Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(OCC)(OCC)([S-])=[S:2].[CH3:10][O:11][C:12]([C:14]1[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N+:28]([O-:30])=[O:29])=[CH:16][CH:17]=[C:18]([C:20]#[N:21])[CH:19]=1)=[O:13]>C1COCC1.O>[CH3:10][O:11][C:12]([C:14]1[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N+:28]([O-:30])=[O:29])=[CH:16][CH:17]=[C:18]([C:20](=[S:2])[NH2:21])[CH:19]=1)=[O:13]
Reactant: COC(=O)c1cc(C#N)ccc1-c1ccccc1[N+](=O)[O-]
Reactant: CCOP(=S)([S-])OCC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 45 h
Yield: 51.8 %

Procedure:
O,O′-Diethyl dithiophosphate (available from Aldrich Chemical Company, Inc.; 6.85 g, 36.8 mmol) was added to a solution of compound 4-cyano-2′-nitro-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 3; 8.62 g, 30.5 mmol) in a mixture of THF (96 mL) and water (24 mL). The resulting mixture was stirred at 80° C. for 45 h and then evaporated to a small volume. Ethyl acetate (500 mL) was added and the mixture was washed with water (250 mL) and sat. NaHCO3 (250 mL), dried over anhydrous sodium sulfate, filtered, evaporated, and purified by silica gel chromatography, using 17-50% ethyl acetate/petroleum ether as eluent, to give 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (5.0 g, 52%). 1H NMR (300 MHz, CDCl3) δ 8.50 (d, J=2.1 Hz, 1H), 8.18-8.15 (m, 2H), 7.70-7.54 (m, 3H), 7.32 (s, 1H), 7.30 (s, 1H), 7.24 (d, J=1.2 Hz, 1H), 3.69 (s, 3H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH2:7][O:6][C:5](=[O:8])[CH:4]=1.[OH-].[Na+].S(OC)(O[CH3:15])(=O)=O>COCCOC>[CH3:1][N:2]([CH3:15])[C:3]1[CH2:7][O:6][C:5](=[O:8])[CH:4]=1
Reactant: CNC1=CC(=O)OC1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: CN(C)C1=CC(=O)OC1
Temperature: 40 °C
Reaction time: 5 h
Yield: 54.1 %

Procedure:
2 g (0.18 mol) of 4-(methylamino)furan-2(5H)-one are introduced in 20 ml of 1,2-dimethoxyethane, and 0.72 g of sodium hydroxide is added. 2.2 g of dimethyl sulphate in 5 ml of 1,2-dimethoxyethane are metered into the suspension and stirred at 40° C. for 5 h. The solvent is removed in vacuo and 50 ml of water are added to the residue. This mixture is then extracted with 50 ml of dichloromethane. The organic phase is dried over sodium sulphate and then evaporated down in vacuo. 1.2 g of 4-(dimethylamino)furan-2(5H)-one are obtained as a solid with a purity of 96% (yield 51%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25](OC(C)(C)C)=O)[CH2:21][CH2:20]3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(O)(C(F)(F)F)=O.ClC1[N:45]=[CH:44][C:43]([CH2:46][CH3:47])=[CH:42][N:41]=1>C(Cl)Cl>[CH2:46]([C:43]1[CH:42]=[N:41][C:25]([N:22]2[CH2:23][CH2:24][CH:19]([CH2:18][O:17][C:14]3[CH:15]=[N:16][C:11]([C:8]4[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=4)=[CH:12][CH:13]=3)[CH2:20][CH2:21]2)=[N:45][CH:44]=1)[CH3:47]
Reactant: CCc1cnc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3)nc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1cnc(N2CCC(COc3ccc(-c4ccc(S(C)(=O)=O)cc4)nc3)CC2)nc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 91 %

Procedure:
1,1-Dimethylethyl 4-[({6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate (prepared as in Example 73, Step 2, 0.15 g, 0.34 mmol) was dissolved in CH2Cl2 (10 mL). TFA (0.35 mL) was added and the mixture was stirred at ambient temperature for 5 h. An excess of TFA and CH2Cl2 was removed under reduced pressure and the residue was taken up in DMSO (6 mL). Potassium carbonate (1 g) was added, followed by addition of 2-chloro-5-ethylpyrimidine (63 μL, 0.50 mmol). The reaction mixture was degassed, purged with N2 and heated at 100° C. overnight. The mixture was cooled to ambient temperature and poured into water and extracted with EtOAc. The combined organic extract was washed with water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a light brown solid. The crude product was triturated with hot hexane containing 1% of MeOH to give 0.14 g (92%) of the title compound as a cream-white solid. 1H NMR (400 MHz, CDCl3): δ 8.40 (d, 1H, J=2.7 Hz), 8.19 (bs, 2H), 8.13 (d, 2H, J=8.6 Hz), 8.00 (d, 2H, J=8.6 Hz), 7.73 (d, 1H, J=8.5 Hz), 7.35-7.25 (m, 1H), 4.90-4.75 (m, 2H), 3.94 (d, 2H, J=6.1 Hz), 3.08 (s, 3H), 3.00-2.90 (m, 2H), 2.55-2.40 (m, 2H), 2.25-2.10 (m, 1H), 2.00-1.90 (m, 2H), 1.50-1.30 (m, 2H), 1.19 (t, 3H, J=7.5 Hz); LRMS (APCI), m/z 453 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]2[NH:17][C:16]3[CH:18]=[CH:19][C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28](=[O:30])[CH3:29])=[CH:21][C:15]=3[N:14]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].CCOC(C)=O>C(O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8](/[CH:11]=[CH:12]/[C:13]2[NH:17][C:16]3[CH:18]=[CH:19][C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH:28]([OH:30])[CH3:29])=[CH:21][C:15]=3[N:14]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)c1ccccc1-c1ccc2[nH]c(/C=C/c3ccc(C(C)(C)C)cc3)nc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(O)c1ccccc1-c1ccc2[nH]c(/C=C/c3ccc(C(C)(C)C)cc3)nc2c1
Reaction time: 3 h

Procedure:
A solution of (E)-1-(2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-ethanone Cpd 1 (0.005 g, 0.01 mmol) in ethanol (0.5 mL) was treated with NaBH4 (0.003 g, 0.08 mmol). After 3 h, the reaction mixture was applied to a preative TLC plate (2000 microns, silica gel, 20×20) and developed using EtOAc:hexanes, 1:1. The desired band was extracted and concentrated to give the title compound (0.002 g). 1H-NMR (400 MHz, CD3OD) δ (ppm) 7.69 (m, 1H) 7.62 (m, 3H) 7.50 (m, 3H) 7.41 (ddd, 2H, J=2.5 Hz, J=10.1 Hz, J=14.1 Hz) 7.32 (dt, 1H, J=1.4 Hz, J=7.5 Hz) 7.23 (m, 2H) 7.17 (d, 1H, J=16.5 Hz) 4.99 (q, 1H, J=6.3 Hz) 1.38 (s, 9H) 1.35 (d, 1.5H, J=6.1 Hz) 1.33 (d, 1.5H, J=6.1 Hz). MS (ESI, pos. ion) m/z: 397.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.Cl.Cl.[CH3:20][C:21]1[C:22]([CH2:27][NH2:28])=[N:23][CH:24]=[CH:25][CH:26]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:28][CH2:27][C:22]2[C:21]([CH3:20])=[CH:26][CH:25]=[CH:24][N:23]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: Cc1cccnc1CN
Agent: Cl
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cccnc1CNc1nc(N)nc(-c2ccco2)c1C#N

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, C-(3-methyl-pyridin-2-yl)-methylamine dihydrochloride and DBU in DME. ES-MS m/e (%): 307 (M+H+, 100).
Reaction SMILES: C(OC(=O)[NH:10][C@@H:11]([CH:20]([CH3:22])[CH3:21])[C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13])C1C=CC=CC=1>C(O)C.[C].[Pd]>[NH2:10][C@@H:11]([CH:20]([CH3:22])[CH3:21])[C:12]([N:14]1[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1)=[O:13]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCOCC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)[C@H](N)C(=O)N1CCOCC1
Yield: 79.9 %

Procedure:
A solution of benzyl[(2S)-3-methyl-1-(morpholin-4-yl)-1-oxobutan-2-yl]carbamate (1.83 g) and 10% palladium carbon (0.608 g) in ethanol (30 mL) was stirred at room temperature overnight under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (850 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH2:12]([CH2:14][NH2:15])[OH:13]>C(O)C.CO>[Cl:1][C:2]1[N:7]=[C:6]([NH:15][CH2:14][CH2:12][OH:13])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: NCCO
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Solvent: CCO
Solvent: CO
Product: O=[N+]([O-])c1cnc(Cl)nc1NCCO
Reaction time: 18 h
Yield: 81 %

Procedure:
19.40 g (0.1 mole) of 2,4-dichloro-5-nitropyrimidine was completely dissolved in 60 ml of ethanol and maintained below 15° C. To this solution, a solution of 12.22 g (0.2 mole) of ethanolamine in 20 ml of methanol was added slowly while maintaining the temperature of a reactor below 20° C. The mixture was stirred below 15° C. for 18 hours. After completion of the reaction, the reaction product was maintained below 5° C., and the resulting crystal was filtered, washed and dried, thereby giving 17.71 g (81% yield) of light yellow-colored 2-chloro-4-(2-hydroxyethylamino)-5-nitropyrimidine.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[C:16]#[N:17])[CH:12]([NH:18][C:19]1[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:21][CH:20]=1)[CH2:11][CH2:10]2)=O.C([OH:34])C.OO.[OH-].[Na+]>O>[CH3:1][O:2][CH2:3][C:4]1[NH:17][C:16](=[O:34])[C:15]2[C:7](=[CH:8][C:9]3[CH2:10][CH2:11][CH:12]([NH:18][C:19]4[CH:20]=[CH:21][C:22]([C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])=[CH:30][CH:31]=4)[C:13]=3[CH:14]=2)[N:6]=1
Reactant: COCC(=O)Nc1cc2c(cc1C#N)C(Nc1ccc(C(=O)OC(C)(C)C)cc1)CC2
Reactant: CCO
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COCc1nc2cc3c(cc2c(=O)[nH]1)C(Nc1ccc(C(=O)OC(C)(C)C)cc1)CC3
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A mixture of tert-butyl 4-[N-(5-methoxyacetamido-6-cyanoindan-1-yl)-amino]benzoate (0.295 g, 0.70 mmol), ethanol (3.2 ml), and water (0.64 ml) was cooled in an ice-bath, then 30% aqueous H2O2 solution (0.60 ml) was added followed by granulated sodium hydroxide pellets (0.047 g, 1.19 mmol). The reaction mixture was stirred at ˜0° C. for 10 min, then it was placed in an oil bath preheated to 55° C. and stirred at this temperature for 30 min. The reaction mixture was allowed to cool to room temperature, then the solvents were removed in vacuo and the residue was suspended in water (˜15 ml). The pH of this mixture was adjusted to ˜12 with 1N NaOH (got a clear solution), then to ˜4 with 1N hydrochloric acid. The off white precipitate was collected by filtration, washed with water, dried in vacuo over P2O5: 0.262 g (89%), m.p. >122° C. (softens); 1H-NMR (250 MHz, DMSO-d6, TMS) 1.50 (s, 9H, C(CH3)3), 1.87, 2.56 (2×m, each 1H, 7-H), 3.00 (m, 2H, 8-H), 3.34 (s, 3H, OCH3), 4.30 (s, 2H, 2-CH2), 5.16 (m, 1H, 6-H), 6.78 (d, J=8.55 Hz, 2H, 3′,5′-H), 6.89 (d, J=8.10, N10—H), 7.52, 7.90 (2×s, each 1H, 5-H, 9-H), 7.67 (d, J=8.45 Hz, 2′,6′-H), 12.12 (s, 1H, N3—H); MS (ESI, m/z) 444 {(M+Na)+, 40%}; Found: C, 67.19; H, 6.31; N, 9.69; C24H27N3O4 0.5H2O requires C, 66.96; H, 6.50; N, 9.76%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][C:24]=1[N+:25]([O-])=O)[NH:7][C:8](=[O:21])[C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1)([O-])=O.[O:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=2)[CH:38]=O)[CH2:30][CH2:29]1>>[O:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:36]=[C:37]([C:38]3[NH:25][C:24]4[CH:23]=[CH:22][C:6]([NH:7][C:8](=[O:21])[C:9]5[CH:14]=[CH:13][C:12]([N:15]6[CH2:20][CH2:19][O:18][CH2:17][CH2:16]6)=[CH:11][CH:10]=5)=[CH:5][C:4]=4[N:1]=3)[CH:40]=[CH:41][CH:42]=2)[CH2:30][CH2:29]1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1ccc(N2CCOCC2)cc1
Reactant: O=Cc1cccc(CN2CCOCC2)c1
Product: O=C(Nc1ccc2[nH]c(-c3cccc(CN4CCOCC4)c3)nc2c1)c1ccc(N2CCOCC2)cc1

Procedure:
Compound 419 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitro-N-(4-morpholinobenzoyl)aniline and 3-morpholinomethylbenzaldehyde. [M+H]+ calcd for C29H31N5O3: 498.24; found: 497.98.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH:8]([CH:17]1[CH:21]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[CH2:20][N:19]([C:30]([C:32]2[CH:37]=C(C)N=[N:34][CH:33]=2)=[O:31])[CH2:18]1)[O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)(C)(C)C.CC[CH2:43][CH2:44][N+:45](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(OCC)(=O)C>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][CH:8]([CH:17]2[CH:21]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[CH2:20][N:19]([C:30]([C:32]3[CH:33]=[N:34][C:44]([CH3:43])=[N:45][CH:37]=3)=[O:31])[CH2:18]2)[CH2:7][OH:6])=[N:11][CH:12]=1
Reactant: Cc1cc(C(=O)N2CC(c3ccc(Cl)c(Cl)c3)C(C(CO[Si](C)(C)C(C)(C)C)Oc3ccc(Cl)cn3)C2)cnn1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ncc(C(=O)N2CC(c3ccc(Cl)c(Cl)c3)C(C(CO)Oc3ccc(Cl)cn3)C2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
To a solution of [(3RS,4SR)-3-[(RS)-2-(tert-butyl-dimethyl-silanyloxy)-1-(5-chloro-pyridin-2-yloxy)-ethyl]-4-(3,4-dichloro-phenyl)-pyrrolidin-1-yl]-(6-methyl-pyridazin-4-yl)-methanone 0.024 g (0.038 mmol) dissolved in THF (4 mL) was added 0.05 mL of TBAF (1.0M in THF). The reaction mixture was stirred for 30 minutes at room temperature. The mixture was diluted with ethyl acetate and washed with water and aq. sodium bicarbonate solution subsequently. The separated organic phase was dried over sodium sulfate and concentrated in vaccuo after filtration. The residue was purified by TLC (SiO2, MeOH/DCM, 1:10) yielded 18 mg (93%) of the title compound as a light yellow oil. ES-MS m/e: 509.2 (M+H+).
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[C:8]([CH3:11])[C:7]([O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:20][C:21]([O:23][CH3:24])=[O:22].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:24][O:23][C:21](=[O:22])[CH2:20][O:1][C:2]1[C:3]([CH:4]=[O:5])=[CH:6][C:7]([O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)=[C:8]([CH3:11])[C:9]=1[CH3:10]
Reactant: COC(=O)CBr
Reactant: Cc1c(OC2CCCCO2)cc(C=O)c(O)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1c(C=O)cc(OC2CCCCO2)c(C)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.8 %

Procedure:
A mixture of 2-hydroxy-3,4-dimethyl-5-(tetrahydro-pyran-2-yloxy)-benzaldehyde (150 mg) from Step 1, methyl bromoacetate (180 mg) and potassium-carbonate (200 mg) in DMF (10 mL) was stirred at room temperature for 2 hours. Then the solution was poured into water and extracted with ethylacetate. The ethyl acetate was washed with water and brine, dried over MgSO4 and concentrated. The residue was purified by silica gel column eluting with hexane and ethyl acetate (9:1) to give 100 mg of [6-formyl-2,3-dimethyl-4-(tetrahydro-pyran-2-yloxy)-phenoxy]-acetic acid methyl ester, which was then dissolved in DMF (15 mL). To this solution was added cesium carbonate (200 mg) and the mixture was stirred at room temperature overnight. Then the solution was poured into water and extracted with ethylacetate. The organic layer was washed with water and brine, dried over MgSO4 and concentrated to give 6,7-dimethyl-5-(tetrahydro-pyran-2-yloxy)-benzofuran-2-carboxylic acid methyl ester. The tetrahydropyranyl ether was dissolved in methanol, p-toluenesulfonic acid monohydrate (20 mg) was added, and the solution was stirred at room temperature for an additional 30 min. After the addition of a small amount of NaHCO3, the methanol was evaporated. The residue was purified by silica gel column chromatography, eluting with hexane and ethyl acetate (7:3) to give 30 mg of 5-hydroxy-6,7-dimethyl-benzofuran-2-carboxylic acid methyl ester. 1H NMR (CDCl3, 300 MHz) δ: 7.39 (s, 1H), 6.87 (s, 1H), 4.75 (s, 1H), 3.95 (s, 3H), 2.50, 2.26 (2s, 6H) ppm.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].C(=O)(O)[O-].[Na+].[CH2:15]([O:22][C:23](ON1C(=O)CCC1=O)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O.O1CCCC1>[CH2:15]([O:22][C:23]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCCCCCC(=O)O
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCCCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-aminocaproic acid (7.8 g) and 5.0 g of sodium bicarbonate in 50 ml of water is added by dropwise addition 16 g of N-benzyloxycarbonyloxysuccinimide in 60 ml of tetrahydrofuran. The mixture is stirred for one hour at room temperature and then the tetrahydrofuran is removed at reduced pressure. The residue is acidified to pH 3 and extracted with methylene chloride and dried over anhydrous magnesium sulfate. The magnesium sulfate is removed by filtration and the solvent is removed by evaporation. Recrystallization from ethyl acetate/hexane provides N-benzyloxycarbonyl-6-aminocaproic acid.
Reaction SMILES: Cl.[CH3:2][CH:3]1[NH:8][CH2:7][CH2:6][N:5]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[C:4]1=[O:20].[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH:31]=O)=[CH:26][CH:25]=1)([O-:23])=[O:22].C(O)C.C([BH3-])#N.[Na+]>C(OCC)(=O)C>[CH3:2][CH:3]1[N:8]([CH2:31][CH2:30][C:27]2[CH:26]=[CH:25][C:24]([N+:21]([O-:23])=[O:22])=[CH:29][CH:28]=2)[CH2:7][CH2:6][N:5]([CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)[C:4]1=[O:20]
Reactant: CC1NCCN(CCc2ccc([N+](=O)[O-])cc2)C1=O
Reactant: O=CCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC1C(=O)N(CCc2ccc([N+](=O)[O-])cc2)CCN1CCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a mixture of 3-Methyl-1-[2-(4-nitrophenyl)ethyl]piperazin-2-one hydrochloride (38 mg, 0.13 mmol) and (4-Nitrophenyl)acetaldehyde (31 mg, 0.19 mmol) was added_titanium(IV) isopropoxide (0.37 mL, 1.3 mmol). After stirring the mixture at RT for 15 minutes, ethanol (2 mL) and sodium cyanoborohydride (80 mg, 1.3 mmol) were added to the reaction. The mixture was allowed to stir at RT for 16 hours. The reaction was diluted with ethyl acetate, washed with brine, dried over sodium sulfate, and concentrated to give the crude title product. The title product was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 413 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([F:9])[CH:3]=1.[N+:10]([O-])([OH:12])=[O:11]>>[Cl:1][C:2]1[CH:3]=[C:4]([F:9])[C:5]([F:8])=[CH:6][C:7]=1[N+:10]([O-:12])=[O:11]
Reactant: Fc1ccc(Cl)cc1F
Reactant: O=[N+]([O-])O
Product: O=[N+]([O-])c1cc(F)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a 1-chloro-3,4-difluorobenzene (25 g, 0.17 mol) cooled to 0° C. was added fuming nitric acid (50 mL) dropwise over 30 min. The orange solution was warmed to room temperature and stirred for 2 h. The solution was poured slowly over ice and the resultant mixture extracted with diethyl ether. The diethyl ether layers were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to give 26 g (80%) of 1-chloro-4,5-difluoro-2-nitro-benzene: Crude 1H NMR (400 MHz, CDCl3): δ 7.88 (dd, J=9.3, 7.6 Hz, 1H), 7.43 (dd, J=9.3, 7.1 Hz, 1H). The crude material was pure enough to carry on to the next step.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:9]1([C:15](=O)[CH2:16][CH2:17][C:18](=O)[CH3:19])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(O)C.C(Cl)Cl>[CH3:19][C:18]1[N:2]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:16][CH:17]=1
Reactant: CC(=O)CCC(=O)c1ccccc1
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)Cn1c(C)ccc1-c1ccccc1
Temperature: 70 °C
Yield: 72.5 %

Procedure:
Ethyl 2-aminoacetate hydrochloride (1.378 g, 9.87 mmol) was diluted with ethanol (50 ml) then charged with TEA (8 ml, 57.4 mmol). 1-Phenylpentane-1,4-dione (1.74 g, 9.87 mmol) was then added and reaction was heated at 70° C. overnight. The reaction mixture was then diluted with 100 mL DCM and washed with water (100 mL). The aqueous was back-extracted with DCM (50 mL×2), the organics were combined, dried (Na2SO4), filtered, and concentrated to yield a crude orange oil. This oil was loaded onto a SiO2 column and purified using a 0-20% gradient of EtOAc in hexanes, affording 1.74 g (72.4% yield) of the desired ethyl 2-(2-methyl-5-phenyl-1H-pyrrol-1-yl)acetate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Br)[CH:3]=1.[CH2:10]([Mg]Br)[CH2:11][CH3:12].[Cl-].[NH4+].O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:10][CH2:11][CH3:12])[CH:3]=1
Reactant: CCC[Mg]Br
Reactant: BrCc1cccc(Br)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Under nitrogen stream, to a solution of 1-bromo-3-bromomethylbenzene (25 g) in tetrahydrofuran (200 ml) were sequentially added dropwise n-propylmagnesium bromide (60 ml, 2M solution in tetrahydrofuran) and lithium tetrachlorocuprate (5 ml, 0.1M solution in tetrahydrofuran) at −78° C. Then, this reaction mixture was stirred at 0° C. for 2 hours. Under ice-cooling, to this reaction mixture were sequentially added a saturated aqueous solution of ammonium chloride (100 ml) and water (100 ml), and the mixture was extracted with ethyl acetate (200 ml). The resulting aqueous layer was again extracted with ethyl acetate (100 ml), the combined organic layer was washed with a saturated aqueous solution of sodium chloride (100 ml), and dried over anhydrous sodium sulfate. This organic layer was concentrated under reduced pressure, the resulting residue was purified by silica gel chromatography (eluent: n-hexane/ethyl acetate=1/0 to 100/1) to give the titled compound (8.5 g).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].Cl[CH2:20][C:21]1[C:22]([CH3:38])=[N:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:28]=2[F:37])=[CH:25][CH:26]=1.O>CN(C)C=O>[F:37][C:28]1[CH:29]=[C:30]([C:33]([F:35])([F:36])[F:34])[CH:31]=[CH:32][C:27]=1[C:24]1[N:23]=[C:22]([CH3:38])[C:21]([CH2:20][O:16][C:13]2[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][CH2:7][CH2:6][N:1]3[CH:5]=[CH:4][N:3]=[N:2]3)=[CH:15][CH:14]=2)=[CH:26][CH:25]=1
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2F)ccc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2F)ccc1COc1ccc(CCCCn2ccnn2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
A solution of 359 mg (1.65 mmol) 4-(4-[1,2,3]triazol-1-yl-butyl)phenol in 20.0 ml N,N-dimethylformamide was treated at 0° C. with 66 mg (1.65 mmol) of 60% sodium hydride and stirred at 0° C. for 30 min. Then 500 mg (1.65 mmol) 3-Chloromethyl-6-(2-fluoro-4-trifluoromethyl-phenyl)-2-methyl-pyridine were added and stirred continued at r. t. over night. After addition of 40 ml water, the precipitate was isolated, washed thoroughly with water and diisopropylether. The residue was dried at 40° C. to give 618 mg (77%) of the title compound as light brown powder.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([Br:15])[C:13]=1[OH:14])[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].[C:16]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([Br:15])[C:13]=1[O:14][CH3:16])[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(Br)c(O)c(C(C)=O)c1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)c1cc(Br)c(OC)c(C(C)=O)c1

Procedure:
1 eq. of methyl 3-acetyl-5-bromo-4-hydroxybenzoate (preparation, see Example 19) was reacted, in acetone, with 2.0 eq. of K2CO3 and 2.1 eq. of methyl iodide to give methyl 3-acetyl-5-bromo-4-methoxybenzoate. Colorless oil, MS (ES): 288 (M+1).