Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.[CH2:14](Br)[CH:15]=[CH2:16]>CN1CCCC1=O>[CH2:16]([N:4]([CH2:3][CH2:2][OH:1])[C:5]1[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)[CH:15]=[CH2:14]
Reactant: O=[N+]([O-])c1ccc(NCCO)cc1
Reactant: C=CCBr
Solvent: CN1CCCC1=O
Product: C=CCN(CCO)c1ccc([N+](=O)[O-])cc1

Procedure:
N-(2-hydroxyethyl)-4-nitrobenzenamine (9.1 g, 0.05 mol) is treated with allyl bromide in N-methylpyrrolidone, also as subsequently discussed in Example 11, to provide N-allyl-N-(2-hydroxyethyl)-4-nitrobenzenamine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:6]([C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20])=[CH:5]2.C(N(CC)CC)C.[CH3:35][C:36]([CH3:42])([CH3:41])[CH2:37][C:38](Cl)=[O:39].Cl>C1COCC1.C(OCC)(=O)C>[NH:21]([C:19]([C:6]1[N:7]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([NH:1][C:38](=[O:39])[CH2:37][C:36]([CH3:42])([CH3:41])[CH3:35])=[CH:10][CH:9]=2)=[O:20])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)Cn1c(C(=O)Nc2ccccc2)cc2cc(N)ccc21
Reactant: CC(C)(C)CC(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)CC(=O)Nc1ccc2c(c1)cc(C(=O)Nc1ccccc1)n2CC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Under argon, 50 mg (0.14 mmol) of tert-butyl [5-amino-2-(anilinecarbonyl)-1H-indol-1-yl]acetate from Example LII and 15.23 mg (0.02 ml, 0.15 mmol) of triethylamine are added to 2 ml of THF. The mixture is cooled to 0° C., and a solution of 20.26 mg (0.02 ml, 0.15 mmol) of 3,3-dimethylbutyryl chloride in 0.2 ml of THF is added. The mixture is stirred at RT for 2 hours and, for work-up, added to dilute hydrochloric acid and ethyl acetate and extracted. The organic phase is washed with sat. sodium bicarbonate solution, dried with sodium sulphate, filtered and dried under reduced pressure. The resulting crude product is purified by column chromatography (silica gel 60, mobile phase: cyclohexane/ethyl acetate 2:1).
Reaction SMILES: Cl.[C@@H:2]12[CH:7]([CH2:8][NH:9][C:10]3[C:15]([C:16]4[CH:21]=[CH:20][C:19]([O:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)=[CH:18][CH:17]=4)=[C:14]([NH2:29])[N:13]=[CH:12][N:11]=3)[C@@H:6]1[CH2:5][NH:4][CH2:3]2.N1C=CC=CC=1.[C:36](Cl)(=[O:39])[CH:37]=[CH2:38].C(Cl)Cl>>[NH2:29][C:14]1[N:13]=[CH:12][N:11]=[C:10]([NH:9][CH2:8][CH:7]2[C@@H:6]3[C@H:2]2[CH2:3][N:4]([C:36](=[O:39])[CH:37]=[CH2:38])[CH2:5]3)[C:15]=1[C:16]1[CH:17]=[CH:18][C:19]([O:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:20][CH:21]=1
Reactant: Nc1ncnc(NCC2[C@H]3CNC[C@@H]23)c1-c1ccc(Oc2ccccc2)cc1
Reactant: C=CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CC(=O)N1C[C@@H]2C(CNc3ncnc(N)c3-c3ccc(Oc4ccccc4)cc3)[C@@H]2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.8 %

Procedure:
To a round bottom flask containing N-[(1S,5R)-1-(3-Aza-bicyclo[3.1.0]hex-6-yl)methyl]-5-(4-phenoxy-phenyl)-pyrimidine-4,6-diamine hydrochloride (259.68 mg; 0.63 mmol; 1.00 eq.) in pyridine (1.00 ml; 12.36 mmol; 19.52 eq.) was added acryloyl chloride (0.05 ml; 0.63 mmol; 1.00 eq.) in DCM (3.00 ml; 46.80 mmol; 73.88 eq.) over 1 h at 0° C. The reaction mixture was allowed to warm to room temperature and stirred overnight. It was concentrated and the crude product was subjected to preparative HPLC. Fractions containing the desired product were combined and lyophilized overnight to afford 1-((1R,5S)-6-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3-azabicyclo[3.1.0]hexan-3-yl)prop-2-en-1-one as a white solid (2.1 mg, 0.6%). HPLC purity: 99%. MS: m/z=428[M+H]+. 1H NMR (CD3OD) δ 8.24 (s, 1H), 7.21-7.46 (m, 9H), 6.53 (m, 1H), 6.22 (m, 1H), 5.74 (m, 1H), 3.77 (m, 2H), 3.69 (m, 1H), 3.41 (m, 2H), 1.70 (m, 2H), 0.93 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][NH:14][C:15]=3[CH3:16])[S:10][C:6]=2[C:5](=[O:17])[NH:4]C1(C)C.Cl.C([O-])(O)=O.[Na+]>CO>[CH3:1][NH:2][C:7]1[CH:8]=[C:9]([C:11]2[CH:12]=[N:13][NH:14][C:15]=2[CH3:16])[S:10][C:6]=1[C:5]([NH2:4])=[O:17]
Reactant: Cc1[nH]ncc1-c1cc2c(s1)C(=O)NC(C)(C)N2C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CNc1cc(-c2cn[nH]c2C)sc1C(N)=O
Temperature: 50 °C
Reaction time: 2 h
Yield: 56.5 %

Procedure:
A mixture of 1,2,2-trimethyl-6-(5-methyl-1H-pyrazol-4-yl)-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (378 mg, 1.37 mmol), 1 M HCl (4.79 mL) and MeOH (12 mL) was stirred for 2 h at 50° C. The mixture was poured into excess saturated aqueous NaHCO3 and extracted with 3:1 EtOAc/THF, and the extract was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was triturated with ethanol (6 mL) and collected by filtration to afford the title compound (183 mg, 57%) as a pale yellow solid:
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>ClCCl>[CH2:20]([O:19][C:17]([N:6]1[CH2:7][CH2:8][CH:3]([CH2:2][OH:1])[CH2:4][CH2:5]1)=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OCC1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC(CO)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred solution of 4-hydroxymethylpiperidine (2.0 g, 17.4 mmol) in dry dichloromethane (DCM, 100 mL) was cooled to 0° C., treated with triethylamine (4.8 mL, 34.8 mmol) followed by benzyl chloroformate (3.7 mL, 34.8 mmol), allowed to warm to room temperature and stirred for two hours. The mixture was partitioned between DCM (50 mL) and water (30 mL). The layers were separated and the aqueous phase was extracted with DCM (2×50 mL). The combined organic phases were washed with brine (1×30 mL), dried over Na2SO4 and evaporated to a residue, that was purified by column chromatography using a gradient of 70 to 100% EtOAc in hexanes as eluant to give 3.85 g (89%) of E-12 as clear oil: 1H NMR (CDCl3) δ 1.17 (m, 2H), 1.72 (m, 3H), 2.15 (br s, 1H), 2.78 (t, 2H, J=12.24), 3.47 (d, 2H, J=6.04), 4.20 (d, 2H, J=11.68), 5.12 (s, 2H), 7.33 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:5]([CH:6]=O)=[C:4]([OH:12])[CH:3]=1.CN(C)C=O.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:25][C:26](=[O:28])[CH3:27]>>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:5]2[CH:6]=[C:25]([C:26](=[O:28])[CH3:27])[O:12][C:4]=2[CH:3]=1
Reactant: COc1cc(Cl)cc(O)c1C=O
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc(Cl)cc2oc(C(C)=O)cc12
Temperature: 65 °C
Yield: 66.4 %

Procedure:
A stirred solution of 4-chloro-2-hydroxy-6-methoxybenzaldehyde (Example 37B, 1.79 g, 9.59 mmol) in N,N-dimethylformamide (15 mL, 9.59 mmol) was charged with cesium carbonate (3.75 g, 11.51 mmol) and 1-chloropropan-2-one (0.975 mL, 11.51 mmol). The reaction mixture was heated in a sealable vessel at 65° C. for 7 hours, was filtered over a Whatman filter paper to remove insolubles rinsing with DCM then washed with sat. NaHCO3. The organic phase was dried (MgSO4), filtered and concentrated to dryness. The residue was purified by ISCO using hexanes/EtOAc as eluent. Fractions containing the desired product were concentrated to give the title material (1.43 g, 6.37 mmol, 66% yield) as a light yellow solid. LC (Method A): 1.952 min. LCMS (APCI) calcd for C11H10ClO3 [M+H]+ m/z 225.03. found 225.0. 1H NMR (CDCl3, 400 MHz) δ ppm: 7.94 (d, J=0.8 Hz, 1H), 7.49 (dd, J=0.8, 1.6 Hz, 1H), 6.97 (d, J=1.6 Hz, 1H), 3.97 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:27]=[CH:26][C:17]([C:18]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[O:19])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[CH2:30]([C:32]1[CH:37]=[C:36]([CH2:38][CH3:39])[CH:35]=[CH:34][C:33]=1[S:40](Cl)(=[O:42])=[O:41])[CH3:31]>C(N(CC)CC)C>[CH2:30]([C:32]1[CH:37]=[C:36]([CH2:38][CH3:39])[CH:35]=[CH:34][C:33]=1[S:40]([N:23]1[CH2:24][CH2:25][N:20]([C:18](=[O:19])[C:17]2[CH:26]=[CH:27][C:14]([NH:13][C:7]3[C:6]4[C:11](=[CH:12][C:3]([C:2]([F:1])([F:28])[F:29])=[CH:4][CH:5]=4)[N:10]=[CH:9][CH:8]=3)=[CH:15][CH:16]=2)[CH2:21][CH2:22]1)(=[O:42])=[O:41])[CH3:31]
Reactant: O=C(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCNCC1
Reactant: CCc1ccc(S(=O)(=O)Cl)c(CC)c1
Solvent: CCN(CC)CC
Product: CCc1ccc(S(=O)(=O)N2CCN(C(=O)c3ccc(Nc4ccnc5cc(C(F)(F)F)ccc45)cc3)CC2)c(CC)c1

Procedure:
In the manner given in Example 15, 4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine is reacted with 2,4-diethylphenylsulfonyl chloride, in the presence of triethylamine to give 1-[(2,4-diethylphenyl)sulfonyl]-4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine.
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.[NH:21]1[CH2:24][CH2:23][CH2:22]1.N1C=CC=CC=1>C(N(CC)CC)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:21]4[CH2:24][CH2:23][CH2:22]4)[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
Reactant: C1CNC1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCC3)c(F)cc2c1=O
Yield: 89.2 %

Procedure:
A mixture of 0.6 g (2.1 mmoles) of 1-cyclopropyl-1,4-dihydro-6,7,8-trifluoro-4-oxo-3-quinolinecarboxylic acid with 0.25 g (4.4 mmoles) of azetidine, 8 ml of pyridine and 1 ml of triethylamine is maintained at 110°-120° C. for 2 hours in a closed vessel. After cooling, evaporating under vacuum, filtering and washing, 0.6 g (88%) of 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(1-azetidinyl)-4-oxo-3-quinolinecarboxylic acid are obtained, melting at 289°-93° C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[C@@H:3]1[CH3:18].[H-].[Na+].IC>C1COCC1.CCOC(C)=O.O>[CH3:18][C@@H:3]1[C@H:2]([N:1]2[CH2:7][CH2:2][CH2:3][N:4]([CH3:5])[C:8]2=[O:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]
Reactant: C[C@@H]1[C@H](N)CCCN1C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CI
Product: C[C@@H]1[C@H](N2CCCN(C)C2=O)CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 185.9 %

Procedure:
(2R,3R)-Benzyl 3-amino-2-methylpiperidine-1-carboxylate (323, 270 mg, 1.09 mmol) was dissolved in 10 mL dry THF. To it was added 3-chloropropyl isocyante (112 μL, 1.09 mmol), and the mixture was stirred at RT for 3 hours. To it was added NaH (60% in mineral oil, 87 mg, 2.18 mmol) and the mixture was stirred for overnight. Another batch of NaH (87 mg, 2.18 mmol) was then added to drive the cyclization to completion in 4 hours. To the mixture was added iodomethane (540 μL, 8.64 mmol), and it was stirred at RT for overnight. It was diluted with 120 mL EtOAc and 30 mL water. The organic phase was separated, washed with water, dried, concentrated and subjected to silica flash column with 0 to 4% MeOH in DCM to isolate (2R,3R)-benzyl 2-methyl-3-(3-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)piperidine-1-carboxylate (403) (350 mg, 93%) as a thick oil. It was dissolved in 100 mL MeOH, and with 10% Pd/C (0.5 g) it was hydrogenated at 40 psi on a Parr shaker for overnight. The mixture was filtered through celite, and the filtrate was concentrated in vacuo to afford 1-methyl-3-((2R,3R)-2-methylpiperidin-3-yl)tetrahydropyrimidin-2(1H)-one (404).
Reaction SMILES: [Cl:1][C:2]1[S:10][C:9]2[S:8](=[O:12])(=[O:11])[N:7]=[CH:6][N:5]([CH2:13][CH2:14][F:15])[C:4]=2[CH:3]=1.[BH4-].[Na+].Cl>C(O)(C)C.O>[Cl:1][C:2]1[S:10][C:9]2[S:8](=[O:12])(=[O:11])[NH:7][CH2:6][N:5]([CH2:13][CH2:14][F:15])[C:4]=2[CH:3]=1
Reactant: O=S1(=O)N=CN(CCF)c2cc(Cl)sc21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: O=S1(=O)NCN(CCF)c2cc(Cl)sc21
Temperature: 60 °C

Procedure:
100 mg of the compound obtained in Step A above are dissolved in 4 ml of isopropanol. The mixture is heated to 60° C., then 200 mg of sodium borohydride are added. After minutes at that temperature, the solvent is evaporated off under reduced pressure. The residue that is obtained is taken up in 10 ml of water, cooled in an ice bath and adjusted to pH 4 by addition of 6N hydrochloric acid. The insoluble material is collected by filtration and washed with water. The product is then dissolved in a minimum of chloroform and precipitated by addition of n-hexane. The precipitate is then collected by filtration.
Reaction SMILES: C([O:8][C:9](=[O:31])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:30])[C@H:16]([CH:27]([CH3:29])[CH3:28])[NH:17][S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19])C1C=CC=CC=1.C(=O)(O)[O-].[Na+].[H][H].Cl>CO.[C].[Pd].O>[C:21]1([S:18]([NH:17][C@H:16]([C:15]([N:11]2[CH2:12][CH2:13][CH2:14][C@H:10]2[C:9]([OH:31])=[O:8])=[O:30])[CH:27]([CH3:29])[CH3:28])(=[O:20])=[O:19])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: [H][H]
Reactant: CC(C)[C@H](NS(=O)(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: O
Product: CC(C)[C@H](NS(=O)(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Yield: 689.7 %

Procedure:
N-benzenesulfonyl-L-valyl-L-proline benzylester 200 g, 4.5 mmole) was dissolved in methanol (40 ml) and water (5 ml) solution of sodium bicarbonate (0.42 g, 5 mmole) was added thereto. Hydrogen gas was passed through the solution in the presence of 5% palladium-carbon as a catalyst for 3 hours. The catalyst was removed by filtration and the filtrate thus obtained was concentrated under reduced pressure. The residue thus obtained was dissolved in water (20 ml), and 1N aqueous hydrochloric acid (10 ml) was added thereto to give white crystals. They were recrystallized from methylene chloride, ethyl acetate and petroleum ether to obtain N-benzenesulfonyl-L-valyl-L-proline (yield: 1 11 g, 69.6%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([C@H:14]1[C@H:18]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[C@:17]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)([C:26]#[N:27])[C@H:16]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[NH:15]1)=[O:13])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([CH:14]1[CH:18]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[C:17]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)([C:26]#[N:27])[CH:16]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[NH:15]1)=[O:13]
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)NCCCNC(=O)OC(C)(C)C)[C@H](c2cccc(Cl)c2)[C@@]1(C#N)c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)NCCCN)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 109.4 %

Procedure:
To a solution of rac-(3-{[(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-propyl)-carbamic acid tert-butyl ester prepared in Example 28 (0.9 g, 1.5 mmol) in dichloromethane (30 mL) was added trifluoroacetic acid (5 mL). The reaction mixture was stirred at room temperature for 1 h, and concentrated. The residue was then neutralized with saturated aqueous NaHCO3 solution, and then extracted with ethyl acetate. The organic layer was separated, dried over MgSO4, concentrated, dried under reduced pressure to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-amino-propyl)-amide as a white solid (0.8 g, 100%)
Reaction SMILES: [CH2:1]([N:4]1[C:9]([O:10][C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=2)=[C:8]([CH2:19][CH3:20])[C:7](=[O:21])[NH:6][C:5]1=[O:22])[CH:2]=[CH2:3].ClC1C(C(OO)=[O:31])=CC=CC=1>ClCCl>[O:31]1[CH2:3][CH:2]1[CH2:1][N:4]1[C:9]([O:10][C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:8]([CH2:19][CH3:20])[C:7](=[O:21])[NH:6][C:5]1=[O:22]
Reactant: O=C(OO)c1ccccc1Cl
Reactant: C=CCn1c(Oc2cc(C)cc(C)c2)c(CC)c(=O)[nH]c1=O
Solvent: ClCCl
Product: CCc1c(Oc2cc(C)cc(C)c2)n(CC2CO2)c(=O)[nH]c1=O
Yield: 34.6 %

Procedure:
1-Allyl-5-ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione 157 mg, 0.52 mmol) was dissolved in dichloromethane (10 ml), and thereto chloro perbenzoic acid (385 mg, 1.56 mmol) was added. The resulting solution was refluxed for 24 hours, washed with a saturated solution of sodium bicarbonate, distilled under the reduced pressure to remove the used solvent and purified with column chromatography to obtain the titled compound as white solid (57 mg, yield: 35.0%).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:14](=[O:24])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N+:21]([O-:23])=[O:22])[CH:11]=2)[C:6]([CH3:26])([CH3:25])[CH2:5]1)(=O)C>CCO.Cl>[CH3:25][C:6]1([CH3:26])[C:7]2[C:12](=[CH:11][C:10]([NH:13][C:14](=[O:24])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N+:21]([O-:23])=[O:22])=[CH:9][CH:8]=2)[NH:4][CH2:5]1
Reactant: CC(=O)N1CC(C)(C)c2ccc(NC(=O)c3ccccc3[N+](=O)[O-])cc21
Agent: Cl
Solvent: CCO
Product: CC1(C)CNc2cc(NC(=O)c3ccccc3[N+](=O)[O-])ccc21
Temperature: 70 °C

Procedure:
N-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-nitro-benzamide (Step A) (3.0 g, 8.5 mmol) was dissolved in EtOH (80 mL) in the presence of HCl (1 N, 18 mL). The solution was heated to 70° C. overnight. Solvent was removed in vacuo and the residue was partitioned in EtOAc and a solution of NaHCO3 (aq. sat.). A yellow precipitate formed in the organic layer. After separation from the aqueous layer, the organic layer was filtered to give a solid. The filtrate was concentrated to give a second batch. The combined batches were used without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:7][CH:6]([N:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=[CH:9]2)[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[O:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Na].[CH:34]1(O)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.C1(O)CCCCC1>CN(C)C=O>[CH3:1][C:2]1([CH3:20])[CH2:7][CH:6]([N:8]2[C:12]([C:13]([O:15][CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[O:14])=[CH:11][N:10]=[CH:9]2)[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[O:3]1
Reactant: CC1(C)CC(n2cncc2C(=O)O)c2ccccc2O1
Reactant: OC1CCCCC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na]
Solvent: CN(C)C=O
Product: CC1(C)CC(n2cncc2C(=O)OC2CCCCC2)c2ccccc2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.5 %

Procedure:
3.3 Parts of 1-(2,3-dihydro-2,2-dimethyl-4H-1-benzopyran-4-yl)-1H-imidazole-5-carboxylic acid were dissolved in 45 parts of warm N,N-dimethylformamide. After cooling to room temperature, 2 parts of 1,1'-carbonylbis[1H-imidazole] were added and the whole was stirred for 1 hour at this temperature. The whole was heated to ±80° C. and a mixture of 0.1 parts of a cyclohexanol sodium salt solution and 3 parts of cyclohexanol was added. After stirring for 5 days at ±80° C., the mixture was evaporated. The residue was taken up trichloromethane and water and the organic layer was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from hexane. The product was filtered off and dried, yielding 0.91 parts (20.5%) of cyclohexyl 1-(2,3-dihydro-2,2-dimethyl-4H-1-benzopyran-4-yl)-1H-imidazole-5-carboxylate; mp. 128.1° C. (compound 1.139).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:26])[CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[Cl:25])=[CH:7][C:6]=1[Cl:27].[NH:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C:33]([O:35][CH2:36][CH3:37])=[O:34]>>[Cl:27][C:6]1[CH:7]=[C:8]([NH:11][C:12](=[O:26])[CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[Cl:25])[CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH2:2][N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C:33]([O:35][CH2:36][CH3:37])=[O:34]
Reactant: CCOC(=O)[C@@H]1CCCN1
Reactant: O=C(COc1ccc(C(F)(F)F)cc1Cl)Nc1ccc(OCCBr)c(Cl)c1
Product: CCOC(=O)[C@@H]1CCCN1CCOc1ccc(NC(=O)COc2ccc(C(F)(F)F)cc2Cl)cc1Cl

Procedure:
Prepared analogously to Example 145 starting from N-[4-(2-bromo-ethoxy)-3-chloro-phenyl]-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide (Z28b) and ethyl (S )-pyrrolidine-2-carboxylate
Reaction SMILES: C([O:3][C:4]([C:6]1([OH:19])[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])C.[H-].[Na+].I[CH3:23].O[Li].O>CN(C=O)C.O>[C:15]([O:14][C:12]([N:9]1[CH2:8][CH2:7][C:6]([O:19][CH3:23])([C:4]([OH:3])=[O:5])[CH2:11][CH2:10]1)=[O:13])([CH3:16])([CH3:17])[CH3:18]
Reactant: CI
Reactant: CCOC(=O)C1(O)CCN(C(=O)OC(C)(C)C)CC1
Agent: [H-]
Agent: [Li]O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC1(C(=O)O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 0.415 g (1.52 mmol) 4-Hydroxy-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester, 68 mg (1.97 mmol) NaH (55% in oil) and 0.3 g (2.12 mmol) iodomethane in 10 mL DMF was stirred for 2 h at room temperature. Water was added and the mixture was concentrated to dryness. The residue was dissolved in THF and water and 0.254 g (6 mmol) LiOH.H2O wad added and the mixture was stirred for 16 h at room temperature. After evaporation the residue was subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and formic acid to yield after evaporation of the product containing fractions 49.7 mg (13%) of the title compound as white solid. MS (m/e): 258.1 [(M−H)].
Reaction SMILES: [OH:1][CH:2]1[CH2:19][CH2:18][C:17]2[C:4](=[C:5]([OH:24])[C:6]3[C:7](=[O:23])[C:8]4[C:13]([C:14](=[O:21])[C:15]=3[C:16]=2[OH:20])=[C:12]([OH:22])[CH:11]=[CH:10][CH:9]=4)[CH2:3]1.C1(N=C=NC2CCCCC2)CCCCC1.FC(F)(F)C(O)=O>CS(C)=O>[OH:20][C:16]1[C:15]2[C:14](=[O:21])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[OH:22])[C:7](=[O:23])[C:6]=2[C:5]([OH:24])=[C:4]2[C:17]=1[CH2:18][CH2:19][C:2](=[O:1])[CH2:3]2
Reactant: O=C1c2cccc(O)c2C(=O)c2c(O)c3c(c(O)c21)CC(O)CC3
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: O=C1CCc2c(O)c3c(c(O)c2C1)C(=O)c1cccc(O)c1C3=O

Procedure:
The alcohol of Example 20 (35 mg) was treated with 130 mg of dicyclohexylcarbodiimide and 0.4 ml of trifluoroacetic acid and 3 ml of dimethyl sulfoxide for 3 hours and then extracted several times with benzene. Evaporation of the benzene layers produced brown-red 5,7,12-trihydroxy-1,2,3,4,6,11-hexahydro-2,6,11-trioxonaphthacene (formula 18), m.p. above 300° C., infrared maximum 1730 cm-1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[C:13](Cl)(=O)C>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1ccc(Cl)cc1
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)CCc1ccc(Cl)cc1
Yield: 100 %

Procedure:
To a stirred solution of 3-(4-chlorophenyl)propanoic acid (commercially available from Maybridge) (14.5 g, 77.1 mmol) in methanol (400 ml) was added acetyl chloride (50 ml) and the reaction mixture was refluxed for 20 h. After this time the reaction mixture was left to cool before being concentrated under reduced pressure. The residue was then dissolved in DCM (200 ml) and washed with 1M sodium hydroxide solution (100 ml). The organic layer was dried with magnesium sulphate and concentrated in vacuo to give the title product as a brown oil (15.7 g, 77 mmol, 100%); 1HNMR (400 MHz, CDCl3) δ: 2.55 (t, 2H), 2.9 (t, 2H), 3.6 (s, 3H), 7.1 (d, 2H), 7.2 (d, 2H).