Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([CH:16]([C:43]1[CH:48]=[CH:47][C:46]([CH2:49][CH:50]([CH3:52])[CH3:51])=[CH:45][CH:44]=1)[O:17][C:18]1[CH:42]=[CH:41][C:21]([C:22]([C:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH2:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:25]=2)=[O:23])=[CH:20][CH:19]=1)([OH:15])=O.[CH2:53]([C:57]1[CH:63]=[CH:62][C:60]([NH2:61])=[CH:59][CH:58]=1)[CH:54]([CH3:56])[CH3:55].ON1C2C=CC=CC=2N=N1>ClCCl>[CH2:49]([C:46]1[CH:47]=[CH:48][C:43]([CH:16]([C:13](=[O:15])[NH:61][C:60]2[CH:62]=[CH:63][C:57]([CH2:53][CH:54]([CH3:56])[CH3:55])=[CH:58][CH:59]=2)[O:17][C:18]2[CH:19]=[CH:20][C:21]([C:22]([C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]([CH2:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:25]=3)=[O:23])=[CH:41][CH:42]=2)=[CH:44][CH:45]=1)[CH:50]([CH3:51])[CH3:52]
Reactant: CCOC(=O)CCCn1cc(C(=O)c2ccc(OC(C(=O)O)c3ccc(CC(C)C)cc3)cc2)c2ccccc21
Reactant: CC(C)Cc1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCOC(=O)CCCn1cc(C(=O)c2ccc(OC(C(=O)Nc3ccc(CC(C)C)cc3)c3ccc(CC(C)C)cc3)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.7 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (30 mg) was added to a mixture of ethyl 4-[3-[4-[(carboxy)(4-isobutylphenyl)methoxy]benzoyl]indol-1-yl]butyrate (70 mg), 4-isobutylaniline (20 mg) and 1-hydroxybenzotriazole (20 mg) in dichloromethane (3 ml). After stirred at 25° C. for 4 hours, the mixture was partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was separated, washed with water and brine, and dried over magnesium sulfate. After evaporation of the solvent, the residue was chromatographed on silica gel (5 g) eluting with chloroform to give ethyl 4-[3-[4-[(4-isobutylphenyl)[(4-isobutylphenyl)carbamoyl]methoxy]benzoyl]indol-1-yl]butyrate (85 mg) as an oil.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[C:9]=1[O:17][CH3:18])C.S(=O)(=O)(O)O.[C:27](O)(=O)C>[Pd]>[CH3:18][O:17][C:9]1[C:10]2[O:16][CH2:15][O:14][C:11]=2[CH:12]=[C:13]2[C:8]=1[CH2:7][N:6]([CH3:27])[CH2:5][CH2:4]2
Reactant: CC(=O)O
Reactant: CCOC(CNCc1ccc2c(c1OC)OCO2)OCC
Agent: [Pd]
Agent: O=S(=O)(O)O
Product: COc1c2c(cc3c1OCO3)CCN(C)C2
Yield: 93 %

Procedure:
1.19 g (5 mmol) of 4-hydroxy-8-methoxy-2-methyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline (1) obtained in Reference Example 1 or 2 was dissolved in 15 ml of acetic acid, to which 0.33 ml (6 mmol) of 97% sulfuric acid and 500 mg of 5% palladium on carbon catalyst were added to carry out catalytic reduction at 75° C. for 2 hours. The catalyst was filtered out and 2 ml of 25% aqueous sodium hydroxide solution and 5 ml of water were added to the reaction mixture, which was concentrated under vacuum. 10 ml of water was added to the residue, the solution was made basic with 25% aqueous sodium hydroxide solution and extracted with 10 ml and then 5 ml of methylene chloride successively. The liquid extract was washed with 5 ml of water, dried over anhydrous magnesium sulfate and then concentrated under vacuum to obtain 1.03 g of 8-methoxy-2-methyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline. Yield 93%.
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.Cl>C(#N)C>[N+:12]([C:11]1[C:2]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[N:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2)([O-:14])=[O:13]
Reactant: Nc1ccc(O)cc1
Reactant: O=[N+]([O-])c1cc2ccccc2nc1Cl
Agent: Cl
Solvent: CC#N
Product: O=[N+]([O-])c1cc2ccccc2nc1Nc1ccc(O)cc1

Procedure:
A mixture of 2-chloro-3-nitroquinoline [0.35 g, prepared by the method of Kaneko, Chem. Pharm. Bull. (Tokyo) 7, 273 (1959)], 4-aminophenol (0.6 g), acetonitrile (20 ml) and dilute hydrochloric acid (30 ml, 1 M) was heated under reflux for 16 hours. The resulting deep orange solution was concentrated under reduced pressure (to 20 ml) and extracted with ethyl acetate (50 ml). The ethyl acetate extract was dried and evaporated to give 4-[N-(3-nitro-2-quinolinyl)amino]phenol as an organge solid, mp 190° C.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([NH:16][C:17](=[O:25])[CH2:18][C:19]([OH:24])([CH3:23])[CH2:20][CH2:21][OH:22])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[Cl:26][C:27]1[CH:34]=[C:33](F)[CH:32]=[CH:31][C:28]=1[C:29]#[N:30].CC(C)([O-])C.[K+].O>C1COCC1>[Cl:26][C:27]1[CH:34]=[C:33]([CH:32]=[CH:31][C:28]=1[C:29]#[N:30])[O:22][CH2:21][CH2:20][C:19]([OH:24])([CH3:23])[CH2:18][C:17]([NH:16][C:12]1[CH:13]=[CH:14][C:15]2[N:3]([CH2:1][CH3:2])[C:4]3[C:9]([C:10]=2[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=3)=[O:25]
Reactant: CCn1c2ccccc2c2cc(NC(=O)CC(C)(O)CCO)ccc21
Reactant: N#Cc1ccc(F)cc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCn1c2ccccc2c2cc(NC(=O)CC(C)(O)CCOc3ccc(C#N)c(Cl)c3)ccc21
Temperature: 25 °C
Reaction time: 14 h
Yield: 48.6 %

Procedure:
To a solution of the compound obtained in Step 1 (348 mg, 1.02 mmol) and 2-chloro-4-fluorobenzonitrile (159 mg, 1.02 mmol) in THF (10 mL) was added potassium t-butoxide (287 mg, 2.56 mmol), and the mixture was stirred at room temperature for 14 hr. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 10 to 100% ethyl acetate/hexane) to give the title compound (236 mg, 0.496 mmol, 48.5%) as a white powder.
Reaction SMILES: Cl.[Br:2][C:3]1[S:7][C:6]2=[C:8](C(OC)=O)[N:9]=[CH:10][N:5]2[CH:4]=1.[OH-].[Na+]>C(O)(=O)CC>[Br:2][C:3]1[S:7][C:6]2=[CH:8][N:9]=[CH:10][N:5]2[CH:4]=1
Reactant: COC(=O)c1ncn2cc(Br)sc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCC(=O)O
Product: Brc1cn2cncc2s1
Yield: 28.1 %

Procedure:
Concentrated hydrochloric acid (0.3 ml) was added to a solution of methyl 2-bromoimidazo[5,1-b]thiazole-7-carboxylate (54 mg, 0.21 mmol) in propionic acid (2 ml), and the mixture was heated under reflux for 11 hr. The reaction solution was neutralized with a 2 M aqueous solution of sodium hydroxide and was extracted with ethyl acetate (7 ml×3). The organic layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:2) to give 2-bromoimidazo[5,1-b]thiazole (12 mg, 28%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][CH2:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15](Br)[CH:16]=3)[N:11]([CH3:22])[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([O:30][C:31]1[CH:36]=[CH:35][NH:34][C:33](=[O:37])[CH:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[K+].[K+].[NH4+].[OH-]>CS(C)=O.C(Cl)Cl.[Cu]I.CO>[CH2:23]([O:30][C:31]1[CH:36]=[CH:35][N:34]([C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[N:11]([CH3:22])[C:10]2[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:20][CH2:19][C:18]3=2)[C:33](=[O:37])[CH:32]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: Cn1c2c(c3cc(Br)ccc31)CCN(C(=O)OC(C)(C)C)C2
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: ClCCl
Solvent: CO
Solvent: CS(C)=O
Product: Cn1c2c(c3cc(-n4ccc(OCc5ccccc5)cc4=O)ccc31)CCN(C(=O)OC(C)(C)C)C2
Temperature: 130 °C
Reaction time: 8 h
Yield: 34.5 %

Procedure:
A solution of tert-Butyl-6-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (750 mg, 2.03 mmol) in DMSO (10 mL) was stirred under nitrogen and treated sequentially with 4-(benzyloxy)pyridin-2(1H)-one (448 mg, 2.23 mmol), 8-hydroxyquinoline (44 mg, 0.305 mmol), CuI (58 mg, 0.305 mmol) and K2CO3 (308 mg, 2.23 mmol). After stirring overnight at 130° C., the mixture was allowed to cool to room temperature and a mixture of MeOH and NH4OH (10:1, 10 mL) was added. After stirring for 15 min, the mixture was diluted with CH2Cl2, washed with brine, dried over Na2SO4, filtered and concentrated to dryness. Purification by flash column chromatography (40 g ISCO column eluting with a 1:1 ethylacetate/hexanes and a methanol/ammonia mixture (10:1); gradient 100% 1:1 ethylacetate/hexanes to 90% 1:1 ethylacetate/hexanes/10% methanol/ammonia mixture (10:1) over 30 min at 25 mL/min) provided the title compound (340 mg, 33%) as a yellow solid; 1H NMR (500 MHz, CDCl3) δ 7.50-7.36 (m, 8H), 7.13 (d, J=7.8, Hz, 1H), 6.09 (d, J=2.6 Hz, 1H), 6.03 (dd, J=7.5, 2.7 Hz, 1H), 5.05 (s, 2H), 4.65 (br s, 2H), 3.73 (br s, 2H), 3.66 (s, 3H), 2.77 (br s, 2H), 1.51 (s, 9H).
Reaction SMILES: [CH2:1]([NH:8][C@@H:9]([C:13]([OH:16])([CH3:15])[CH3:14])[C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:24][C:25](Cl)=[O:26].[OH-].[Na+]>O.O1CCCC1>[CH2:1]([N:8]1[C:25](=[O:26])[CH2:24][O:16][C:13]([CH3:14])([CH3:15])[C@H:9]1[C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(O)[C@H](NCc1ccccc1)C(=O)O
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)OCC(=O)N(Cc2ccccc2)[C@@H]1C(=O)O
Temperature: 0 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
To a mixture of (S)-2-(benzylamino)-3-hydroxy-3-methylbutanoic acid (22.86 g, 102.4 mmol), tetrahydrofuran (110 mL), potassium carbonate (42.5 g, 307.2 mmol) and water (70 mL) was added chloroacetyl chloride slowly (17.8 g, 157.7 mmol) at 0° C. over a period of 1 hour, then the mixture was stirred at 0° C. for 3 hours. To the reaction mixture was added a solution of sodium hydroxide (16.4 g, 409.6 mmol) in water (40 mL) over a period of 1 hour. At the end of addition, the mixture was cooled to 3° C.-5° C., and the mixture was stirred at the temperature for 4 hours. Then the reaction mixture was warmed to room temperature, and washed with Petroleum ether (50 mL×2). The aqueous layer was cooled to 3° C. below and adjusted to pH 2 with con. HCl. The mixture was stirred at 6° C. below for 12 hours, then filtered. The filter cake was washed with water to give the title compound as a white solid (18.6 g, 69%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[N:7][NH:8][CH:9]=1.Cl[C:11]1[N:12]=[N+:13]([O-:22])[C:14]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:15]=2[N:16]=1>CN(C)C=O>[CH3:3][O:4][C:5]1[CH:6]=[N:7][N:8]([C:11]2[N:12]=[N+:13]([O-:22])[C:14]3[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:15]=3[N:16]=2)[CH:9]=1
Reactant: COc1cn[nH]c1
Reactant: [O-][n+]1nc(Cl)nc2ccc(Cl)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cnn(-c2nc3ccc(Cl)cc3[n+]([O-])n2)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 62.3 %

Procedure:
3.45 g (0.115 mol) of sodium hydride (80% pure) were introduced into a solution of 12.6 g (0.13 mol) of 4-methoxy-pyrazole in 100 ml of absolute dimethylformamide at room temperature and the mixture was subsequently warmed briefly to 60° C. 21.6 g (0.1 mol) of 3,7-dichloro-benzo-1,2,4-triazine 1-oxide were added in portions to the mixture, which had been cooled to room temperature. After the exothermic reaction had subsided, the mixture was subsequently stirred at 30° to 40° C. for a further 3 hours and the reaction product was then precipitated with water. This product was filtered off, stirred in 150 ml of methanol, filtered off again and dried. 17.3 g of 3-(4-methoxypyrazol-1-yl)-7-chloro-benzo-1,2,4-triazine 1-oxide of melting point 253°-255° C. (with decomposition) were obtained, that is to say 62.3% of theory. The compound could be recrystallized from dimethylformamide.
Reaction SMILES: [CH2:1]([P:3]([CH2:6][OH:7])(=[O:5])[OH:4])[CH3:2].[CH2:8](O)[CH2:9][CH2:10][CH3:11]>O>[CH2:1]([P:3]([CH2:6][OH:7])(=[O:4])[O:5][CH2:8][CH2:9][CH2:10][CH3:11])[CH3:2]
Reactant: CCCCO
Reactant: CCP(=O)(O)CO
Solvent: O
Product: CCCCOP(=O)(CC)CO
Yield: 66.6 %

Procedure:
405.5 g of ethylhydroxymethylphosphinic acid (prepared according to example 1) are admixed with 1115 g of butanol and the water of condensation is removed with a water trap by boiling at atmospheric pressure. After the esterification has ended, the butanol is separated off in vacuo and the residue is vacuum distilled via a Vigreux column to obtain 392 g of n-butyl ethylhydroxymethylphosphinate in a 79% yield.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])[N:5]=[C:4]([NH:13][CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[N:3]=1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:10][C:9]([NH:8][C:6]1[CH:7]=[C:2]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[N:3]=[C:4]([NH:13][CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[N:5]=1)([CH3:12])[CH3:11]
Reactant: C1CNCCN1
Reactant: CC(C)(C)CNc1nc(Cl)cc(NC(C)(C)C)n1
Product: CC(C)(C)CNc1nc(NC(C)(C)C)cc(N2CCNCC2)n1
Yield: 82.3 %

Procedure:
The reaction of 4-chloro-6-(1,1-dimethylethylamino)-2-(2,2-dimethylpropylamino)pyrimidine with piperazine as described in Example 4 gives the title product in a yield of 82.3%, m.p.: 146°-148° C.
Reaction SMILES: [BH4-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[C:8]1([S:14](Cl)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+]>CC(O)C>[C:8]1([S:14]([N:3]2[CH:7]=[CH:6][CH:5]=[CH:4]2)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: c1cc[nH]c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: O=S(=O)(c1ccccc1)n1cccc1

Procedure:
Papireddy, K. et al. have recently disclosed the antimalarial activity of prodiginines. In this paper, the authors disclosed the synthesis of 2-alkylated pyrroles and 3-alkylated pyrroles. The intermediates were subsequently used to generate synthetic analogs of prodiginines. In order to generate 2-alkylated pyrroles, pyrrole was acylated using zinc powder to afford 2-acylpyrroles. The 2-acylpyrroles were reduced to the corresponding 2-alkylated pyrroles using an excess of sodium borohydride in 2-propanol under reflux. In order to generate 3-alkylated pyrroles, pyrrole was treated with phenylsulfonyl chloride in the presence of sodium hydroxide to provide N-phenylsulfonylpyrrole. Use of aluminum trichloride permitted the regioselective acylation of the N-phenylsulfonylpyrrole at the 3 position with an acyl chloride to afford N-phenylsulfonyl-3-acylpyrroles. The N-phenylsulfonyl-3-acylpyrroles were hydrolyzed under basic conditions to afford 3-acylpyrroles. In the final step, 3-acylpyrroles were reduced to afford 3-alkylpyrroles using sodium borohydride under reflux. See, Papireddy, K. et al., “Antimalarial Activity of Natural and Synthetic Prodiginines”, J. Med. Chem., 54:5296-5306 (2011).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]2=[C:7](C(O)=O)[N:8]=[CH:9][N:4]2[CH:3]=1.C1CCN2C(=NCCC2)CC1>ClC1C=CC(Cl)=CC=1Cl.CCCCCC>[Br:1][C:2]1[S:6][C:5]2=[CH:7][N:8]=[CH:9][N:4]2[CH:3]=1
Reactant: O=C(O)c1ncn2cc(Br)sc12
Solvent: Clc1ccc(Cl)c(Cl)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCCCCC
Product: Brc1cn2cncc2s1
Temperature: 180 °C
Reaction time: 5.5 h
Yield: 42.2 %

Procedure:
A solution of 2-bromoimidazo[5,1-b]thiazole-7-carboxylic acid (34 mg, 0.14 mmol) and 1,8-diazabicyclo[5,4,0]-7-undecene (21 μl, 0.14 mmol) dissolved in 1,2,4-trichlorobenzene (1 ml) was stirred at 180° C. for 5.5 hr. The reaction solution was allowed to cool to room temperature, was diluted with hexane, and was extracted with 2 M hydrochloric acid (3 ml×3). The aqueous layer was neutralized with a 2 M aqueous solution of sodium hydroxide and was extracted with ethyl acetate (5 ml×3). The organic layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1) to give 2-bromoimidazo[5,1-b]thiazole (12 mg, 41%) as a white solid.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:13]=[C:14]([N:29]2[CH2:34][C:33](=[O:35])[O:32][C:31](=[O:36])[CH2:30]2)[CH:15]=[C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:37][OH:38]>>[CH3:37][O:38][C:33](=[O:35])[CH2:34][N:29]([C:14]1[CH:15]=[C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:17]=[C:12]([O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH:13]=1)[CH2:30][C:31]([OH:36])=[O:32]
Reactant: CO
Reactant: CCCCCCCCCCOc1cc(OCCCCCCCCCC)cc(N2CC(=O)OC(=O)C2)c1
Product: CCCCCCCCCCOc1cc(OCCCCCCCCCC)cc(N(CC(=O)O)CC(=O)OC)c1
Reaction time: 17 h

Procedure:
A solution of 0.469 g of 4-[3,5-bis(decyloxy)phenyl]2,6-morpholinedione in 50 ml of methanol was warmed to 50° and then was left at room temperature for 17 hours. The solvent was removed at reduced pressure to give 0.44 g, mp 61°-62° of pure N-(2-methoxy-2-oxoethyl)-N-[3,5-bis(decyloxy)phenyl]glycine.
Reaction SMILES: [CH3:1][C:2]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([CH2:14][CH2:15][N:16]1[C@H:21]2[CH2:22][CH2:23][C@@H:17]1[CH2:18][CH:19]([N:24]1[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]=[C:25]1[CH3:33])[CH2:20]2)[CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:7])=[O:6].[H-].[Na+].I[CH3:43].O>C1COCC1>[CH3:43][N:4]([CH2:3][C:2]([CH3:1])([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:14][CH2:15][N:16]1[C@H:21]2[CH2:22][CH2:23][C@@H:17]1[CH2:18][CH:19]([N:24]1[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]=[C:25]1[CH3:33])[CH2:20]2)[S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:7])=[O:6]
Reactant: CI
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC(C)(CNS(=O)(=O)c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC(C)(CN(C)S(=O)(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
To a solution of the title compound from example 19 (65 mg, 0.12 mmol) in dry THF (2 mL) was added sodium hydride (6 mg, 0.14 mmol) as a 60% suspension in mineral oil and the solution stirred under a nitrogen atmosphere at room temperature for 30 min. Iodomethane (0.03 mL, 0.48 mmol) was added and the reaction stirred at room temperature for 1 h. An additional portion of iodomethane (0.02 mL, 0.32 mmol) was added and the solution stirred for 1 h more at room temperature. Water was added and the reaction partitioned between ethyl acetate and water. The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 0-4% methanol/CH2Cl2 to afford the title compound (50 mg, 75%) as a white solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:12])[CH2:10][CH3:11])=[CH:5][CH:4]=1.C([N-]C(C)C)(C)C.[Li+].Br[CH2:22][C:23]([O:25][CH3:26])=[O:24].Cl>C1COCC1.O>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:12])[CH:10]([CH3:11])[CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:5][CH:4]=1
Reactant: CCC(=O)c1ccc(SC)cc1
Reactant: COC(=O)CBr
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CC(C)C(=O)c1ccc(SC)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The ketone from Step A (180 mg) in THF (2 ml) was added to a solution of lithium diisopropylamide (1.1 mmole) in THF (3 ml) at -78° under N2 atmosphere. After 15 minutes methyl bromoacetate (100 μl) was added and the mixture was warmed to ambient temperature and stirred 12 hours. The mixture was poured into water (15 ml) and conc. HCl (2 ml), extracted with CH2Cl2 and the extracts were dried (Na2SO4) evaporated to dryness and the residue purified by chromatography on silica gel to provide the title compound as an oil. NMR (CDCl3): 1.2 (3H, d), 2.55 (3H, s), 2.3-3.1 (2H, m), 3.65 (3H, s), 3.95 (1H, m), 7.3 (2H, d), 7.95 (2H, d).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]1[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:14]=[CH:13][C:11]=1[NH2:12].O>CN(C)C=O>[Br:1][C:15]1[CH:14]=[CH:13][C:11]([NH2:12])=[C:10]([F:9])[C:16]=1[C:17]([F:18])([F:19])[F:20]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cccc(C(F)(F)F)c1F
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(Br)c(C(F)(F)F)c1F
Yield: 76.2 %

Procedure:
A solution of N-bromosuccinimide (24.9 g) in N,N-dimethyl formamide was added to a solution of 2-fluoro-3-trifluoromethylaniline (25 g) in dimethyl formamide. The mixture was stirred for four and a half hours. It was poured into water and the oil was separated. The aqueous layers was extracted with ether and the combined organic layers were washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was distilled to give 4-bromo-2-fluoro-3-trifluoromethylaniline (27.44 g) as an orange oil, b.p. 88°-94° C./4 mbar.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[F:22][C:23]([F:33])([F:32])[C:24]([NH:26][CH2:27][CH:28]1[CH2:31][NH:30][CH2:29]1)=[O:25].N1C=CC=CC=1>C(N(CC)CC)C>[F:33][C:23]([F:22])([F:32])[C:24]([NH:26][CH2:27][CH:28]1[CH2:29][N:30]([C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[CH:9][C:10]=2[F:16])[CH2:31]1)=[O:25]
Reactant: O=C(NCC1CNC1)C(F)(F)F
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CC(CNC(=O)C(F)(F)F)C3)c(F)cc2c1=O
Yield: 89.8 %

Procedure:
A solution of 0.8 g (2.8 mmoles) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.92 g (4.2 mmoles) of 3-trifluoroacetamidomethylazetidine hydrochloride, 8 ml of pyridine and 1.7 g of triethylamine is heated under reflux for 3 hours. It is then evaporated under vacuum, diluted with water and filtered. 1.12 g (88.9%) of 7-(3-trifluoroacetamidomethyl-1-azetidinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are obtained, melting at 145°-150° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Cl:31])=[CH:27][C:28]=4[F:30])[NH:23][C:22]3=[O:32])[CH:13]2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=2[F:40])=[O:11])=[C:5]([F:41])[CH:4]=1)#[N:2].[OH:42]O.[OH-].[Na+]>CS(C)=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Cl:31])=[CH:27][C:28]=4[F:30])[NH:23][C:22]3=[O:32])[CH:13]2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=2[F:40])=[O:11])=[C:5]([F:41])[CH:4]=1)(=[O:42])[NH2:2]
Reactant: OO
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccc(C#N)cc2F)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)cc(F)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C(N)=O)cc2F)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)cc(F)c12
Temperature: 10 °C
Reaction time: 1 h
Yield: 24.8 %

Procedure:
To the solution of rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-4-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-2-fluoro-phenyl)-amide (0.08 g, 0.13 mmol) prepared in Example 78 in DMSO (2 mL) at 0° C. was added an aqueous solution (30% Aldrich) of H2O2 (0.23 g, 2 mmol), then aqueous solution (1N) of NaOH (0.7 mL, 0.7 mmol) was added dropwise. The reaction mixture was stirred at 10° C. for 1 h. The mixture was partitioned between ethyl acetate and saturated aqueous Na2SO3 solution. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (50-100% EtOAc in dichloromethane) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-4-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-carbamoyl-2-fluoro-phenyl)-amide as a white solid (Yield 0.02 g, 24%)