 mL). The combined organic phase was dried (Na2SO4), solvent evaporated in vacuo, and the resulting residue purified by chromatography on silica gel with a gradient of methanol:dichloromethane (1:19, v/v) to methanol:dichloromethane (1:4, v/v) as eluent. The resultant solid was recrystallised from diethyl ether:hexane to afford (S)-(+)-2-[6-(3-diethylamino-2-methylpropoxy)-2-(3-methoxyphenyl)-4-oxo-4H-quinazolin-3-yl]-N-isopropy-acetamide (EXAMPLE 4a) (0.69 g, 1.40 mmol, 65% from (S)-(+)-2-[6-(3-hydroxy-2-methylpropoxy)-2-(3-methoxyphenyl)-4-oxo-4H-quinazolin-3-yl]-N-isopropylacetamide) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6](=[O:12])[CH2:5]2.[Br:13][CH2:14][CH2:15][CH2:16]Br.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(Cl)Cl.C(C(C)=O)C>[Br:13][CH2:14][CH2:15][CH2:16][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6](=[O:12])[CH2:5]2
Reactant: CN1C(=O)Cc2cc(O)ccc21
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCC(C)=O
Product: CN1C(=O)Cc2cc(OCCCBr)ccc21

Procedure:
A mixture of 11.9 g of 5-hydroxy-1-methyl-2-indolinone, 29.2 g of 1,3-dibromopropane, 11 g of potassium carbonate, 1 g of potassium iodide and 75 ml of ethylmethyl ketone is refluxed for 20 hours. The mixture is then diluted with 300 ml of methylene dichloride, washed with water and the solvent is removed under reduced pressure.
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].[Cl-].[OH:17][NH3+:18].C(=O)([O-])[O-].[K+].[K+]>C(O)C.C(OCC)(=O)C>[OH:17][NH:18][C:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7][CH2:8]1)=[NH:2]
Reactant: [NH3+]O
Reactant: CC(C)(C)OC(=O)N1CCN(C#N)CC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(C(=N)NO)CC1
Yield: 86.4 %

Procedure:
In a nitrogen atmosphere, a suspension of 7.52 g of tert-butyl 4-cyanopiperazine-1-carboxylate (JMC, 1988, 31, 1036), 7.46 g of hydroxyammonium chloride and 19.7 g of potassium carbonate in 40 ml of ethanol was heated to reflux for 2 hours. The residue prepared by evaporation of the solvent was diluted with ethyl acetate, washed with water and then with a saturated saline solution and dried over sodium sulfate. The solvent was evaporated in vacuo to give 7.51 g of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:19][C:20]2[C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=[CH:22][N:21]=2)[C:11](=[O:30])[CH:10]([NH:31][C:32]([NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[CH:36]=2)=[O:33])[N:9]=1.[OH-].[K+]>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:19][C:20]2[C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=[CH:22][N:21]=2)[C:11](=[O:30])[CH:10]([NH:31][C:32]([NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[CH:36]=2)=[O:33])[N:9]=1
Reactant: COC(=O)c1cccnc1CN1C(=O)C(NC(=O)Nc2cccc(C)c2)N=C(c2ccccc2F)c2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1cccc(NC(=O)NC2N=C(c3ccccc3F)c3ccccc3N(Cc3ncccc3C(=O)O)C2=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-[(3RS)-2,3-dihydro-5-(2-fluorophenyl)-1-(3-methoxycarbonylpyridin-2-yl)methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea (0.35 g) in 1,4-dioxane (13 ml) was added an aqueous solution of potassium hydroxide (0.35 g in 5 ml of water) at room temperature and the mixture was stirred overnight at ambient temperature. The resultant mixture was concentrated in vacuo and the residue was taken up with 10 ml water and washed with isopropyl ether. The aqueous layer was adjusted to pH 7.0 with 10% citric acid aqueous solution and extracted with chloroform. The organic layer was dried over sodium sulfate, filtered and concentrarted in vacuo. The crude compound was purified by column chromatography on silica gel with a mixture of chloroform and methanol to give N-[(3RS)-2,3-dihydro-5-(2-fluorophenyl)-1-(3-hydroxycarbonyl-pyridin-2-yl)methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea as a yellow form, which was triturated by isopropyl ether and collected by suction (0.08 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].C(N(CC)CC)C.[C:15](Cl)(=[O:19])[CH:16]([CH3:18])[CH3:17]>ClCCl>[CH3:17][CH:16]([CH3:18])[C:15]([NH:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6])=[O:19]
Reactant: CC(C)C(=O)Cl
Reactant: NCCCC(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)NCCCC(=O)O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 41.6 %

Procedure:
To a solution of 20 gm (194 mMol) 4-aminobutanoic acid in dichloromethane (700 ml) were added 54 ml (407 mMol) triethylamine and the reaction mixture was stirred at room temperature for 10 minutes. To this mixture was then added a solution of 40.6 ml (407 mMol) isobutyryl chloride in dichloromethane (300 ml) dropwise and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered and the filtrate concentrated under reduced pressure. The residue was dissolved in 1N sodium hydroxide and stirred for 30 minutes. This solution was then poured into diethyl ether, diluted with water and the phases separated. The aqueous phase was acidified with hydrochloric acid and then extracted with ethyl acetate. The organic extracts were combined, dried over magnesium sulfate and concentrated under reduced pressure to give an oil. Bulb to bulb distillation (0.05 mm Hg, pot temperature=235° C.) gave 13.98 gm (43.1%) N-(2-methyl)propionyl-4-aminobutanoic acid.
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH:6]C(=O)CCCCCCCCCCCCC)=[N+:2]=[N-:3].[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[S:27](Cl)(=[O:29])=[O:28].N(CCN)=[N+]=[N-].C(N(CC)CC)C>ClCCl>[N:1]([CH2:4][CH2:5][NH:6][S:27]([C:23]1[S:22][CH:26]=[CH:25][CH:24]=1)(=[O:29])=[O:28])=[N+:2]=[N-:3]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Agent: [N-]=[N+]=NCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NCCNS(=O)(=O)c1cccs1
Yield: 80 %

Procedure:
As in the synthesis of N-(2-azidoethyl)tetradecanamide, thiophene-2-sulfonyl chloride (0.218 g, 1.19 mmol) was reacted with 2-azidoethanamine (0.103 g, 1.19 mmol) and triethylamine (0.241 g, 2.39 mmol) in dichloromethane (5 mL) to give N-(2-azidoethyl)thiophene-2-sulfonamide (0.221 g, 80%). 1H NMR (300 MHz, CDCl3) δ 7.62 (d, 1H), δ 7.59 (d, 1H), 7.08 (t, 1H), 5.52 (s, 1H), 3.41 (t, 2H), 3.17 (q, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 140.6, 132.7, 132.6, 127.9, 50.9, 42.9 ppm; HRMS (ESI) calcd for C6H8N4O2S2 (M+) 232.0089. Found 232.0084.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:42]=[C:43]([C:45]([O:47][CH3:48])=[O:46])[CH:44]=1)[CH2:8][C:9]1([CH2:19][CH2:20][CH2:21][S:22][C:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:14](=[O:15])[O:13]C(C)(C)[O:11][C:10]1=[O:18])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>O1CCOCC1.O>[C:1]([C:5]1[CH:6]=[C:7]([CH:42]=[C:43]([C:45]([O:47][CH3:48])=[O:46])[CH:44]=1)[CH2:8][C:9]([CH2:19][CH2:20][CH2:21][S:22][C:23]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([C:10]([OH:18])=[O:11])[C:14]([OH:15])=[O:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(CC2(CCCSC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)OC(C)(C)OC2=O)cc(C(C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(CC(CCCSC(c2ccccc2)(c2ccccc2)c2ccccc2)(C(=O)O)C(=O)O)cc(C(C)(C)C)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of 5-(3-tert-butyl-5-methoxycarbonyl-benzyl)-2,2-dimethyl-5-[3-[(triphenylmethyl)thio]propyl]-[1,3]dioxane-4,6-dione X (11 g, 16.5 mmol) in 1,4-dioxane (15 ml) was added a solution of sodium hydroxide (4.63 g, 115.5 mmol) in H2O (15 mL) at 25° C., and the mixture was stirred at 100° C. for 1 hour. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and a 10% aqueous KHSO4 solution. The organic layer was dried over MgSO4, concentrated. The crude material was recrystallized from ethyl acetate/hexane mixture to afford 2-(3-tert-butyl-5-methoxycarbonyl-benzyl)-2-[3-[(triphenyl-methyl)thio]propyl]malonic acid XI (9.0 g, 90%) as a white solid: 1H NMR (CD3OD) δ 1.4 (s, 9H), 1.4 (m, 2H), 1.6 (m, 2H), 2.1 (t, J=8.0 Hz, 2H), 3.2 (s, 2H), 7.1–7.4 (m, 16H), 7.7 (s, 1H), 7.9 (s, 1H); 13C NMR (CD3OD) δ 24.8, 31.8 (3C), 32.4, 33.3, 35.6, 39.0, 59.5, 67.7, 126.2, 127.7, 128.9, 129.6, 130.7, 131.5, 132.9, 137.8, 146.2, 152.6, 170.1, 174.5.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].Cl.Cl.[CH3:8][C:9]1[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:10]=1[NH:16][C:17]1[CH2:21][CH2:20][CH2:19][N:18]=1>>[ClH:1].[CH3:8][C:9]1[CH:14]=[C:13]([NH:15][C:3](=[O:4])[CH2:2][Cl:1])[CH:12]=[CH:11][C:10]=1[NH:16][C:17]1[CH2:21][CH2:20][CH2:19][N:18]=1
Reactant: O=C(Cl)CCl
Reactant: Cc1cc(N)ccc1NC1=NCCC1
Agent: Cl
Product: Cc1cc(NC(=O)CCl)ccc1NC1=NCCC1

Procedure:
The title compound was prepared by the method of Example 16 using 30.5 mmole of chloroacetyl chloride and 1.0 g (3.8 mmole) of the product compound of Example 9. Structure assignment was supported by the nmr spectrum and by elemental analysis.