Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:26]=[CH:27][CH:28]=1)[CH2:7][NH:8][C:9]([C:11]1[CH:12]=[C:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]([F:19])=[CH:15][C:16]=1[O:17]C)=[O:10])([O-:3])=[O:2].B(Br)(Br)Br>ClCCl>[N+:1]([C:4]1[CH:5]=[C:6]([CH:26]=[CH:27][CH:28]=1)[CH2:7][NH:8][C:9]([C:11]1[CH:12]=[C:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]([F:19])=[CH:15][C:16]=1[OH:17])=[O:10])([O-:3])=[O:2]
Reactant: COc1cc(F)c(-c2ccccc2)cc1C(=O)NCc1cccc([N+](=O)[O-])c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(NCc1cccc([N+](=O)[O-])c1)c1cc(-c2ccccc2)c(F)cc1O
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 100.6 %

Procedure:
A stirring solution of 6-fluoro-4-methoxy-biphenyl-3-carboxylic acid 3-nitro-benzylamide (2.18 g, 5.7 mmol) in dichloromethane (150 mL, 0.4 M) at −78° C. was treated with BBr3 (27 mL, 27 mmol). The mixture was allowed to stir for 45 min at −78° C. and was then quenched with 100 mL of methanol. The mixture was allowed to warm to room temperature, concentrated, and filtered through a plug of silica gel using 50% ethyl acetate as the eluant. The filtrate was concentrated to provide 6-fluoro-4-hydroxy-biphenyl-3-carboxylic acid 3-nitro-benzylamide (2.1 g, 100%) as a yellow powder: Rf 0.68 (50% ethyl acetate in heptane); 1H NMR (CDCl3, 300 MHz) δ 12.29 (bd s, 1 H), 8.14–8.09 (m, 2 H), 7.65 (d, J=7.2 Hz, 1 H), 7.48 (t, J=8.0 Hz, 1H), 7.38–7.29 (m, 5H), 6.74 (d, J=11.4 Hz, 1 H), 6.60 (bd s, 1H), 4.68 (d, J=6.0 Hz, 2H).
Reaction SMILES: [CH3:1][Mg]I.[CH:4]([C:7]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:10][CH2:9][C:8]1=[O:12])([CH3:6])[CH3:5].S(=O)(=O)(O)O>CCOCC>[C:13]([C:7]1([CH:4]([CH3:6])[CH3:5])[CH2:11][CH2:10][CH2:9][C:8]1([CH3:1])[OH:12])([O:15][CH2:16][CH3:17])=[O:14]
Reactant: C[Mg]I
Reactant: CCOC(=O)C1(C(C)C)CCCC1=O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CCOC(=O)C1(C(C)C)CCCC1(C)O

Procedure:
Methylmagnesium iodide (0.22 mole) in ether (200 ml.) was added dropwise to a solution of 2-isopropyl-2-carbethoxycyclopentanone (40 g, 0.2 mole) in ether (150 ml.), and the mixture was heated under reflux for 17 hours. Dilute sulphuric acid was then added and the ether layer was separated and dried (MgSO4). The ether was removed to leave 2-carbethoxy-1-methyl-2-isopropylcyclopentanol. This compound was dissolved in pyridine (200 ml.) and cooled to -10° C. Thionyl chloride (25 ml.) was then added keeping the temperature at -5° C. After 2 hours at -5° C., ether (500 ml) and an excess of 2 N sulphuric acid were added and the organic layer was separated. The aqueous layer was extracted with ether and the combined extracts were dried (MgSO4). The solvent was removed and the residue was distilled to give 1-carbethoxy-1-isopropyl-2-methylcyclopent-2-ene, bp. 107°-110°/17 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:31])[C:5]([C:25]2[N:29]=[C:28]([CH3:30])[O:27][N:26]=2)=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([F:17])[CH:16]=2)[CH:13]([NH:18][C:19]([C:21]2([NH2:24])[CH2:23][CH2:22]2)=[O:20])[CH2:12][CH2:11]3)[CH:7]=1.[CH3:32][O:33][C:34]1[N:39]=[CH:38][C:37]([C:40](O)=[O:41])=[CH:36][N:35]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([F:31])[C:5]([C:25]2[N:29]=[C:28]([CH3:30])[O:27][N:26]=2)=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([F:17])[CH:16]=2)[CH:13]([NH:18][C:19]([C:21]2([NH:24][C:40]([C:37]4[CH:36]=[N:35][C:34]([O:33][CH3:32])=[N:39][CH:38]=4)=[O:41])[CH2:23][CH2:22]2)=[O:20])[CH2:12][CH2:11]3)[CH:7]=1
Reactant: COc1ncc(C(=O)O)cn1
Reactant: Cc1nc(-c2c(F)cc(Cl)cc2-c2cc(F)c3c(c2)CCC3NC(=O)C2(N)CC2)no1
Product: COc1ncc(C(=O)NC2(C(=O)NC3CCc4cc(-c5cc(Cl)cc(F)c5-c5noc(C)n5)cc(F)c43)CC2)cn1

Procedure:
In analogy to the procedure described for the preparation of intermediate A-1 [B], 1-amino-cyclopropanecarboxylic acid{(rac)-5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-7-fluoro-indan-1-yl}-amide (example 32) has been coupled with 2-methoxy-pyrimidine-5-carboxylic acid to yield the title compound as light yellow solid. MS: 581.2 (MH+, 1Cl).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=O)[CH2:14][CH2:13]1)=[O:11].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.Cl.[CH3:41][O:42][C:43](=[O:48])[CH:44]([CH2:46][OH:47])[NH2:45]>ClCCl>[CH3:41][O:42][C:43](=[O:48])[CH:44]([CH2:46][OH:47])[NH:45][C:18]([CH:15]1[CH2:14][CH2:13][N:12]([C:10](=[O:11])[CH2:9][C:3]2[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=2[CH3:1])[CH2:17][CH2:16]1)=[O:20]
Reactant: Cc1ccc(C)c(CC(=O)N2CCC(C(=O)O)CC2)c1
Reactant: COC(=O)C(N)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)C(CO)NC(=O)C1CCN(C(=O)Cc2cc(C)ccc2C)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 1-[(2,5-dimethylphenyl)acetyl]-4-piperidinecarboxylic acid (i.e. the product of Example 9, Step B) (1.44 g, 5.23 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.1 g, 5.75 mmol), and N-methylmorpholine (529 mg, 5.23 mmol) in 5 mL of dichloromethane was stirred at room temperature for 15 minutes. DL-Serine methyl ester hydrochloride (814 mg, 5.23 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. The reaction was partitioned between 1 N aqueous hydrochloric acid (10 mL) and dichloromethane (10 mL), and the organic layer was washed with 1 N aqueous hydrochloric acid, water and brine, dried over MgSO4 and concentrated under reduced pressure to give 1.61 g of the title compound.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C@H:2]([CH3:4])[OH:3].C(N(CC)CC)C.[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[C:15]1([S:21]([O:3][C@@H:2]([CH3:4])[C:1]([O:6][CH3:7])=[O:5])(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)[C@H](C)O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](C)OS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a solution of 200g (1.92 mol) of methyl (2S)-lactate (5) and 295 g (2.11 mol) of triethylamine in toluene (1 L) at 0° C. was added 270 mL, 2.11 mol) of benzenesulfonyl chloride dropwise over a 2 hour period under a nitrogen atmosphere. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature and stir there overnight. The reaction was worked-up by washing with water (3×1 L) and dried (MgSO4). Filtration, concentration and purification by vacuum distillation afforded 440 g (94%) of methyl (2S)-2-(phenylsulfonyl)oxypropanate (12) as a pale yellow liquid: bp 140°-142° C. (0.1 mm Hg); 1H NMR (CDCl3) δ1.51-1.56 (d, 3 H), 3.66 (s, 3 H), 4.95-5.01 (q, 1 H), 7.54-7.59 (m, 2 H), 7.65-7.70 (m, 1 H), 7.93-7.95 (d, 2 H); 13C NMR (CDCl3) δ169.3, 133.9, 129.1, 127.7, 112.3, 74.2, 52.5, 18.3; IR (neat) 2958 (w), 1762 (s), 1586 (m), 1451 (s), 1190 (vs), 1084 (s), 926 (m), 753 (m) cm-1.
Reaction SMILES: C([O:5][C:6]([C:8]1([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]3[C:20]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:21]=4[S:22][CH:23]=3)[CH2:15][CH2:14]2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[F:30][C:28]([F:29])([F:31])[C:25]1[CH:26]=[CH:27][C:20]2[C:19]([N:16]3[CH2:17][CH2:18][N:13]([CH2:12][CH2:11][C:8]4([C:6]([OH:7])=[O:5])[CH2:10][CH2:9]4)[CH2:14][CH2:15]3)=[CH:23][S:22][C:21]=2[CH:24]=1
Reactant: CC(C)(C)OC(=O)C1(CCN2CCN(c3csc4cc(C(F)(F)F)ccc34)CC2)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1(CCN2CCN(c3csc4cc(C(F)(F)F)ccc34)CC2)CC1

Procedure:
1-{2-[4-(6-Trifluoromethyl-benzo[b]thiophen-3-yl)-piperazin-1-yl]-ethyl}-cyclopropanecarboxylic acid tert-butyl ester, 0.7 g (1.54 mmol), was stirred in 10 mL of trifluoroacetic acid. After 2 hours the reaction mixture was concentrated to an oil. This was taken up in methanolic hydrogen chloride. The salt thus obtained was recrystallized from ethyl acetate/methanol to deliver 0.4 g (60%) of white powder as the desired carboxylic acid mp=255–7° C.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][CH2:8][O:9]C(=O)C)=[C:4]([CH:15]=O)[CH:3]=1.[Cl:17][C:18]1[CH:26]=[C:25]2[C:21]([CH2:22][C:23](=[O:27])[NH:24]2)=[CH:20][CH:19]=1.N1CCCC1>CO>[Cl:17][C:18]1[CH:26]=[C:25]2[C:21](/[C:22](=[CH:15]/[C:4]3[CH:3]=[C:2]([Cl:1])[CH:14]=[CH:13][C:5]=3[O:6][CH2:7][CH2:8][OH:9])/[C:23](=[O:27])[NH:24]2)=[CH:20][CH:19]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: CC(=O)OCCOc1ccc(Cl)cc1C=O
Solvent: C1CCNC1
Solvent: CO
Product: O=C1Nc2cc(Cl)ccc2/C1=C/c1cc(Cl)ccc1OCCO
Temperature: 70 °C
Yield: 43 %

Procedure:
Acetic acid 2-(4-chloro-2-formyl-phenoxy)-ethyl ester (1.5 g, 9.3 mmol) and 6-chlorooxindole (2.7 g, 11.2 mmol) were mixed in anhydrous methanol (20 mL) at room temperature. Then Pyrrolidine (0.8 g, 11.2 mmol) was added slowly. The reaction mixture was heated at 70° C. for 3 h, then cooled to r.t and the precipitation was collected by filtration to obtain title compound as a yellow solid (1.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)=[O:26])[CH:22]=[C:21]([Cl:36])[C:3]=1[C:4]([NH:6][C@H:7]([C:17]([O:19]C)=[O:18])[CH2:8][NH:9][C:10]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=[O:11])=[O:5].[OH-].[Na+]>CO.O>[Cl:1][C:2]1[CH:24]=[C:23]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)=[O:26])[CH:22]=[C:21]([Cl:36])[C:3]=1[C:4]([NH:6][C@H:7]([C:17]([OH:19])=[O:18])[CH2:8][NH:9][C:10]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=[O:11])=[O:5]
Reactant: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1c(Cl)cc(C(=O)NCc2cccc(O)c2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(NCc1cccc(O)c1)c1cc(Cl)c(C(=O)N[C@@H](CNC(=O)c2cccs2)C(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
A mixture of N-[2,6-dichloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-[(thiophene-2-carbonyl)amino]-L-alanine, methyl ester (2.41 g, 4.4 mmol) in methanol (100 Ml) and sodium hydroxide (0.35 g, 8.8 mmol) in water (2 Ml) was stirred at room temperature overnight and then the solvents were evaporated. The residue was partitioned between water and ethyl acetate and the ethyl acetate layer was discarded. The aqueous layer was acidified with 1 M HCl, and extracted twice with ethyl acetate. The combined organic extracts were washed with brine, and the product started to precipitate. The solvents were evaporated from the organic layer, and dichloromethane/hexanes was added to the residue. The solid was filtered off, dried overnight under high vacuum, and taken up again in dichloromethane/hexanes. The solid was filtered off, and then dried overnight under high vacuum to give N-[2,6-dichloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-[(thiophene-2-carbonyl)amino]-L-alanine (2.10 g, 89%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19])[CH2:6][CH:7]([C:13]#[N:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH:22](OCC)([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25]>>[C:8]([C:7]([CH:22]([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])([CH2:6][C:5]1[CH:15]=[C:16]([O:20][CH3:21])[C:17]([O:18][CH3:19])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:13]#[N:14])([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)C(C#N)Cc1cc(OC)c(OC)c(OC)c1
Product: CCOC(=O)C(C#N)(Cc1cc(OC)c(OC)c(OC)c1)C(OCC)OCC
Yield: 82 %

Procedure:
A solution of ethyl 3,4,5-trimethoxybenzylcyanoacetate (14.7g) in triethyl orthoformate (100 ml) was heated at reflux for 18 hours using a steam-jacketed column for continuous removal of ethanol. The solution was cooled, and most of the excess orthoformate was removed in vacuo. The crystals obtained were washed with ether and dried to yield colourless crystals of α-carbethoxy-α-diethoxymethyl-β-(3,4,5-trimethoxy phenyl)propionitrile (16.3 g, 82%), m.p. 91θ ; nmr (CDCl3) δ1.13, 1.20. and 1.32 (triplets, 9, CH3CH2O-), 3.15 (s, 2, Ar-CH2 -C), 3.4-4.0 (m, 4, m, 4, CH3CH2 -O), 3.85 (s, 9, -C6H2 -(OCH3)3), 4.13 (q, 2, CH3CH2 -OCO), 4.80 (s, 1, -CH (OEt)2), and 6.55 (s, 2, aromatic H). Anal. Calcd. for C20H29NO7 : C, 60.74; H, 7.39; N, 3.54. Found: C, 60.56; H, 7.33; N, 3.64.
Reaction SMILES: [C:1]([C:4]1[N:8]=[CH:7][NH:6][C:5]=1[C:9]#[N:10])(=O)[CH3:2].O.[NH2:12][NH2:13]>C(O)C>[NH2:10][C:9]1[N:13]=[N:12][C:1]([CH3:2])=[C:4]2[N:8]=[CH:7][NH:6][C:5]=12
Reactant: CC(=O)c1nc[nH]c1C#N
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1nnc(N)c2[nH]cnc12
Temperature: 100 °C

Procedure:
A mixture of 2.00 g 5-acetyl-3H-imidazole-4-carbonitrile and 4.00 ml hydrazine hydrate in 50 ml of ethanol is heated to 100° C., until the reaction is complete according to HPLC-MS. After cooling to ambient temperature the reaction mixture is evaporated down, stirred with 20 ml of cold ethanol and suction filtered. The filter cake is washed with diethyl ether and dried.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:16]=[CH:15][C:6]([CH:7]([NH2:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[C:17](O)(=[O:28])[CH2:18][NH:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21]>>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH:7]([NH:14][C:17]([CH2:18][NH:19][C:20](=[O:21])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: NC(c1ccccc1)c1ccc(Cl)cc1
Reactant: O=C(O)CNC(=O)c1ccccc1
Agent: Cl
Product: O=C(CNC(=O)c1ccccc1)NC(c1ccccc1)c1ccc(Cl)cc1

Procedure:
Prepared in analogy to example 1.1 from rac-4-chlorobenzhydrylamine hydrochloride and hippuric acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:11](=[O:12])[CH:10]2[C:5](=[C:6]3[N:16]=[C:15]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:14]=[C:7]3[C:8](=[O:13])[CH2:9]2)[CH:4]=[N:3]1.[ClH:25].[O:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][Cl:34])[CH2:28][CH2:27]1>>[ClH:34].[ClH:25].[CH3:1][C:2]1([CH3:24])[C:11](=[O:12])[CH:10]2[C:5](=[C:6]3[N:16]=[C:15]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:14]=[C:7]3[C:8](=[O:13])[CH:9]2[CH2:33][CH2:32][N:29]2[CH2:30][CH2:31][O:26][CH2:27][CH2:28]2)[CH:4]=[N:3]1
Reactant: ClCCN1CCOCC1
Reactant: CC1(C)N=CC2=C3N=C(Cc4ccccc4)N=C3C(=O)CC2C1=O
Agent: Cl
Product: CC1(C)N=CC2=C3N=C(Cc4ccccc4)N=C3C(=O)C(CCN3CCOCC3)C2C1=O

Procedure:
Prepared analogous to Example 23 from 1.6 gm of 7,7-dimethyl-2-benzyl-5H,7H-imidazo[4,5-h]isoquinoline-4,6-dione and 1.2 gm of 2-morpholino-ethyl chloride hydrochloride.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:17][C:16]3[C:11](=[N:12][CH:13]=[CH:14][C:15]=3[O:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=3[F:28])[CH:10]=2)=[CH:5][CH:4]=1.[CH2:29]([CH2:31][NH2:32])[OH:30]>COCCOC>[F:28][C:20]1[CH:21]=[C:22]([N+:25]([O-:27])=[O:26])[CH:23]=[CH:24][C:19]=1[O:18][C:15]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:10]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([CH2:2][NH:32][CH2:31][CH2:29][OH:30])=[CH:8][CH:7]=3)[S:17][C:16]=12
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(CCl)cc4)sc23)c(F)c1
Reactant: NCCO
Solvent: COCCOC
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(CNCCO)cc4)sc23)c(F)c1
Yield: 41.4 %

Procedure:
To a suspension of the chloride 52 (500 mg, 1.1 mmol) in DME (10 mL) was added ethanolamine (336 mg, 5.5 mmol). The reaction mixture refluxed for 2 hrs, the solvent was removed under reduced pressure; the residue was dissolved in EtOAc and washed with water. The organic phase was collected, dried over sodium sulfate, filtered and evaporated. The remaining solid was triturated with Et2O to afford the title compound 59 as a yellow solid (200 mg, 41% yield). 1H NMR (DMSO) δ (ppm): 8.57 (d, J=5.5 Hz, 1H), 8.47 (dd, J=2.7 and 10.4 Hz, 1H), 8.21 (m, 1H), 8.17 (s, 1H), 7.83 (d, J=8.0 Hz, 1H), 7.71 (t, J=8.6 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H), 6.91 (d, J=5.5 Hz, 1H), 4.48 (t, J=5.5 Hz, 1H), 3.75 (s, 2H), 3.45 (q, J=5.6 Hz, 2H), 3.33 (m, 1H), 3.15 (d, J=5.1 Hz, 2H), 2.56 (t, J=5.7 Hz, 2H).
Reaction SMILES: C[O:2][C:3](=[O:27])[C@@H:4]([N:9]1[CH2:13][C:12]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([OH:24])([CH3:23])[CH3:22])[C:16]=2[F:25])=[CH:11][C:10]1=[O:26])[CH2:5][CH:6]([CH3:8])[CH3:7].O.[OH-].[Li+]>O1CCCC1>[F:25][C:16]1[C:17]([C:21]([OH:24])([CH3:22])[CH3:23])=[CH:18][CH:19]=[CH:20][C:15]=1[O:14][C:12]1[CH2:13][N:9]([C@@H:4]([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]([OH:27])=[O:2])[C:10](=[O:26])[CH:11]=1
Reactant: COC(=O)[C@H](CC(C)C)N1CC(Oc2cccc(C(C)(C)O)c2F)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C[C@@H](C(=O)O)N1CC(Oc2cccc(C(C)(C)O)c2F)=CC1=O
Temperature: 25 °C
Yield: 105.6 %

Procedure:
To a solution containing (S)-2-{4-[2-fluoro-3-(1-hydroxy-1-methyl-ethyl)-phenoxy]-2-oxo-2,5-dihydro-pyrrol-1-yl}-4-methyl-pentanoic acid methyl ester (2.00 g, 0.005 mol) in tetrahydrofuran (20 mL) was treated with an aqueous solution of lithium hydroxide monohydrate (0.5N, 20 mL, 0.010 mol). The mixture was stirred at 25° C. for 2H, and the solvents evaporated. The residue was dissolved in water and washed with diethyl ether, and the diethyl ether layer discarded. The aqueous phase was acidified with dilute hydrochloric acid (pH <2), and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to afford (S)-2-{4-[2-fluoro-3-(1-hydroxy-1-methyl-ethyl)-phenoxy]-2-oxo-2,5-dihydro-pyrrol-1-yl}-4-methyl-pentanoic acid (1.93 g, 100%) as a fluffy solid.
Reaction SMILES: [NH:1]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@@H:2]([C:11]([OH:13])=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[C:17]([O:16][C:14](=[O:15])[NH:1][CH:2]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]([Cl:10])=[CH:8][CH:9]=1)[C:11](=[O:13])[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: C1CNCCN1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(Cc1ccc(Cl)cc1)C(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 12.9 %

Procedure:
To a solution of Boc-D-Phe(4-Cl)—OH (3.65 g, 12.2 mmol), piperazine (10 g, 116 mmol) in DCM (200 mL) were added HOBT (3.3 g, 24 mmol) and EDCI (4.7 g, 25 mmol). The mixture was stirred at room temperature for 12 hours. The solution was washed with water, brine and dried over magnesium sulfate. After filtration, the organic solvent was evaporated and the residue was subject to silica gel chromatography to afford the product [1-(4-chlorobenzyl)-2-oxo-2-piperazin-1-yl-ethyl]-carbamic acid tert-butyl ester (0.58 g, 13%). 1H NMR (CDCl3, 400 Hz) δ 7.25 (d, J=8.4 Hz, 2H), 7.12 (d, J=8.0 Hz, 2H), 5.52 (d, J=8.4 Hz, 1H), 4.83-4.77 (m, 1H), 3.63-3.45 (m, 2H), 3.37-3.32 (m, 1H), 3.08-3.04 (m, 1H), 2.99-2.90 (m, 2H), 2.81-2.70 (m, 3H), 2.42-2.38 (m, 1H), 1.41 (s, 9H). MS (ESI+) [M+H]+ 369.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[NH:14][C@@H:15]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)[CH2:16][OH:17])(C)(C)C>C(Cl)Cl>[NH2:14][C@@H:15]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)[CH2:16][OH:17]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H](CO)Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
TFA (171 mL) was added to a solution of (S)-tert-butyl-1-hydroxy-3-(4-nitrophenyl)propan-2-ylcarbamate 20 (Erlanson et al., U.S. Pat. No. 7,214,487 B2; 13.9 g, 46.9 mmol) in DCM (272 mL) at 0° C. The reaction mixture was warmed to RT and reaction was allowed to proceed for 25 minutes. The solution was concentrated to afford 9.2 g of crude (S)-2-amino-3-(4-nitrophenyl)propan-1-ol as a white solid. To a solution of this crude product and sodium carbonate (12.4 g, 117.3 mmol) in THF (87 mL) and water (87 mL) was added N-carbethoxyphthalimide (“CEPT,” 12.3 g, 56.3 mmol). After the reaction mixture was stirred at RT for 4 h, EtOAc (150 mL) was added. The aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give a crude residue which was purified by flash chromatography eluting from silica gel with a gradient of 0-100% EtOAc in hexanes to give 12.3 g of alcohol 30. MS: (+) m/z 327.0 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14](S(C)(=O)=O)=[N:15][CH:16]=2)[N:11]([CH3:23])[C:10]1=[O:24].[NH2:25][C:26]1[CH:27]=[CH:28][C:29]2[O:34][CH2:33][CH2:32][S:31](=[O:36])(=[O:35])[C:30]=2[CH:37]=1.Cl>CN1C(=O)CCC1.CCOCC>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([NH:25][C:26]3[CH:27]=[CH:28][C:29]4[O:34][CH2:33][CH2:32][S:31](=[O:36])(=[O:35])[C:30]=4[CH:37]=3)=[N:15][CH:16]=2)[N:11]([CH3:23])[C:10]1=[O:24]
Reactant: Nc1ccc2c(c1)S(=O)(=O)CCO2
Reactant: CN1C(=O)N(c2c(F)cccc2Br)Cc2cnc(S(C)(=O)=O)nc21
Agent: Cl
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: CN1C(=O)N(c2c(F)cccc2Br)Cc2cnc(Nc3ccc4c(c3)S(=O)(=O)CCO4)nc21
Temperature: 120 °C

Procedure:
83 mg 3-(2-bromo-6-fluorophenyl)-3,4-dihydro-7-methanesulphonyl-1-methyl-pyrimido[4,5-d]pyrimidin-2(1H)-one and 80 mg 6-Amino-2,3-dihydro-benzo[1,4]oxathiine-4,4-dioxide (starting material h)) in 0.8 ml NMP were treated with 0.2 ml 2M HCl in ether and heated to 120° C. for 6 hrs. From this mixture 21 mg of the title product were isolated by preparative HPLC-MS (mp: 230–233° C.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[O:11][CH3:12].C(N(CC)CC)C.[C:21](Cl)(=[O:25])[CH:22]([CH3:24])[CH3:23]>ClCCl>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])=[CH:6][C:5]=1[O:11][CH3:12]
Reactant: COC(=O)c1ccc(N)cc1OC
Reactant: CC(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(NC(=O)C(C)C)cc1OC
Reaction time: 3 h
Yield: 75.7 %

Procedure:
1.81 g of 4-amino-2-methoxy-benzoic acid methyl ester and 1.4 g of triethylamine were dissolved in 20 ml of dichloromethane. 1.23 g of isobutyryl chloride in 5 ml of dichloromethane was added dropwise at 0° C. The reaction mixture was allowed to reach room temperature and stirred for 3 hours. The reaction mixture was washed with water, dried and the solvents were evaporated to yield 1.9 g of the title product.
Reaction SMILES: CN(C=O)C.[H-].[Na+].[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[SH:18].[NH2:19][C:20]1[N:28]=[C:27](Cl)[N:26]=[C:25]2[C:21]=1[N:22]=[CH:23][N:24]2[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>[Cl-].[Na+].O>[NH2:19][C:20]1[N:28]=[C:27]([S:18][C:9]2[CH:10]=[CH:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=2)[N:26]=[C:25]2[C:21]=1[N:22]=[CH:23][N:24]2[CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Reactant: Sc1ccc2ccccc2c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(Sc2ccc3ccccc3c2)nc2c1ncn2Cc1ccccc1
Temperature: 100 °C
Yield: 82.6 %

Procedure:
To DMF suspension (20 ml) containing sodium hydride (800 mg, 20 mmol, 60% in mineral oil) were added 2-naphthalenethiol (3.8 g, 24 mmol) and 6-amino-9-benzyl-2-chloropurine (200 mg, 0.77 mmol) in order. The mixture was stirred under heating at 100° C. for 10.5 hours. Brine was added thereto and the mixture was extracted with chloroform. The organic layer was dried on magnesium sulfate, filtrated and the solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (0.5% methanol/chloroform) to give the subject compound (244 mg, yield 83%).