Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:9][N:10]([CH3:29])[CH2:11][CH2:12][CH2:13][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=O>C(N(CC)CC)C>[Cl:8][C:3]1[C:2]([N:1]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[NH:14][CH2:13][CH2:12][CH2:11][N:10]([CH3:29])[CH3:9])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CN(C)CCCNc1ccccc1C(=O)c1ccccc1
Reactant: Nc1cccnc1Cl
Solvent: CCN(CC)CC
Product: CN(C)CCCNc1ccccc1C(=Nc1cccnc1Cl)c1ccccc1

Procedure:
To a mixture of 2.82 g (0.01 mole) of [2-[[3-(dimethylamino)propyl]amino]phenyl]phenylmethanone and 1.29 g (0.01 mole) of 3-amino-2-chloropyridine, 6.2 ml (0.048 mole) of triethylamine and 20 ml of methylene chloride stirred in an ice bath under nitrogen atmosphere was added 2.28 g (0.012 mole) of titanium tetrachloride in 10 ml of methylene chloride during a 5 minute period. The mixture was then stirred at room temperature for 2 days during which time mass spec-CI showed little change in relative intensity of M.W. 129 (starting pyridine) and M.W. 393 (title product). Water was added to the reaction mixture and stirring was continued for 1.5 hr. The mixture was filtered to remove solid and the filter cake was rinsed with methylene chloride. Saturated sodium chloride solution was added to facilitate separation of layers. The methylene chloride layer was washed once with more sodium chloride solution. The aqueous layer having a pH of about 6 was basified to about pH 8-9 with potassium carbonate and then extracted twice with methylene chloride. The latter methylene chloride layers were washed with sodium chloride solution. All the methylene chloride extracts were combined, dried and evaporated to give 4.8 g of semi-solid product. TLC of the product showed it contained evey little starting 3-amino-2-chloropyridine. Mass Spec. analysis showed the presence of compounds with molecular weight corresponding to title product (393), 3-amino-2-chloropyridine (129) and triethylamine (102) but no [2-[[3-(dimethylamino)propyl]amino]phenyl]phenylmethanone. 1HNMR spectrum in CDCl3 containing 1% TMS indicated the product was mostly title compound and some triethylamine. No 3-amino-2-chloropyridine was seen. The chemical shifts, multiplicities and assignments are given below. ##STR52##
Reaction SMILES: C([N:14]1[CH2:17][C:16]([NH:21][CH2:22][CH3:23])([C:18]([NH2:20])=[O:19])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.[ClH:24]>CO.C(OC)(C)(C)C.[OH-].[OH-].[Pd+2]>[ClH:24].[CH2:22]([NH:21][C:16]1([C:18]([NH2:20])=[O:19])[CH2:17][NH:14][CH2:15]1)[CH3:23]
Reactant: CCNC1(C(N)=O)CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: COC(C)(C)C
Product: CCNC1(C(N)=O)CNC1

Procedure:
To a suspension of 1-benzhydryl-3-ethylaminoazetidine-3-carboxylic acid amide (I-1A-6b; 36.1 g, 117 mmol) in methanol (560 ml) at room temperature was added concentrated aqueous HCl (19.5 ml, 234 mmol), resulting in a clear solution. To 20% Pd(OH)2 on carbon (3.75 g) was added methanol (85 ml), followed by the methanolic solution of I-1A-6b. The mixture was placed on a Parr® shaker and then reduced (50 psi H2) at room temperature for 20 hours. The reaction was then filtered through Celite® and concentrated to a fraction of the original volume under reduced pressure, at which point a precipitate formed. The suspension was diluted with t-butylmethyl ether (MTBE; 500 ml), stirred for an additional hour, and the precipitate collected by vacuum filtration. The solid was washed with MTBE and then dried, in vacuo, to afford I-1A-6c (24.8 g, 98%) as a colorless solid: +APcl MS (M+1) 144.1; 1H NMR (400 MHz, CD2Cl2) δ 4.56 (br s, 4H), 3.00 (q, J=7.2 Hz, 2H), 1.36 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[N:9][CH:8]=[C:7]([CH:12]=[CH:13][O:14]CC)[CH:6]=2.C(O)=O>ClCCCl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH2:12][CH:13]=[O:14])[CH:8]=[N:9]2)=[N:4][CH:3]=1
Reactant: CCOC=Cc1cnc2cc(Br)cnc2c1
Solvent: ClCCCl
Solvent: O=CO
Product: O=CCc1cnc2cc(Br)cnc2c1

Procedure:
1,5-Naphthyridines of formula (53), wherein R4 and R5 are as defined in formula (I) and R6 is aryl or heteroaryl, can be prepared as described in Scheme 7. 3,7-Dibromo-[1,5]naphthyridine, prepared as described by W. W. Paudler, J. Org. Chem., 33:1384 (1968), can be treated with (2-ethoxyvinyl)tributylstannane, a halide source, such as, but not limited to, tetraethylammonium chloride, and a palladium source, such as, but not limited to, dichlorobis(triphenylphosphine)palladium (II) in a solvent, such as, but not limited to, N,N-dimethylformamide with heat (about 50° C. to about 150° C.) to provide 3-bromo-7-[2-ethoxyvinyl]-1,5-naphthyridine. 3-Bromo-7-[2-ethoxyvinyl]-1,5-naphthyridine can be treated with an acid, such as, but not limited to, formic acid at about 0° C. to about 60° C. in a solvent, such as, but not limited to, 1,2-dichloroethane to provide (7-bromo-1,5-naphthyridin-3-yl)acetaldehyde. Alternatively, 3-bromo-7-[2-ethoxyvinyl]-1,5-naphthyridine in a solvent, such as, but not limited to, tetrahydrofuran can be treated with an aqueous acid, such as, but not limited to, hydrochloric acid at about 0° C. to about 60° C. to provide (7-bromo-1,5-naphthyridin-3-yl)acetaldehyde. (7-Bromo-1,5-naphthyridin-3-yl)acetaldehyde can be treated with an amine of formula (5) under reductive amination conditions, such as, but not limited to, sodium triacetoxyborohydride and an acid, such as, but not limited to, acetic acid in a solvent, such as, but not limited to, 1,2-dichloroethane at about 0° C. to about 50° C. to povide amines of formula (52). Amines of formula (52) can be treated with boronic acids of formula (7), a palladium source, such as, but not limited to, tris(dibenzylideneacetone)dipalladium (0), a ligand, such as, but not limited to, tri(tert-butyl)phosphine, and a base, such as, but not limited to, potassium fluoride in a solvent, such as, but not limited to, tetrahydrofuran at about 20° C. to about 80° C. to provide 1,5-naphthyridines of formula (53).
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[NH:10][C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[CH:6]=1>C(O)C>[NH:2]([C:5]1[NH:10][C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[CH:6]=1)[NH2:3]
Reactant: Cn1c(=O)cc(Cl)[nH]c1=O
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cn1c(=O)cc(NN)[nH]c1=O
Temperature: 75 °C

Procedure:
Hydrazine hydrate (12.7 ml) was added to a suspension 6-chloro-3-methyl-2,4(1H,3H)-pyrimidinedione (10 g) in ethanol (190 ml). The mixture was heated at 75° C. for 40 hours, cooled to room temperature. The yellow solid precipitated was filtered and dried give the subtitle compound (8.5 g). Mass: 156.76 (M+H).
Reaction SMILES: [CH3:1][C:2]([CH3:30])([CH3:29])[CH2:3][CH2:4][N:5]1[C:10](=[O:11])[C:9]([C:12]2[NH:17][C:16]3[CH:18]=[CH:19][C:20](I)=[CH:21][C:15]=3[S:14](=[O:24])(=[O:23])[N:13]=2)=[C:8]([OH:25])[C:7]2=[CH:26][CH:27]=[CH:28][N:6]12.[O-]P(OP(OP([O-])([O-])=O)([O-])=O)(=O)[O-].[K+].[K+].[K+].[K+].[K+].N(CC(O)=O)C.[CH3:55][NH:56][S:57]([CH3:60])(=[O:59])=[O:58]>C(OCC)(=O)C.[Cu]I.CN(C)C=O>[CH3:1][C:2]([CH3:30])([CH3:29])[CH2:3][CH2:4][N:5]1[C:10](=[O:11])[C:9]([C:12]2[NH:17][C:16]3[CH:18]=[CH:19][C:20]([N:56]([CH3:55])[S:57]([CH3:60])(=[O:59])=[O:58])=[CH:21][C:15]=3[S:14](=[O:24])(=[O:23])[N:13]=2)=[C:8]([OH:25])[C:7]2=[CH:26][CH:27]=[CH:28][N:6]12
Reactant: CC(C)(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(I)ccc3N2)c(O)c2cccn21
Reactant: CNS(C)(=O)=O
Agent: [Cu]I
Agent: CNCC(=O)O
Agent: O=P([O-])([O-])OP(=O)([O-])OP(=O)([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(c1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3cccn3n(CCC(C)(C)C)c1=O)N2)S(C)(=O)=O
Yield: 33 %

Procedure:
1-(3,3-Dimethyl-butyl)-4-hydroxy-3-(7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-pyrrolo[1,2-b]pyridazin-2-one (Example 4d, 0.257 g, 0.476 mmol), potassium triphosphate (0.505 g, 2.38 mmol), sarcosine (0.025 g, 0.285 mmol), and copper (I) iodide (0.022 g, 0.119 mmol) were combined. Anhydrous N,N-dimethylformamide (9.5 mL) was added followed by N-methyl-methanesulfonamide (0.519 g, 4.76 mmol). The solution was degassed while stirring under vacuum and the flask purged with nitrogen. The mixture was stirred at 100° C. for 1 h. Additional copper (I) iodide (0.1 g, 0.525 mmol) was added. The mixture continued to stir at 100° C. for 3 h. Upon cooling, the mixture was diluted with ethyl acetate (200 mL), washed with 1.0 M aqueous hydrochloric acid solution (2×100 mL), dried over magnesium sulfate. The entire organic layer was passed through a plug of silica gel. Upon concentrating in vacuo to a volume of approximately 10 mL, the desired product precipitated. The solid was collected by vacuum filtration. The solid was recrystallized in ethyl acetate, collected by vacuum filtration and dried in vacuo to afford the desired product, N-{3-[1-(3,3-dimethyl-butyl)-4-hydroxy-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-N-methyl-methanesulfonamide (0.082 g, 0.157 mmol, 33% yield) as a pale yellow powder. 1H NMR (400 MHz, DMSO-d6) δ: 1.02 (9H, s), 1.58-1.62 (2H, m), 3.01 (3H, s), 3.31 (3H, s), 4.40-4.44 (2H, m), 6.72-6.72 (1H, m), 7.04 (1H, d, J=3.9 Hz), 7.70-7.76 (3H, m), 7.88 (1H, s), 13.78 (1H, bs). LC-MS (ESI) calcd for C22H27N5O6S2. found 521.14. found 522.6 [M+H+].
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.Br[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.C(=O)(O)[O-].[Na+]>O.COCCOC>[N+:1]([C:4]1[CH:5]=[C:6]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: Brc1ccncc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=[N+]([O-])c1cccc(-c2ccncc2)c1
Yield: 74.1 %

Procedure:
A stirred mixture of 3-nitrophenylboronic acid (2.00 g), 4-bromopyridine hydrochloride (1.56 g), bis(diphenylphosphino)butanepalladium(II) chloride (0.48 g), sodium bicarbonate (2.69 g), water (30 ml) and 1,2 dimethoxyethane (100 ml) is heated under reflux for 3 hours. The cool mixture is added to water (300 nil) and extracted with chloroform (3×150 ml), and the combined organic extracts washed with water and brine, dried (MgSO4), charcoaled and filtered. The solvent is evaporated to give a residue which is purified by flash chromatography (silica, ether) to give 1.19 g of 4-(3nitrophenyl)pyridine, mp 109-110.5° C. (from acetone/hexane).
Reaction SMILES: C[O:2][C:3]([C:5]1([C:8]2[CH:9]=[CH:10][C:11]3[O:15][CH:14]=[N:13][C:12]=3[CH:16]=2)[CH2:7][CH2:6]1)=[O:4].[Al+3].[Cl-].[Cl-].[Cl-].O>CCS>[O:15]1[C:11]2[CH:10]=[CH:9][C:8]([C:5]3([C:3]([OH:4])=[O:2])[CH2:7][CH2:6]3)=[CH:16][C:12]=2[N:13]=[CH:14]1
Reactant: COC(=O)C1(c2ccc3ocnc3c2)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CCS
Product: O=C(O)C1(c2ccc3ocnc3c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 10.3 %

Procedure:
To a solution of 1-benzooxazol-5-yl-cyclopropanecarboxylic acid methyl ester (2.9 g) in EtSH (30 mL) was added AlCl3 (5.3 g, 40 mmol) in portions at 0° C. The reaction mixture was stirred for 18 hours at room temperature. Water (20 mL) was added dropwise at 0° C. The resulting mixture was extracted with EtOAc (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give the crude product, which was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 1:2) to give 1-(benzo[d]oxazol-5-yl)cyclopropanecarboxylic acid (280 mg, 11% over two steps). 1H NMR (DMSO, 400 MHz) δ 12.25 (brs, 1H), 8.71 (s, 1H), 7.70-7.64 (m, 2H), 7.40 (dd, J=1.6, 8.4 Hz, 1H), 1.49-1.46 (m, 2H), 1.21-1.18 (m, 2H). MS (ESI) m/e (M+H+) 204.4.
Reaction SMILES: ClC(OCC)=O.[CH2:7]([O:14][C:15]([NH:17][C:18]1([C:21](O)=[O:22])[CH2:20][CH2:19]1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[BH4-].[Na+]>C1COCC1.O>[CH2:7]([O:14][C:15](=[O:16])[NH:17][C:18]1([CH2:21][OH:22])[CH2:20][CH2:19]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(NC1(C(=O)O)CC1)OCc1ccccc1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NC1(CO)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
Ethyl chloroformate (0.17 mL, 0.0018 mol) was added to a solution of 1-[(benzyloxy)carbonyl]aminocyclopropanecarboxylic acid (0.35 g, 0.0015 mol) and triethylamine (0.25 mL, 0.0018 mol) in THF (5.0 mL) at −10° C. The mixture was stirred at RT for 30 min., filtered, and washed with THF. Sodium tetrahydroborate (0.11 g, 0.0030 mol) in water (1.0 mL) was added to the filtrate at 0° C., and stirred at RT for 2 h. The reaction mixture was carefully quenched with 1N HCl, and extracted with EtOAc. The extract was washed with saturated NaHCO3, brine, dried over MgSO4, filtered, and concentrated to give the crude product (0.32 g, 97%). LCMS: (M+H)=222.0, (M+Na)=244.0.
Reaction SMILES: CO.O=[C:4]([CH3:17])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:7]=1.Cl.CN.[C:21]([BH3-])#[N:22].[Na+]>Cl.C(N(CC)CC)C>[CH3:21][NH:22][CH:4]([CH3:17])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:7]=1
Reactant: COC(=O)Cc1ccc(CC(C)=O)cc1
Reactant: [BH3-]C#N
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: CNC(C)Cc1ccc(CC(=O)OC)cc1
Reaction time: 3 h

Procedure:
To 25 mL of methanol 0.59 g of methyl 4-(2-oxopropyl)phenylacetate, prepared above, was added and dissolved. Then with stirring the following were added: 2.0 g methylamine hydrochloride, 0.3 g sodium cyanoborohydride, and 0.3 mL of triethylamine. After approximately 12 hours an additional 0.1 g of sodium cyanoborohydride was added to the mixture. After 3 hours more, the reaction was diluted with 100 mL of 0.1M hydrochloric acid, washed with diethylether, and the resulting aqueous phase was basified to a pH of 12 by addition of 5 mL portions of 1N sodiumhydroxide solution. This was extracted three times with 100 mL portions of diethylether, combined extracts washed with brine and dried. The solvents were removed in vacuo to yield 0.44 g of a light yellow oil.
Reaction SMILES: [NH2:1][CH:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:13]([OH:23])(=[O:22])[C@@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[OH:15]>C(O)(=O)C>[NH2:1][C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:13]([OH:23])(=[O:22])[C@@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[OH:15]
Reactant: NC(Cc1ccccc1)C(=O)O
Agent: O=C(O)[C@H](O)c1ccccc1
Solvent: CC(=O)O
Product: N[C@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C

Procedure:
To a vessel, were added 34.24 g of DL-phenylalanine, 47.31 g of D-mandelic acid and 174.2 g of an aqueous 50% acetic acid solution (the total weight of 255.75 g) while stirring. The resultant mixture was heated to form a solution. The solution was slowly cooled to 25° C. for 3 hours and then, was stirred at the same temperature for 2 hours. As a result, a complex of D-phenylalanine and D-mandelic acid was crystallized and the crystals were collected by filtration, were washed with 10 ml of water and were dried. A crude complex of D-phenylalanine and D-mandelic acid having [α]D20 of -56.50° (c=2, in H2O) and an optical purity of 91.0% was obtained in yield of 25.59 g.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)[CH2:5][C@@H:4]([CH3:19])[N:3]1[S:20]([C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][CH:26]([C:32]#[N:33])[CH2:27]2)(=[O:22])=[O:21].C([Sn](=O)CCCC)CCC.[N:44]([Si](C)(C)C)=[N+:45]=[N-:46]>C1(C)C=CC=CC=1>[CH3:1][C@H:2]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:16])([F:18])[F:17])=[CH:10][CH:9]=2)[CH2:5][C@@H:4]([CH3:19])[N:3]1[S:20]([C:23]1[C:24]2[CH2:25][CH:26]([C:32]3[NH:46][N:45]=[N:44][N:33]=3)[CH2:27][C:28]=2[CH:29]=[CH:30][CH:31]=1)(=[O:22])=[O:21]
Reactant: C[C@@H]1CN(c2ccc(OC(F)(F)F)cc2)C[C@H](C)N1S(=O)(=O)c1cccc2c1CC(C#N)C2
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(c2ccc(OC(F)(F)F)cc2)C[C@H](C)N1S(=O)(=O)c1cccc2c1CC(c1nnn[nH]1)C2
Temperature: 105 °C
Reaction time: 4 h
Yield: 71.1 %

Procedure:
To a solution of 4-[cis-2,6-dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indan-2-carbonitrile (23 mg, 0.0440 mmol) in toluene (1 ml) was added dibutyltin oxide (13 mg, 0.0281 mmol) and azidotrimethylsilane (5 μL, 0.0377 mmol). The reaction mixture was stirred at 105° C. for 20 h upon which an additional amount of dibutyltin oxide (13 mg, 0.0281 mmol) and azidotrimethylsilane (25 μL, 0.1884 mmol) was added and stirred at 105° C. for 4 h. The reaction mixture was cooled to room temperature and then directly purified by silica gel column chromatography (0-10% MeOH in dichloromethane) to afford cis-2,6-dimethyl-1-[2-(1H-tetrazol-5-yl)-indane-4-sulfonyl]-4-(4-trifluoromethoxy-phenyl)-piperazine (14 mg, 61%). 1H NMR (400 MHz, CD3OD) δ ppm 7.75 (d, 1H), 7.54 (d, 1H), 7.39 (t, 1H), 7.09 (d, 2H), 6.90 (d, 2H), 4.18-4.02 (m, 3H), 3.89 (dd, 1H), 3.59-3.51 (m, 2H), 3.36-3.31 (m, 3H), 2.66-2.60 (m, 2H), 1.48 (d, 6H). LCMS: 523.11 (M+1)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[Br:9][C:10]1[CH:11]=[N:12][C:13](Cl)=[N:14][CH:15]=1.[H-].[Na+]>CN(C=O)C>[Br:9][C:10]1[CH:11]=[N:12][C:13]([O:1][CH2:2][CH2:3][N:4]2[CH2:8][CH2:7][CH2:6][CH2:5]2)=[N:14][CH:15]=1
Reactant: Clc1ncc(Br)cn1
Reactant: OCCN1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1cnc(OCCN2CCCC2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.9 %

Procedure:
To a solution of N-2-hydroxyethylpyrrolidine (0.9 ml, 7.71 mmol) and 5-bromo-2-chloropyrimidine (1.2 g, 6.20 mmol), in DMF (7 ml), was added sodium hydride (60% in mineral oil, 0.35 g, 8.75 mmol). The mixture was stirred, under argon, at ambient temperature for 1 hour, before being heated to 90° C. and stirred for a further hour. The reaction mixture was then partitioned between ethyl acetate and water. The organics were separated, dried over magnesium sulfate and evaporated to dryness. The resultant oil was purified by flash chromatography on silica, eluting with an increasing gradient of methanol in dichloromethane (which contained 1% aqueous ammonia solution, 0.88 M) to give the title compound (640 mg, 38%); NMR Spectrum: (CDCl3) 1.76 (m, 4H), 2.39 (m, 4H), 3.90 (t, 2H), 4.48 (t, 2H), 8.50 (s, 2H); Mass Spectrum: M+H+ 272.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.C1CCCCC1>ClCCl.[O-2].[O-2].[Mn+4]>[CH:2]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2)=[O:1]
Reactant: OCc1cccc2[nH]ccc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: C1CCCCC1
Product: O=Cc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 86.3 %

Procedure:
Manganese dioxide (MnO2) is added slowly with stirring to a solution of 74 g of 4-hydroxymethylindole (2) in 3 litres of dichloromethane, and the mixture is subsequently stirred at room temperature for 72 hours. The reaction mixture is subsequently filtered through kieselguhr, and the filtrate is evaporated. The crystalline residue obtained is stirred with cyclohexane and filtered under reduced pressure. Drying gives 63 g (86% of theory) of crystalline 4-formylindole (3).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([Br:11])[N+:3]=1[O-].CCOCC.CCCCCC>C(O)(=O)C.[Fe]>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Br:11])[N:3]=1
Reactant: O=[N+]([O-])c1cc(Br)[n+]([O-])c(Br)c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCCCCC
Solvent: CCOCC
Product: Nc1cc(Br)nc(Br)c1
Temperature: 100 °C

Procedure:
To a solution of 2,6-dibromo-4-nitropyridine 1-oxide (6.80 g, 22.82 mmol) in acetic acid (100 mL) at rt was added Fe powder (6.40 g, 114.13 mmol). The resulting reaction mixture was heated to 100° C. for 1 h. After completion of reaction (by TLC), acetic acid was distilled off under reduced pressure, the residue was basified with aqueous ammonia solution and extracted with EtOAc (3×250 mL). The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue thus obtained was treated with ether and hexane and filtered to obtain the desired product as an off white solid (5.40 g, 94%).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15].Cl[C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=[CH:22][C:21]=1[N+:30]([O-:32])=[O:31]>ClCCl>[N+:30]([C:21]1[CH:22]=[N:23][C:24]2[C:29]([C:20]=1[NH:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[CH:28][CH:27]=[CH:26][CH:25]=2)([O-:32])=[O:31]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCNc1c([N+](=O)[O-])cnc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (66.8 g, 0.33 mol) was added to a solution of tert-butyl N-(2-aminoethyl)carbamate (55.0 g, 0.34 mol) in anhydrous dichloromethane (500 mL). 4-Chloro-3-nitroquinoline was slowly added and the reaction exothermed. The reaction mixture was allowed to stir at ambient temperature overnight. The resulting precipitate was isolated by filtration to provide product as a yellow solid. The filtrate was washed with water, dried over magnesium sulfate and then concentrated under vacuum. The resulting residue was slurried with hexane and filtered to provide additional product as a yellow solid. The two crops were combined to provide 101 g of tert-butyl N-[2-(3-nitroquinolin-4-yl)aminoethyl]carbamate as a yellow solid, m.p. 157-158.
Reaction SMILES: [Na].[N:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([SH:13])[S:11][CH:12]=2)=[CH:4][CH:3]=1.[C:14]1([CH2:20][C:21]([NH:23][C@@H:24]2[C:52](=[O:53])[N:26]3[C:27]([C:36]([O:38][CH:39]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[O:37])=[C:28](OS(C)(=O)=O)[CH2:29][S:30][C@H:25]23)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1.[Cl-].[Na+].O>[C:14]1([CH2:20][C:21]([NH:23][C@@H:24]2[C:52](=[O:53])[N:26]3[C:27]([C:36]([O:38][CH:39]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)[C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)=[O:37])=[C:28]([S:13][C:10]4[S:11][CH:12]=[C:8]([C:5]5[CH:4]=[CH:3][N:2]=[CH:7][CH:6]=5)[N:9]=4)[CH2:29][S:30][C@H:25]23)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CS(=O)(=O)OC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1
Reactant: Sc1nc(-c2ccncc2)cs1
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(Sc3nc(-c4ccncc4)cs3)CS[C@H]12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
4-(4-Pyridyl)-1,3-thiazole-2-thiol sodium salt (194 g, 1 mol) prepared according to the method of Reference Example 5 was suspended in tetrahydrofuran (1.5 L) and benzhydryl 7β-[(phenylacetyl)amino]-3-[(methylsulfonyl)oxy]-3-cephem-4-carboxylate (196 g, 0.91 mol) dissolved in tetrahydrofuran (3.0 L) was added dropwise under ice-cooling over 30 min. The mixture was stirred at 0° C. for 2 hr and saturated brine (7 L) was added. The mixture was extracted with ethyl acetate (5 L). The organic layer was washed with saturated brine (5 L) and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure to give the title compound as crystals. The crystals were suspended in ethyl acetate (0.5 L), collected by filtration on a glass filter and washed with methanol (1 L×2). The crystals were dried in vacuo to give the title compound (412 g, 0.71 mol). yield: 78%. melting point: 134° C. Anal Calcd for C36H28N4O4S3.0.5H2O: C 63.05, H 4.11, N 8.17, S 14.02. Found: C 63.16, H 4.15, N 8.27, S 13.98. 1H-NMR(CDCl3)δ:3.41-3.73 (4H,m), 5.02 (1H,d,J=4.8 Hz), 5.84 (1H,dd,J=4.8 Hz,8.8 Hz), 6.23 (1H,d,J=8.8 Hz), 6.97 (1H,s), 7.27-7.72 (17H,m), 7.73 (1H,s), 8.67 (1H,d,J=6.2 Hz).