Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([C:34](OC)=[O:35])=[N:14][C:15]=2[NH:19][CH2:20][CH:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[CH:38]([CH:41]1[CH2:46][CH2:45][N:44]([CH2:47][CH2:48][NH2:49])[CH2:43][CH2:42]1)([CH3:40])[CH3:39]>C(OCC)C>[OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([C:34]([NH:49][CH2:48][CH2:47][N:44]1[CH2:45][CH2:46][CH:41]([CH:38]([CH3:40])[CH3:39])[CH2:42][CH2:43]1)=[O:35])=[N:14][C:15]=2[NH:19][CH2:20][CH:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)C1CCN(CCN)CC1
Reactant: COC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Solvent: CCOCC
Product: CC(C)C1CCN(CCNC(=O)c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)CC1
Temperature: 120 °C
Yield: 50.9 %

Procedure:
A mixture of methyl 9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)-tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9H-purine-2-carboxylate (Preparation 18) (92 mg, 0.18 mmol) and 2-(4-isopropyl-1-piperidinyl)ethylamine (Preparation 20) (100 mg, 0.6 mmol) was heated at 120° C. under a nitrogen atmosphere for 75 minutes. The reaction mixture was allowed to cool to room temperature and diethyl ether (2 ml) added to precipitate a crude product. The solvent was decanted off the gum which was then triturated with ethyl acetate (2 ml). The resulting white solid was filtered off and dried to give the title compound (59 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:17][CH3:18]>CN(C=O)C.CC(=O)OCC>[Cl:1][C:2]1[N:7]([CH2:17][CH3:18])[C:6](=[O:8])[CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: Oc1cc(Cl)nc(Cl)n1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCn1c(Cl)nc(Cl)cc1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 28 %

Procedure:
A solution of 2,6-dichloro-pyrimidin-4-ol (1.0 g, 6.1 mmol) and K2CO3 (1.1 g, 7.9 mmol) in DMF (10 mL) was stirred at RT for 15 min. The reaction mixture was cooled to 0° C., and iodoethane (1.1 mL, 6.7 mmol) was added dropwise. After stirring overnight at RT, the reaction mixture was diluted with EA, washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica chromatography (20:1, EA:PE) to give 330 mg (28%) of the title compound. 1H NMR (400 MHz, CDCl3): δ 1.37 (t, J=7.6 Hz, 3H), 4.76 (q, J=6.8 Hz, 2H), 6.67 (s, 1H). [M+H] Calc'd for C6H6Cl2N2O, 193, 195, 197. Found, 193, 195, 197.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH3:23])[C:6]=1[C:7]1[C:8]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=2[F:22])=[N:9][N:10]([CH3:14])[C:11]=1[C:12]#[N:13].[NH2:24][OH:25].CCOC(C)=O.O>CS(C)=O>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH3:23])[C:6]=1[C:7]1[C:8]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=2[F:22])=[N:9][N:10]([CH3:14])[C:11]=1[C:12](=[N:24][OH:25])[NH2:13]
Reactant: Cc1csc(C)c1-c1c(-c2ccc(O)cc2F)nn(C)c1C#N
Reactant: NO
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1csc(C)c1-c1c(-c2ccc(O)cc2F)nn(C)c1C(N)=NO
Temperature: 150 °C
Yield: 50.2 %

Procedure:
To a solution of 4-(2,4-dimethylthiophen-3-yl)-3-(2-fluoro-4-hydroxyphenyl)-1-methyl-1H-pyrazole-5-carbonitrile (7 mg, 0.02 mmol) in DMSO (0.6 mL) was added neutral hydroxylamine solution (16 M in water, 0.33 mL, 5.35 mmol) The reaction was heated at 150° C. in the microwave for 15 min. EtOAc and water were added and the phases were separated. The crude product was purified on preparative HPLC to give 4-(2,4-dimethylthiophen-3-yl)-3-(2-fluoro-4-hydroxyphenyl)-N′-hydroxy-1-methyl-1H-pyrazole-5-carboximidamide (3.62 mg, 47%). Identification of the title compound by 1H-NMR showed that the oxime product was a single isomer, but did not confirm whether the (E) or (Z) oxime isomer had been obtained. ES/MS m/z: 361.06 (M+H), 359.14 (M−H); 1H NMR (acetone-d6, 500 MHz): 7.05 (t, 1H, J=8.6 Hz), 6.77 (q, 1H, J=0.9 Hz), 6.59 (dd, 1H, J=8.6, 2.5 Hz), 6.51 (dd, 1H, J=11.7, 2.5 Hz), 4.01 (s, 3H), 2.07 (s, 3H) and 1.88 (d, 3H, J=0.9 Hz).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[F:20][C:21]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=1[C:28]1[N:29]=[C:30]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[S:31][CH:32]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12]([N:36]2[CH2:37][CH2:38][N:33]([C:30]3[S:31][CH:32]=[C:28]([C:22]4[CH:23]=[CH:24][CH:25]=[C:26]([F:27])[C:21]=4[F:20])[N:29]=3)[CH2:34][CH2:35]2)=[O:19])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: Fc1cccc(-c2csc(N3CCNCC3)n2)c1F
Reactant: CC(=O)Nc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)Nc1ccc(NC(=O)N2CCN(c3nc(-c4cccc(F)c4F)cs3)CC2)cn1
Temperature: 70 °C
Reaction time: 15 h
Yield: 36.5 %

Procedure:
A mixture of 2,2,2-trichloroethyl [6-(acetylamino)pyridin-3-yl]carbamate (255 mg, 0.782 mmol), 1-[4-(2,3-difluorophenyl)-1,3-thiazol-2-yl]piperazine (200 mg, 0.711 mmol) and diisopropylethylamine (0.248 ml, 1.42 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 15 hours. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over magnesium sulfate anhydrous, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 119 mg (36.6%) of the desired product as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([N+:10]([O-])=O)[CH:3]=1.[Cl-].[NH4+].C(O)C>[Fe].O>[NH2:10][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=1[CH2:8][OH:9]
Reactant: O=[N+]([O-])c1cc(Br)ccc1CO
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cc(Br)ccc1CO
Temperature: 75 °C
Yield: 95 %

Procedure:
A mixture of (4-bromo-2-nitro-phenyl)-methanol (1.85 g, 7.97 mmol), iron powder (2.23 g, 39.9 mmol), ammonium chloride (213 mg, 3.99 mmol), ethanol (20 mL), and water (10 mL) was heated at 75° C. for 1 h, then after cooling filtered through a pad of diatomaceous earth. The filtrate was evaporated and the residue partitioned between ethyl acetate and water, the organic layer was washed with brine, dried (MgSO4), and evaporated to produce (2-amino-4-bromo-phenyl)-methanol (1.53 g, 90%). Off-white solid, MS (EI)=201.0 (M+).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)[S:4][N:3]=1.Cl[C:15]1[N:20]=[C:19]([C:21]([OH:24])([CH3:23])[CH3:22])[CH:18]=[C:17]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[N:16]=1>>[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([C:17]2[N:16]=[C:15]([NH:13][CH:10]3[CH2:9][CH2:8][N:7]([C:5]4[S:4][N:3]=[C:2]([CH3:1])[N:6]=4)[CH2:12][CH2:11]3)[N:20]=[C:19]([C:21]([OH:24])([CH3:22])[CH3:23])[CH:18]=2)=[CH:30][CH:29]=1
Reactant: CC(C)(O)c1cc(-c2ccc(Cl)cc2)nc(Cl)n1
Reactant: Cc1nsc(N2CCC(N)CC2)n1
Product: Cc1nsc(N2CCC(Nc3nc(-c4ccc(Cl)cc4)cc(C(C)(C)O)n3)CC2)n1
Yield: 41.2 %

Procedure:
In analogy to example 29, 1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-ylamine (59.5 mg, 0.3 mmol) was reacted with 2-[2-chloro-6-(4-chloro-phenyl)-pyrimidin-4-yl]-propan-2-ol (85 mg, 0.3 mmol) to give the title compound (55 mg, 41%) as off-white foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]([N:13]2[CH2:18][CH2:17][NH:16][CH:15]([CH2:19][F:20])[CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[C:21]([NH:25][C:26](=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33]Cl)[CH:28]=1)([CH3:24])([CH3:23])[CH3:22].C(N(CC)CC)C.[I-].[Na+]>C(#N)C>[C:21]([NH:25][C:26](=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][N:16]2[CH2:17][CH2:18][N:13]([C:11](=[O:12])[C:4]3[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([F:1])[CH:3]=3)[CH2:14][CH:15]2[CH2:19][F:20])[CH:28]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: O=C(c1ccc([N+](=O)[O-])c(F)c1)N1CCNC(CF)C1
Reactant: CC(C)(C)NC(=O)c1cccc(CCl)c1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc([N+](=O)[O-])c(F)c3)CC2CF)c1
Temperature: 60 °C
Yield: 57.3 %

Procedure:
A stirred mixture of (3-fluoro-4-nitrophenyl)(3-(fluoromethyl)piperazin-1-yl)methanone (456 mg, 1.6 mmol), N-tert-butyl-3-(chloromethyl)benzamide (361 mg, 1.6 mmol), triethylamine (3.1 mmol, 341 mg) and sodium iodide (1.6 mmol, 240 mg) in acetonitrile (10 mL) was heated to 60° C. for several hours. The reaction was concentrated under reduced pressure. The residue was then dissolved in dichloromethane and extracted with water (×3). The organic phase was dried (sodium sulfate) and concentrated under vacuum. The crude material was purified using silica chromatography to give the title compound (435 mg). MS (ESI) m/z 475.7[M+H]+
Reaction SMILES: [NH2:1][C@H:2]([C@H:7]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[OH:8])[CH2:3][CH:4]([CH3:6])[CH3:5].Cl.[NH:15]([C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[C@H:16]([C@H:21]([CH2:23][C:24]([NH:26][C@H:27]([C:29](O)=[O:30])[CH3:28])=[O:25])[OH:22])[CH2:17][CH:18]([CH3:20])[CH3:19].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.C1CCC(N=C=NC2CCCCC2)CC1>O>[NH:15]([C:32]([O:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:33])[C@H:16]([C@H:21]([CH2:23][C:24]([NH:26][C@H:27]([C:29]([NH:1][C@H:2]([C@H:7]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[OH:8])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:30])[CH3:28])=[O:25])[OH:22])[CH2:17][CH:18]([CH3:20])[CH3:19]
Reactant: COC(=O)C[C@H](O)[C@@H](N)CC(C)C
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)[C@@H](O)CC(=O)N[C@@H](C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Product: COC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)OCc1ccccc1

Procedure:
In a manner analogous to that described in stage 13.1, using as starting materials 150 mg of H-Sta-OMe×HCl (from stage 13.4), 253 mg of Z-Sta-Ala-OH (from stage 13.2), 102 mg of HOBt×H2O, 67 mg of N-methylmorpholine and 178 mg of DCCI, Z-Sta-Ala-Sta-OMe is obtained; Rf (chloroform/methanol ]9:1])=0.37.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[N:9][CH:8]=[CH:7][CH:6]=2.ClC1C=CC=C(C(OO)=[O:20])C=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]=[CH:7][CH:8]=[N+:9]([O-:20])[C:10]=2[CH:11]=1.[Br:1][C:2]1[CH:3]=[N+:4]([O-:20])[C:5]2[C:10]([CH:11]=1)=[N:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Brc1cnc2cccnc2c1
Solvent: ClCCl
Product: [O-][n+]1cc(Br)cc2ncccc21
Product: [O-][n+]1cccc2ncc(Br)cc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4.43 g (21.2 mmol, 1 eq) of 3-bromo-1,5-naphthyridine (W. Czuba, Recueil des Travaux Chimiques des Pays-Bas 1963, 82, 988-996) were introduced in 165 mL of methylene chloride. 5.23 g (21.2 mmol, 1 eq) of meta-chloroperbenzoic acid were then added portionwise at 0° C. The mixture was stirred at rt for 18 h. The mixture was washed with 1M aqueous NaOH solution and water. Organic layer was dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by column chromatography using methylene chloride and then methylene chloride/ethanol: 98/2 as eluent. The solvent was evaporated to dryness to afford 3.08 g of 3-bromo-1,5-naphthyridine-5-oxide (pale yellow powder) with 64% yield and 1.00 g of 3-bromo-1,5-naphthyridine-1-oxide (yellow powder) with 21% yield.
Reaction SMILES: C(OC([N:8]([C:40](OC(C)(C)C)=O)[C:9](=[O:39])[C:10]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][S:17]2(=[O:22])=[O:21])[CH:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[C:36]([CH3:37])=[CH:35][C:34]([CH3:38])=[CH:33][N:32]=2)[CH2:27][CH2:26]1)=[O:24])=O)(C)(C)C.N1C[CH2:50][CH2:49][CH2:48]1>>[CH3:37][C:36]1[C:31]([N:28]2[CH2:27][CH2:26][N:25]([C:23]([C:11]3[CH:12]=[CH:13][C:14]([N:16]4[CH2:20][CH2:19][CH2:18][S:17]4(=[O:21])=[O:22])=[CH:15][C:10]=3[C:9]([N:8]3[CH2:40][CH2:50][CH2:49][CH2:48]3)=[O:39])=[O:24])[CH2:30][CH2:29]2)=[N:32][CH:33]=[C:34]([CH3:38])[CH:35]=1
Reactant: C1CCNC1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3C(=O)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3C(=O)N3CCCC3)CC2)c(C)c1

Procedure:
Using N,N-di-tert-butyloxycarbonyl-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-5-(1,1-dioxo-1λ6-isothiazolidin-2-yl)benzamide (100 mg) described in Example 808 and pyrrolidine (15 μL) and by the reaction and treatment in the same manner as in Example 770, the title compound (56 mg) was obtained.
Reaction SMILES: [C:1]([O:4][C:5](=[O:17])[CH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])[OH:7])(=[O:3])[CH3:2].[C:18]([O:21][CH2:22]Br)(=[O:20])[CH3:19].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:18]([O:21][CH2:22][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])([OH:7])[C:5]([O:4][C:1](=[O:3])[CH3:2])=[O:17])(=[O:20])[CH3:19]
Reactant: CC(=O)OC(=O)C(O)c1ccccc1[N+](=O)[O-]
Reactant: CC(=O)OCBr
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)OCC(O)(C(=O)OC(C)=O)c1ccccc1[N+](=O)[O-]
Yield: 87.1 %

Procedure:
A pale brown solution of O-Acetyl-2-nitromandelic acid (23) (14 mg, 0.059 mmol), bromomethyl acetate (10 μL, 0.10 mmol), and triethylamine (10 μL, 0.072 mmol) in chloroform (1 mL) is incubated overnight. The volatiles are removed in vacuo, and the residue is purified by flash chromatography (chloroform) to give 16 mg of the title compound (24) as a clear colorless oil, Rf 0.65 (5% MeOH/chloroform.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[C:8]([CH3:15])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[N:16]1([C@@H:21]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][C:27]=3[F:33])[CH2:22]2)[CH2:20][CH2:19][CH2:18][CH2:17]1>>[N:16]1([C@@H:21]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:10](=[O:12])[C:9]4[CH:13]=[CH:14][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:7][C:8]=4[CH3:15])=[CH:28][C:27]=3[F:33])[CH2:22]2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Nc1ccc(N2CC[C@@H](N3CCCC3)C2)c(F)c1
Reactant: CCCCOc1ccc(C(=O)O)c(C)c1
Product: CCCCOc1ccc(C(=O)Nc2ccc(N3CC[C@@H](N4CCCC4)C3)c(F)c2)c(C)c1

Procedure:
4-Butoxy-2-methyl-benzoic acid was reacted with (R)-4-[1,3′]bipyrrolidinyl-1′-yl-3-fluorophenylamine according to Method P. In this way the product was obtained with molecular weight 439.58 (C26H34FN3O2); MS (ESI): 440 (M+H+).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:18]=[C:17]([C:19]([OH:21])=O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1.Cl.[OH:25][C:26]1[C:35]([O:36][CH3:37])=[CH:34][CH:33]=[C:32]2[C:27]=1[CH2:28][CH2:29][NH:30][CH2:31]2>>[F:22][C:2]([F:23])([F:1])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:18]=[C:17]([C:19]([N:30]3[CH2:29][CH2:28][C:27]4[C:32](=[CH:33][CH:34]=[C:35]([O:36][CH3:37])[C:26]=4[OH:25])[CH2:31]3)=[O:21])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:7][CH:8]=1
Reactant: O=C(O)c1nc(-c2ccc(C(F)(F)F)cc2)nc2ccccc12
Reactant: COc1ccc2c(c1O)CCNC2
Agent: Cl
Product: COc1ccc2c(c1O)CCN(C(=O)c1nc(-c3ccc(C(F)(F)F)cc3)nc3ccccc13)C2
Yield: 15 %

Procedure:
Reaction of 2-(4-(trifluoromethyl)phenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 37 (15% yield) as off-white oil. 1H NMR (300 MHz, DMSO-d6) δ 2.62 and 2.91 (2t, 2H), 3.50 and 4.04 (2t, 2H), 3.74 and 3.80 (2s, 3H), 4.40 and 4.93 (2s, 2H), 6.31 and 6.77 (2d, 1H), 6.71 and 6.91 (2d, 1H), 7.26-7.84 (m, 1H), 7.90-8.02 (m, 3H), 8.11-8.24 (m, 2H), 8.68-8.76 (m, 3H); MS (ESI) m/z 480 ([M+H]+).
Reaction SMILES: C(N(CC)CC)C.Cl[CH2:9][CH2:10][S:11]([CH2:14][CH2:15][C:16]([NH:18][CH2:19][CH2:20][S:21][CH:22]=[CH2:23])=[O:17])(=[O:13])=[O:12].CN(C)C=[O:27]>>[CH:10]([S:11]([CH2:14][CH2:15][C:16]([NH:18][CH2:19][CH2:20][S:21]([CH:22]=[CH2:23])=[O:27])=[O:17])(=[O:13])=[O:12])=[CH2:9]
Reactant: CN(C)C=O
Reactant: C=CSCCNC(=O)CCS(=O)(=O)CCCl
Solvent: CCN(CC)CC
Product: C=CS(=O)CCNC(=O)CCS(=O)(=O)C=C
Reaction time: 1 h

Procedure:
0.8 g Triethylamine was added to a solution of 2.0 g Intermediate 2 in 10 ml dimethylformamide. After stirring 1 hour the mixture was filtered and the filtrate evaporated. The residue was recrystallised form ethyl acetate and then from dichloromethanepetrolether. Yield 1.1 g; Mp. 93° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:23][CH2:24][CH2:25][NH:26]C(OC(C)(C)C)=O)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:23][CH2:24][CH2:25][NH2:26])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2n1CCCNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2n1CCCN
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
The solution of 14.3 g (31.6 mmol) 5-benzyloxy-1-(3-tert-butoxycarbonylamino-propyl)-1H-indole-2-carboxylic acid ethyl ester in 140 mL dichloromethane was cooled to 0° C. and 70 mL (104.2 g, 914 mmol) trifluoroacetic acid was added. The cooling bath was removed and after stirring at room temperature for 1 h, the solution was neutralized with 1M aqueous sodium hydroxide solution and was extracted with dichloromethane. The organic phase was washed with brine, dried over magnesium sulfate, filtered and evaporated to give the crude product as yellow oil (>100%). The compound was pure enough for the next step without further purification.
Reaction SMILES: CN(C)[C:3]1[CH:4]=[C:5]([C:21](=[O:40])[NH:22][CH2:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][N:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[O:38][CH3:39])[CH2:28][CH2:27]2)[C:6]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:9]([CH3:18])[C:8](=[O:19])[C:7]=2[CH:20]=1.NC1C=CC(C2OC3C([C:61](=O)[NH:62][CH2:63]CCN4CCN(C5C=CC=CC=5OC)CC4)=CC=CC=3C(=O)C=2C)=CC=1>O.[OH-].[Na+]>[CH3:61][N:62]([CH3:63])[C:15]1[CH:14]=[CH:13][C:12]([C:10]2[O:11][C:6]3[C:5]([C:21](=[O:40])[NH:22][CH2:23][CH2:24][CH2:25][N:26]4[CH2:31][CH2:30][N:29]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[O:38][CH3:39])[CH2:28][CH2:27]4)=[CH:4][CH:3]=[CH:20][C:7]=3[C:8](=[O:19])[C:9]=2[CH3:18])=[CH:17][CH:16]=1
Reactant: COc1ccccc1N1CCN(CCCNC(=O)c2cc(N(C)C)cc3c(=O)c(C)c(-c4ccccc4)oc23)CC1
Reactant: COc1ccccc1N1CCN(CCCNC(=O)c2cccc3c(=O)c(C)c(-c4ccc(N)cc4)oc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccccc1N1CCN(CCCNC(=O)c2cccc3c(=O)c(C)c(-c4ccc(N(C)C)cc4)oc23)CC1

Procedure:
The title compound was prepared by the same method as described for compound of Example 97, but using the compound prepared in Example 124 instead of compound of Example 94. The reaction mixture was diluted with water and 3N aqueous sodium hydroxide solution, under vigorous stirring. The precipitated solid was filtered by suction, washed with water, desiccated and purified by flash chromatography on silica gel eluting with ethyl acetate - methanol (8.5:1.5). Evaporation in vacuo of the collected fractions yielded the title compound which melted at 146°-150 (164) ° C after crystallization from acetonitrile.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([C@@H:15]([CH3:22])[C:16](=[O:21])C(O)(C)C)[NH:13][C:12]1=[O:23])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].I([O-])(=O)(=O)=[O:25].[Na+].C(O)(=O)C>O1CCCC1>[Si:1]([O:8][C@@H:9]([C@H:11]1[C:12](=[O:23])[NH:13][C@@H:14]1[C@@H:15]([CH3:22])[C:16]([OH:21])=[O:25])[CH3:10])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)C(C)(C)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)O
Reaction time: 24 h

Procedure:
To a solution of (3S,4R)-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[(1R)-3-hydroxy-1,3-dimethyl-2-oxobutyl]-2-azetidinone (135 mg) in tetrahydrofuran (4 ml) was added 1M solution of sodium periodate buffered with acetic acid (mole ratio 1:1) (7.8 ml) at room temperature and the mixture was stirred for 1 day at the same temperature. The reaction mixture was evaporated, acidified, and extracted twice with dichloromethane. The organic layer was washed twice with brine, dried over magnesium sulfate and evaporated to give (2R)-2-[(2S,3S)-3-{(1R)-1-(t-butyldimethylsilyloxy)ethyl}-4-oxoazetidin-2-yl]propionic acid (85 mg).
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:9][CH2:10][CH2:11][C@@H:12]([C:21]2[O:25][N:24]=[C:23]([CH2:26][OH:27])[N:22]=2)[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Br[CH2:29][C:30]([NH2:32])=[O:31]>O1CCCC1.C(OCC)(=O)C>[NH2:32][C:30](=[O:31])[CH2:29][O:27][CH2:26][C:23]1[N:22]=[C:21]([C@H:12]([CH2:11][CH2:10][CH2:9][CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[O:25][N:24]=1
Reactant: NC(=O)CBr
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CO)no1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(COCC(N)=O)no1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 268.6 %

Procedure:
A suspension of sodium hydride 60% suspension in mineral oil (51 mg, 1.28 mmol) in anhydrous tetrahydrofuran (3 ml) was cooled to 0° C. and treated with a solution of tert-butyl (3R)-6-cyclohexyl-3-[3-(hydroxymethyl)-1,2,4-oxadiazol-5-yl]hexanoate (Preparation 85) (105 mg, 0.30 mmol) in anhydrous tetrahydrofuran (3 ml) and stirred under a nitrogen atmosphere for 30 minutes. 2-Bromoacetamide (235 mg, 1.70 mmol) was added and the mixture was allowed to warm to room temperature and then heated at 40° C. for 15 hours. The cooled reaction mixture was diluted with ethyl acetate and washed with water and brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The solid was purified by column chromatography on silica gel eluting with a gradient system of pentane:ethyl acetate (99:1) to pentane:ethyl acetate (0:100) to afford the title compound as a colourless oil (330 mg).
Reaction SMILES: [Br:1]Br.[CH2:3]([O:5][P:6]([CH2:11][O:12][CH2:13][CH2:14][N:15]1[CH:23]=[N:22][C:21]2[C:20](=[O:24])[NH:19][C:18]([NH2:25])=[N:17][C:16]1=2)([O:8][CH2:9][CH3:10])=[O:7])[CH3:4]>O>[Br:1][C:23]1[N:15]([CH2:14][CH2:13][O:12][CH2:11][P:6]([O:5][CH2:3][CH3:4])([O:8][CH2:9][CH3:10])=[O:7])[C:16]2[N:17]=[C:18]([NH2:25])[NH:19][C:20](=[O:24])[C:21]=2[N:22]=1
Reactant: CCOP(=O)(COCCn1cnc2c(=O)[nH]c(N)nc21)OCC
Reactant: BrBr
Solvent: O
Product: CCOP(=O)(COCCn1c(Br)nc2c(=O)[nH]c(N)nc21)OCC
Reaction time: 1 h

Procedure:
Bromine (1 mL) was added to 100 mL of water and the mixture stirred vigorously at rt until all the bromine had dissolved (15 min.). 9-(2'-(diethylphosphonomethoxy)ethyl)guanine (0.360 g, 1.04 mmol) was then dissolved in 10 ml H2O and treated dropwise with the aqueous bromine solution until the color of Br2 persisted. The reaction mixture was allowed to stand at 0° C. for 1 h and then was concentrated to afford a dark yellow viscous gum. Purification was accomplished by column chromatography on silica gel (MeOH--CH2Cl2) to provide 0.31 g of 8-bromo-9-(2'-(diethylphosphonomethoxy)ethyl)guanine as an orange powder.
Reaction SMILES: [NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:2]([C:4](O)=[O:5])[CH3:3]>O1CCCC1>[C:10]([O:9][C:7](=[O:8])[NH:1][C@H:2]([CH3:3])[CH2:4][OH:5])([CH3:13])([CH3:11])[CH3:12]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: C1CCOC1
Product: C[C@H](CO)NC(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
A solution of Boc-D-Ala-OH (1.0 g, 5.28 mmol) in tetrahydrofuran (10 ml) was added dropwise to a stirred solution of BH3, 1M in tetrahydrofuran (10 ml) at 0° C. The mixture was stirred for a further hour at 0° C., then quenched with 10% acetic acid in methanol. After solvent evaporation, the crude product was dissolved in ethyl acetate and washed with 1M HCl, water and then 1M sodium hydrogencarbonate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the desired product. Yield 0.39 g, 42%.: NMR 1H (300 MHz, CDC3): 0.97 (d, 3H), 1.36 (s, 9H), 3.14 (m, 1H), 3.29 (m, 1H), 3.40 (m, 1H), 4.57 (m, 1H)