Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:14](=[O:15])[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:12]([OH:21])[C:11]([CH:22]([CH3:24])[CH3:23])=[N:10]2)[CH:5]=[CH:6][CH:7]=1.OC1C(C(C)C)=NNC(=O)[C:27]=1[C:36]([O:38]CC)=[O:37].[H-].[Na+].BrC1C=C(C=CC=1)CBr.C[N:53](C)C=O>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:14](=[O:15])[C:13]([C:16]([NH:53][CH2:27][C:36]([OH:38])=[O:37])=[O:17])=[C:12]([OH:21])[C:11]([CH:22]([CH3:24])[CH3:23])=[N:10]2)[CH:5]=[CH:6][CH:7]=1.[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:14](=[O:15])[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:12]([OH:21])[C:11]([CH:22]([CH3:23])[CH3:24])=[N:10]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1c(O)c(C(C)C)n[nH]c1=O
Agent: BrCc1cccc(Br)c1
Agent: CCOC(=O)c1c(O)c(C(C)C)nn(Cc2cccc(Br)c2)c1=O
Agent: [H-]
Product: CC(C)c1nn(Cc2cccc(Br)c2)c(=O)c(C(=O)NCC(=O)O)c1O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Ethyl 2-[(3-bromophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinecarboxylate. To a solution of ethyl 5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinecarboxylate (example 46(a), 3 g, 13.26 mmol) in N,N-Dimethylformamide (DMF) (50 ml) at 0° C. was added sodium hydride (0.796 g, 19.89 mmol) in portions. The reaction mixture was stirred at room temperature for 45 minutes and then cooled back to 0° C. and 3-bromobenzyl bromide (3.31 g, 13.26 mmol) was added portionwise. The mixture was stirred at ambient temperature for 2.5 hours then quenched with 1N HCl (10 ml) and diluted with water (30 ml). The aqueous solution was extracted with ethyl acetate (2×100 ml), the organic layers combined and washed with water (100 ml) and brine (100 ml), dried over Magnesium sulfate, filtered and solvents removed with rotary evaporation. The crude oil was purified by flash column chromatography (10-100% ethyl acetate in hexanes) to provide the title compound (ethyl 2-[(3-bromophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinecarboxylate (890 mg, 1.801 mmol, 13.58% yield) as a pale yellow solid. The product isolated was a 5:1 mixture of the desired mono alkylated to the bis-alkylated(4-O-benzyl)(LCMS=564). 1H NMR (400 MHz, DMSO-d6) d ppm 12.33 (s, 1H), 7.46-7.53 (m, 2H), 7.24-7.35 (m, 2H), 5.14 (s, 2 H), 4.26 (q, J=7.07 Hz, 2H), 3.17 (sept, J=6.78 Hz, 1H), 1.26 (t, J=7.20 Hz, 3H), 1.16 (d, J=6.82 Hz, 6H). MS (ES+) m/e 396 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[N:11][C:10]=2[C:21]2[CH:30]=[CH:29][C:24]([C:25]([NH:27][NH2:28])=[O:26])=[CH:23][CH:22]=2)=[CH:4][CH:3]=1.[CH:31](O)=[O:32]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[N:11][C:10]=2[C:21]2[CH:22]=[CH:23][C:24]([C:25]([NH:27][NH:28][CH:31]=[O:32])=[O:26])=[CH:29][CH:30]=2)=[CH:4][CH:3]=1
Reactant: O=CO
Reactant: Cn1c(-c2ccccn2)nc(-c2ccc(C(=O)NN)cc2)c1Sc1ccc(Cl)cc1
Product: Cn1c(-c2ccccn2)nc(-c2ccc(C(=O)NNC=O)cc2)c1Sc1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
4-{5-[(4-Chlorophenyl)thio]-1-methyl-2-pyridin-2-yl-1H-imidazol-4-yl}benzohydrazide (Step 1 of Example 48, 400 mg) was dissolved in 3 mL of formic acid. After stirring overnight, the volatiles were removed under reduced pressure to afford the title compound. 1H NMR (500 MHz, (CDCl3): 8.84 (broad d, 1H), 8.41 (d, 1H), 8.19 (d, 2H), 7.85 (t, 1H), 7.48 (broad d, 2H), 7.38 (t, 1H), 7.23 (d, 2H), 7.04 (d, 2H), 4.14 (s, 3H). LCMS: m/z 464, (M+H)+.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([O:14][CH3:15])=[C:11]([NH2:13])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:16]([O-])(O)=[O:17].[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([O:14][CH3:15])=[C:11]([N:13]=[C:16]=[O:17])[CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc(C2CCCCC2)cc1N
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1ccc(C2CCCCC2)cc1N=C=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 5-cyclohexyl-2-methoxy-phenylamine (106 mg, 0.49 mmol), CH2Cl2 (10 mL) and saturated NaHCO3 (5 mL) was added a 20% solution of COCl2 in toluene (0.39 mL) directly to the organic layer. The mixture was stirred for 15 min at RT, diluted with CH2Cl2 and extracted with water. The organic layer was dried over Na2SO4, filtered and concentrated to yield 4-cyclohexyl-2-isocyanato-1-methoxy-benzene.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](F)[C:5]2[C:6]3[NH:14][C:13](=[O:15])[NH:12][C:11](=[O:16])[C:7]=3[NH:8][C:9]=2[CH:10]=1.[O:18]([CH3:20])[K]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([O:18][CH3:20])[C:5]2[C:6]3[NH:14][C:13](=[O:15])[NH:12][C:11](=[O:16])[C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: O=c1[nH]c(=O)c2[nH]c3cc(Br)cc(F)c3c2[nH]1
Reactant: CO[K]
Solvent: C1COCCO1
Product: COc1cc(Br)cc2[nH]c3c(=O)[nH]c(=O)[nH]c3c12
Temperature: 25 °C
Yield: 36.8 %

Procedure:
1.7 g (5.7 mmol) 7-bromo-9-fluoro-1H-pyrimido[5,4-b]indole-2,4(3H,5H)-dione, 4.5 g (17.0 mmol) 18-Krone-6 and 12 ml (162.5 mmol) 30% KOMe solution (MeOH) were refluxed in 600 ml dioxan for 20 h. Having cooled down to room temperature, the solvent was concentrated, water was added and acidified using 1 N HCl. The resulting precipitate was sucked off and washed with water. 650 mg (37%) 7-bromo-9-methoxy-1H-pyrimido[5,4-b]indole-2,4(3H,5H)-dione was obtained. ESI-MS [m/z]: 308, 310 [M−H]−
Reaction SMILES: [C:1]([O:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])(=[O:4])[C:2]#[CH:3].C([Li])CCC.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1.[Cl-].[NH4+]>O1CCCC1>[OH:23][CH:22]([C:21]1[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1)[C:3]#[C:2][C:1]([O:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])=[O:4]
Reactant: C#CC(=O)OCC=C(C)C
Reactant: COc1ccc(C=O)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C(O)C#CC(=O)OCC=C(C)C)cc1
Reaction time: 0.17 h

Procedure:
A solution of 10 g (72 mmol) of 3-methyl-2-butenyl propiolate in 100 ml of tetrahydrofuran was treated at -78° under argon with 47 ml of n-butyllithium (1.6M in hexane). The mixture was stirred at -78° for 10 minutes and then a solution of 8.8 ml (72 mmol) of 4-methoxybenzaldehyde in 100 ml of tetrahydrofuran was added within 30 minutes. The reaction mixture was stirred at -78° for a further 30 minutes, then brought to room temperature and treated with 100 ml of saturated ammonium chloride solution. The aqueous phase was extracted twice with ether. The organic phases were washed in succession with saturated sodium chloride solution and with water, dried over sodium sulphate and concentrated. The residue was purified by flash chromatography on 1000 g of silica gel (elution agent methylene chloride/ethyl acetate 9:1). There was obtained 3-methyl-2-butenyl 4-hydroxy-4-(4-methoxyphenyl)-2-butynoate as a yellow oil.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[C:22](=[O:23])[C:21](=[O:24])[N:20]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32](Cl)=[O:33])=[CH:28][CH:27]=3)[C:19]2([CH3:36])[CH3:35])=[CH:13][CH:12]=1)=[O:10]>N1C=CC=CC=1>[O:7]([C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[C:22](=[O:23])[C:21](=[O:24])[N:20]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]([O:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[O:33])=[CH:28][CH:27]=3)[C:19]2([CH3:36])[CH3:35])=[CH:13][CH:12]=1)=[O:10])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: CC1(C)N(Cc2ccc(C(=O)Cl)cc2)C(=O)C(=O)N1Cc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Product: CC1(C)N(Cc2ccc(C(=O)Oc3ccccc3)cc2)C(=O)C(=O)N1Cc1ccc(C(=O)Oc2ccccc2)cc1

Procedure:
To a solution of 10 g (0.106 mole) of phenol in 20 ml of pyridine are added at room temperature, with stirring, 5 g (0.0115 mole) of 1,3-bis-(4'-chlorocarbonylphenylmethyl)-2,2-dimethylimidazolidine-4,5-dione.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[N+:27]([C:30]1[CH:81]=[CH:80][C:33]([CH2:34][O:35][C:36]([NH:38][C:39](=[N:66][C:67]([O:69][CH2:70][C:71]2[CH:76]=[CH:75][C:74]([N+:77]([O-:79])=[O:78])=[CH:73][CH:72]=2)=[O:68])[NH:40][CH2:41][CH2:42][CH2:43][S:44][C:45]2[N:46]=[CH:47][N:48]3[CH:52]=[C:51]([Sn](CCCC)(CCCC)CCCC)[S:50][C:49]=23)=[O:37])=[CH:32][CH:31]=1)([O-:29])=[O:28]>>[N+:77]([C:74]1[CH:75]=[CH:76][C:71]([CH2:70][O:69][C:67]([NH:66][C:39](=[N:38][C:36]([O:35][CH2:34][C:33]2[CH:32]=[CH:31][C:30]([N+:27]([O-:29])=[O:28])=[CH:81][CH:80]=2)=[O:37])[NH:40][CH2:41][CH2:42][CH2:43][S:44][C:45]2[N:46]=[CH:47][N:48]3[CH:52]=[C:51]([C:8]4[C@H:9]([CH3:10])[C@@H:5]5[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:25](=[O:26])[N:6]5[C:7]=4[C:12]([O:14][CH2:15][C:16]4[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=4)=[O:13])[S:50][C:49]=23)=[O:68])=[CH:72][CH:73]=1)([O-:79])=[O:78]
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(SCCCNC(=NC(=O)OCc3ccc([N+](=O)[O-])cc3)NC(=O)OCc3ccc([N+](=O)[O-])cc3)c2s1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(SCCCNC(=NC(=O)OCc5ccc([N+](=O)[O-])cc5)NC(=O)OCc5ccc([N+](=O)[O-])cc5)c4s3)[C@H](C)[C@H]12
Yield: 55.5 %

Procedure:
The procedure of Example 1a) was repeated, except that 297 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 777 mg of 7-[3-N,N′-bis(4-nitrobenzyloxycarbonyl)guanidinopropyl]thio-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds. Thus, 436 mg of 4-nitrobenzyl (1S,5R,6S)-2-[7-[3-N,N′-bis(4-nitrobenzyloxycarbonyl)guanidinopropyl]thioimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate was prepared.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:16])[C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][CH:6]=1.[H-].[Na+].[CH3:19]I.O>CN(C=O)C>[CH3:19][O:1][CH2:2][CH2:3][N:4]([CH3:16])[C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][CH:6]=1
Reactant: CI
Reactant: CCOC(=O)c1ccc(N(C)CCO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(N(C)CCOC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.8 %

Procedure:
To a solution of ethyl 4-[(2-hydroxyethyl) (methyl)amino]benzoate (611 mg, 2.74 mmol) in DMF (10 ml) were added sodium hydride (60% in oil, 143 mg, 3.56 mmol) and methyl iodide (0.222 ml, 3.56 mmol), and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous MgSO4, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (1:0-7:3, v/v) to give the title compound (467 mg, 72%) as a colorless oil.
Reaction SMILES: Cl[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[O:3]1.[H][H].Cl>[Pt].C1(C)C(C)=CC=CC=1>[C:4]1([C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2][O:3]1)=[O:5]
Reactant: O=C1OC(Cl)c2ccccc21
Reactant: [H][H]
Agent: [Pt]
Agent: Cl
Solvent: Cc1ccccc1C
Product: O=C1OCc2ccccc21

Procedure:
842.5 parts of 3-chlorophthalide and 750 parts of xylene were heated in a stirring vessel with 25.3 parts of a catalyst composed of 5% Pt on charcoal, at 85° C., and 160 liters of hydrogen were fed in hourly. After a reaction time of 13 hours, hydrogen chloride ceased to evolve. The reaction mixture was separated from the catalyst and worked up by distillation. 549 parts of phthalide were obtained, corresponding to 81.9% of the theory.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13](=[O:21])[C:14]3[CH:19]=[CH:18][CH:17]=[N:16][C:15]=3F)=[CH:9][CH:10]=2)[NH:5][CH2:4][CH2:3]1.Cl.Cl.[NH:25]1[C:29]2=[N:30][CH:31]=[CH:32][C:33]([CH2:34][NH2:35])=[C:28]2[CH2:27][CH2:26]1>>[NH:25]1[C:29]2=[N:30][CH:31]=[CH:32][C:33]([CH2:34][NH:35][C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13]([NH:12][C:8]3[CH:7]=[C:6]4[C:11]([C:2]([CH3:22])([CH3:1])[CH2:3][CH2:4][NH:5]4)=[CH:10][CH:9]=3)=[O:21])=[C:28]2[CH2:27][CH2:26]1
Reactant: CC1(C)CCNc2cc(NC(=O)c3cccnc3F)ccc21
Reactant: NCc1ccnc2c1CCN2
Agent: Cl
Product: CC1(C)CCNc2cc(NC(=O)c3cccnc3NCc3ccnc4c3CCN4)ccc21

Procedure:
The titled compound was prepared from N-(4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-2-fluoro-nicotinamide and C-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-methylamine dihydrochloride by the method described in Step A of Example 1. MS (ES+): 429 (M+H). Calc'd. for C25H28N6O—428.54.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:20][S:21][C:22]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:10][NH:11][C@H:12]([C:17]([OH:19])=O)[C@H:13]([CH2:15][CH3:16])[CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C)CCCN=C=NCC.ON1C(=O)C2C=CC=CC=2N=N1.[CH2:64]([NH2:72])[CH2:65][C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1.C(N(C(C)C)CC)(C)C>CCOC(C)=O.C(Cl)(Cl)Cl>[CH2:64]([NH:72][C:17](=[O:19])[C@H:12]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH:11][CH2:10][C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:20][S:21][C:22]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[CH2:65][C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1
Reactant: NCCc1ccccc1
Reactant: CC[C@H](C)[C@H](NC[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: O=c1c2ccccc2nnn1O
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)[C@H](NC[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)OC(C)(C)C)C(=O)NCCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
The product of Step C (0.108 g, 0.2 mmol), 1-(3-dimethylaminopropyl )-3-ethylcarbodiimide (EDC) (0.042 g, 0.22 mmol), and 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine (HOOBT) (0.036g, 0.22 mmol) were dissolved in 4 mL of 1:1 EtOAc/CHCl3 and stirred at ambient temperature for 0.5 hr. To this yellow solution was added phenethylamine (0.028 mL, 0.22 mmol) and diisopropylethylamine (0.038 mL, 0.22 mmol) and stirring was continued for 48 h. The solution was concentrated and the residue was partitioned between EtOAc and H2O. The organic layer was washed with water, aqueous saturated NaHCO3, brine, and dried (Na2SO4). Filtration and concentration followed by chromatography (SiO2, EtOAc: hexane, 1:3) gave 0.09 g (69%) of the title compound.
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:9]2[N:10]=[C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:12]=[CH:13][C:8]=2[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4]1.[O:23]1[CH2:28][CH2:27][N:26]([S:29]([C:32]2[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[S:40])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH2:25][CH2:24]1.C(N(CC)CC)C>>[O:23]1[CH2:24][CH2:25][N:26]([S:29]([C:32]2[CH:33]=[CH:34][C:35]([NH:38][C:39]([N:17]3[CH2:18][CH2:19][N:14]([C:11]4[N:12]=[CH:13][C:8]5[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4][N:3]([CH2:2][CH3:1])[C:9]=5[N:10]=4)[CH2:15][CH2:16]3)=[S:40])=[CH:36][CH:37]=2)(=[O:31])=[O:30])[CH2:27][CH2:28]1
Reactant: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCNCC3)nc21
Reactant: O=S(=O)(c1ccc(N=C=S)cc1)N1CCOCC1
Solvent: CCN(CC)CC
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(C(=S)Nc4ccc(S(=O)(=O)N5CCOCC5)cc4)CC3)nc21
Yield: 87.3 %

Procedure:
Pipemidic acid (14.2 mg, 0.0468 mmol), 4-(morpholinosulfonyl)phenyl isothiocyanate (14 mg, 0.0468 mmol) and triethylamine (13 μL, 0.0935 mmol) were used. Purification on silica yielded 6 (24 mg, 85%). 1H NMR (300 MHz, CDCl3) δ 9.28 (s, 1H), 8.65 (s, 1H), 8.09 (s, 1H), 7.64 (d, J=8.71 Hz, 2H), 7.51 (d, J=8.61 Hz, 2H), 4.43-4.01 (m, 10H), 3.80-3.70 (m, 4H), 3.04-2.98 (m, 4H), 1.49 (t, J=7.17 Hz, 3H) ppm.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][C:5]1[S:9][C:8]2[CH:10]=[C:11]([CH3:14])[CH:12]=[CH:13][C:7]=2[CH:6]=1.[Br:16]Br.CC(OC)(C)C>CC(O)=O>[Br:16][C:6]1[C:7]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:8]=2[S:9][C:5]=1[CH2:4][CH2:3][N:2]([CH3:1])[CH3:15]
Reactant: Cc1ccc2cc(CCN(C)C)sc2c1
Reactant: BrBr
Solvent: COC(C)(C)C
Solvent: CC(=O)O
Product: Cc1ccc2c(Br)c(CCN(C)C)sc2c1
Reaction time: 8 h
Yield: 77 %

Procedure:
To a suspension of dimethyl-[2-(6-methyl-benzo[b]thiophen-2-yl)-ethyl]-amine (1.05 g, 4.78 mmol) in HOAc (5 mL) at 0° C., bromine was added slowly. The mixture was stirred overnight while it was allowed to slowly reach room temperature. MTBE (6 mL) was added and the solid was filtered, washed with MTBE and dried under vacuum. It was taken up in dichloromethane, washed with sat. NaHCO3 and brine, dried (Na2SO4), filtered and concentrated in vacuo to give 1.1 g of [2-(3-bromo-6-methyl-benzo[b]thiophen-2-yl)-ethyl]-dimethyl-amine (77% yield).
Reaction SMILES: C[O:2][C:3](=[O:46])[C@@H:4]([NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38](=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]([CH2:29][CH3:30])=[CH:15][C:16]2[CH:28]=[CH:27][C:26]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][C:18]=3[CH:17]=2)=[CH:8][CH:7]=1.[OH-].[Na+]>C(O)C.C1COCC1>[C:38]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[NH:31][C@@H:4]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]([CH2:29][CH3:30])=[CH:15][C:16]2[CH:28]=[CH:27][C:26]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][C:18]=3[CH:17]=2)=[CH:8][CH:7]=1)[C:3]([OH:46])=[O:2])(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CCC(=Cc1ccc2c(c1)Cc1ccccc1-2)COc1ccc(C[C@H](Nc2ccccc2C(=O)c2ccccc2)C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCC(=Cc1ccc2c(c1)Cc1ccccc1-2)COc1ccc(C[C@H](Nc2ccccc2C(=O)c2ccccc2)C(=O)O)cc1
Temperature: 5 °C
Reaction time: 16 h
Yield: 73.2 %

Procedure:
(S)-2-(2-Benzoyl-phenylamino)-3-{4-[2-ethyl-3-(9H-fluoren-2-yl)-allyloxy]-phenyl}-propionic acid methyl ester (example 5) (700 mg, 1.15 mmol) was dissolved in a mixture of ethanol (20 ml) and THF (20 ml). 1N NaOH (10 ml) was added and the mixture was stirred for 16 h at 5° C. The mixture was concentrated in vacuo. 1N HCl and ethyl acetate (10 ml) was added. The aqueous phase was isolated and extracted with ethyl acetate (×2) The organic layers were combined, washed with water, dried (MgSO4) and evaporated to give 500 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:17]=[N:16][C:15]3[C:14]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[N:13][C:12]([C:24]4[CH:25]=[N:26][C:27]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[N:28][CH:29]=4)=[N:11][C:10]=3[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH:38]1([C:41](O)=[O:42])[CH2:40][CH2:39]1.CN(C=O)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O>[CH:38]1([C:41]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[CH:17]=[N:16][C:15]4[C:14]([N:18]5[CH2:23][CH2:22][O:21][CH2:20][CH2:19]5)=[N:13][C:12]([C:24]5[CH:25]=[N:26][C:27]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[N:28][CH:29]=5)=[N:11][C:10]=4[CH:9]=3)[CH:5]=[CH:6][CH:7]=2)=[O:42])[CH2:40][CH2:39]1
Reactant: O=C(O)C1CC1
Reactant: CC(C)(C)OC(=O)Nc1ncc(-c2nc(N3CCOCC3)c3ncc(-c4cccc(N)c4)cc3n2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ncc(-c2nc(N3CCOCC3)c3ncc(-c4cccc(NC(=O)C5CC5)c4)cc3n2)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.9 %

Procedure:
To a 25 mL round bottom flask, tert-butyl (5-(7-(3-aminophenyl)-4-morpholinopyrido[3,2-d]pyrimidin-2-yl)pyrimidin-2-yl)carbamate (0.2 g, 0.0004 mol), cyclopropane carboxylic acid (0.041 g, 0.00048 mol) and DMF (8 mL) were added. To the same flask, HATU (0.46 g, 0.0012 mol) and TEA (0.22 mL, 0.0016 mol) were added. The reaction mass was stirred at room temperature for 12 hours. The volatiles were evaporated to dryness under reduced pressure to provide a residue. The residue was stirred with water to provide a solid and the solid was collected by filtration. The solid was washed with diethyl ether to provide the crude product. The crude product was purified by flash column chromatography (1-2% methanol in chloroform) to afford the title compound (0.15 g, 66%). 1H NMR (300 MHz, DMSO-d6): δ 10.42 (br s, 2H), 9.48 (s, 1H), 9.07 (d, J=2.4 Hz, 1H), 8.31 (d, J=1.8 Hz, 1H), 8.20 (s, 1H), 7.47-7.67 (m, 3H), 4.57 (br s, 4H), 3.84 (s, 4H), 1.84-1.80 (m, 1H), 1.49 (s, 9H), 0.85-0.83 (m, 4H): LC-MS (ESI): Calculated mass: 568.2; Observed mass [M+H]+: 569.2 (RT=1.56 min).
Reaction SMILES: [CH:1]12[CH2:13][CH:4]([C:5]3[C:6]([OH:12])=[CH:7][CH:8]=[C:9]([OH:11])[C:10]=31)[CH2:3][CH2:2]2.B(F)(F)F.CCOCC.[Cl:23][CH2:24][CH2:25][CH2:26][C:27]([CH3:31])(O)[CH:28]=[CH2:29].O>O1CCOCC1>[Cl:23][CH2:24][CH2:25][CH2:26][C:27]1([CH3:31])[CH2:28][CH2:29][C:7]2[C:6](=[C:5]3[CH:4]4[CH2:13][CH:1]([CH2:2][CH2:3]4)[C:10]3=[C:9]([OH:11])[CH:8]=2)[O:12]1
Reactant: Oc1ccc(O)c2c1C1CCC2C1
Reactant: C=CC(C)(O)CCCCl
Agent: FB(F)F
Solvent: CCOCC
Solvent: O
Solvent: C1COCCO1
Product: CC1(CCCCl)CCc2cc(O)c3c(c2O1)C1CCC3C1
Temperature: 110 °C
Reaction time: 2 h
Yield: 49.3 %

Procedure:
A mixture of 1,2,3,4-tetrahydro-1,4-methano-naphthalene-5,8-diol (1.34 g, 794 mmol), 1.0 mL (3.97 mmol) of BF3.Et2O and 25 ml of dioxane was heated up to 110° C. under a N2 atmosphere. A solution of 6-chloro-3-methyl-hex-1-en-3-ol (1.12 g, 8.6 mmol) in 24 ml of dioxane was added slowly to the mixture. The addition was completed after two hours and the mixture was continued to reflux for an additional 3 hours. After cooling down to room temperature, the mixture was poured to water, extracted with ethyl acetate, washed with water and dried over MgSO4. After removal of the solvents, the residue was mixed with methanol/HCl and let stand overnight at room temperature. After the removal of the solvents the residue was purified via flash column chromatography on silica gel (1:3 EtOAc/Hex) twice to give 1.30 g of 2-(3-chloro-propyl)-2-methyl-3,4,7,8,9,10-hexahydro-7,10-methano-2H-benzo[h]chromen-6-ol. 1H-NMR (300 MHz, CDCl3) δ (ppm): 6.39 (s, 1H), 4.27 (s, 1H), 3.63-3.47 (m, 4H), 2.73-2.70 (m, 2H), 2.00-1.47 (m, 8H), 1.43-1.15 (m, 4H); MS: 307 (M+H+, 100%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][CH2:6][CH:5]([CH3:9])[N:4]([CH2:10][C:11]([O:13]C(C)(C)C)=[O:12])[C:3]1=[O:18].FC(F)(F)C(O)=O>>[NH2:1][CH:2]1[CH2:8][CH2:7][CH2:6][CH:5]([CH3:9])[N:4]([CH2:10][C:11]([OH:13])=[O:12])[C:3]1=[O:18]
Reactant: CC1CCCC(N)C(=O)N1CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC1CCCC(N)C(=O)N1CC(=O)O

Procedure:
Alternatively, the t-butyl ester of the major diastereomer of 3-amino-1-t-butoxycarbonylmethyl-7-methylperhydroazepin2-one may be cleaved with trifluoroacetic acid to afford 3-amino-1-carboxymethyl-7-methylperhydroazepin-2-one. Reductive condensation of this compound with the α-ketoacids listed in Table III following the procedure described in Example I affords the products of Formula I described above.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([CH3:19])([CH3:18])[C:6](=[O:17])[CH:7](Br)[O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[CH3:2].[NH:21]1[CH:25]=[N:24][CH:23]=[N:22]1>C(#N)C>[CH2:1]([O:3][C:4](=[O:20])[C:5]([CH3:19])([CH3:18])[C:6](=[O:17])[CH:7]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[N:21]1[CH:25]=[N:24][CH:23]=[N:22]1)[CH3:2]
Reactant: c1nc[nH]n1
Reactant: CCOC(=O)C(C)(C)C(=O)C(Br)Oc1ccc(Cl)cc1
Solvent: CC#N
Product: CCOC(=O)C(C)(C)C(=O)C(Oc1ccc(Cl)cc1)n1cncn1
Yield: 77.8 %

Procedure:
34 g (0.091 mol) of 4-bromo-4-(4-chlorophenoxy)-2,2-dimethyl-3-keto-butanoic acid ethyl ester were dissolved in 240 ml of acetonitrile. 24 g (0.345 mol) of 1,2,4-triazole were added and the mixture was heated for 48 hours under reflux. The solvent was then distilled off in vacuo, the residue was dissolved in 200 ml of methylene chloride and the solution was washed three times with 50 ml of water each time, dried over sodium sulphate and concentrated. The oil which remained was boiled up with 100 ml of petroleum ether, whereupon it crystallized. The solid was filtered off and dried. 24.9 g (78% of theory) of 4-(4-chlorophenoxy)-2,2-dimethyl-3-keto-4-(1,2,4-triazol-1-yl)-butanoic acid ethyl ester of melting point 88°-89° C. were obtained.