Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH3:3].[O:4]1[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[C:11]([C:14](=[O:24])[CH2:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:17])[CH:12]=[CH:13][C:5]1=2.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O.CCOCC>[O:4]1[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[C:11]([C:14](=[O:24])[CH:15]([CH2:2][CH3:3])[C:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:17])[CH:12]=[CH:13][C:5]1=2
Reactant: CCBr
Reactant: O=C(CC(=O)c1ccc2c(c1)OCCO2)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Solvent: O
Product: CCC(C(=O)c1ccccc1)C(=O)c1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
Bromoethane (0.87 mmol) was added slowly to a solution 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-phenylpropane-1,3-dione (XX) (0.39 mmol) and K2CO3(1.58 mmol) in DMSO (4 mL) stirred at room temperature under nitrogen. The solution was further stirred overnight at room temperature under nitrogen. The solution was poured into a mixture of water and ether. The etheric layer was separated, washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography to get 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-ethyl-3-phenylpropane-1,3-dione 17 as colorless viscous oil (35% yield). 1H NMR (DMSO-d6, 400 MHz): δ ppm 0.93 (t, J=7.4 Hz, 3H), 1.93 (m, 2H), 4.28 (m, 2H), 4.33 (m, 2H), 5.60 (t, J=6.5 Hz, 1H), 6.99 (d, J=8.6 Hz, 1H), 7.51-7.55 (m, 4H), 7.66 (m, 1H), 7.98 (d, J=7.3 Hz, 2H); ESIMS found C19H18O4 m/z 311 (M+H) and 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2,2-diethyl-3-phenylpropane-1,3-dione 18 as a white solids. ESIMS found C21H22O4 m/z 339 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][C:9]([Cl:17])=[C:8]2[C:3]=1[C:4](=[O:18])[CH2:5][CH2:6][S:7]2.[BH4-].[Na+].O>C(O)C>[OH:18][CH:4]1[C:3]2[C:8](=[C:9]([Cl:17])[CH:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]=2[CH3:1])[S:7][CH2:6][CH2:5]1
Reactant: CCOC(=O)c1cc(Cl)c2c(c1C)C(=O)CCS2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(Cl)c2c(c1C)C(O)CCS2
Reaction time: 1 h
Yield: 106.8 %

Procedure:
13.0 Grams (45.7 mmol) of 5-methyl-6-ethoxycarbonyl-8-chlorothiochroman-4-one was dissolved in 50 ml of ethanol, and 1.73 g (45.7 mmol, 1 eq.) of sodium borohydride was added with an ice bath cooling. The reaction mixture was stirred for 1 hour. After the completion of the reaction, 20 ml of water was added, and the solvent was distilled off. Then, the reaction mixture was extracted with ethyl acetate twice. An organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and the solvent was distilled off to give 14.0 g (yield 100%) of 4-hydroxy-5-methyl-6-ethoxycarbonyl-8-chlorothiochroman.
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]([C:12]([F:15])([F:14])[F:13])[CH2:10][OH:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[I-].[Na+].[O:18]([C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(COC)OC>[C:3]1([CH:9]([C:12]([F:13])([F:14])[F:15])[CH2:10][O:11][CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[C:25]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:26]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: OCC(c1ccccc1)C(F)(F)F
Reactant: BrCc1cccc(Oc2ccccc2)c1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: COCCOC
Product: FC(F)(F)C(COCc1cccc(Oc2ccccc2)c1)c1ccccc1
Temperature: 0 °C
Yield: 58.3 %

Procedure:
Sodium hydride (138 mg; 5.75 mmol) was suspended in dimethoxyethane (20 ml). There was then added in turn, with stirring, 2-phenyl-2-trifluoromethylethanol (1.0 g; 5.25 mmol), a spatula full of sodium iodide and 3-phenoxybenzyl bromide (1.39 g; 5.25 mmol). After stirring for 4 hours at room temperature, the mixture was added to ice-water, extracted with ether, the extract washed with water, dried over sodium sulphate and concentrated. After chromatogrpahy on silica gel using a mixture of hexane and toluene, there was obtained 1.14 g of product (=58.3% of theory).
Reaction SMILES: [BrH:1].[CH2:2]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]O)=[CH:6][CH:5]=1)[CH3:3].O>CC(O)=O>[CH2:2]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][Br:1])=[CH:6][CH:5]=1)[CH3:3]
Reactant: Br
Reactant: CCc1ccc(CO)cc1
Solvent: CC(=O)O
Solvent: O
Product: CCc1ccc(CBr)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
35 ml of a 33% solution of HBr in AcOH are cooled to 0° C., 5 g of 4-ethylbenzyl alcohol are added dropwise and the reaction mixture is stirred for 30 minutes at 0° C. and then overnight at RT. It is poured into 200 ml of iced water, the mixture is extracted with AcOEt, the organic phase is washed with saturated aqueous NaHCO3 solution and with saturated NaCl solution, dried over Na2SO4 and the solvent is evaporated off under vacuum to give 5.6 g of the expected product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Cl:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32]([C:37](O)=[O:38])=[CH:31]2.CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1>CN(C)C=O.O>[C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:37]([C:32]2[NH:33][C:34]3[C:30]([CH:31]=2)=[CH:29][C:28]([Cl:27])=[CH:36][CH:35]=3)=[O:38])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: CCCCCCCNCCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)C(=O)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
2-({4-[2-(Heptylamino)ethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid tert-butyl ester (400 mg) obtained in Example 303-2 and 5-chloro-1H-indole-2-carboxylic acid (196 mg) were dissolved in N,N-dimethylformamide (5 mL), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC) hydrochloride (211 mg) and hydroxybenzotriazole (HOBT) (168 mg) were successively added thereto, and the mixture was stirred at room temperature for 14 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and ether was added to the residue to give the title compound as a white powder.
Reaction SMILES: [H-].[Na+].[C@@H:3]1([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[O:10][C@H:7]([CH2:8][OH:9])[C@@H:5]([OH:6])[CH2:4]1.Cl[CH2:21][C:22]1[C:35]2[C:36]3=[C:37]4[C:32](=[CH:33][CH:34]=2)[CH:31]=[CH:30][CH:29]=[C:28]4[CH:27]=[CH:26][C:25]3=[CH:24][CH:23]=1.C(Cl)Cl>CS(C)=O.CO>[C:22]1([CH2:21][O:9][CH2:8][C@H:7]2[O:10][C@@H:3]([N:11]3[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]3=[O:13])[CH2:4][C@@H:5]2[OH:6])[C:35]2[C:36]3=[C:37]4[C:32](=[CH:33][CH:34]=2)[CH:31]=[CH:30][CH:29]=[C:28]4[CH:27]=[CH:26][C:25]3=[CH:24][CH:23]=1
Reactant: ClCc1ccc2ccc3cccc4ccc1c2c34
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Solvent: ClCCl
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](COCc3ccc4ccc5cccc6ccc3c4c56)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 6.4 %

Procedure:
A mixture of 875 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) in 5 ml of dimethyl sulfoxide was stirred at room temperature for 30 minutes in an atmosphere of nitrogen, and then a solution of 2.42 g (10 mmol) of thymidine in 5 ml of dimethyl sulfoxide was added dropwise to the resulting mixture. The mixture was stirred at room temperature for 30 minutes, after which a suspension of 2.51 g (10 mmol) of 1-(chloromethyl)pyrene [Acta Chem. Scand., 10, 1362 (1936)] in 15 ml of dimethyl sulfoxide was added. The mixture was then stirred at room temperature for 90 minutes. At the end of this time, the reaction mixture was poured into 100 ml of ice-water, and the aqueous mixture was extracted with 100 ml of ethyl acetate and then with 100 ml of methylene chloride. The extract was dried over anhydrous magnesium sulfate, and then the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through 150 g of silica gel (230-400 mesh), using a gradient elution method, with mixtures of methylene chloride containing from 0 to 4% by volume of methanol as the eluent, to give 292.4 mg (yield 6.4%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:3]=1[CH2:14][N:15]1[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([CH2:14][N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[C:4]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(Cl)cccc2N2CCOCC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1cccc(N2CCOCC2)c1CN1CCNCC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 73.6 %

Procedure:
A 50 mL round-bottom flask was charged with tert-butyl 4-[[2-chloro-6-(morpholin-4-yl)phenyl]methyl]piperazine-1-carboxylate (1.80 g, 4.55 mmol, 1.00 equiv), dichloromethane (30 mL). The mixture was cooled to 0° C. and then trifluoroacetic acid (5 mL) was added dropwise at 0° C. The resulting solution was stirred overnight at room temperature and concentrated under reduced pressure to provide 0.990 g (crude) of 4-[3-chloro-2-(piperazin-1-ylmethyl)phenyl]morpholine as light yellow oil. LCMS (ESI, m/z): 296 [M+H]+.
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][C@@H:8]([CH2:35]O)[NH:9][C:10]([C@@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18](=[O:34])[CH2:19][CH2:20][CH:21]2[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]2)[CH2:13]1)=[O:11])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:24]1[CH2:23][CH2:22][CH:21]([CH2:20][CH2:19][C:18]([N:14]2[CH2:15][CH2:16][CH2:17][C@@H:12]([C:10]([NH:9][C@@H:8]3[CH2:35][O:37][C:6](=[O:5])[CH2:7]3)=[O:11])[CH2:13]2)=[O:34])[CH2:26][CH2:25]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CO)NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1C[C@H](NC(=O)[C@@H]2CCCN(C(=O)CCC3CCNCC3)C2)CO1
Reaction time: 1 h
Yield: 127.1 %

Procedure:
To a solution of N-[(R)-1-{3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl}-3-piperidylcarbonyl]-3(S)-hydroxymethyl-β-alanine tert-butyl ester (0.2 g) in dichloromethane (3 ml) was added trifluoroacetic acid (3 ml) at ambient temperature. After stirring for 1 hour, the mixture was evaporated in vacuo. The residue was dissolved in water and freeze-dried to give (S)-4-[(R)-1-{3-(4-piperidyl)propionyl}-3-piperidylcarbonylamino]-1,2,3,4-tetrahydro-2-furanone (0.17 g) as a pale yellow oil.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1Cl)=[O:13])[CH2:8]2.[CH3:26][NH:27][CH2:28][CH2:29][OH:30]>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1[N:27]([CH2:28][CH2:29][OH:30])[CH3:26])=[O:13])[CH2:8]2
Reactant: CNCCO
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1Cl
Product: CN(CCO)c1c(C(=O)NC2C3CC4CC(C3)CC2C4)cnn1-c1ccccc1

Procedure:
5-[(2-Hydroxy-ethyl)-methyl-amino]-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide was prepared using Procedure A from 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Intermediate 3) and 2-(methylamino)ethanol. Mass spectrum (ES) MH+=396.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5](=[O:9])[O:6][C:7]=1[CH3:8].[Cl:10][C:11]1[S:15][C:14]([C:16]2[O:20][N:19]=[C:18]([CH2:21][N:22]3[C:30]4[CH:29]=[CH:28][CH:27]=[C:26]([C:31]([OH:33])=[O:32])[C:25]=4[CH:24]=[C:23]3[C:34](=[O:45])[NH:35][CH:36]3[CH2:41][CH2:40][N:39]([CH:42]([CH3:44])[CH3:43])[CH2:38][CH2:37]3)[CH:17]=2)=[CH:13][CH:12]=1.ClC1C=CC(NC(CN2C3C=CC=C(C(O)=O)C=3C=C2C(=O)NC2CCN(C(C)C)CC2)=O)=NC=1>>[CH3:8][C:7]1[O:6][C:5](=[O:9])[O:4][C:3]=1[CH2:2][O:33][C:31]([C:26]1[C:25]2[CH:24]=[C:23]([C:34](=[O:45])[NH:35][CH:36]3[CH2:41][CH2:40][N:39]([CH:42]([CH3:43])[CH3:44])[CH2:38][CH2:37]3)[N:22]([CH2:21][C:18]3[CH:17]=[C:16]([C:14]4[S:15][C:11]([Cl:10])=[CH:12][CH:13]=4)[O:20][N:19]=3)[C:30]=2[CH:29]=[CH:28][CH:27]=1)=[O:32]
Reactant: CC(C)N1CCC(NC(=O)c2cc3c(C(=O)O)cccc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Reactant: Cc1oc(=O)oc1CCl
Agent: CC(C)N1CCC(NC(=O)c2cc3c(C(=O)O)cccc3n2CC(=O)Nc2ccc(Cl)cn2)CC1
Product: Cc1oc(=O)oc1COC(=O)c1cccc2c1cc(C(=O)NC1CCN(C(C)C)CC1)n2Cc1cc(-c2ccc(Cl)s2)on1

Procedure:
The title compound was prepared analogously to example 5 with the difference that 4-Chloromethyl-5-methyl-[1,3]dioxol-2-one and 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-indole-4-carboxylic acid was used instead of Carbonic acid 1-chloro-ethyl ester 2-methoxy-ethyl ester and 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-indole-4-carboxylic acid. MS (ES+): m/e=639, chloro pattern.
Reaction SMILES: [CH3:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:13]([NH2:15])=[O:14])[C:6](=[O:12])[NH:7]2.O.[NH2:17]N.O>C(O)(=O)C>[CH3:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:13]([NH:15][NH2:17])=[O:14])[C:6](=[O:12])[NH:7]2
Reactant: NN
Reactant: Cc1nccc2[nH]c(=O)c(C(N)=O)cc12
Solvent: O
Solvent: CC(=O)O
Product: Cc1nccc2[nH]c(=O)c(C(=O)NN)cc12

Procedure:
A mixture containing 34 g of 1,2-dihydro-5-methyl-2-oxo-1,6-naphthyridine-3-carboxamide and 150 ml of hydrazine hydrate was heated on a steam bath for 18 hours and then stripped to dryness on a steam bath. To the residue was added 100 ml of water and the aqueous mixture was neutralized by adding acetic acid. The fine yellow needles were collected, washed successively with water and methanol, and then dried at 90° C. to produce 32.6 g of 1,2-dihydro-5-methyl-2-oxo-1,6-naphthyridine-3-carboxylic acid hydrazide, m.p.>310° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13]2[N:19]([CH3:32])[C:20](=[O:31])[C:21]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=4[Cl:30])=[CH:22][C:12]3=2)[CH:4]=1.C([O-])([O-])=O.[K+].[K+].[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.Cl>CN(C=O)C.CCOC(C)=O.O>[ClH:1].[Cl:30][C:24]1[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:23]=1[C:21]1[C:20](=[O:31])[N:19]([CH3:32])[C:13]2[N:14]([CH3:18])[C:15]3[C:11]([C:12]=2[CH:22]=1)=[CH:10][C:9]([C:5]1[CH:4]=[C:3]([CH2:2][N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)[N:7]([CH3:8])[N:6]=1)=[CH:17][CH:16]=3
Reactant: Cn1nc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)cc1CCl
Reactant: C1COCCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1nc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)cc1CN1CCOCC1
Temperature: 80 °C

Procedure:
100 mg (0.2 mmol) of compound A, 6-(5-chloromethyl-1-methyl-1H-pyrazol-3-yl)-3-(2,4-dichlorophenyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one are dissolved in 5 ml of anhydrous DMF. 55 mg (0.4 mmol) of K2CO3 and 22 μl (0.25 mmol) of morpholine are added. The mixture is heated at 80° C. overnight. It is allowed to return to ambient temperature and poured into water. The mixture is extracted with EtOAc. The organic phase is washed with a saturated NaCl solution. It is dried over Na2SO4, filtered and evaporated to dryness. Purification is carried out on a silica column, elution being carried out with a 95/05 EtOAc/MeOH mixture. The product obtained is dissolved in EtOAc and 0.5 ml of a saturated solution of HCl in Et2O/petroleum ether is added. The precipitate formed is filtered off and washed with ether. The product is taken up in MeOH and evaporated to dryness.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[C:30]([O:31][CH3:32])=[C:29]4[C:24]([C:25](=[O:39])[C:26]([C:36]([OH:38])=[O:37])=[CH:27][N:28]4[CH:33]4[CH2:35][CH2:34]4)=[CH:23][C:22]=3[F:40])[CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+].C(O)(=O)C>ClC(Cl)C>[CH:33]1([N:28]2[C:29]3[C:24](=[CH:23][C:22]([F:40])=[C:21]([N:18]4[CH2:19][CH2:20][CH:15]([NH:14][CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)[CH2:16][CH2:17]4)[C:30]=3[O:31][CH3:32])[C:25](=[O:39])[C:26]([C:36]([OH:38])=[O:37])=[CH:27]2)[CH2:34][CH2:35]1
Reactant: COc1c(N2CCC(NC3CCN(C(=O)OC(C)(C)C)CC3)CC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: COc1c(N2CCC(NC3CCNCC3)CC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reaction time: 3 h

Procedure:
To a stirred solution of 7-[4-(1-tert-Butoxycarbonyl-piperidin-4-ylamino)-piperidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (113 mg, 0.2 mmol) in dichloroethane (1.5 mL) was added trifluoroacetic acid (692 mg, 6.07 mmol). The resulting mixture was stirred for 3 hours before condensed to dryness. To this residue was added saturated aqueous sodium carbonate followed by the addition of acetic acid to pH around 6. This aqueous solution was extracted with 20% (v/v) isopropanol/dichloromethane. The combined organic layers were dried over sodium sulfate and condensed to give product as slightly yellow syrup, which was used directly for next reaction. ESI MS m/z 459 (M+H+); 1H NMR (400 MHz, CDCl3) δ 8.74 (s, 1H), 7.78 (d, J=11.6 Hz, 1H), 3.98 (m, 3H), 3.71 (s, 3H), 3.54 (d, J=13.2 Hz, 2H), 3.33 (t, J=13.3 Hz, 2H), 3.14 (m, 1H), 2.91 (d, J=12.5 Hz, 2H), 2.11 (d, J=11.7 Hz, 2H), 2.00 (m, 2H), 1.78 (m, 4H), 1.16 (d, J=7.0 Hz, 2H), 0.93 (d, J=3.3 Hz, 2H).
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([CH2:25][C:26](=O)[CH3:27])=[CH:17]1.ClC1C=CC=CC=1I>C(O)C>[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([CH2:25][C:26](=[N:2][OH:3])[CH3:27])=[CH:17]1
Reactant: NO
Reactant: CC(=O)Cc1cn(-c2ccccc2Cl)c2ccccc12
Agent: CC(=O)[O-]
Agent: Cl
Agent: Clc1ccccc1I
Solvent: CCO
Product: CC(Cc1cn(-c2ccccc2Cl)c2ccccc12)=NO
Reaction time: 8 h
Yield: 71 %

Procedure:
2.1 G (0.03 mole) of hydroxylamine hydrochloride and 2.1 g of sodium acetate are added, all at once, to 5.8 g (0.02 mole) of 1-(2-chlorophenyl)-3-(2-oxopropyl)indole prepared as described in example 1 but using 2-chloroiodobenzene instead of iodobenzene are dissolved in 50 ml of ethanol. The mixture is stirred overnight. The oxime formed is then filtered, washed in water and recrystallised, after drying, from 30 ml of di-isopropyl ether. Product = 4.3 g: Melting point (k) = 127°. Yield = 71%.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[Br:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1.C(N(CC)CC)C>C1COCC1>[Br:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH:5][CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[Cl:1])=[O:16])=[CH:13][CH:12]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: NCc1ccccc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCc1ccccc1Cl)c1ccc(Br)cc1
Yield: 98 %

Procedure:
To a stirred solution of 2-chlorobenzylamine (2.42 mL, 20 mmol) in THF (80 mL, anhyd) at 0° C. added a solution of 4-bromobenzoyl chloride (4.39 g, 20 mmol) in THF (20 mL, anhyd.) and then triethylamine (2.93 mL, 21 mmol). After 12 h the resulting mixture was filtered and the solids rinsed with EtOAc. The combined filtrates were diluted with EtOAc (100 mL), washed with 1N HCl, satd NaHCO3 and brine, then dried (anhyd Na2SO4) and concentrated to afford the title compound (6.36 g, 98%) as a white solid, which was used in the next step without purification. GC-MS (EI): 322, 324.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[N:12]([CH3:19])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][P:26]([O:31][CH2:32][CH3:33])(=[O:30])[O:27][CH2:28][CH3:29]>>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][P:26](=[O:30])([O:31][CH2:32][CH3:33])[O:27][CH2:28][CH3:29])[C:13](=[O:18])[N:12]([CH3:19])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOP(=O)(CCCCCBr)OCC
Reactant: Cn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Product: CCOP(=O)(CCCCCn1c(=O)c2c(ncn2Cc2ccccc2)n(C)c1=O)OCC

Procedure:
The title compound was prepared from 7-benzyl-3-methylxanthine (0.059 mol) and diethyl 5-bromopentanephosphonate (0.07 mol) analogously to Example 23.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1.Cl.[O-:13][C:14]#[N:15].[K+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH:11][C:14]([NH2:15])=[O:13])[CH:6]=[CH:7][CH:8]=1
Reactant: N#C[O-]
Reactant: COc1cccc(CCN)c1
Agent: Cl
Agent: [K+]
Solvent: O
Product: COc1cccc(CCNC(N)=O)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 83.1 %

Procedure:
To a solution of 2-(3-methoxy-phenyl)-ethylamine (1) (50.0 g, 331 mmol) and concentrated HCl (27.6 mL) in water (350 mL), potassium cyanate (28.2 g, 348 mmol) was added and stirred at 50° C. for 2 hours, then at room temperature for 2 days. Formed precipitate was collected by filtration. The solid was washed with water and dried under reduced pressure to give the title compound (53.4 g, 83%). MS (ESI) (M+H)+ 195.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([O:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[N:18]=[C:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:20][C:21]=3[C:22]([F:25])([F:24])[F:23])=[O:16])=[CH:10][CH:9]=2)[CH2:2]1.[CH3:32][C:33]1([CH3:41])[CH2:38][CH2:37][C:36](=[O:39])[O:35][C:34]1=[O:40].C(N(CC)CC)C>CS(C)=O>[CH3:32][C:33]([CH3:41])([CH2:38][CH2:37][C:36](=[O:39])[N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([O:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[N:18]=[C:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:20][C:21]=3[C:22]([F:25])([F:23])[F:24])=[O:16])=[CH:10][CH:9]=2)[CH2:2]1)[C:34]([OH:40])=[O:35]
Reactant: CC1(C)CCC(=O)OC1=O
Reactant: O=C(Nc1ccc(OC2CCCNC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(CCC(=O)N1CCCC(Oc2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cc2)C1)C(=O)O
Yield: 56.4 %

Procedure:
2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [4-(piperidin-3-yloxy)-phenyl]-amide (44.1 mg, 0.102 mmol), 3,3-dimethyl-dihydro-pyran-2,6-dione (17.5 mg, 0.122 mmol) and triethylamine (28.5 uL, 0.204 mmol) in 1 mL DMSO were treated as above. The crude product was purified by flash chromatography to yield 2,2-dimethyl-5-oxo-5-(3-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenoxy}-piperidin-1-yl)-pentanoic acid as a white solid (33 mg, 56%). ES-MS calcd for C29H30F3N3O6 (m/e) 573.57, obsd 574 (M+H).
Reaction SMILES: [CH:1]1([C:9]([OH:11])=O)[C:3]2([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[CH2:2]1.C(N1C=CN=C1)([N:14]1C=CN=C1)=O.[OH-].[NH4+]>C(OCC)(=O)C>[CH:1]1([C:9]([NH2:14])=[O:11])[C:3]2([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[CH2:2]1
Reactant: O=C(O)C1CC12CCCCC2
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: NC(=O)C1CC12CCCCC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 108.8 %

Procedure:
A 100 mL flask was charged with the product from Example 1B (2.8 g, 18 mmol), 1,1′-carbonyldiimidazole (2.9 g, 18 mmol) and ethyl acetate (20 mL). The mixture was stirred under nitrogen at ambient temperature for 4 hours, then 20 mL of concentrated ammonium hydroxide was added and the mixture stirred for 18 hours. The mixture was diluted with ethyl acetate (50 mL) and the layers were separated. The organic extract was washed with water (3×15 mL), dried over magnesium sulfate and concentrated under reduced pressure. The crude product was treated with carbon and recrystallized from aqueous methanol to provide the title compound as white crystals (3 g, 78% yield). 1H NMR (CDCl3, 300 MHz) δ 5.55 (s, 2H), 1.3-1.7 (m, 10H), 1.28 (dd, 1H), 1.11 (t, 1H), 0.75 (dd, 1H); 13C NMR (CDCl3, 100 MHz) δ 174.1, 37.6, 28.9, 28.6, 27.5, 26.2, 25.8, 25.6, 19.4; MS m/z 154 (M+H)+.