Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:26]=[C:25]([CH2:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH2:35][C:36]([O-:38])=O)[C:24]([C:39]([F:42])([F:41])[F:40])=[CH:23][N:22]=3)=[C:16]([O:43][CH3:44])[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Li+].O[N:47]1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.Cl.C(N(CC)C(C)C)(C)C.C(=O)([O-])[O-].[NH4+].[NH4+]>O1CCCC1.CN(C)C=O>[CH3:44][O:43][C:16]1[CH:15]=[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:19]=[CH:18][C:17]=1[NH:20][C:21]1[N:26]=[C:25]([CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH2:35][C:36]([NH2:47])=[O:38])[C:24]([C:39]([F:42])([F:40])[F:41])=[CH:23][N:22]=1
Reactant: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2ccccc2CC(=O)[O-])n1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc(N2CCNCC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2ccccc2CC(N)=O)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of lithium 2-(2-(2-(2-((4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetate (I7) (0.352 g, 0.672 mmol), 1-hydroxybenzotriazole (0.093 g, 0.686 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide) hydrochloride (0.121 g, 0.629 mmol) in dry tetrahydrofuran (16 mL) and dimethylformamide (7 mL) was added N,N-diisopropylethylamine (0.498 mL, 2.86 mmol) under a nitrogen atmosphere. The reaction mixture was stirred for 10 minutes at room temperature then ammonium carbonate (0.263 g, 2.859 mmol) was added and the resulting suspension was stirred at room temperature for 18 hours. The reaction volatiles were evaporated in vacuo and the resulting residue was diluted with ethyl acetate (15 mL) and water (10 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×15 mL). The combined organic extracts were washed with water, brine, dried (magnesium sulfate) and concentrated in vacuo to give a yellow foam which was purified by flash column chromatography on silica gel (55-85% ethyl acetate/petroleum ether) to give the title compound (I8) (0.276 g, 87%) as a yellow foam; 1H NMR (300 MHz, CDCl3) δ 1.48 (d, 9 H, J=1.1 Hz), 3.09 (d, 8 H, J=3.9 Hz), 3.58 (brs, 4 H), 3.66 (s, 2 H), 3.88 (d, 3 H, J=1.0 Hz), 5.48 (brs, 1 H), 5.78 (brs, 1 H), 6.54 (d, 1 H, J=1.3 Hz), 6.57 (s, 1 H), 7.23-7.25 (brs, 4 H), 7.72 (s, 1 H), 8.13 (d, 1 H, J=8.6 Hz) and 8.48 (s, 1 H). LCMS Method B: rt 8.52 min; m/z 615.4 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:30]=[CH:29][CH:28]=[CH:27][C:10]=2[C:11]([NH:13][C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[C:19]([C:24](O)=[O:25])[CH:20]=[N:21]3)=[CH:16][CH:15]=2)=[O:12])=[N:7][CH:8]=1.[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C@H:39]([NH2:42])[CH2:40][CH3:41].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C@H:39]([NH:42][C:24]([C:19]1[CH:20]=[N:21][C:22]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[C:14]([NH:13][C:11](=[O:12])[C:10]1[CH:27]=[CH:28][CH:29]=[CH:30][C:9]=1[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:31])[F:32])=[CH:8][N:7]=1)[CH:23]=2)=[O:25])[CH2:40][CH3:41]
Reactant: CC[C@@H](N)c1ccccn1
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cn3)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@@H](NC(=O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cn3)ccc2c1)c1ccccn1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
7-[2-(5-Trifluoromethyl-pyridin-2-yl)-benzoylamino]-quinoline-3-carboxylic acid (25 mg, 0.06 mmol), [R]-1-pyridin-2-yl-propylamine (23 mg, 0.17 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (33 mg, 0.17 mmol), 1-hydroxybenzotriazole (23 mg, 0.17 mmol), and triethylamine (69 mg, 0.69 mmol) were combined in 5 ml of dichloromethane. After stirring 5 h at room temperature, the mixture was diluted with dichloromethane and washed with 10 ml of 1 N HCl, the organic layer was dried (magnesium sulfate), filtered and concentrated under vacuum. Purification of the residue by silica gel chromatography eluting with 5% methanol in ethyl acetate afforded the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[C:12]1(=O)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.N1CCCC1.Cl>CO.O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][C:12]1([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH2:9][C:8]2=[O:10]
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: O=C1CCCCCC1
Agent: Cl
Solvent: O
Solvent: CO
Solvent: C1CCNC1
Product: O=C1CC2(CCCCCC2)Oc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 126.7 %

Procedure:
A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (10 g, 46.7 mmol), cycloheptanone (11 mL, 93.5 mmol) and pyrrolidine (7.7 mL, 93.5 mmol) in MeOH (190 mL) was stirred at room temperature overnight. The mixture was concentrated in vacuo to give the residue, which was added water and HCl (36%) until pH=1. The mixture was extracted with EtOAc and then the organic layer was concentrated to give 6-bromospiro[chroman-2,1′-cycloheptan]-4-one (18.3 g, 100%). 1H-NMR (CDCl3): 1.34 (m, 1H), 1.49 (m, 1H), 1.62 (m, 10H), 1.71 (m, 1H), 2.02 (m, 1H), 6.78 (m, 1H), 7.47 (m, 1H), 7.86 (m, 1H).
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[Li]CCCC.[Si:15]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30]I)=[CH:26][CH:25]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].O>C1COCC1.CCOCC>[Si:15]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[CH:26][CH:25]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(CI)cc1
Reactant: C#CCCCCCCC
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCC#CCc1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.7 %

Procedure:
To a solution of 1; -nonyne (150 mg, 1.2 mmol) in THF (5 mL) at -78° C., was added n-BuLi (0.47 mL, 1.19 mmol). The resulting mixture was stirred for 30 minutes and a solution of [(tertButyldimethylsilyl)oxymethyl]-4-iodomethyl benzene (40) (361 mg, 2 mmol) in THF (1 mL) was added. The reaction mixture was then stirred at -78° C. for 1 hour, allowed to warm to 0° C. and stirred for an additional 30 minutes. At this time, water (2 mL) was slowly added and the mixture was poured into water (50 mL) and Et2O (50 mL). The organic layer was separated, dried (MgSO4) and concentrated in vacuo to yield a yellow oil. Purification by flash silica gel chromatography (95:05 hexane/EtOAc) afforded (51) (313 mg, 87%) as a colorless oil: Rf 0.85 (95:05 hexane/EtOAc); 1H NMR (CDCl3) δ 7.34 (d, J=8.7 Hz, 2 H), 7.29 (d, J=7.8 Hz, 2 H), 4.75 (s, 2 H), 3.59 (t, J=2.4 Hz, 2 H), 2.24 (tt, J1 =7.2 Hz, J2 =2.4 Hz, 2 H), 1.55 (m, 2 H), 1.42 (m, 2 H), 1.32 (m, 6 H), 0.97 (s, 9 H), 0.92 (t, J=6.9 Hz, 3 H), 0.12 (s, 6 H); 13 C NMR (CDCl3) δ 139.68, 136,38, 127.83, 126.32, 82.74, 77.76, 64.93, 31.91, 29.18, 29.98, 26.08, 24.97, 22.77, 18.97, 14.23, -5.11. ##STR25##
Reaction SMILES: [N+](C1C=CC(COC(=O)/[C:11](/[N:22]2[CH:25]([S:26]S(C3C=CC(C)=CC=3)(=O)=O)[CH:24](NC(=O)COC3C=CC=CC=3)[C:23]2=[O:48])=[C:12](\OCC2C=CC=CC=2)/[CH3:13])=CC=1)([O-])=O.[N+](C1C=CC(COC(=O)/C=C\C)=CC=1)([O-])=O.N12CCCCC1C=NCCC2.C(Cl)Cl>O1CCCC1>[S:26]1[C@@H:25]2[CH2:24][C:23](=[O:48])[N:22]2[CH:11]=[CH:12][CH2:13]1
Reactant: C/C(OCc1ccccc1)=C(/C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccc(C)cc1
Agent: C/C=C\C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: C1=NCCCN2CCCCC12
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C1C[C@H]2SCC=CN12
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
A solution of 731 mg (1 mmol) of a 1:1 mixture consisting of 2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-benzoxy-crotonic acid p-nitrobenzyl ester and the corresponding isocrotonic acid p-nitrobenzyl ester in a mixture of 0.185 ml (1.2 mmols) of 1,5-diazabicyclo[5.4.0]undec-5-ene in 20 ml of dry tetrahydrofurane is stirred for precisely 35 minutes at room temperature. 50 ml of methylene chloride are added to the mixture and the whole is washed successively with dilute hydrochloric acid, water and dilute aqueous sodium bicarbonate solution. The organic phase is dried over sodium sulphate and concentrated by evaporation in vacuo. The residue is chromatographed on 25 mg of acid-washed silica gel, using toluene/ethyl acetate (3:1). A mixture consisting of the ceph-2-em compound and the ceph-3-em compound in the ratio of about 3:1 is obtained; this mixture can be separated by repeated chromatography into the pure isomers, giving 7β-phenoxyacetamido-3-benzoxy-ceph-2-em-4α-carboxylic acid p-nitrobenzyl ester of melting point 160° C.-162° C. (diethyl ether/pentane); IR spectrum (methylene chloride): characteristic bands at 5.6, 5.7, 5.9 and 7.4μ, and 7β-phenoxyacetamido-3-benzoxy-ceph-3-em-4-carboxylic acid p-nitrobenzyl ester in the form of a colourless foam, IR spectrum (methylene chloride): characteristic bands at 5.6, 5.8 sh, 5.9, 7.9 and 8.4μ.
Reaction SMILES: [CH2:1]([C:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N:26]3C(C)=CC=C3C)[N:21]=2)[C:9]=1[C:33]1[O:34][CH:35]=[CH:36][N:37]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.NO>CCO.O>[NH2:26][C:22]1[N:21]=[C:20]([N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[C:13]([Cl:19])[CH:12]=3)[C:17](=[O:18])[C:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:9]2[C:33]2[O:34][CH:35]=[CH:36][N:37]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: Cc1ccc(C)n1-c1cccc(-n2c(-c3ncco3)c(Cc3ccccc3)c(=O)c3ccc(Cl)cc32)n1
Agent: Cl
Agent: NO
Solvent: O
Solvent: CCO
Product: Nc1cccc(-n2c(-c3ncco3)c(Cc3ccccc3)c(=O)c3ccc(Cl)cc32)n1

Procedure:
A solution of 3-benzyl-7-chloro-1-[6-(2,5-dimethyl-pyrrol-1-yl)-pyridin-2-yl]-2-oxazol-2-yl-1H-quinolin-4-one (640 mg) in EtOH (3.5 mL) and water (1.3 mL) and hydroxylamine hydrochloride (450 mg) was stirred for 48 h at 60° C. After evaporation of volatiles, the dark brown residue was partitioned into EtOAc and H2O, and the organic phase adsorbed on silica to provide 1-(6-amino-pyridin-2-yl)-3-benzyl-7-chloro-2-oxazol-2-yl-1H-quinolin-4-one (Compound 141). M+H=428; mp=279.3-282.8° C.
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][NH2:7])(=[O:4])=[O:3].Cl[C:9]1[N:14]=[C:13]([C:15]2[S:19][C:18]([CH:20]([CH3:22])[CH3:21])=[N:17][C:16]=2[C:23]2[CH:24]=[CH:25][C:26]([F:41])=[C:27]([NH:29][S:30]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=3[F:40])(=[O:32])=[O:31])[CH:28]=2)[CH:12]=[CH:11][N:10]=1>C(O)(C)C>[F:40][C:34]1[CH:35]=[C:36]([F:39])[CH:37]=[CH:38][C:33]=1[S:30]([NH:29][C:27]1[CH:28]=[C:23]([C:16]2[N:17]=[C:18]([CH:20]([CH3:21])[CH3:22])[S:19][C:15]=2[C:13]2[CH:12]=[CH:11][N:10]=[C:9]([NH:7][CH2:6][CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])[N:14]=2)[CH:24]=[CH:25][C:26]=1[F:41])(=[O:32])=[O:31]
Reactant: CC(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3ccc(F)cc3F)c2)c(-c2ccnc(Cl)n2)s1
Reactant: CS(=O)(=O)CCN
Solvent: CC(C)O
Product: CC(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3ccc(F)cc3F)c2)c(-c2ccnc(NCCS(C)(=O)=O)n2)s1
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 46.9 %

Procedure:
[2-(Methylsulfonyl)ethyl]amine (352 mg, 2.86 mmol) and N-{5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,4-difluorobenzenesulfonamide (150 mg, 0.286 mmol) were combined and heated to 55° C. overnight. Isopropanol (1 mL) was added to the reaction mixture and stirred an additional 30 min. The reaction mixture was cooled to rt and partitioned between DCM and 10% aqueous HCl. The organic layer was separated and dried over MgSO4, filtered, and concentrated over silica gel. The crude product was chromatographed on silica gel eluting with 100% DCM to 6:4 [DCM:(9:1 EtOAc:MeOH)]. The clean fractions were combined and concentrated to obtain the title compound as a white foam (82.1 mg; 45% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.65 (s, 1H) 8.14 (d, J=4.2 Hz, 1H) 7.72 (q, J=7.6 Hz, 1H) 7.54 (t, J=9.7 Hz, 1H) 7.47 (br. s., 1H) 7.30-7.42 (m, 2H) 7.11-7.30 (m, 2H) 6.23 (d, J=1.2 Hz, 1H) 3.64 (d, J=0.9 Hz, 2H) 3.20-3.40 (m, 2H range includes water peak) 2.99 (s, 3H) 1.33 (d, J=6.7 Hz, 6H). MS (ESI): 612.2 [M+H]+.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:15])[CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:5][C:4]=1[N+:16]([O-])=O>[Fe]>[NH2:16][C:4]1[CH:5]=[C:6]([C:9](=[O:15])[CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:7]=[CH:8][C:3]=1[Br:2]
Reactant: O=C(O)CCC(=O)c1ccc(Br)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: Cl
Product: Nc1cc(C(=O)CCC(=O)O)ccc1Br
Reaction time: 4 h

Procedure:
3.6 ml of concentrated HCl are added dropwise to a mixture of 10 g of 4-(4-bromo-3-nitrophenyl)-4-oxobutanoic acid and 6.5 g of iron powder, the mixture is then boiled under a reflux condenser for 4 hours and undissolved material is filtered off hot. The filtrate is evaporated and, after adding water and 5 ml of 2 N HCl, the oily residue is extracted with ethyl acetate and, after drying the organic phase over sodium sulfate, the solvent is distilled off. Colorless crystalline 4-(3-amino-4-bromophenyl)-4-oxobutanoic acid is obtained, melting point 169°-171° (from water/glacial acetic acid).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([NH:8][C:9]1[NH:13][N:12]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:10]=1)=[O:7])C>C(O)C.O>[OH:7][C:6]1[CH:5]=[C:4]([OH:3])[N:13]2[N:12]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:10]=[C:9]2[N:8]=1
Reactant: CCOC(=O)CC(=O)Nc1cc(C(=O)OCC)n[nH]1
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc2nc(O)cc(O)n2n1
Reaction time: 22 h

Procedure:
To a suspension of ethyl 5-[(3-ethoxy-3-oxopropanoyl)amino]-1H-pyrazole-3-carboxylate (2.60 g, 9.66 mmol) in ethanol (50 mL) and water (50 mL) was added N,N-dimethylaminopyridine (3.54 g, 29.0 mmol) at room temperature. After being stirred for 22 h, the reaction mixture was concentrated in vacuo. The residue was triturated with ethyl acetate/ethanol to give ethyl 5,7-dihydroxypyrazolo[1,5-a]pyrimidine-2-carboxylate. MS (APCI): m/z 224 (M+H), 123 (M+H, DMAP).
Reaction SMILES: [CH3:1][CH:2]([CH3:40])[C:3]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:39]=[CH:38][S:37][CH:36]=2)[CH:30]=1)([C:5]1[N:6]=[CH:7][N:8](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:9]=1)[OH:4].Cl.N1C=CC=CC=1>>[NH:8]1[CH:9]=[C:5]([C:3]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]3[CH:39]=[CH:38][S:37][CH:36]=3)[CH:30]=2)([OH:4])[CH:2]([CH3:40])[CH3:1])[N:6]=[CH:7]1
Reactant: CC(C)C(O)(c1cccc(-c2ccsc2)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)C(O)(c1cccc(-c2ccsc2)c1)c1c[nH]cn1
Yield: 74.1 %

Procedure:
By the reaction in the same manner as in Example 4-(iii) using 2-methyl-1-[3-(3-thienyl)phenyl]-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (1.43 g) and pyridine hydrochloride (550 mg), the title compound (585 mg) was obtained as colorless plate crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:40])[C@@H:12]([NH:21][C:22](=[O:39])[C@@H:23]([C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[S:8][CH:9]=1)=[O:4].C(N(CC)CC)C.[C:48](OC(=O)C)(=[O:50])[CH3:49]>ClCCl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:40])[C@@H:12]([NH:21][C:22](=[O:39])[C@@H:23]([C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:48](=[O:50])[CH3:49])=[CH:34][CH:33]=2)[NH:24][C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[C@H:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH3:14])[S:8][CH:9]=1)=[O:4]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1csc(NC(=O)[C@@H](NC(=O)[C@H](NC(=O)OC(C)(C)C)c2ccc(N)cc2)[C@@H](C)c2ccccc2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1csc(NC(=O)[C@@H](NC(=O)[C@H](NC(=O)OC(C)(C)C)c2ccc(NC(C)=O)cc2)[C@@H](C)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cold solution of 2-{(2S,3S)-2-[(R)-2-(4-amino-phenyl)-2-tert-butoxycarbonylamino-acetylamino]-3-phenyl-butyrylamino}-thiazole-4-carboxylic acid methyl ester (100 mg, 0.177 mmol) in dichloromethane (10 mL) was added triethylamine (50 μL, 0.354 mmol) followed by acetic anhydride (22 μL 0.212 mmol). The reaction mixture was then stirred overnight at room temperature. The solvent was removed in vacuo and the residue was purified by chromatography over silica gel gradient eluted from 10% to 75% ethyl acetate in hexanes to afforded 2-{(2S,3S)-2-[(R)-2-(4-acetylamino-phenyl)-2-tert-butoxycarbonylamino-acetylamino]-3-phenyl-butyryl-amino}-thiazole-4-carboxylic acid methyl ester which was used immediately in the following step of the synthesis (107 mg, 98%).
Reaction SMILES: C(OC([N:8]1[CH2:34][CH2:33][C:12]2=[C:13]([N:20]3[CH2:23][CH:22]([C:24]([N:26]4[CH2:30][CH2:29][CH:28]([C:31]#[CH:32])[CH2:27]4)=[O:25])[CH2:21]3)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=O)(C)(C)C.C(O)(C(F)(F)F)=O.CO>C(Cl)Cl>[C:31]([CH:28]1[CH2:29][CH2:30][N:26]([C:24]([CH:22]2[CH2:21][N:20]([C:13]3[N:14]4[C:18]([N:19]=[C:11]5[CH2:10][CH2:9][NH:8][CH2:34][CH2:33][C:12]=35)=[CH:17][CH:16]=[N:15]4)[CH2:23]2)=[O:25])[CH2:27]1)#[CH:32]
Reactant: C#CC1CCN(C(=O)C2CN(c3c4c(nc5ccnn35)CCN(C(=O)OC(C)(C)C)CC4)C2)C1
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: C#CC1CCN(C(=O)C2CN(c3c4c(nc5ccnn35)CCNCC4)C2)C1
Reaction time: 3 h

Procedure:
To 36 mg (0.08 mmol) 10-[3-(3-Ethynyl-pyrrolidine-1-carbonyl)-azetidin-1-yl]-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohept[f]indene-7-carboxylic acid tert-butyl ester in 10 mL DCM was added 0.4 mL TFA and stirring was continued for 3 h at room temperature. After addition of 2 mL of MeOH 2M NaOH added drop wise to neutralize the reaction mixture. The solvents were evaporated and the residue was purified by HPLC.
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][CH2:4][C:5](=O)[CH3:6].Br.[Br:10][C:11]1[S:15][C:14]([NH2:16])=[N:13][C:12]=1[C:17]([F:20])([F:19])[F:18].P([O-])([O-])([O-])=O>CO>[Br:10][C:11]1[S:15][C:14]([N:16]2[C:2]([CH3:1])=[CH:3][CH:4]=[C:5]2[CH3:6])=[N:13][C:12]=1[C:17]([F:20])([F:19])[F:18]
Reactant: Nc1nc(C(F)(F)F)c(Br)s1
Reactant: CC(=O)CCC(C)=O
Agent: Br
Agent: O=P([O-])([O-])[O-]
Solvent: CO
Product: Cc1ccc(C)n1-c1nc(C(F)(F)F)c(Br)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 1261 %

Procedure:
Add hexane-2,5-dione (3.5 mL, 3.4 g, 30 2 mmol) to a solution of 5-bromo-4-trifluoromethyl-thiazol-2-ylamine hydrobromide (9.0 g, 27.4 mmol) in methanol (60 mL). Stir at room temperature overnight. Add phosphate buffer (50 mL, pH=7). Collect the resulting precipitate by filtration, washing with water. Dissolve the filter cake in CH2Cl2 and dry over sodium sulfate. Filter and concentrate under vacuum to obtain the title compound (8.2 g, 92%). 1H NMR (400 MHz, CDCl3) δ 5.91 (s, 2H), 2.27 (s, 6H).
Reaction SMILES: C([BH3-])#N.[Na+].[CH:5]([C:7]1[C:16]2[O:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:13]([CH3:23])[C:12](=[O:24])[C:11]=2[CH:10]=[CH:9][CH:8]=1)=O.[CH2:25]([CH2:27][NH2:28])[OH:26]>CO.[Cl-].[Zn+2].[Cl-]>[OH:26][CH2:25][CH2:27][NH:28][CH2:5][C:7]1[C:16]2[O:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:13]([CH3:23])[C:12](=[O:24])[C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: Cc1c(-c2ccccc2)oc2c(C=O)cccc2c1=O
Reactant: NCCO
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: Cc1c(-c2ccccc2)oc2c(CNCCO)cccc2c1=O
Yield: 78.6 %

Procedure:
A solution of 2.38 g of anhydrous zinc chloride and 2.30 g of sodium cyanoborohydride in 71 ml of anhydrous methanol was added dropwise under stirring to a mixture of 9.24 g of 8-formyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran and 9.12 g of ethanolamine in 90 ml of anhydrous methanol. Stirring was continued at 20°-25° C. for 5 hours, before removal of the solvent in vacuo. 250 ml of water was added to the residue, and the insoluble matter was collected by suction filtration and washed with water. The crude product was dissolved in 1N aqueous acetic acid solution and the solution was washed with ethyl acetate. The aqueous solution was then made alkaline by addition of 2N aqueous sodium hydroxide solution and the precipitate was collected by suction filtration and washed with water to give 8.5 g of the title compound, m.p. 117°-121° C. after drying at 60° C.
Reaction SMILES: [O:1]=C1CNC(=O)N1CC([O-])=O.[N+:12]([C:15]1[CH:16]=[C:17]([CH:31]=[CH:32][CH:33]=1)[CH2:18][N:19]1[C:23](=[O:24])[C:22](=[O:25])[N:21]([CH2:26][C:27]([OH:29])=[O:28])[C:20]1=S)([O-:14])=[O:13]>Cl.O1CCOCC1>[OH:24][CH:23]1[N:19]([CH2:18][C:17]2[CH:31]=[CH:32][CH:33]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=2)[C:20](=[O:1])[N:21]([CH2:26][C:27]([OH:29])=[O:28])[C:22]1=[O:25]
Reactant: O=C(O)CN1C(=O)C(=O)N(Cc2cccc([N+](=O)[O-])c2)C1=S
Reactant: O=C([O-])CN1C(=O)CNC1=O
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)CN1C(=O)C(O)N(Cc2cccc([N+](=O)[O-])c2)C1=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
The above-prepared dioxoimidazolidine-3-acetate product of paragraph (2) (3.6 g) was dissolved in a mixed solvent of 4N hydrochloric acid and dioxane and the solution was stirred at room temperature for six hours. The reaction solution was concentrated in vacuo to dryness and then chloroform was added to the residue. The crystals were dislodged from the wall of the reaction flask with a spatula. The solid was collected by filtration, washed with chloroform and dried to give 0.8 g of 5-hydroxy-1-(3-nitrobenzyl)-2,4-dioxoimidazolidine-3-acetic acid [Compound 14] as amorphous crystals. The melting point, MS, IR, NMR, and elementary analysis for the compound were:
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH:8](P(OCC)(OCC)=O)[CH3:9])=[O:7].[CH:18](=O)[C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=1.O>C(COC)OC>[CH:23]([C:22]1[CH:25]=[CH:26][C:19]([CH:18]=[C:8]([CH3:9])[C:6]([O:5][CH2:4][CH3:3])=[O:7])=[CH:20][CH:21]=1)=[O:24]
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Reactant: O=Cc1ccc(C=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C(C)=Cc1ccc(C=O)cc1

Procedure:
To a suspension of 10.0 g of 50% sodium hydride (dispersion in mineral oil) in freshly distilled dimethoxyethane (DME, 350 ml) stirred under nitrogen at 10° is added 53.6 ml of triethyl 2-phosphonopropionate in ca. 40 minutes. The mixture is stirred for 0.5 hour at 10° and for an additional 1.5 hours during which time the temperature is allowed to rise to room temperature. This solution is transferred under nitrogen by cannula to a 500 ml addition funnel and is added dropwise to a solution of terephthalaldehyde (33.53 g) in dry DME (475 ml) over a period of 1 hour at 22°-34°. After addition is complete the reaction mixture is stirred mechanically at room temperature for 2 hours, poured into 1 L of water and extracted with 4×500 ml of ether. The ether extract is washed with a saturated sodium chloride solution (700 ml), dried over magnesium sulfate, filtered, and concentrated in vacuo to give a yellow oil which partially crystallizes on standing. This crude mixture is purified by suspending in petroleum ether and ethyl acetate (93:7). The filtrate, after removal of unreacted dialdehyde, is concentrated in vacuo to give a mixture which is further purified by high pressure liquid chromatography (using petroleum ether/ethyl acetate 93:7). There is obtained pure ethyl 4-formyl-α-methylcinnamate. A solution of the aldehyde (34.80 g) in 820 ml of absolute ethanol is treated with 12.11 g of granular sodium borohydride at room temperature under nitrogen. The resulting mixture is stirred at room temperature for 3 hours (or until all borohydride has dissolved) and then concentrated to ca. 200 ml volume, diluted with 400 ml of water, and extracted with 3×200 ml of ether. The ether extract is washed with 100 ml of water and brine (100 ml), is dried over magnesium sulfate, filtered, and the filtrate concentrated in vacuo to give ethyl 3-(p-hydroxymethylphenyl)-2-methylacrylate. To a solution of this product in 350 ml of methylene chloride is added at room temperature 11.53 ml of thionyl chloride dropwise over 25 minutes. The clear, colorless solution is stirred for 2 hours. The solution is washed with 100 ml of water, 200 ml of saturated sodium bicarbonate, 100 ml of water, and 100 ml of brine. The organic layer after drying and removal of solvent yields ethyl 3-(p-chloromethylphenyl)-2-methylacrylate.