Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([C:4]1[C:9]2[CH2:10][C@@H:11]3[C:21]([C:22](=[O:23])[C:8]=2[C:7]([OH:33])=[CH:6][CH:5]=1)=[C:20]([OH:24])[C@@:19]1([OH:25])[C@H:13]([C@H:14]([N:30]([CH3:32])[CH3:31])[C:15]([OH:29])=[C:16]([C:26]([NH2:28])=[O:27])[C:17]1=[O:18])[CH2:12]3)[CH3:3].[OH2:34].[ClH:35].C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=[O:41]>CO>[CH3:32][N:30]([C@@H:14]1[C:15](=[O:29])[C:16]([C:26]([NH2:28])=[O:27])=[C:17]([OH:18])[C@:19]2([OH:25])[C@H:13]1[CH2:12][C@H:11]1[C:21]([C:20]2=[O:24])=[C:22]([OH:23])[C:8]2[C:9](=[C:4]([N:2]([CH3:3])[CH3:1])[CH:5]=[CH:6][C:7]=2[OH:33])[CH2:10]1)[CH3:31].[OH2:41].[OH2:34].[ClH:35]
Reactant: CN(C)c1ccc(O)c2c1C[C@H]1C[C@H]3[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]3(O)C(O)=C1C2=O
Reactant: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: Cl
Solvent: O
Solvent: CO
Product: CN(C)c1ccc(O)c2c1C[C@H]1C[C@H]3[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]3(O)C(=O)C1=C2O
Yield: 99.4 %

Procedure:
Ten grams of a crude minocycline [HPLC. purity, 94.8% (percentage area)] was suspended at 15° to 20° C. in a mixed solvent of 30 ml of water and 45 ml of methanol and dissolved at a pH of 0.8 to 1.0 by adding conc. hydrochloric acid with stirring. Subsequently, 1 g of activated carbon and 10 mg of EDTA.2Na were added, and after 30 minutes' stirring, the activated carbon was separated by filtration. To the filtrate was added dropwise a 5% aqueous sodium hydroxide solution to adjust the pH of the filtrate to 4.0, whereby minocycline precipitated in the form of a hydrochloride. This hydrochloride was separated by filtration and dried in vacuo to obtain 11.0 g of a purified minocycline hydrochloride dihydrate [HPLC. purity, 99.4% (area percentage)].
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[CH:12]([NH:14][CH:15]=[O:16])=[CH2:13].C(N(CC)CC)C.C(OC)(C)(C)C>CN(C)C1C=CN=CC=1.ClCCl.O>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([N:14]([CH:15]=[O:16])[CH:12]=[CH2:13])=[O:5]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: C=CNC=O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: C=CN(C=O)C(=O)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.3 %

Procedure:
2,6-difluorobenzoyl chloride (35.4 ml, 50 g, 284 mmol) was added dropwise with stirring to a solution of N-vinylformamide (18 ml, 18.3 g, 258 mmol), 4-dimethylaminopyridine (3.1 g, 25.8 mmol), and triethylamine (53.8 ml, 39 g, 387 mmol) in dichloromethane (200 ml). The temperature was kept at ca 20° C. with an ice/water bath. After the addition the mixture was stirred two hours at room temperature then shaken between tBuOMe and water. The organic phase was washed with half saturated brine, dried with Na2SO4 and evaporated to give 47 g (87% crude) of 2,6-difluoro-N-formyl-N-vinyl-benzamide, which contained ca 60% of 2,6-difluoro-N-vinyl-benzamide, which is the product of the next step, in which the formyl group has already been cleaved.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]([S:5][C:6]1[C:11]2=[N:12][CH:13]=[C:14]([C:17]([O:19]CC3C=CC(OC)=CC=3)=[O:18])[C:15](=[O:16])[N:10]2[CH:9]=[CH:8][CH:7]=1)=[O:4].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:17]([C:14]1[C:15](=[O:16])[N:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:5][C:3](=[O:4])[N:2]([CH3:1])[CH3:29])[C:11]2=[N:12][CH:13]=1)([OH:19])=[O:18]
Reactant: COc1ccc(COC(=O)c2cnc3c(SC(=O)N(C)C)cccn3c2=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: CN(C)C(=O)Sc1cccn2c(=O)c(C(=O)O)cnc12
Temperature: 0 °C

Procedure:
A mixture of 0.508 g of 9-(dimethylcarbamoyl)thio-3-(4-methoxybenzyloxycarbonyl)-4H-pyrido[1,2-a]pyrimidin-4-one Ib-82, 2,5 g of anisole and 5 ml of dry methylene chloride is cooled with ice water, mixed with 5 ml of trifluoroacetic acid and stirred under cooling with ice water for 3 hours. The reaction mixture is concentrated in vacuo to dryness, and the residue is washed with ether to give 0.32 g of crude product, which is recrystallized from 95% ethanol to give the titled compound Ib-81.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].CCN(C(C)C)C(C)C.C[Al](C)C.[CH2:19]([O:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH:38]=[C:37]([O:39][CH3:40])[C:36](=[O:41])[C:35]([C:42](OC)=[O:43])=[N:34]2)=[C:29]([F:46])[CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[CH2:19]([O:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH:38]=[C:37]([O:39][CH3:40])[C:36](=[O:41])[C:35]([C:42]([N:3]([O:4][CH3:5])[CH3:2])=[O:43])=[N:34]2)=[C:29]([F:46])[CH:28]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)c1nn(-c2ccc(OCc3ccccc3)cc2F)cc(OC)c1=O
Reactant: CNOC
Agent: C[Al](C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cn(-c2ccc(OCc3ccccc3)cc2F)nc(C(=O)N(C)OC)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
To a solution of N,O-dimethylhydroxylamine hydrochloride (5.27 g, 54 mmol) and iPr2NEt (9.41 mL, 54 mmol) in CH2Cl2 (50 mL) was added AlMe3 (1.8 M solution in toluene, 30 mL, 54 mmol) slowly at 0° C. under Ar atmosphere. After stirring for 1 h, a solution of methyl 1-[4-(benzyloxy)-2-fluorophenyl]-5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate (8.07 g, 21 mmol) in CH2Cl2 (50 mL) was added slowly, and the mixture was stirred for 1 h at 0° C. The reaction mixture was poured into ice-water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with AcOEt to give the title compound (7.79 g, 90% yield) as a pale yellow amorphous solid: 1H NMR (300 MHz, CDCl3): δ ppm 3.38 (3H, s), 3.70 (3H, s), 3.89 (3H, s), 5.11 (2H, s), 6.82-6.91 (2H, m), 7.33-7.45 (5H, m), 7.48-7.55 (1H, m), 7.73 (1H, d, J=1.9 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][N:15]=[N+]=[N-])[N:11]([CH2:18][C:19]([N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([Cl:30])[CH:28]=3)[C:23]([CH3:32])([CH3:31])[CH2:22]2)=[O:20])[CH2:10][C@H:9]1[CH3:33])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:34]([OH:37])(=S)[CH3:35]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][NH:15][C:34](=[O:37])[CH3:35])[N:11]([CH2:18][C:19]([N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([Cl:30])[CH:28]=3)[C:23]([CH3:32])([CH3:31])[CH2:22]2)=[O:20])[CH2:10][C@H:9]1[CH3:33])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(O)=S
Reactant: C[C@@H]1CN(CC(=O)N2CC(C)(C)c3ccc(Cl)cc32)[C@@H](CN=[N+]=[N-])CN1C(=O)OC(C)(C)C
Product: CC(=O)NC[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1CC(=O)N1CC(C)(C)c2ccc(Cl)cc21
Reaction time: 18.5 h
Yield: 56 %

Procedure:
(2R,5R)-5-Azidomethyl-4-[2-(6-chloro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-2-oxo-ethyl]-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (81 mg, 0.17 mmol) was dissolved in thioacetic acid (459 μL) and left to stir for 18.5 h, then concentrated. The crude oil was purified by column chromatography on silica gel (gradient elution, 0-100%, EtOAc/petrol) to give the title compound (47 mg, 56%) as a colourless solid. 1H NMR (Me-d3-OD): 8.15 (1H, d), 7.21 (1H, d), 7.09 (1H, dd), 4.24-4.14 (1H, m), 4.06-3.96 (2H, m), 3.84 (1H, d), 3.71 (1H, d), 3.56 (1H, d), 3.48-3.40 (1H, m), 3.25-3.13 (1H, m), 3.04-2.96 (1H, m), 2.92 (1H, dd), 2.65 (1H, dd), 1.97 (3H, s), 1.49 (9H, s), 1.38 (6H, s), 1.32-1.19 (3H, m).
Reaction SMILES: [C@H:1]1([NH:11][CH:12]=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C(OC(=O)C)(=[O:16])C>>[O:16]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C@H:1]([NH:11][CH:12]=[O:13])[CH2:2][CH2:3]1
Reactant: CC(=O)OC(C)=O
Reactant: O=CN[C@@H]1CCCc2ccccc21
Product: O=CN[C@@H]1CCC(=O)c2ccccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (R)—N-(1,2,3,4-tetrahydronaphthalen-1-yl)formamide (4.01 g, 22.9 mmol) in 40 mL of acetic anhydride at 0° C. was added Chomium(VI) oxide (6.00 g, 60.0 mmol). The solution was stirred at 0° C. for 1 h. The solution was filtered, extracted with EtOAc, washed with brine, dried over Na2SO4 and evaporated to dryness. flash chomatograph (SiO2, EtOAc/hexane=1:1 to 2:1 to pure EtOActo EtOAc/MeOH=10:1 to 10:2) afforded (R)—N-(4-oxo-1,2,3,4-tetrahydro-naphthalen-1-yl)formamide as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([NH2:13])[CH:7]=1.C[O:16][C:17](=O)[CH:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[Cl:31])[C:19](=O)[CH2:20][CH3:21].O1CCOCC1>O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:7]=1[C:17](=[O:16])[C:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[Cl:31])=[C:19]([CH2:20][CH3:21])[NH:13]2
Reactant: CCC(=O)C(Cc1ccc(F)cc1Cl)C(=O)OC
Reactant: COC(=O)COc1ccc(F)c(N)c1
Solvent: C1COCCO1
Solvent: O
Product: CCc1[nH]c2c(F)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(F)cc1Cl
Temperature: 130 °C

Procedure:
A mixture of (3-amino-4-fluorophenoxy)acetic acid methyl ester (1.1 g), 2-(2-chloro-4-fluorobenzyl)-3-oxopentanoic acid methyl ester (2.4 g), polyphosphoric acid (5 g) and dioxane (10 mL) was heated at 130° C. for 17 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the solid washed with diethyl ether and dried to afford title compound, 1.5 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([O:16]C)=[O:15])=[C:12]([S:18][C:19]3[N:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[N:20]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].O>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([OH:16])=[O:15])=[C:12]([S:18][C:19]3[N:20]=[C:21]([O:27][CH3:28])[CH:22]=[C:23]([O:25][CH3:26])[N:24]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(-c2ccc(Cl)cc2)ccnc1Sc1nc(OC)cc(OC)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(OC)nc(Sc2nccc(-c3ccc(Cl)cc3)c2C(=O)O)n1
Temperature: 60 °C
Yield: 0.1 %

Procedure:
16.8 g (0,040 mol) of methyl 4-(4-chlorophenyl)-2-(4,6-dimethoxypyrimidin-2-ylthio)nicotinate was dissolved in 150 ml of dimethylsulfoxide, and 35 ml (0,070 mol) of 2N sodium hydroxide added with stirring at 60° C. After stirring at 60° C. for 30 minutes, the mixture was poured into water, and washed twice with ethyl acetate. The aqueous layer was acidified with 10% hydrochloric acid, and extracted with 500 ml of ethyl acetate. The extract was washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, and concentrated. The concentrate was washed with methanol and isopropyl ether to obtain 11.5 g of a white crystal of the aimed product.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:2]#[CH:3].C(N(CC)CC)C.[C:18](Cl)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]>C1(C)C=CC=CC=1.[Cu]Br>[CH3:20][C:19]([CH3:22])([C:18](=[O:23])[C:3]#[C:2][CH2:1][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:21]
Reactant: C#CCOc1ccccc1
Reactant: CC(C)(C)C(=O)Cl
Agent: [Cu]Br
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)C#CCOc1ccccc1
Temperature: 80 °C
Yield: 74 %

Procedure:
13.2 g (0.1 mol) of phenyl propargyl ether are added dropwise to a mixture of 10.1 g (0.1 mol) of triethylamine and 1.43 g of copper-(I) bromide in 60 ml of toluene at 20° C., under a nitrogen atmosphere and with stirring. The mixture is subsequently stirred at 20° C. for 30 minutes. Thereafter, 12 g (0.1 mol) of pivaloyl chloride are added dropwise in the course of 15 minutes. The reaction mixture is heated to 80° C. and is stirred at this temperature for 10 hours. After cooling to room temperature, the reaction mixture is washed first with dilute aqueous hydrochloric acid and then with water. The organic phase is concentrated by stripping off the solvent and the residue which remains is distilled under a high vacuum. 16 g (75% of theory) of 2,2-dimethyl-6-phenoxyhex-4-in-3-one are obtained in this manner in the form of a liquid.
Reaction SMILES: C([O:8][CH2:9][C@@H:10]([CH2:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])C1C=CC=CC=1.C1CCCCC=1.Cl>C1COCC1.[C].[Pd]>[OH:8][CH2:9][C@@H:10]([CH2:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12]
Reactant: O=C(O)[C@@H](COCc1ccccc1)Cc1cccc2ccccc12
Agent: [Pd]
Agent: Cl
Solvent: C1=CCCCC1
Solvent: C1CCOC1
Product: O=C(O)[C@@H](CO)Cc1cccc2ccccc12

Procedure:
(2R)-3-benzyloxy-2-(1-naphthylmethyl)propionic acid was dissolved in 6 ml of THF, and 3 ml of cyclohexene, 2.5 ml of 1N hydrochloric acid and 400 mg of 10% palladium carbon were added thereto. The mixture was refluxed under heating for 48 hours. After filtration, the solvent was distilled off under reduced pressure, and the residue was divided with ethyl acetate and a 4% sodium hydrogencarbonate aqueous solution. The aqueous layer was adjusted to pH2 with 1N hydrochloric acid under cooling with ice and extracted with ethyl acetate. The ethyl acetate layer was washed sequentially with water and a saturated sodium chloride aqueous solution and dried over anhydride sodium sulfate to obtain 212 mg of (2R)-3-hydroxy-2-(1-naphthylmethyl)propionic acid as colorless oily substance.
Reaction SMILES: [OH:1][C:2]([C:4](F)(F)F)=O.OC(C(F)(F)F)=O.[F:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+].BrCCO.BrC(O)C>C(#N)C>[F:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21]([CH2:4][CH2:2][OH:1])[CH2:20][CH2:19]1
Reactant: FCCN1CCNCC1
Reactant: O=C(O)C(F)(F)F
Agent: CC(O)Br
Agent: O=C([O-])[O-]
Agent: OCCBr
Solvent: CC#N
Product: OCCN1CCN(CCF)CC1
Temperature: 85 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
1-(2-Fluoroethyl)piperazine diTFA salt (464 mg, 1.29 mmol), (prepared as described for the starting material in Example 27), was dissolved in acetonitrile (3.5 ml). Potassium carbonate (889 mg, 6.44 mmol) and 2-bromoethanol (95 μl, 1.34 mmol) were added and the mixture heated to 85° C. and left overnight. More bromoethanol (95 μl, 1.34 mmol) was added and the reaction mixture heated at 85° C. for a further 2 hours. The reaction mixture was cooled, filtered and concentrated. The residue was purified by column chromatography eluting with methylene chloride/methanol (saturated with ammonia) (92/8) to give 2-[4-(2-fluoroethyl)piperazin-1-yl]ethanol (151 mg, 66%).
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[C:8]([OH:10])=O.O1CCCC1.S(Cl)(Cl)=O.[NH2:20][C:21]1[CH:22]=[C:23]([CH:40]=[CH:41][C:42]=1[CH3:43])[O:24][C:25]1[CH:26]=[CH:27][C:28]2[N:29]([N:31]=[C:32]([NH:34][C:35]([CH:37]3[CH2:39][CH2:38]3)=[O:36])[N:33]=2)[CH:30]=1>CN(C)C=O.CN(C)C(=O)C>[Cl:1][C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[C:8]([NH:20][C:21]1[CH:22]=[C:23]([O:24][C:25]2[CH:26]=[CH:27][C:28]3[N:29]([N:31]=[C:32]([NH:34][C:35]([CH:37]4[CH2:38][CH2:39]4)=[O:36])[N:33]=3)[CH:30]=2)[CH:40]=[CH:41][C:42]=1[CH3:43])=[O:10]
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)cc1N
Reactant: Cc1csc(C(=O)O)c1Cl
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)cc1NC(=O)c1scc(C)c1Cl
Yield: 77.8 %

Procedure:
In the same manner as in Example 55 and using 3-chloro-4-methylthiophene-2-carboxylic acid (90.0 mg, 0.510 mmol), tetrahydrofuran (5 mL), thionyl chloride (89.0 μL, 1.02 mmol), N,N-dimethylformamide (2 drops), N-[6-(3-amino-4-methylphenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (150 mg, 0.464 mmol) and N,N-dimethylacetamide (6 mL) as starting materials, the title compound (174 mg, 78%) was obtained as a pale-yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([OH:12])=[CH:7][CH:6]=2.[I-:13].[Na+].CN(C)CCN(C)C.N.Cl>O1CCOCC1.[Cu](I)I>[I:13][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([OH:12])=[CH:7][CH:6]=2
Reactant: Oc1ccc2ncc(Br)cc2c1
Reactant: [I-]
Agent: I[Cu]I
Agent: CN(C)CCN(C)C
Agent: Cl
Solvent: C1COCCO1
Product: Oc1ccc2ncc(I)cc2c1
Temperature: 120 °C
Reaction time: 12 h

Procedure:
To a stirred mixture of 3-bromo-6-hydroxyquinoline (preparation described in Liebigs Ann Chem (1966), 98-106) (1.0 g), sodium iodide (1.34 g) and copper iodide (0.09 g) in dioxane (6.5 ml) was added N,N,N′,N′-tetramethyl-ethane-1,2-diamine (0.1 ml) in a sealed tube. The mixture was stirred at 120° C. for 12 h and upon cooling was treated with aqueous ammonia followed by aqueous hydrochloric acid. Extraction with ethyl acetate, drying of the organic phase over magnesium sulphate, filtration and evaporation under reduced pressure gave the required product (MH+ 272) as a light brown coloured powder that was used as such in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]2[NH:16][C@@H:15]([CH:17]([CH2:19][CH3:20])[CH3:18])[CH2:14][S:13]2)=[C:7]([CH3:21])[CH:6]=1)=[O:4].[CH2:22](Br)[CH:23]([CH3:25])[CH3:24]>>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]2[N:16]([CH2:22][CH:23]([CH3:25])[CH3:24])[C@@H:15]([CH:17]([CH2:19][CH3:20])[CH3:18])[CH2:14][S:13]2)=[C:7]([CH3:21])[CH:6]=1)=[O:4]
Reactant: CC(C)CBr
Reactant: CCC(C)[C@H]1CSC(=Nc2ccc(C(=O)OC)cc2C)N1
Product: CCC(C)[C@H]1CSC(=Nc2ccc(C(=O)OC)cc2C)N1CC(C)C

Procedure:
(1S)-1-(Hydroxymethyl)-2-methylbutylamine was made from (L)-isoleucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-2-methylbutanammonium chloride as described in Method B7a. 4-Methoxycarbonyl-2-methylphenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-2-methylbutanammonium chloride to Method C1a to give (4S)-2-(4-methoxycarbonyl-2-methylphenylimino)-4-(2-butyl)-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4S)-2-(4-methoxycarbonyl-2-methylphenylimino)-4-(2-butyl)-3-isobutyl-1,3-thiazolidine.
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=2)[CH:16]=[C:15]1[CH:24]=O)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:26]([CH3:29])([O-:28])=[O:27]>CCOC(C)=O>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=2)[CH:16]=[C:15]1[CH:24]=[CH:29][N+:26]([O-:28])=[O:27])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cc2ccc(Cl)cc2n1C(c1ccccc1)c1ccccc1
Reactant: C[N+](=O)[O-]
Solvent: CCOC(C)=O
Product: O=[N+]([O-])C=Cc1cc2ccc(Cl)cc2n1C(c1ccccc1)c1ccccc1
Yield: 48 %

Procedure:
A solution of 1-benzhydryl-6-chloro-1H-indole-2-carbaldehyde (0.5M, 1 equiv.) and NH4OAc (1 equiv.) in nitromethane was heated at 95° C. for 70 min. The mixture was diluted with EtOAc, washed with water, and dried. Evaporation of the volatiles, followed by trituration with ether/hexane produced 1-Benzhydryl-6-chloro-2-(2-nitro-vinyl)-1H-indole in 48% yield.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][C:14]([OH:16])=O.ClC(OCC)=O.[NH2:23][C:24]1[CH:37]=[CH:36][C:27]([CH2:28][CH:29]2[S:33][C:32](=[O:34])[NH:31][C:30]2=[O:35])=[CH:26][CH:25]=1.Cl>C(Cl)Cl.C(OCC)(=O)C.C(N(CC)CC)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][C:14]([NH:23][C:24]1[CH:37]=[CH:36][C:27]([CH2:28][CH:29]2[S:33][C:32](=[O:34])[NH:31][C:30]2=[O:35])=[CH:26][CH:25]=1)=[O:16]
Reactant: Cc1oc(-c2ccccc2)nc1CC(=O)O
Reactant: Nc1ccc(CC2SC(=O)NC2=O)cc1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1oc(-c2ccccc2)nc1CC(=O)Nc1ccc(CC2SC(=O)NC2=O)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 110.7 %

Procedure:
2-(5-Methyl-2-phenyl-4-oxazolyl) acetic acid (0.40 g, 1.8 mmol) dissolved in 5 mL of CH2Cl2 was cooled to 0°-5° C. Triethylamine (0.46 mL) and then ethyl chloroformate (0.30 mL) were each added dropwise. After stirring at 15 minutes at 0° C. to assure complete conversion of the acid to the intermediate mixed anhydride, a solution of 5-(4-aminobenzyl) thiazolidine-2,4-dione (0.71 g, 3.2 mmol; Chem. Pharm. Bull. Japan, v. 30, p. 3580, 1982) and 0.24 mL triethylamine in 15 mL were added dropwise as the temperature was maintained at 0°-5° C. The resulting solution was then stirred for 18 hours at room temperature, stripped of solvent and the residue distributedbetween 25 mL 2N HCl and 25 mL ethyl acetate. The aqueous layer was extracted with 25 mL additional ethyl acetate, and the organic layers combined, washed sequentially 1×30 mL water, 1×30 mL saturatedNaHCO3 and 1×30 mL saturated NaCl, dried (Na2SO4) andstripped to yield 0.84 g of solids. The latter was flash chromatographed onsilica gel using 1:2 ethyl acetate:hexane as eluant to yield 0.23 g of impure title product suitable for rechromatography and 0.20 g of purified title product.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[C:7]([O:11][C:12]([CH2:14][O:15][N:16]=[C:17]([C:21]1[N:25]=[C:24]([NH2:26])[S:23][N:22]=1)[C:18]([OH:20])=O)=[O:13])([CH3:10])([CH3:9])[CH3:8].[NH2:27][CH:28]1[C:48](=[O:49])[N:30]2[C:31]([C:45]([OH:47])=[O:46])=[C:32]([CH2:35][S:36][C:37]3[N:41]([CH2:42][C:43]#[CH:44])[N:40]=[N:39][N:38]=3)[CH2:33][S:34][C@H:29]12.C[Si](CC(N)=O)(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:7]([O:11][C:12]([CH2:14][O:15][N:16]=[C:17]([C:21]1[N:25]=[C:24]([NH2:26])[S:23][N:22]=1)[C:18]([NH:27][CH:28]1[C:48](=[O:49])[N:30]2[C:31]([C:45]([OH:47])=[O:46])=[C:32]([CH2:35][S:36][C:37]3[N:41]([CH2:42][C:43]#[CH:44])[N:40]=[N:39][N:38]=3)[CH2:33][S:34][C@H:29]12)=[O:20])=[O:13])([CH3:8])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)O)c1nsc(N)n1
Reactant: C#CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: C[Si](C)(C)CC(N)=O
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: C#CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3nsc(N)n3)[C@H]2SC1
Temperature: -10 °C
Reaction time: 0.75 h
Yield: 59.8 %

Procedure:
To a solution of phosphorus pentachloride (2.50 g) in methylene chloride (60 ml) was added 2-tert-butoxycarbonylmethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer)(3.02 g) at -15° C. and the mixture was stirred for 45 minutes at -10° to -13° C. On the other hand, a mixture of 7-amino-3-[1-(2-propynyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (3.52 g) and trimethylsilylacetamide (10 g) in methylene chloride (50 ml) was warmed to make a clear solution and then cooled to -10° C. The solution was added to the above activated mixture at a time and the mixture was stirred for 15 minutes at -5° to 10° C. The reaction mixture was poured into an aqueous solution (120 ml) of sodium bicarbonate (6.7 g) and stirred for 30 minutes at room temperature. The aqueous layer was separated and ethyl acetate was added thereto. The resulting mixture was adjusted to pH 3 with 6 N hydrochloric acid. The ethyl acetate layer was separated, dried over magnesium sulfate and then evaporated. The residue was pulverized with isopropyl ether and then dried to give 7-[2-tert-butoxycarbonylmethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-propynyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer)(3.8 g), mp. 120° to 125° C. (dec.).