Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1](/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)([O-:3])=[O:2].[BH4-].[Na+].O>CO>[N+:1]([CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])/C=C/c1ccc(Oc2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=[N+]([O-])CCc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 28.2 %

Procedure:
To a solution of 1-((E)-2-nitro-vinyl)-4-phenoxy-benzene (1.40 g, 2.90 mmol, purity: 50%) described in Manufacturing Example 17-1-2 in methanol (15 mL) was added sodium borohydride (274 mg, 7.25 mmol) at room temperature while cooling appropriately under nitrogen atmosphere, which was stirred for 10 minutes at room temperature. Water was then added dropwise at room temperature while cooling appropriately. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:5) to obtain the title compound (199 mg, 28%).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]=[CH2:12].[CH3:13][NH2:14].O.Cl.CN>C1COCC1>[CH3:13][NH:14][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]=[CH2:12]
Reactant: CN
Reactant: C=Cn1cnc2c(Cl)ncnc21
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: C=Cn1cnc2c(NC)ncnc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
6-Chloro-9-vinylpurine (JOC 1968, 33, 1341) (0.54 g, 3 mmol), was added to methylamine (15 mmol, 2.0M in THF) in THF (5 mL) and the mixture was stirred for 5 h at rt. Water was added to dissolve the white precipitate (methylamine hydrochloride). The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate, concentrated on a rotavap, and then subjected to silica gel column chromatography (5% methanol/methylene chloride) yielding the desired product.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:21]=[CH:20][C:13]([O:14][C@H:15]([CH3:19])[C:16](Cl)=[O:17])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.FC(F)(F)C1C=CC(OC2C=CC(O[C@H](C)C(O)=O)=CC=2)=NC=1.S(Cl)(Cl)=O.[Na].[C:52]([O:58][CH2:59][CH3:60])(=[O:57])[CH2:53][C:54]([CH3:56])=[O:55]>>[C:54]([C@H:53]([C:16](=[O:17])[CH:15]([O:14][C:13]1[CH:20]=[CH:21][C:10]([O:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:23])([F:22])[F:1])=[CH:8][N:7]=2)=[CH:11][CH:12]=1)[CH3:19])[C:52]([O:58][CH2:59][CH3:60])=[O:57])(=[O:55])[CH3:56]
Reactant: C[C@@H](Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)C(=O)Cl
Reactant: CCOC(=O)CC(C)=O
Agent: C[C@@H](Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)C(=O)O
Agent: [Na]
Solvent: O=S(Cl)Cl
Product: CCOC(=O)[C@H](C(C)=O)C(=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1

Procedure:
Following the above procedures, (R)-2-[4-(5-trifluoromethyl-2-pyridyloxy)phenoxy]propionic acid chloride, prepared from (R)-2-[4-(5-trifluoromethyl-2-pyridyloxy)phenoxy]propionic acid and thionyl chloride, is reacted with the sodium salt of ethyl acetoacetate to give ethyl (R)-2-acetyl-4-[4-(5-trifluoromethyl-2-pyridyloxy)phenoxy]-3-oxopentanoate (XVIII: Q1 is N, Y is hydrogen, Z is trifluoromethyl and R3 is ethyl). This pentanoate is then heated with sodium chloride to give (R)-5-[4-(5-trifluoromethyl-2-pyridyloxy)phenoxy]2,4-hexanedione (XIX; Q1 is N, Y is hydrogen and Z is trifluoromethyl).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([NH2:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].COCCO[Al+]OCCOC.[Na+].[H-]>C1(C)C=CC=CC=1>[CH2:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[CH2:11][NH2:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1cccc(Cc2ccccc2)c1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: NCc1cccc(Cc2ccccc2)c1
Temperature: 60 °C

Procedure:
To a solution of 3-(benzyl)benzamide (0.0094 moles) from Step B in 70 of toluene was added 8 mL of Red-A17 (65+wt. % solution of sodium bis(2-methoxyethoxy)aluminum hydride in toluene, Aldrich) (CAUTION—reaction very exothermic). The reaction mixture was then heated at 60° C. for 2 hours and then poured over ice. The resulting mixture was extracted with ethyl acetate and the combined extracts were washed with water and brine. The organic layer was extracted with 1N HCl and the aqueous layer washed with ethyl acetate. The pH of the aqueous layer was then adjusted to about 9.0 with 1N NaOH and extracted with ethyl acetate. The organic extracts were washed with water and brine and then concentrated to give 3-(benzyl)benzyl amine.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[CH2:15]([N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=2)[CH2:19][CH2:18]1)[CH3:16].OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>CN(C)C(=O)C.O>[CH2:15]([N:17]1[CH2:18][CH2:19][N:20]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:28]3[NH:6][C:4](=[O:5])[C:3]4[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=4[O:13][CH3:14])[N:1]=3)=[CH:30][CH:31]=2)[CH2:21][CH2:22]1)[CH3:16]
Reactant: CCN1CCN(Cc2ccc(C=O)cc2)CC1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: O=S([O-])O
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCN1CCN(Cc2ccc(-c3nc4cc(OC)cc(OC)c4c(=O)[nH]3)cc2)CC1
Temperature: 150 °C
Yield: 28 %

Procedure:
To a solution of 2-amino-4,6-dimethoxy-benzamide (150 mg, 0.76 mmol) and 4-(4-ethyl piperazin-1-ylmethyl)benzaldehyde (177 mg, 0.76 mmol) in N,N-dimethyl acetamide (10 mL), NaHSO3 (150 mg, 0.84 mmol) and p-TSA (319 mg, 1.68 mmol) were added and the reaction mixture was heated at 150° C. for 5 h. The reaction mixture was cooled to room temperature, water was added and the mixture was neutralized with NaHCO3. The solvent was removed under reduced pressure to give the crude product, which was purified by column chromatography to give 2-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one (87 mg, 27%), which was converted to the hydrochloride salt. Selected data: MS (ES) m/z: 409.11; MP 278-280° C. (at decomposition).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=2)[CH:13]=[C:12]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[N:11]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[CH:13]=[C:12]([NH:22][C:23]3[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=3)[N:11]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2c1
Reactant: Oc1ccc(F)cc1
Product: COc1ccc2cc(Nc3cc(C)[nH]n3)nc(Oc3ccc(F)cc3)c2c1

Procedure:
Similar procedure as described in example 10 was used, starting from 4-fluoro-phenol and (1-chloro-7-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(4-fluoro-phenoxy)-7-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 365(MH+).
Reaction SMILES: [C:1]1([S:7](NC2SC3CCCCC=3C=2C(OCC)=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:25][C:26]1[S:30][C:29]2[CH2:31][CH2:32][C:33]([CH3:36])([CH3:35])[CH2:34][C:28]=2[C:27]=1[C:37]([O:39][CH2:40][CH3:41])=[O:38].C1(S(Cl)(=O)=O)C=CC=CC=1>>[CH3:36][C:33]1([CH3:35])[CH2:32][CH2:31][C:29]2[S:30][C:26]([NH:25][S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])=[C:27]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:28]=2[CH2:34]1
Reactant: CCOC(=O)c1c(N)sc2c1CC(C)(C)CC2
Reactant: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2)sc2c1CCCC2
Agent: O=S(=O)(Cl)c1ccccc1
Product: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2)sc2c1CC(C)(C)CC2

Procedure:
Prepared by proceeding in a similar manner to Intermediate 1, starting from ethyl 2-amino-5,5-dimethyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (prepared according to Pinkerton et al., Bioorg. Med. Chem. Lett., 2007, 17, 3562-3569) and benzenesulphonyl chloride.
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([NH:18][C:19](=[O:41])[CH2:20][C@H:21]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:16][OH:17])=O)C1C=CC=CC=1.[CH2:42](Cl)[O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:44]([O:43][CH2:42][O:17][CH2:16][C@H:15]([NH:18][C:19](=[O:41])[CH2:20][C@H:21]([O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:14][CH2:13][CH2:12][NH2:11])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: CCCCCCCCCCC[C@H](CC(=O)N[C@@H](CO)CCCNC(=O)OCc1ccccc1)OCc1ccccc1
Reactant: ClCOCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCCCCCC[C@H](CC(=O)N[C@H](CCCN)COCOCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
To a solution of (2R)-5-(benzyloxycarbonylamino)-2-[(R)-3-benzyloxytetradecanoylamino]pentan-1-ol (Section 1.1.2.) (2.05 g; 3.60 mmol.) in anhydrous CH2Cl2 (40 ml) at room temperature and under argon flow, there are added in succession BOMCl (benzyl chloromethyl ether) (reagent grade 60%, 1.25 ml; 5.41 mmol; 1.5 eq.) and diisopropylethylamine (942 μl; 5.41 mmol.; 1.5 eq.). The reaction mixture is then stirred overnight at room temperature and evaporated thereafter to dryness. By running a flash chromatography purification on a silica gel (2/1 petroleum ether/EtOAc eluent), there is recovered the O-benzyloxymethyl derivative (2.28 g; 92%) as a white cristalline solid. (Rf=0.70 in 1/3 petroleum ether/EtOAc mixture, phosphomolybdinium acid and UV color developer) m.p.=97-100° C. A solution of this product (2.00 g; 2.90 mmol.) in HPLC-grade EtOH (220 ml) containing Et3N (4 ml) is hydrogenated in presence of 20% Pd(OH)2 on carbon (200 mg) at room temperature and under atmospheric pressure hydrogen for a period of 3 hours. The catalyst is filtered off. The filtrate is evaporated to dryness and the residue is then dried by suction from a vacuum pump to obtain the free amine (1.58 g; 98%) as an amorphous solid. [α]D=1° (c=1.20; CHCl3); 1H-NMR (250 MHz, CDCl3), δ in ppm: 7.45-7.21 (m, 10H, Ar), 6.52 (d, 1H, NH), 4.80-4.45 (m, 6H, 2×CH2-ph, O—CH2—O), 4.10 (m, 1H, H−3′), 3.83 (m, 1H, H−2), 3.62 (dd, 1H, H−1), 3.47 (dd, 1H, H−1), 2.65 (t, 2×H−5), 2.40 (m, 2H, 2×H−2′), 1.80-1.40 (m, 8H, 2×H−4, 2×H−3, 2×H−4′, NH2), 1.40-1.20 (m, 18H, 9×CH2), 0.88 (t, 3H, CH3); 13C-NMR (62.89 MHz, CDCl3), δ in ppm: 170.78; 138.24; 137.63; 128.38; 128.32; 127.66; 127.62; 94.82; 76.70; 71.26; 69.63; 69.44; 48.48; 41.82; 41.47; 33.83; 31.84; 29.88; 29.58; 29.56; 29.51; 29.27; 29.04; 25.11; 22.62; 14.06.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH3:11])[C:8](=[O:12])[C:7]2[CH:13]=[CH:14][CH:15]=[N:16][C:6]=2[CH2:5]1.[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1>CN(C)C=O>[N:17]1([CH2:2][CH2:3][CH:4]2[CH2:10][N:9]([CH3:11])[C:8](=[O:12])[C:7]3[CH:13]=[CH:14][CH:15]=[N:16][C:6]=3[CH2:5]2)[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: c1c[nH]cn1
Reactant: CN1CC(CCCl)Cc2ncccc2C1=O
Solvent: CN(C)C=O
Product: CN1CC(CCn2ccnc2)Cc2ncccc2C1=O
Temperature: 130 °C

Procedure:
To a solution of 8-(2-chloroethyl)-6,7,8,9-tetrahydro-6-methyl-5H-pyrido[3,2-c]azepin-5-one in dimethylformamide (DMF) is added imidazole. The solution is heated to about 130° C. for several hr. DMF is removed by evaporation in vacuo and the residue is taken up in chloroform. The chloroform solution is washed with dilute aqueous sodium hydroxie, dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to give the title compound.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:16])([CH3:15])[CH:8]1[CH2:13][CH:12]([OH:14])[CH2:11][CH2:10][O:9]1)([CH3:4])([CH3:3])[CH3:2]>CS(C)=O.CCN(CC)CC>[C:1]([SiH2:5][O:6][C:7]([CH3:16])([CH3:15])[CH:8]1[CH2:13][C:12](=[O:14])[CH2:11][CH2:10][O:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[SiH2]OC(C)(C)C1CC(O)CCO1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[SiH2]OC(C)(C)C1CC(=O)CCO1
Reaction time: 1 h
Yield: 65.8 %

Procedure:
A solution of 2-(tert-butyl-dimethyl-silanyloxymethyl)-tetrahydro-pyran-4-ol (2.27 g, 9.21 mmol) in anhydrous DMSO/Et3N (15/13 mL) was treated with sulfur trioxide pyridine complex (7.33 g, 46.1 mmol) portionwise at room temperature. After stirring for 1 hour, the reaction was concentrated and the residue was partitioned between EtOAc (100 mL) and water (50 ml). The separated organic layer was washed with brine (70 mL), dried over sodium sulfate, and concentrated. Purification by silica gel column using 10-20% of EtOAc in hexane afforded 1.48 g (66%) of colorless oil: 1H NMR (CDCl3) δ 0.05 (s, 6H), 0.88 (s, 9H), 2.32 (dt, 1H), 2.41 (m, 2H), 2.58 (m, 1H), 3.62 (m, 2H), 3.70 (d, 2H), 4.31 (m, 1H).
Reaction SMILES: [N:1]([N:3]1[CH2:9][CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)=[O:2].C(N(CC)CC)C.[CH2:17]([O:24][C:25](Cl)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>ClCCl.O>[CH2:17]([O:24][C:25]([N:6]1[CH2:7][CH2:8][CH2:9][N:3]([N:1]=[O:2])[CH2:4][CH2:5]1)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=NN1CCCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=NN1CCCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1-nitrosohomopiperazine (4.174 g) and triethylamine (9 ml) in dichloromethane (25 ml) was added dropwise benzyloxycarbonyl chloride (5 ml) at 0° C. The reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was diluted with water and separated. The organic layer was washed with water (×2), brine, dried over magnesium sulfate and concentrated to give 1-benzyloxycarbonyl-4-nitrosohomopiperazine (6.0 g). This product was used for the next step without purification.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([C@@H:15]([CH2:35][CH2:36][C@@H:37]([C:47](=[O:65])[NH:48][C@H:49]1[CH2:55][CH2:54][S:53][C@H:52]2[CH2:56][CH2:57][CH2:58][C@@H:59]([C:60]([O:62][CH3:63])=[O:61])[N:51]2[C:50]1=[O:64])[CH2:38][CH2:39][C:40]([O:42]C(C)(C)C)=[O:41])[C:16]([NH:18][C@H:19]1[CH2:25][CH2:24][S:23][C@H:22]2[CH2:26][CH2:27][CH2:28][C@@H:29]([C:30]([O:32][CH3:33])=[O:31])[N:21]2[C:20]1=[O:34])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[CH2:8]([C@H:15]([C:16]([NH:18][C@H:19]1[CH2:25][CH2:24][S:23][C@H:22]2[CH2:26][CH2:27][CH2:28][C@@H:29]([C:30]([O:32][CH3:33])=[O:31])[N:21]2[C:20]1=[O:34])=[O:17])[CH2:35][CH2:36][C@@H:37]([C:47](=[O:65])[NH:48][C@H:49]1[CH2:55][CH2:54][S:53][C@H:52]2[CH2:56][CH2:57][CH2:58][C@@H:59]([C:60]([O:62][CH3:63])=[O:61])[N:51]2[C:50]1=[O:64])[CH2:38][CH2:39][C:40]([OH:42])=[O:41])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@@H](CCC(=O)OC(C)(C)C)CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCS[C@H]4CCC[C@@H](C(=O)OC)N4C3=O)C(=O)N21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@@H](CCC(=O)O)CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCS[C@H]4CCC[C@@H](C(=O)OC)N4C3=O)C(=O)N21
Temperature: 25 °C
Reaction time: 4 h
Yield: 20.8 %

Procedure:
TFA (0.1 mL) was added to a 0° C. solution of methyl (4S,7S,10aS)-4-(((2R,5R)-2-benzyl-8-tert-butoxy-5-(((4S,7S,10aS)-7-(methoxycarbonyl)-5-oxooctahydro-7H-pyrido[2,1-b][1,3]thiazepin-4-yl)carbamoyl)-8-oxooctanoyl)amino)-5-oxooctahydro-7H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate (45 mg, 0.053 mmol) in DCM (0.2 mL). The reaction mixture was then stirred at rt for 4 hr. The reaction mixture was concentrated and dried under vacuum. The residue was purified by RP prep-HPLC to give (4R,7R)-7-benzyl-8-((4S,7S,10aS)-7-(methoxycarbonyl)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylamino)-4-((4S,7S,10aS)-7-(methoxycarbonyl)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylcarbamoyl)-8-oxooctanoic acid (8.5 mg, 0.011 mmol, 20% yield) as a white solid. Anal. Calcd. for C38H52N4O10S2 m/z 788.5. found: 789.0 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.59 (1H, d, J=5.5 Hz), 7.29-7.10 (6H, m), 5.44-5.29 (2H, m), 5.24-4.96 (6H, m), 3.72 (3H, s), 3.69 (3H, s), 3.30-3.19 (1H, m), 3.18-3.08 (1H, m), 2.97-2.68 (4H, m), 2.50-2.17 (6H, m), 2.10-1.91 (5H, m), 1.90-1.54 (11H, m), 1.53-1.39 (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([N:12]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:11])=[CH:5][CH:4]=1.Cl.Cl[CH2:29][C:30]1[N:31]=[C:32]([CH3:35])[S:33][CH:34]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([N:12]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)[CH:13]2[CH2:14][CH2:15][N:16]([CH2:29][C:30]3[N:31]=[C:32]([CH3:35])[S:33][CH:34]=3)[CH2:17][CH2:18]2)=[O:11])=[CH:7][CH:8]=1
Reactant: Cc1nc(CCl)cs1
Reactant: COc1ccc(CC(=O)N(Cc2ccc(C)cc2)C2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: COc1ccc(CC(=O)N(Cc2ccc(C)cc2)C2CCN(Cc3csc(C)n3)CC2)cc1
Temperature: 82 °C
Reaction time: 20 h

Procedure:
50ELH87 (0.3 g, 0.852 mmol, 1.0 eq) and 4-(chloromethyl)-2-methylthiazole hydrochloride (0.235 g, 1.5 eq) were added to a 7 ml vial and dissolved in acetonitrile (3 ml). Potassium carbonate (141.3 g, 1.2 eq) and a crystal of potassium iodide were added and the vial was sealed and shaken for 20 h at 82° C. The reaction mixture was extracted with distilled water (made basic by potassium carbonate, pH 10) and dichloromethane. The crude product was dried with sodium sulfate and concentrated. After purification by HPLC the product was converted into the hydrochloride salt by dissolving the free base in 1 ml dichloromethane and adding 1 eq. HCl in ether (2M). This mixture was added drop-wise to an excess of heptane where the product precipitated. The solvent was removed by evaporation leaving a white powder as the product. yield 83.8 mg (21%), UV/MS 100/90 (M+ 463), rt (B, MS) 11.82.
Reaction SMILES: C(#N)C.[Cl:4][C:5]1[C:6]([N:11]2[CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14][C:13](=O)[NH:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1.P(Br)(Br)([Br:24])=O.C(=O)(O)[O-].[Na+]>ClCCl.O>[Br:24][C:13]1[CH2:14][CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:11]([C:6]2[C:5]([Cl:4])=[CH:10][CH:9]=[CH:8][N:7]=2)[N:12]=1
Reactant: O=P(Br)(Br)Br
Reactant: CCOC(=O)C1CC(=O)NN1c1ncccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: CCOC(=O)C1CC(Br)=NN1c1ncccc1Cl
Temperature: 83 °C
Reaction time: 0.08 h
Yield: 95 %

Procedure:
A 1-L four-necked flask equipped with a mechanical stirrer, thermometer, reflux condenser, and nitrogen inlet was charged with acetonitrile (400 mL), ethyl 2-(3-chloro-2-pyridinyl)-5-oxo-3-pyrazolidinecarboxylate (i.e. the product of Step A) (50.0 g, 0.185 mol) and phosphorus oxybromide (34.0 g, 0.119 mol). The orange slurry was heated to reflux at 83° C. over a period of 20 minutes. The resulting turbid, orange solution was held at reflux for 75 minutes, at which time a dense, tan, crystalline precipitate had formed. The reflux condenser was replaced with a distillation head, and a cloudy, colorless distillate (300 mL) was collected. A second 1-L four-necked flask equipped with a mechanical stirrer was charged with sodium bicarbonate (45 g, 0.54 mol) and water (200 mL). The concentrated reaction mixture was added to the sodium bicarbonate slurry over a period of 5 minutes. The resulting two-phase mixture was stirred vigorously for 5 minutes, at which time gas evolution had ceased. The mixture was diluted with dichloromethane (200 mL) and then was stirred for 75 minutes. The mixture was treated with 5 g of Celite® 545 diatomaceous filter aid and then filtered to remove a brown, tarry substance. The filtrate was transferred to a separatory funnel. The brown organic layer (400 mL) was separated and then was treated with magnesium sulfate (15 g) and Darco® G60 activated charcoal (2.0 g). The resulting slurry was stirred magnetically for 15 minutes and then filtered to remove the magnesium sulfate and charcoal. The green filtrate was treated with silica gel (3 g) and stirred for several minutes. The deep blue-green silica gel was removed by filtration, and the filtrate was concentrated on a rotary evaporator. The product consisted of a light amber oil (58.6 g, 95% yield), which crystallized upon standing. The only appreciable impurity observed by 1H NMR was 0.3% acetonitrile.
Reaction SMILES: COC1C=C(OC)C=CC=1[CH2:5][N:6](C)[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12](=[C:16]1[C:24]3[C:19](=[CH:20][C:21]([F:25])=[CH:22][CH:23]=3)[NH:18][C:17]1=[O:26])[O:11][CH2:10]2.FC(F)(F)C(O)=O.CO>C(Cl)Cl.O>[F:25][C:21]1[CH:20]=[C:19]2[C:24]([C:16](=[C:12]3[C:13]4[C:9](=[CH:8][C:7]([NH:6][CH3:5])=[CH:15][CH:14]=4)[CH2:10][O:11]3)[C:17](=[O:26])[NH:18]2)=[CH:23][CH:22]=1
Reactant: COc1ccc(CN(C)c2ccc3c(c2)COC3=C2C(=O)Nc3cc(F)ccc32)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CNc1ccc2c(c1)COC2=C1C(=O)Nc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
To a stirred suspension of (3-{5-[(2,4-dimethoxy-benzyl)-methyl-amino]-3H-isobenzofuran-1-ylidene}-6-fluoro-1,3-dihydro-indol-2-one (197 mg, 0.44 mmol) in methylene chloride (10 ml) was added trifluoroacetic acid (1 ml). The mixture was stirred for 30 minutes at room temperature and then evaporated to give a residue. The residue was treated with 50% MeOH in water (25 ml, containing 1 ml of triethylamine) with heating for 30 minutes. After filtered and dried under vacuum, the resulting solid was mixed with acetone (50 ml), and heated at 50° C. for 30 minutes. The mixture was cooled to room temperature and filtered. The filtrate solution was concentrated under reduced pressure to give a crude product. Trituration of the crude product with CHCl3/hexanes afforded 6-fluoro-3-(5-methylamino-3H-isobenzofuran-1-ylidene)-1,3-dihydro-indol-2-one as a yellow solid (100 mg, 76%).
Reaction SMILES: [Cl-].[NH4+].O.[CH3:4][O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([N+:15]([O-])=O)[CH:12]=[CH:13][CH:14]=1)=[O:7]>[Fe].CC(O)C>[CH3:4][O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[NH2:15])=[O:7]
Reactant: COC(=O)Nc1cccc([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)O
Solvent: O
Product: COC(=O)Nc1cccc(N)c1
Yield: 95.3 %

Procedure:
After refluxing a mixture of 37 g of iron powder, 1.9 g of ammonium chloride, 33 g of water, 13 g of 3-(methoxycarbonylamino)nitrobenzene, and 260 g of 2-propanol for 30 minutes, the reaction mixture was filtered under suction using sellaite. After extracting the product formed from the filtrate with ethyl acetate followed by washing with water, the product was dried by Glauber's salt. The solvent was distilled off from the product using an evaporator to provide 10.5 g (yield: 95%) of a black oily product.