Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:24])([C@H:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[C:25](=O)([O-])[O-:26].[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:24])([C@H:16]([N:18]1[CH2:19][CH2:20][N:21]([CH:25]=[O:26])[CH2:22][CH2:23]1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: O=C([O-])[O-]
Reactant: C[C@@H](N1CCNCC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](N1CCN(C=O)CC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 120 °C
Yield: 36.5 %

Procedure:
A mixture of compound 2 (200 mg, 0.6 mmol) and potassium carbonate (248 mg, 1.8 mmol) in DMF (5 ml) was heated at 120° C. for 24 h. The contents were poured into cold water and extracted with ethyl acetate (3×20 ml). The combined organic extract was washed with water, brine and dried over sodium suphate. The solvent was removed under reduced pressure and the resulting product was purified on a column of silica gel (EtOAc/MeOH; 98:2) to give the title compound as colorless solid (80 mg, 36%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]([C:22]([N:24]3[CH2:28][C:27](=[O:29])[NH:26][CH2:25]3)=[O:23])=[CH:11][C:12]=2[C:13]2[CH:14]=[C:15]([C:20]#[N:21])[CH:16]=[C:17]([F:19])[CH:18]=2)[CH:5]=[CH:6][CH:7]=1.Cl[C:31]1C=C(C2OC(C(OCC)=O)=CC=2C2C=C(F)C=C(C#N)C=2)C=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]([C:22]([N:24]3[CH2:31][CH2:25][NH:26][C:27](=[O:29])[CH2:28]3)=[O:23])=[CH:11][C:12]=2[C:13]2[CH:14]=[C:15]([C:20]#[N:21])[CH:16]=[C:17]([F:19])[CH:18]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(C#N)c2)c(-c2cccc(Cl)c2)o1
Reactant: N#Cc1cc(F)cc(-c2cc(C(=O)N3CNC(=O)C3)oc2-c2cccc(Cl)c2)c1
Product: N#Cc1cc(F)cc(-c2cc(C(=O)N3CCNC(=O)C3)oc2-c2cccc(Cl)c2)c1

Procedure:
The preparation of the title compound takes place in analogy to the synthesis of the compound from Example 32 starting with the compound from Example 16A. 39.5 mg (62% of theory) of the title compound are obtained.
Reaction SMILES: [O:1]=[C:2]([NH:24][CH2:25][C:26]1[C:27]([C:36]2[CH:37]=[C:38]([CH3:42])[CH:39]=[CH:40][CH:41]=2)=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=1)[CH:3]([C:5]1[CH:23]=[CH:22][C:8]([CH2:9][NH:10][S:11]([NH:14]C(=O)OC(C)(C)C)(=[O:13])=[O:12])=[CH:7][CH:6]=1)[CH3:4].C(=O)(O)[O-].[Na+]>ClCCl>[S:11]([NH:10][CH2:9][C:8]1[CH:22]=[CH:23][C:5]([CH:3]([CH3:4])[C:2]([NH:24][CH2:25][C:26]2[C:27]([C:36]3[CH:37]=[C:38]([CH3:42])[CH:39]=[CH:40][CH:41]=3)=[N:28][C:29]([C:32]([F:33])([F:35])[F:34])=[CH:30][CH:31]=2)=[O:1])=[CH:6][CH:7]=1)(=[O:12])(=[O:13])[NH2:14]
Reactant: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)C(C)c2ccc(CNS(=O)(=O)NC(=O)OC(C)(C)C)cc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)C(C)c2ccc(CNS(N)(=O)=O)cc2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.1 %

Procedure:
To a solution of tert-butyl N-(4-(1-oxo-1-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methylamino)propan-2-yl)benzyl)sulfamoylcarbamate (250 mg, 0.412 mmol) in dichloromethane (2 mL) trifluoroacetic acid (0.2 mL) was added at room temperature. The mixture was stirred 12 h at room temperature. The mixture was neutralized by sodium bicarbonate to pH 7-8 and extracted with ethyl acetate and washed with brine. Drying over magnesium sulfate, evaporation of the ethyl acetate and purification by column chromatography gave 2-(4-((sulfamoylamino)methyl)phenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide (example 88) (138 mg, 66%).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][C:14]=2[F:23])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](O)=[O:6].C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:36][O:37][CH2:38][CH2:39][OH:40]>>[F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:15][C:14]=2[F:23])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([NH:36][O:37][CH2:38][CH2:39][OH:40])=[O:6]
Reactant: CS(=O)(=O)c1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1
Reactant: NOCCO
Agent: O=C(n1ccnc1)n1ccnc1
Product: CS(=O)(=O)c1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Yield: 52 %

Procedure:
The title compound was prepared from reaction of the product of Example 28, Step A, 3,4-difluoro-2-[[2-fluoro-4-(methylsulfonyl)phenyl]amino]benzoic acid, with CDI and 2-(aminooxy)ethanol by the general procedure of Example 1, Step E. Then, after workup, the crude solid purified by dry flash column chromatography on silica (5% isopropanol/hexanes as eluant) to afford 3,4-difluoro-2-[[2-fluoro-4-(methylsulfonyl)phenyl]amino]-N-(2-hydroxyethoxy)benzamide as a white solid (52%); m.p. (Et2O) 85–88° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.78 (br s, 1 H), 8.88 (br s, 1 H), 7.72 (dd, J=11.1, 2.1 Hz, 1 H), 7.55 (ddd, J=8.8, 2.1, 0.6 Hz, 1 H), 7.48–7.35 (m, 2 H), 6.87 (td, J=8.8, 4.0 Hz, 1 H), 4.68 (br s, 1 H), 3.81 (t, J=4.6 Hz, 2 H), 3.54 (td, J=4.9, 4.2 Hz, 2 H), 3.18 (s, 3 H). Anal. Calcd for C16H15F3N2O5S: C, 47.5; H, 3.6; N, 6.9. Found: C, 47.3; H, 3.8; N, 6.6.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=1[S:12](Cl)(=[O:14])=[O:13].C(=O)([O-])[O-].[Na+].[Na+].[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=1[S:12]([N:26]1[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]1)(=[O:14])=[O:13]
Reactant: CN1CCNCC1
Reactant: CC(=O)Cc1ccc(Cl)c(S(=O)(=O)Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)Cc1ccc(Cl)c(S(=O)(=O)N2CCN(C)CC2)c1

Procedure:
2-Chloro-5-(2-oxopropyl)-benzenesulphonyl chloride (174a) (2.0 g, 7.5 mmol) is dissolved in dioxan (50 ml) with stirring. Sodium carbonate (7.5 ml, 2M solution, 2 eq.) is added followed by 1-methyl piperazine (0.75 g, 7.5 mmol). After 30 min the reaction mixture is poured onto water (250 ml) and extracted with ethyl acetate (3×100 ml). The combined organic extracts are washed with water (2×100 ml) followed by brine (100 ml) and dried (MgSO4). After filtration the solvent is removed and the product is purified by chromatography on silica, eluting with ethyl acetate/hexane (1:2) to afford the titled compound.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:8][CH2:7][O:6][CH2:5]1.Cl[C:10]1[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]2[N:17]([C:21]3[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=3[CH3:29])[N:18]=[C:19]([CH3:20])[C:11]=12>CCCCCC.O1CCCC1>[CH3:20][C:19]1[C:11]2[C:12](=[N:13][C:14]([CH3:16])=[CH:15][C:10]=2[O:3][CH:4]2[CH2:8][CH2:7][O:6][CH2:5]2)[N:17]([C:21]2[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=2[CH3:29])[N:18]=1
Reactant: OC1CCOC1
Reactant: Cc1cc(C)c(-n2nc(C)c3c(Cl)cc(C)nc32)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(C)c(-n2nc(C)c3c(OC4CCOC4)cc(C)nc32)c(C)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Sodium hydride (60% in oil, 176 mg, 4.4 mmol) was washed with hexane and suspended in 2 ml of tetrahydrofuran. 3-Hydroxytetrahydrofuran (1 ml) was added and stirred at room temperature for 5 minutes. A solution of 4-chloro-3,6-dimethyl-1-(2,4,6-trimethylphenyl)-1H-pyrazolo[3,4-b]pyridine (200 mg, 0.665 mmol) in 1 ml of THF was added and the resulting mixture was heated at reflux for 8 hours. The mixture was quenched with water and extracted with EtOAc. The organic layer was dried and concentrated to give 334 mg of crude product. The crude material was purified through silica gel column chromatography using 1% methanol in chloroform as eluent to give 127 mg of a beige solid, mp 117-119° C.; IR(KBr) 2950, 1600, 1580 cm−1; high MS, calc. 351.1941, found, 351.19386; 1H NMR (CDCl3): 6.90 (s, 2H), 6.15 (s, 1H), 5.07 (m, 1H), 3.9-4.05 (m, 4H), 2.6 (s, 3H), 2.47 (s, 3H), 2.38 (s, 3H), 2.2-2.3 (m, 2H), 1.98 (s, 3H), 1.96 (s, 3H) ppm.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([NH:12][C@H:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)=[O:11])=O)(C)(C)C.[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31]>ClCCl>[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31].[NH2:8][CH2:9][C:10]([NH:12][C@H:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)=[O:11]
Reactant: CCOC(=O)[C@H](Cc1cccc(OC)c1)NC(=O)CNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@H](Cc1cccc(OC)c1)NC(=O)CN
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 100-mL round-bottomed flask was added ethyl N-(tert-butoxycarbonyl)glycyl-3-methoxyphenylalaninate (812 mg, 2.13 mmol) and trifluoroacetic acid (5 mL, 67.3 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 30 min. The solvent was removed in vacuo to give crude ethyl glycyl-3-methoxyphenylalaninate trifluoroacetate as a viscous oil which was used without purification.
Reaction SMILES: [C:1]([O:4][CH2:5][N:6]1[CH:9]([S:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH:8]([CH2:20][CH2:21][CH3:22])[C:7]1=[O:23])(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:32])C=1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:1]([O:4][CH2:5][N:6]1[CH:9]([S:10]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:32])[CH:8]([CH2:20][CH2:21][CH3:22])[C:7]1=[O:23])(=[O:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCC1C(=O)N(COC(C)=O)C1Sc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCC1C(=O)N(COC(C)=O)C1S(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 0.25 h
Yield: 33.3 %

Procedure:
To a solution of 46 mg (0.127 mmole) azetidinone from Step B in 4 ml CH2Cl2 and 4 ml saturated aqueous NaHCO3 was added 27 mg (0.127 mM) 80% m-chloroperbenzoic acid and the reaction mixture stirred vigorously 15 minutes. The phases were separated and the organic phase was dried over MgSO4, filtered and stripped to yield 57 mg crude product which was chromatographed on a 1000μ silica gel prep TLC plate in chloroform-ethyl acetate 4:1 to yield 15 mg (31%) of 1-acetoxymethyl-4-p-nitrophenylsulfinyl-3-n-propylazetidin-2-one.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:17]([O-])=O)=[C:6]([CH:16]=1)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1.O.NN>CO.O.[Ni]>[Br:1][C:2]1[CH:16]=[C:6]([NH:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)[C:5]([NH2:17])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1NCc1cccc(F)c1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: Nc1ccc(Br)cc1NCc1cccc(F)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To suspension of Example 2A (700 mg, 2.153 mmol) in methanol (10 mL) was added hydrazine monohydrate (0.2 mL, 4.08 mmol) followed by 50% Raney® nickel in water (100 mg). The mixture was stirred at 50° C. for 2 hours, filtered through diatomaceous earth with dichloromethane and concentrated. Purification by flash chromatography (Isco®, Redi-Sep® column) eluting with 100% dichloromethane gave the title compound.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7].[F:15][C:16]([F:26])([F:25])[C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1>CN(C=O)C>[F:15][C:16]([F:25])([F:26])[C:17]1[CH:24]=[CH:23][C:20]([CH2:21][O:3][C:4]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:5]=2[C:6]([O:8][CH3:9])=[O:7])=[CH:19][CH:18]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: COC(=O)c1cccc(C)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(C)c1OCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydride is added to a solution of methyl 2-hydroxy-3-methylbenzoate (694 mg, 4.18 mmol) in 15 mL of DMF at 0° C. The reaction is stirred for 15 minutes after which 4-trifluoromethyl-benzyl bromide (1.0 g, 4.18 mmol) is added. The reaction is allowed to warm up to room temperature and stirred overnight. The mixture is partitioned between ethyl acetate and water. The organic phase is washed with brine, dried over sodium sulfate, filtered and concentrated. The residue is chromatographed on silica gel using 4% ethyl acetate in hexane as the eluent to obtain methyl 2-(4-trifluoromethylbenzyloxy)-3-methylbenzoate as a clear liquid.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=1[F:32].C(O)C.O.Cl>>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=4[F:32])=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: Nc1ccc(C(=O)O)cc1F
Agent: Cl
Solvent: O
Solvent: CCO
Product: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3F)ncc21
Yield: 79 %

Procedure:
A mixture of 0.1 g (0.32 mmole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-20), 0.059 g (0.57 mmole) of 4-amino-3-fluoro-benzoic acid and 0.7 mL of ethanol-water-hydrochloric acid (20:80:1) was refluxed for 18 hours, then cooled and partially concentrated under reduced pressure. The resulting solid was collected by filtration, washed with water and dried to give 0.11 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-fluoro-benzoic acid (I-182).
Reaction SMILES: [C:1]([Si:5]([CH3:11])([CH3:10])[O:6][CH2:7][C:8]#[CH:9])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[O:17]=[C:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1>C1COCC1>[Si:5]([O:6][CH2:7][C:8]#[C:9][C:18]1([OH:17])[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:22][CH2:23]1)([C:1]([CH3:3])([CH3:4])[CH3:2])([CH3:10])[CH3:11]
Reactant: C#CCO[Si](C)(C)C(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(C#CCO[Si](C)(C)C(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 121 %

Procedure:
To a solution of tert-butyldimethyl(prop-2-yn-1-yloxy)silane (0.5 mL, 2.46 mmol) in 30 mL of anhydrous THF was added dropwise n-BuLi (1.2 mL, 2.95 mmol) at −78° C. under N2. After stirring for 1 h at −78° C., tert-butyl 4-oxopiperidine-1-carboxylate (588.4 mg, 2.95 mmol) in THF (2 mL) was added dropwise to the above solution at −78° C. under N2. The resulting mixture was stirred at −78° C. under N2 for 2 h, then allowed to warm to r.t. and stirred for another 1.5 h. The reaction mixture was cooled to −78° C. and quenched by sat. NH4Cl aq., and the resulting mixture was extracted with EtOAc (50 mL, 30 mL). The combined organic phase was washed with brine, dried over anhy. Na2SO4 and concentrated in vacuo to afford 1.10 g of title compound. LC-MS: m/z 370.7 (M+H)+. 1H NMR (CHLOROFORM-d) δ: 4.37 (s, 2H), 3.74 (d, J=6.2 Hz, 2H), 3.35-3.24 (m, 2H), 2.46 (t, J=6.2 Hz, 1H), 1.92-1.84 (m, 2H), 1.71 (ddd, J=12.9, 9.1, 3.8 Hz, 2H), 1.47 (s, 9H), 0.92 (s, 9H), 0.13 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:15])=[C:4](S(O)(=O)=O)[CH:5]=[C:6]([Cl:10])[C:7]=1[CH2:8][CH3:9].[N+:16]([O-])([OH:18])=[O:17]>>[Cl:1][C:2]1[C:7]([CH2:8][CH3:9])=[C:6]([Cl:10])[CH:5]=[C:4]([N+:16]([O-:18])=[O:17])[C:3]=1[OH:15]
Reactant: CCc1c(Cl)cc(S(=O)(=O)O)c(O)c1Cl
Reactant: O=[N+]([O-])O
Product: CCc1c(Cl)cc([N+](=O)[O-])c(O)c1Cl
Yield: 83.4 %

Procedure:
In the same manner as in Example 13 except that an aqueous solution of 3,5-dichloro-4-ethyl-2-hydroxybenzenesulfonic acid is added dropwise to a 50% aqueous nitric acid solution which have been preliminarily charged, the aimed product of 2,4-dichloro-3-ethyl-6-nitrophenol is obtained.
Reaction SMILES: [OH:1][C@H:2]1[C@@H:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[NH:4][C:3]1=[O:12].[CH:13]([O:15][CH2:16][CH3:17])=[CH2:14].CS(O)(=O)=O>C1COCC1.C(=O)(O)[O-].[Na+]>[CH2:13]([O:15][CH:16]([O:1][C@H:2]1[C@@H:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[NH:4][C:3]1=[O:12])[CH3:17])[CH3:14]
Reactant: O=C1N[C@H](c2ccccc2)[C@@H]1O
Reactant: C=COCC
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(C)O[C@@H]1C(=O)N[C@@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 99 %

Procedure:
To a solution of 3.41 g (20.9 mmol) of cis-3-hydroxy-4-phenylazetidin-2-one in 15 mL of THF at 0° C. was added 5 mL of ethyl vinyl ether and 20 mg (0.2 mmol) of methane-sulfonic acid. The mixture was stirred at 0° C. for 20 min, diluted with 20 mL of saturated aqueous sodium bicarbonate, and extracted with three 40 mL portions of ethyl acetate. The combined ethyl acetate layers were dried over sodium sulfate and concentrated to give 4.87 g (99%) of cis-3-(1-ethoxyethoxy)-4-phenylazetidin-2-one as a colorless oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26].C(N(CC)CC)C>ClCCl>[O:11]=[CH:12][CH2:13][CH2:14][CH2:15][N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26]
Reactant: O=C1c2ccccc2C(=O)N1CCCCO
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=CCCCN1C(=O)c2ccccc2C1=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 82.8 %

Procedure:
Oxalyl Chloride (4.01 ml; 46 mmol) in 90 ml dichloromethane was cooled at -78° C. in a dry ice-acetone bath. Dimethylsulfoxide (4.26 ml; 60 mmol) in 22 ml dichloromethane was then added dropwise and the mixture stirred at -78° C. for 30 minutes. N-(4-Hydroxybutyl)phthalimide (9.108 g; 41.5 mmol) in 45 ml dichloromethane was then added and the mixture stirred in the -78° C. bath for 45 minutes. The mixture was then warmed in a 0° C. ice bath and stirred for one hour. Triethylamine (23 g; 230 mmol) in 23 ml dichloromethane was then added and the stirred for an additional 30 minutes. The mixture was worked up by washing with water. The organic layer was separated, dried (MgSO4), filtered, concentrated and the residue purified by flash chromatography; 200 g silica gel column using 1:3 ethyl acetate:Hexane to provide N-(4-oxobutyl)phthalimide as a white solid (7.469 g; 82.8% yield). 1 H NMR (300 MHz, CDCl3): 2.023 (m, 2H); 2.546 (dt, 2H, J1 =7.324 Hz, J2 =1.098 Hz); 3.749 (t, 2H, J=6.958 Hz); 7.734 (m, 2H); 7.845 (m, 2H); 9.777 (t, 1H, J=1.099 Hz).
Reaction SMILES: [CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].C(O)C>[Fe].O>[CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:19][CH2:20][N:21]([C:24]3[N:25]=[CH:26][C:27]([NH2:30])=[CH:28][CH:29]=3)[CH2:22][CH2:23]2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)nc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)nc1
Temperature: 70 °C
Yield: 69.6 %

Procedure:
1-Benzyl-4-[4-(5-nitro-pyridin-2-yl)-piperazin-1-yl]-phthalazine (500 mg, 1.17 mmol), iron powder (523 mg, 9.38 mmol), ammonium chloride (125 mg, 0.234 mmol), ethanol (6 mL) and water (1.5 mL) are all combined in 50 mL round bottom flask with stir bar. The mixture is stirred and heated to 70° C. for 4 h. Material is filtered through a pad of Celite and washed with CH2Cl2. Concentrate to remove all ethanol and residual water. The residue is purified by flash chromatography on silica gel (0-18% MeOH/CH2Cl2) to afford the title compound (323 mg, 70%).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:11][C@@H:12]([NH:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[CH2:31][CH2:30][C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[NH:27][C:26]3=[O:36])[CH2:21][CH2:20]2)=[O:18])[C:13]([OH:15])=O)[CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2].[N:37]1([CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH2:40][CH2:39][CH2:38]1>>[N:37]1([CH:41]2[CH2:46][CH2:45][N:44]([C:13](=[O:15])[C@H:12]([NH:16][C:17]([N:19]3[CH2:24][CH2:23][CH:22]([N:25]4[CH2:31][CH2:30][C:29]5[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=5[NH:27][C:26]4=[O:36])[CH2:21][CH2:20]3)=[O:18])[CH2:11][C:5]3[CH:6]=[CH:7][C:8]([CH2:9][CH3:10])=[C:3]([CH2:1][CH3:2])[CH:4]=3)[CH2:43][CH2:42]2)[CH2:40][CH2:39][CH2:38]1
Reactant: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1CC
Reactant: C1CN(C2CCNCC2)C1
Product: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCC3)CC2)cc1CC

Procedure:
Prepared analogously to Example 34 from (R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid and 4-azetidin-1-yl-piperidine.
Reaction SMILES: [NH2:1][C:2]1[CH:42]=[CH:41][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([NH:22][C:23](=O)[CH2:24][O:25][C:26]3[CH:31]=[CH:30][C:29]([CH2:32][CH:33]4[S:37][C:36](=[O:38])[NH:35][C:34]4=[O:39])=[CH:28][CH:27]=3)=[C:11]([N:13](C)[C:14](=O)OC(C)(C)C)[CH:12]=2)=[CH:4][CH:3]=1.[ClH:43].O1CCOCC1>O1CCOCC1>[ClH:43].[ClH:43].[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:22]=[C:23]([CH2:24][O:25][C:26]4[CH:31]=[CH:30][C:29]([CH2:32][CH:33]5[S:37][C:36](=[O:38])[NH:35][C:34]5=[O:39])=[CH:28][CH:27]=4)[N:13]([CH3:14])[C:11]=3[CH:12]=2)=[CH:41][CH:42]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(N)cc2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(N)cc3)cc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of a solution of t-butyl N-{5-(4-aminophenoxy)-2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]phenyl}-N-methylcarbamate (27.08 g) in 1,4-dioxane (50 ml) and 4N hydrogen chloride/dioxane (150 ml) was stirred at ambient temperature for 2 days. The insoluble product was isolated by filtration and washed with ethyl acetate to give the title compound (14.43 g).
Reaction SMILES: C([C:8]([NH2:12])([OH:11])[CH2:9][CH3:10])(OC(C)(C)C)=O.[CH3:13][C:14]([NH:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][C:24]([OH:26])=[O:25])=[CH:21][CH:22]=1)=[O:15].[ClH:27].C(OCC)(=O)C.C(OCC)C>ClCCl>[NH2:12][CH:8]([OH:11])[CH2:9][CH3:10].[CH3:13][C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([OH:26])=[O:25])=[CH:19][CH:18]=1)=[O:15].[ClH:27]
Reactant: CCC(N)(O)C(=O)OC(C)(C)C
Agent: CC(=O)Nc1ccc(CC(=O)O)cc1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCC(N)O
Reaction time: 3 h

Procedure:
In 2 ml of dichloromethane, 201.3 mg (0.574 mmol) of the Boc-aminopropanol-actarit obtained above was dissolved, and 3 ml of 4 M hydrochloric acid/ethyl acetate was added thereto under ice-cooling, followed by stirring for 3 hours. Diethyl ether was added thereto for precipitation, and the precipitate was washed twice with diethyl ether and then dried under reduced pressure to give 161.3 mg (98%) of the titled compound. The structure was identified by 1H-NMR.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[CH:17]([OH:20])(C)[CH3:18].C1CCN2C(=NCCC2)CC1>O1CCOCC1>[Br:1][C:2]1[C:7]([O:20][CH2:17][CH3:18])=[N:6][C:5]([NH2:11])=[N:4][C:3]=1[C:12]1[O:13][CH:14]=[CH:15][CH:16]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Br
Reactant: CC(C)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: CCOc1nc(N)nc(-c2ccco2)c1Br

Procedure:
From 5-bromo-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine, isopropanol and DBU in dioxane. EI-MS m/e (%): 299 (M{81Br}+, 43), 297 (M{79Br}+, 45), 257 ([M—C6H10]+, 98), 255 ([M—C6H10]+, 100), 206 (32), 94 (44), 43 (52).