Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:24]1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.NC1C(C)=CC=CC=1>C(O)(=O)C>[C:17]1([C:16]2[C:10]3[N:9]=[CH:8][N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=4[CH3:24])[C:12](=[O:13])[C:11]=3[S:14][CH:15]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Solvent: Cc1ccccc1N
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: Cc1ccccc1-n1cnc2c(-c3ccccc3)csc2c1=O
Yield: 23 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (200 mg, 0.86 mmol), triethyl orthoformate (2 ml), o-toluidine (175 mg, 1.63 mmol), and acetic acid (0.2 ml) were used to give 62 mg (0.19 mmol, 23% yield) of the title compound.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:5]([CH2:10][NH2:11])=[N:6][CH:7]=[CH:8][N:9]=1.C(N(CC)C(C)C)(C)C.ON1C2C=CC=CC=2N=N1.[CH2:31]([O:38][C:39]([N:41]1[CH2:46][CH2:45][CH:44]([C:47](O)=[O:48])[CH2:43][CH2:42]1)=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[Cl:3][C:4]1[C:5]([CH2:10][NH:11][C:47]([CH:44]2[CH2:45][CH2:46][N:41]([C:39]([O:38][CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[O:40])[CH2:42][CH2:43]2)=[O:48])=[N:6][CH:7]=[CH:8][N:9]=1
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: NCc1nccnc1Cl
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1nccnc1Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of C-(3-Chloropyrazin-2-yl)methylamine bis-hydrochloride (2.00 g, 0.0107 mol) and N,N-diisopropylethylamine (2.2 g, 0.017 mol) in DCM (27.0 mL) was treated with and N-(3-dimethylaminopropyl)-Al-ethylcarbodiimide hydrochloride (3.2 g, 0.017 mol), 1-hydroxybenzotriazole (1.5 g, 0.011 mol) and 1-[(benzyloxy)carbonyl]-4-piperidine carboxylic acid (3.8 g, 0.014 mol). The mixture was stirred at rt overnight then diluted with DCM (30 mL), washed with sat. NaHCO3 (20 mL) and brine (20 mL), then dried over Na2SO4 and concentrated in vacuo. The crude material thus obtained was chromatographed over silica gel eluting with EtOAc:hexane 1:1 yielding 3.38 g of the title compound. 1H NMR (400 MHz, CDCl3): δ 1.68-1.78 (m, 2H), 1.91-1.94 (m, 2H), 2.44 (m, 1H), 2.89-2.92 (m, 2H), 4.24-4.26 (m, 2H), 4.70 (d, J=4.8 Hz, 2H), 5.14 (s, 2H), 6.85 (br, 1H), 7.30-7.37 (m, 5H), 8.34 (d, J=2.8 Hz, 1H), 8.45 (d, J=2.8 Hz, 1H). MS (ES+): m/z 389.17 [MH+].
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:17]=[C:16]([N:18]2[CH:22]=[CH:21][CH:20]=[N:19]2)[CH:15]=[CH:14][C:9]=1[C:10](OC)=[O:11].O>C1COCC1>[F:7][C:8]1[CH:17]=[C:16]([N:18]2[CH:22]=[CH:21][CH:20]=[N:19]2)[CH:15]=[CH:14][C:9]=1[CH2:10][OH:11]
Reactant: COC(=O)c1ccc(-n2cccn2)cc1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc(-n2cccn2)cc1F
Reaction time: 1 h
Yield: 91.4 %

Procedure:
To a solution of lithium aluminium hydride (0.16 g) in THF (5.50 mL) was added a solution of methyl 2-fluoro-4-(1H-pyrazol-1-yl)benzoate (0.89 g) in THF (5.50 mL) under ice-cooling, and the mixture was stirred for 1 hr. To the reaction solution was added water, the insoluble substance was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (0.71 g) as a crude product.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([F:16])[CH:15]=1)[C:10]([OH:12])=[O:11].[CH2:17](O)[CH3:18]>C(OCC)C.O>[Br:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([F:16])[CH:15]=1)[C:10]([O:12][CH2:17][CH3:18])=[O:11]
Reactant: CCO
Reactant: O=C(O)c1cc(F)cc(Br)c1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)c1cc(F)cc(Br)c1
Temperature: 25 °C

Procedure:
Sulphuric acid (0.5 mL) was added to a stirring solution of 3-bromo-5-fluorobenzoic acid (473 mgs, 2.16 mmol) in ethanol (10 mL) and refluxed for 17 hours. The reaction mixture was cooled to room temperature and diluted with diethyl ether and water. The ether layer was washed with 5% sodium hydrogen carbonate solution, dried over magnesium sulphate and evaporated to dryness to give the title compound as a brown oil. (506 mg).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.I[C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[CH:28]=2)[N:23]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[N:22]=1.[C:41]1([C:47]#[CH:48])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(N(CC)CC)C>C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu](I)I>[N+:30]([C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[N:23]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[N:22]=[C:21]2[C:48]#[C:47][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([O-:32])=[O:31]
Reactant: C#Cc1ccccc1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2cc([N+](=O)[O-])ccc21
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[Si](C)(C)CCOCn1nc(C#Cc2ccccc2)c2cc([N+](=O)[O-])ccc21
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
5-Nitro-3-phenylethynyl-1-(2-trimethylsilanylethoxymethyl)-1H-indazole can be obtained in the following way: 0.16 g of triphenylphosphine, 0.54 g of tetrakis(triphenylphosphine)palladium(0) and 0.27 g of copper iodide are added to a solution, under argon, of 3 g of 3-iodo-5-nitro-1-(2-trimethylsilanylethoxymethyl)-1H-indazole in 200 ml of acetonitrile. After stirring for 10 minutes, 1.57 ml of phenylacetylene and 2 ml of triethylamine are added, and the reaction mixture is then refluxed for 16 hours. After cooling to a temperature in the region of 20° C., the reaction mixture is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 35° C. The residue is taken up in 150 ml of dichloromethane and then washed with 2 times 120 ml of water. The aqueous phases are pooled and extracted with 100 ml of dichloromethane. The organic extracts are pooled, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 30° C. The residue is purified by chromatography under argon pressure (50 kPa), on a column of 200 g of silica (particle size 40-63 μm), eluting successively with pure cyclohexane then with cyclohexane/ethyl acetate (98/2; 97/3; 95/5; 90/10 by volume) mixtures. The fractions containing the expected product are pooled and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 35° C. 2.31 g of 5-nitro-3-phenylethynyl-1-(2trimethylsilanylethoxymethyl)-1H-indazole are thus obtained in the form of a brown solid melting at 88° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[C:10]1(Br)[CH2:14][CH2:13][CH2:12][C:11]1=[O:15].CCN(C(C)C)C(C)C>C(#N)C.C(OC(=O)C)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[C:11](=[O:15])[CH2:12][CH2:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCCC1(Br)Br
Reactant: Oc1ccc(Br)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C1CCC=C1Oc1ccc(Br)cc1
Reaction time: 8 h
Yield: 62.8 %

Procedure:
To a solution of 4-bromophenol (500 mg, 2.9 mmol) in ACN (14.5 mL), 2,2-dibromo cyclopentanone (1.4 g, 8.7 mmol) and DIPEA (500 mg, 2.9 mmol) were added. The resulting mixture was stirred at r.t overnight. After completion of the reaction as confirmed by TLC, the reaction mixture was diluted with ethylacetate (150 mL), washed with water (50 mL) and brine (50 mL) successively. The combined organic layers were dried over Na2SO4 and the volatiles were evaporated in vacuo. The residue obtained was purified by column chromatography (silica gel, 1:9 EtOAc:hexane) to provide title compound (461 mg, 63%) as pale brown liquid.
Reaction SMILES: C[O:2][C:3](=[O:43])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C@@H:13]2[NH:17][C@@H:16]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C@:15]3([C:30]4[C:25](=[CH:26][C:27]([Br:31])=[CH:28][CH:29]=4)[NH:24][C:23]3=[O:32])[C@H:14]2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=2[F:40])=[O:12])=[C:6]([O:41][CH3:42])[CH:5]=1.[OH-].[Na+].Cl>CO.C1COCC1.O>[Br:31][C:27]1[CH:26]=[C:25]2[NH:24][C:23](=[O:32])[C@:15]3([C@@H:14]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=4[F:40])[C@H:13]([C:11]([NH:10][C:7]4[CH:8]=[CH:9][C:4]([C:3]([OH:43])=[O:2])=[CH:5][C:6]=4[O:41][CH3:42])=[O:12])[NH:17][C@H:16]3[CH2:18][C:19]([CH3:21])([CH3:20])[CH3:22])[C:30]2=[CH:29][CH:28]=1
Reactant: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Br)ccc43)[C@H]2c2cccc(Cl)c2F)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@@]2(C(=O)Nc3cc(Br)ccc32)[C@H]1c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of rac-4-{[(2′S,3′R,4′S,5′R)-6-bromo-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-3-methoxy-benzoic acid methyl ester (0.19 g, 0.28 mmol) in MeOH (3 mL) and THF (9 mL) was added an aqueous solution (1N) of NaOH (6 mL, 6 mmol). The reaction mixture was stirred at room temperature for 18 h. The crude mixture was diluted with water (5 mL), and acidified to “pH” 5-6 by dilute aqueous HCl solution. The mixture was then extracted with ethyl acetate three times. The combined organic extract was washed with water, brine, dried over MgSO4, and concentrated. The residue was triturated with dichlormethane and hexanes to give rac-4-{[(2′S,3′R,4′S,5′R)-6-bromo-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-3-methoxy-benzoic acid as a white powder (Yield, 0.15 g, 81%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:21]O)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[N:11]=[C:12]([C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)[O:13][C:14]=1[CH3:15].S(Cl)([Cl:25])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:21][Cl:25])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[N:11]=[C:12]([C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)[O:13][C:14]=1[CH3:15]
Reactant: O=S(Cl)Cl
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(CO)cc1Cl
Product: Cc1oc(-c2ccco2)nc1COc1ccc(CCl)cc1Cl
Reaction time: 2 h
Yield: 94 %

Procedure:
(3-Chloro-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}phenyl)methanol (4.0 g) was added to thionyl chloride (10 mL) at 0° C., and the mixture was stirred for 2 hrs. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 4-(2-chloro-4-chloromethylphenoxy)methyl-2-(2-furyl)-5-methyl-1,3-oxazole as colorless crystals (3.96 g, yield 94%). Recrystallization from ethyl acetate-hexane gave colorless needle crystals. melting point: 103-104° C.
Reaction SMILES: [C:1]([C:4]1[C:9](=O)[NH:8][C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:5]=1)(=O)[CH3:2].[Cl:21][C:22]1[CH:23]=[C:24]([CH2:28][C:29]([OH:31])=[O:30])[CH:25]=[CH:26][CH:27]=1.C(N(CC)CC)C.[OH-].[NH4+]>C(OC(=O)C)(=O)C>[Cl:21][C:22]1[CH:23]=[C:24]([C:28]2[C:29](=[O:31])[O:30][C:9]3=[N:8][C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:5]=[C:4]3[C:1]=2[CH3:2])[CH:25]=[CH:26][CH:27]=1
Reactant: O=C(O)Cc1cccc(Cl)c1
Reactant: CCOC(=O)c1cc(C(C)=O)c(=O)[nH]c1C(=O)OCC
Agent: [NH4+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1cc2c(C)c(-c3cccc(Cl)c3)c(=O)oc2nc1C(=O)OCC
Temperature: 0 °C
Yield: 95.1 %

Procedure:
Diethyl 5-acetyl-1,6-dihydro-6-oxo-2,3-pyridinedicarboxylate (12.0 g, 0.043 mol), 3-chlorophenyl acetic acid (7.33 g, 0.043 mol) and triethylamine (6.52 g) are refluxed in 120 mL of acetic anhydride for three hours. The reaction mixture is cooled, poured into 120 mL of ice-cold water and made alkaline to pH 8 with an ammonium hydroxide solution. The crystalline solid is filtered and washed with water to give (17.0 g, 95%) of the product after drying. Recrystallization from ethyl acetate affords the pure product (13.29, 74% yield), melting point 170°-172° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1.C(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>O1CCOCC1>[OH:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([CH3:13])[CH:3]=[C:2]2[N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1
Reactant: c1c[nH]cn1
Reactant: Cc1cc(Cl)c2cccc(O)c2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: Cc1cc(-n2ccnc2)c2cccc(O)c2n1
Yield: 85.5 %

Procedure:
The solution of 4-chloro-8-hydroxy-2-methylquinoline (2.0 g), imidazole (3.52 g) in dioxane (20 ml) was refluxed for 18 hours. The cooled reaction mixture was added chloroform and aqueous sodium bicarbonate solution. The organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized from ether to give 8-hydroxy-4-(imidazol-1-yl)-2-methylquinoline (1.99 g) as colorless crystals.
Reaction SMILES: C(OC1C=CC2C(=CC=CC=2)N1C(OCC)=O)C.[C:19]([O:23][C:24]([NH:26][C@H:27]([C:30]([OH:32])=O)[CH2:28][OH:29])=[O:25])([CH3:22])([CH3:21])[CH3:20].Cl.[CH3:34][O:35][C:36](=[O:45])[C@@H:37]([CH2:39][CH2:40][C:41]([O:43][CH3:44])=[O:42])[NH2:38].CN1CCOCC1>CN(C)C=O>[CH3:34][O:35][C:36](=[O:45])[C@@H:37]([CH2:39][CH2:40][C:41]([O:43][CH3:44])=[O:42])[NH:38][C:30](=[O:32])[C@H:27]([CH2:28][OH:29])[NH:26][C:24]([O:23][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:25]
Reactant: COC(=O)CC[C@@H](N)C(=O)OC
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)CC[C@@H](NC(=O)[C@H](CO)NC(=O)OC(C)(C)C)C(=O)OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 683 %

Procedure:
5.4 g (2.2 mmol) of 2-ethoxy-N-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ) are added to 4.1 g (2 mmol) of tert-butoxycarbonyl-L-serine, 4.23 g (2 mmol) of D-glutamic acid dimethyl ester hydrochloride and 1.01 g (2 mmol) of N-methylmorpholine in 40 ml of dimethylformamide. After stirring for 16 hours at room temperature, the resulting suspension is filtered and the filtrate is evaporated to dryness. The oily residue is taken up in 150 ml of ethyl acetate and, in the cold, is washed 5 times with 50 ml of 2 N citric acid solution each time, then twice with 50 ml of water each time. The organic phase is dried, concentrated to approximately 40 ml and caused to crystallise by adding, in portions, 150 ml of ether/petroleum ether 2:1. 4.95 g (79%) of tert-butoxycarbonyl-L-seryl-D-glutamic acid dimethyl ester are obtained as colourless needles;
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[NH:2]1.C(=O)([O-])[O-].[K+].[K+].[Cl:18][CH2:19][C:20]#[C:21][CH2:22]Cl.O>CN(C=O)C>[Cl:18][CH2:19][C:20]#[C:21][CH2:22][N:2]1[C:3](=[O:10])[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]1=[O:11]
Reactant: ClCC#CCCl
Reactant: O=C1NC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CC#CCCl
Temperature: 80 °C
Reaction time: 5 h
Yield: 28.8 %

Procedure:
To a solution of 1H-isoindole-1,3(2H)-dione (441 mg) in DMF (5 mL) were added potassium carbonate (829 mg) and 1,4-dichlorobut-2-yne (2.21 g) at room temperature. The reaction mixture was stirred at 80° C. for 5 hr. The reaction mixture was added to water at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (202 mg).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[C:10]1([NH:16][C:17]2[N:22]=[C:21]([CH2:23]O)[CH:20]=[C:19]([CH:25]3[CH2:27][CH2:26]3)[N:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])O.[Na+].C(=O)=O>ClCCl>[C:10]1([NH:16][C:17]2[N:22]=[C:21]([CH2:23][F:7])[CH:20]=[C:19]([CH:25]3[CH2:27][CH2:26]3)[N:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OCc1cc(C2CC2)nc(Nc2ccccc2)n1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Solvent: ClCCl
Product: FCc1cc(C2CC2)nc(Nc2ccccc2)n1
Temperature: 0 °C

Procedure:
6.1 g (37.8 mmol) of diethylaminosulfur trifluoride in 15 ml of dichloromethane are slowly added dropwise within a period of one hour, with stirring, to a suspension of 9.1 g (37.8 mmol) of 2-phenylamino-4-hydroxymethyl-6-cyclopropylpyrimidine in 80 ml of dichloromethane. After the addition of 50 ml of ice-water, 50 ml of 10% aqueous sodium hydrogen carbonate solution are added dropwise. When the evolution of carbon dioxide has ceased, the organic phase is separated off and the aqueous phase is extracted twice with 20 ml of dichloromethane each time. The combined dichloromethane solutions are washed with 15 ml of water, dried over sodium sulfate and filtered, and the solvent is evaporated. The black oil which remains is purified by column chromatography over silica gel (toluene/chloroform/diethyl ether/petroleum ether (b.p. 50°-70° C.); 5/3/1/1). After the eluant mixture has been evaporated off, the yellow oil is diluted with 20 ml of petroleum ether (b.p. 50°-70° C.) and crystallised at reduced temperature. The yellowish crystals melt at 50°-52° C. Yield: 4.9 g (20.1 mmol; 53% of the theoretical yield).
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([NH2:12])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([CH:16]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:17](OC)=[O:18])(=O)[CH3:14]>C1(C)C(C)=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:14][C:13]1[NH:12][C:10]2[N:9]([N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:11]=2)[C:17](=[O:18])[C:16]=1[CH2:21][C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)CC(C(C)=O)C(=O)OC
Reactant: Nc1cc(-c2ccccc2)n[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: COC(=O)Cc1c(C)[nH]c2cc(-c3ccccc3)nn2c1=O
Yield: 85.8 %

Procedure:
To a solution of 3-phenyl-1H-pyrazol-5-amine (4 g, 25.1 mmol) and dimethyl 2-acetylsuccinate (12 mL, 74.0 mmol) in xylene (120 mL) was added p-toluenesulfonic acid monohydrate (50 mg, 0.263 mmol). The reaction mixture was heated at reflux under a Dean-Stark trap for 20 h. The solid was filtered and washed with hexanes to afford the title compound (6.4 g, 86%). 1H-NMR (400 MHz, MeOD) δ 2.37 (3 H, s), 3.66 (2 H, s), 3.72 (3 H, s), 6.46 (1 H, s), 7.34-7.53 (3 H, m), 7.87-8.06 (2 H, m).
Reaction SMILES: [CH3:1][N:2]([C@@H:4]1[C:24](=[O:25])[C:23]([C:26]([NH2:28])=[O:27])=[C:22]([OH:29])[C@:21]2([OH:30])[C@H:5]1[CH2:6][C@H:7]1[C:18]([C:19]2=[O:20])=[C:17]([OH:31])[C:10]2[C:11]([OH:16])=[C:12](N)[CH:13]=[CH:14][C:9]=2[CH2:8]1)[CH3:3].Cl.S(=O)(=O)(O)O.[Cl:38][CH2:39][C:40]([O:42]C(=O)CCl)=O.[OH-].[NH4+:48]>CN(C)C=O.O>[Cl:38][CH2:39][C:40]([NH:48][C:4]1([N:2]([CH3:3])[CH3:1])[CH:5]2[C:21]([OH:30])([C:19]([OH:20])=[C:18]3[CH:7]([CH2:6]2)[CH2:8][C:9]2[C:10](=[C:11]([OH:16])[CH:12]=[CH:13][CH:14]=2)[C:17]3=[O:31])[C:22](=[O:29])[C:23]([C:26]([NH2:28])=[O:27])=[C:24]1[OH:25])=[O:42]
Reactant: [NH4+]
Reactant: O=C(CCl)OC(=O)CCl
Reactant: CN(C)[C@@H]1C(=O)C(C(N)=O)=C(O)[C@@]2(O)C(=O)C3=C(O)c4c(ccc(N)c4O)C[C@H]3C[C@@H]12
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C1(NC(=O)CCl)C(O)=C(C(N)=O)C(=O)C2(O)C(O)=C3C(=O)c4c(O)cccc4CC3CC21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Two and a half grams of 9-amino-6-demethyl-6-deoxytetracycline hydrochloride is added in portions, at 15°-20° C., to a solution of 17 ml of dimethylformamide and 0.6 ml of concentrated sulfuric acid. The added solid is completely in solution after 15 minutes. The solution is then cooled to 0° C. and 2.3 g of chloroacetic anhydride in 5 ml of dimethylformamide is added, dropwise, while maintaining the temperature at 0°-2° C. The reaction mixture is stirred for 30 minutes, poured into 40 g of ice and 35 ml of water, and the pH is adjusted to pH 5.34 with concentrated ammonium hydroxide. The resulting solid is stirred for 30 minutes, collected, washed 2× with water, washed 2× acetone and dried in vacuo to give 2.4 g of the desired intermediate.
Reaction SMILES: [CH3:1][CH2:2][OH:3].[C:4]([OH:12])(=O)/C(=C(\C=O)/Br)/Br.[N+:13]([O-])([O-:15])=[O:14].[Na+:17]>O>[O:3]=[CH:2][C:1](=[N+:13]([O-:15])[O-:14])[CH:4]=[O:12].[Na+:17]
Reactant: CCO
Reactant: O=C/C(Br)=C(/Br)C(=O)O
Reactant: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=CC(C=O)=[N+]([O-])[O-]
Reaction time: 0.5 h

Procedure:
An EtOH (12.5 ml) solution containing mucobromic acid (12.9 g) was added dropwise to a solution comprising sodium nitrate (13.1 g) and water (12.5 ml) at 50° C., followed by stirring for 0.5 hours. The reaction solution was adjusted to room temperature, a solid precipitate was collected by filtration. The obtained residue was washed with EtOH. A yellow solid of sodium (1,3-dioxopropan-2-ylidene)azinate (3.82 g) was thus obtained.
Reaction SMILES: C[O:2][C:3](=[O:43])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C@@H:13]2[NH:17][C@@H:16]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C@:15]3([C:30]4[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=4)[NH:24][C:23]3=[O:32])[C@H:14]2[C:33]2[CH:38]=[C:37]([F:39])[CH:36]=[C:35]([Cl:40])[CH:34]=2)=[O:12])=[C:6]([O:41][CH3:42])[CH:5]=1.[OH-].[Na+].Cl>CO.C1COCC1.O>[Cl:31][C:27]1[CH:26]=[C:25]2[NH:24][C:23](=[O:32])[C@:15]3([C@@H:14]([C:33]4[CH:38]=[C:37]([F:39])[CH:36]=[C:35]([Cl:40])[CH:34]=4)[C@H:13]([C:11]([NH:10][C:7]4[CH:8]=[CH:9][C:4]([C:3]([OH:43])=[O:2])=[CH:5][C:6]=4[O:41][CH3:42])=[O:12])[NH:17][C@H:16]3[CH2:18][C:19]([CH3:21])([CH3:20])[CH3:22])[C:30]2=[CH:29][CH:28]=1
Reactant: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cc(F)cc(Cl)c2)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1cc(F)cc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of rac-4-{[(2′S,3′R,4′R,5′R)-6-chloro-4′-(3-chloro-5-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-3-methoxy-benzoic acid methyl ester (0.17 g, 0.27 mmol) in MeOH (3 mL) and THF (9 mL) was added an aqueous solution (1N) of NaOH (6 mL, 6 mmol). The reaction mixture was stirred at room temperature for 18 h. The crude mixture was diluted with water (5 mL), and acidified to “pH” 5-6 by dilute aqueous HCl solution. The mixture was then extracted with ethyl acetate three times. The combined organic extract was washed with water, brine, dried over MgSO4, and concentrated. The residue was triturated with dichlormethane and hexanes to give rac-4-{[(2′S,3′R,4′R,5′R)-6-chloro-4′-(3-chloro-5-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-3-methoxy-benzoic acid as a white powder (Yield, 0.14 g, 84%).