Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=2[C:20]#[N:21])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Br.O>CN(C)C=O>[C:20]([C:19]1[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][C:9]=1[NH:8][C@H:5]1[CH2:6][CH2:7][C@H:2]([N:1]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:3][CH2:4]1)#[N:21]
Reactant: BrCCCCCBr
Reactant: CCOC(=O)c1ccc(C#N)c(N[C@H]2CC[C@H](N)CC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(C#N)c(N[C@H]2CC[C@H](N3CCCCC3)CC2)c1

Procedure:
A mixture of ethyl 3-[(trans-4-aminocyclohexyl)amino]-4-cyanobenzoate (0.490 g, 0.96 mmol), potassium carbonate (0.66 g, 4.78 mmol) and 1,5 dibromopentane (0.130 mL, 0.96 mmol) was stirred in dimethylformamide (10 mL) at room temperature for 48 h. Water (20 mL) was then added to the mixture, and the water phase was extracted with dichloromethane (2×30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography using methanol in dichloromethane (5% to 10%) to afford ethyl 4-cyano-3-[(trans-4-piperidin-1-ylcyclohexyl)amino]benzoate (0.145 g, 43% yield). MS (EI) for C21H29N3O2: 356 (MH+).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH2:3][CH2:2]1.[Br:10]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>N1C=CC=CC=1.ClCCl>[Br:10][C:8]1[CH:9]=[C:4]2[CH2:3][CH2:2][NH:1][C:5]2=[N:6][CH:7]=1
Reactant: c1cnc2c(c1)CCN2
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Brc1cnc2c(c1)CCN2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 38.8 %

Procedure:
2,3-Dihydro-1H-pyrrolo[2,3-b]pyridine (4.40 g, 36.6 mmol) in a mixture of pyridine (4.4 mL) and dichloromethane (20 mL) was gradually added dropwise to bromine (7.00 g, 43.8 mmol) in dichloromethane (20 mL) cooled to 0° C., and the resulting reaction mixture was stirred at 0° C. for 20 minutes, after addition of saturated aqueous sodium thiosulfate, the reaction mixture was extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1→0/1 (v/v)) to give the title compound as a brown solid (2.83 g, yield 39%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7](=[O:15])[C:8]1[C:9](=[CH:11][CH:12]=[CH:13][CH:14]=1)[OH:10].Cl[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>CN(C)C=O>[C:21]([O:20][C:18]([CH2:17][O:10][C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[CH:7]=[O:15])=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: O=Cc1ccccc1O
Reactant: CC(C)(C)OC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccccc1C=O
Temperature: 50 °C
Reaction time: 3 h
Yield: 51.8 %

Procedure:
366 g of dimethylformamide and 165.9 g (1.2 mol) of potassium carbonate were placed in a flask, followed by dropwise addition of 122 g (1 mol) of salicylaldehyde. 181.2 g (1.2 mol) of t-butyl chloroacetate were added dropwise to the mixture at a temperature of 50° C. for three hours. After the addition, the mixture was stirred for three hours at a temperature of 50° C. The resulting reaction mixture was washed with 122 g of toluene and 662 g of water. 130 g of the solvent was removed from the mixture by distillation and then 122 g of n-heptane were added to the distillation residue to effect crystallization. The resulting crystals were collected by filtration to provide 122.3 g of 2-t-butoxycarbonylmethoxybenzaldehyde having a purity of 98.5% as brown or pale yellow crystals. The filtrate was concentrated and provided 52.6 g of 2-t-butoxycarbonylmethoxybenzaldehyde having a purity of 98.0%. FIG. 1 is an infrared absorption spectrum of the compound. The overall yield was 74%.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[C:11]([Br:12])=[CH:10][CH:9]=[CH:8][N:7]=2)[CH2:3]1.Cl[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[Br:12][C:11]1[C:6]([CH:4]2[CH2:3][N:2]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]=3)[CH2:5]2)=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: Clc1ccc2ccccc2n1
Reactant: Brc1cccnc1C1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1cccnc1C1CN(c2ccc3ccccc3n2)C1
Temperature: 110 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
A mixture of 2-(azetidin-3-yl)-3-bromopyridine hydrochloride (4) (221 g, 0.886 mol), 2-chloroquinoline (133.5 g, 0.816 mol, 0.92 eq., Combi-Blocks) and cesium carbonate (866 g, 2.658 mol, 3 eq.) in anhydrous DMF (7 L) was heated to 110° C. and stirred for 16 hrs. After cooling to RT, the mixture was transferred to 50 L separatory funnel and diluted with water (14 L). The precipitated solid was filtered, stirred in water (4 L), filtered and dried to obtain 222 g of 2-(3-(3-bromopyridin-2-yl)azetidin-1-yl)quinoline. Yield: 80% over two steps.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][CH2:20][CH2:21][CH3:22])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@@H:9]1[OH:10])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N+:29]([O-])([N+]([O-])=O)=[O:30]>O1CCCC1.C(Cl)Cl>[Cl:1][CH2:2][CH2:3][N:4]([N:29]=[O:30])[C:5]([N:7]([CH2:19][CH2:20][CH2:21][CH3:22])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@@H:9]1[OH:10])=[O:6]
Reactant: CCCCN(C(=O)NCCCl)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O
Reactant: O=[N+]([O-])[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCCN(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O
Yield: 78.6 %

Procedure:
3.4 g of 1-(2-chloroethyl)-3-n-butyl-3-D-mannopyranosylurea are dissolved in a mixture of 60 ml of tetrahydrofuran and 60 ml of methylene chloride, and 15 g of sodium carbonate anhydrate are added thereto. 5 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes under ice-cooling. The mixture is treated in the same manner as described in Example 2. 2.9 g of 1-(2-chloroethyl)-1-nitroso-3-n-butyl-3-D-mannopyranosylurea are thereby obtained as yellow caramel.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH2:12][C:13]([OH:15])=O)(=[O:11])=[O:10])=[CH:4][C:3]=1[C:16]([F:19])([F:18])[F:17].Cl.[CH2:21]([O:23][C:24](=[O:30])[C@H:25]([C@@H:27]([CH3:29])[OH:28])[NH2:26])[CH3:22].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH2:21]([O:23][C:24](=[O:30])[CH:25]([NH:26][C:13](=[O:15])[CH2:12][S:9](=[O:10])(=[O:11])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:16]([F:19])([F:18])[F:17])[CH:4]=1)[CH:27]([OH:28])[CH3:29])[CH3:22]
Reactant: CCOC(=O)[C@@H](N)[C@@H](C)O
Reactant: O=C(O)CS(=O)(=O)Nc1ccc(F)c(C(F)(F)F)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(NC(=O)CS(=O)(=O)Nc1ccc(F)c(C(F)(F)F)c1)C(C)O

Procedure:
Under the conditions of Example 2(a), 3.012 g (10 mmol) of 2-[N-(4-fluoro-3-trifluoromethylphenyl)sulfamoyl]acetic acid, 1.736 g (10 mmol) of L-threonine ethyl ester hydrochloride, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is chromatographed on silica gel. The title compound is eluted with ethyl acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:16]3[C:17]([Cl:34])=[CH:18][C:19]([F:33])=[C:20]([NH:22][C:23]([NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=4)=[O:24])[CH:21]=3)[C:8](=[O:15])[N:9]2[CH:12]([CH3:14])[CH3:13])=[CH:4][N:3]=1.[C:35](Cl)(=[O:37])[CH3:36]>N1C=CC=CC=1>[Cl:34][C:17]1[CH:18]=[C:19]([F:33])[C:20]([NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)=[O:24])=[CH:21][C:16]=1[C:7]1[C:8](=[O:15])[N:9]([CH:12]([CH3:14])[CH3:13])[C:10]2[C:5]([CH:6]=1)=[CH:4][N:3]=[C:2]([NH:1][C:35](=[O:37])[CH3:36])[CH:11]=2
Reactant: CC(C)n1c(=O)c(-c2cc(NC(=O)Nc3cccc(F)c3)c(F)cc2Cl)cc2cnc(N)cc21
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1cc2c(cn1)cc(-c1cc(NC(=O)Nc3cccc(F)c3)c(F)cc1Cl)c(=O)n2C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.2 %

Procedure:
A solution of 1-(5-(7-amino-1-isopropyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-chloro-2-fluorophenyl)-3-(3-fluorophenyl)urea (0.07 g, 0.145 mmol) in pyridine (2 mL) was treated with acetyl chloride (0.011 mL, 0.159 mmol) and stirred at RT for 2 h. The mixture was concentrated to dryness, treated with EtOAc, washed with brine, dried over Na2SO4 and concentrated to dryness. The material was treated with Et2O and the solid collected via filtration to afford N-(3-(2-chloro-4-fluoro-5-(3-(3-fluorophenyl)ureido)phenyl)-1-isopropyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)acetamide (65 mg, 84% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.81 (s, 1H), 9.31 (s, 1H), 8.78 (s, 1H), 8.68 (s, 1H), 8.54 (s, 1H), 8.18 (d, J=8.6 Hz, 1H), 7.93 (s, 1H), 7.58 (d, J=11.0 Hz, 1H), 7.46 (dt, J=11.9, 2.3 Hz, 1H), 7.29 (m, 1H), 7.06 (m, 1H), 6.79 (td, J=8.5, 2.6 Hz, 1H), 5.36 (m, 1H), 2.14 (s, 3H), 1.56 (d, J=7.0 Hz, 6H); MS (ESI) m/z: 526.1 [M+H]+.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:11])[CH:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1.Cl.[NH2:13][OH:14].N1C=CC=CC=1>C(O)C>[CH3:2][N:3]([CH3:11])[CH:4]1[CH2:9][CH2:8][C:7](=[N:13][OH:14])[CH2:6][CH2:5]1
Reactant: CN(C)C1CCC(=O)CC1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CN(C)C1CCC(=NO)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.2 %

Procedure:
A mixture of 1.78 gm (10 mMol) of 4-dimethylaminocyclohexanone hydrochloride and 0.70 gm (10 mMol) of hydroxylamine hydrochloride in 25 mL ethanol was treated with 3 mL pyridine and then heated at reflux for 30 minutes. The reaction mixture was then cooled to room temperature and stored at 4° C. for 18 hours. The resulting crystalline solid was collected and washed with cold ethanol. The solid was then dissolved in water and the aqueous solution made basic by the addition of potassium carbonate. The aqueous phase was then extracted with dichloromethane which contained a small amount of isopropanol. The organic extracts were combined, dried over sodium sulfate and concentrated under reduced pressure to provide a crystalline solid. This solid was recrystallized from ethanol to provide 1.05 gm (67%) of the desired oxime.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[Na+].Br[CH2:27][CH2:28][O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1>O1CCCC1.[Cl-].[Na+].O>[CH2:18]([O:17][C:15](=[O:16])[C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])([CH2:27][CH2:28][O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:19]
Reactant: CCOC(=O)C(NC(=O)OC(C)(C)C)C(=O)OCC
Reactant: BrCCOC1CCCCO1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(CCOC1CCCCO1)(NC(=O)OC(C)(C)C)C(=O)OCC
Yield: 65.2 %

Procedure:
Diethyl (t-butyloxycarbonyl)aminomalonate (52.3 g) was dissolved in tetrahydrofuran (400 ml), sodium t-butoxide (19.2 g) was added thereto, a solution of 2-(2-bromoethoxy)tetrahydro-2H-pyran (40.4 g) in tetrahydrofuran (100 ml) was added to the reaction mixture at 70° C., and the mixture was stirred with heating for 10 hr. After cooling, the reaction mixture was poured into saturated brine. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give the object product (50.0 g) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([CH:13]=[CH2:14])=[CH:10][CH:11]=2)[N:6]([CH3:15])[C:5]1=[O:16].[N+](=[CH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N-]>C1(C)C=CC=CC=1>[CH3:17][C:2]([CH3:1])([CH3:18])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C@@H:13]3[CH2:14][C@H:21]3[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10][CH:11]=2)[N:6]([CH3:15])[C:5]1=[O:16]
Reactant: C=Cc1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Reactant: CCOC(=O)C=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Temperature: 100 °C

Procedure:
1-(2,2-Dimethylpropyl)-5-ethenyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (31-2, 636.4 mg, 2.6 mmol, 1.0 equiv) was added to anhydrous toluene (5.5 mL). Ethyl diazoacetate (807 μL, 7.8 mmol, 3.0 equiv) was added and the resulting solution was heated to 100° C. for 18 h. Following this duration, LCMS showed complete consumption of 31-2. The reaction mixture was diluted with ethyl acetate (50 mL) and saturated NaHCO3 (25 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to give an orange oil. Purification by normal-phase HPLC (0-40% EtOAc:hexanes) provided 31-3 as a white solid. MS m/z (M+H): calculated=332.1969; observed=332.1971.
Reaction SMILES: [OH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][Cl:23]>C(#N)C.CCOC(C)=O>[Cl:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][O:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Oc1nc2ccccc2s1
Reactant: ClCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: ClCCCCCOc1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-hydroxybenzothiazole (0.2 g, 1.32 mmol) in 10 mL of acetonitrile was added K2CO3 (0.274 g, 1.98 mmol), followed by stirring at 50˜55° C. for 30 min. Then, 1-bromo-5-chloropentane (0.245 g, 1.32 mmol) was added to and reacted with the solution of 2-hydroxybenzothiazole at 80˜90° C. for 3 hours. The reaction was cooled to room temperature, diluted with 10 mL of EtOAc, and washed with distilled water and a saturated NaCl aqueous solution. It was dried over MgSO4 and the solvent was removed by concentration under reduced pressure to afford K23 (0.333 g, 98%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][CH:10]([C:13](N)=[O:14])[O:9][C:8]=2[CH:16]=1)(=[O:3])[CH3:2].[CH2:17]([OH:19])[CH3:18]>Cl>[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][CH:10]([C:13]([O:19][CH2:17][CH3:18])=[O:14])[O:9][C:8]=2[CH:16]=1)(=[O:3])[CH3:2]
Reactant: CCO
Reactant: CC(=O)c1ccc2c(c1)OC(C(N)=O)CO2
Agent: Cl
Product: CCOC(=O)C1COc2ccc(C(C)=O)cc2O1
Yield: 75 %

Procedure:
Heat a solution of 3 g (13.5 mmol) of 7-acetyl-2,3-dihydro-1,4-benzodioxin-2-carboxamide dissolved in 100 cm3 of ethanol saturated with hydrochloric acid at reflux for 18 hours under a nitrogen atmosphere. After cooling, the reaction mixture is filtered, concentrated and, after neutralisation with sodium hydrogen carbonate, extracted with methylene chloride. The crude product obtained by concentrating the organic phase to dryness is purified by chromatography on a silica column (eluant: petroleum ether/diethyl ether, 50:50). Ethyl 7-acetyl-2,3-dihydro-1,4-benzodioxin-2-carboxylate is thereby obtained in a yield of 75%. Melting point: 57° C. ##STR35##
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:20][CH2:21][C@@H:22]([OH:51])[CH2:23][NH:24][CH2:25][CH2:26][C:27]2[CH:50]=[CH:49][C:30]([NH:31][CH:32]3[CH2:37][CH2:36][N:35]([C:38]([NH:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:39])[CH2:34][CH2:33]3)=[CH:29][CH:28]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH2:15][CH2:14]2)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH2:41]([NH:40][C:38]([N:35]1[CH2:36][CH2:37][CH:32]([NH:31][C:30]2[CH:49]=[CH:50][C:27]([CH2:26][CH2:25][NH:24][CH2:23][C@H:22]([OH:51])[CH2:21][O:20][C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[C:18]4[C:13]=3[CH2:14][CH2:15][C:16](=[O:19])[NH:17]4)=[CH:28][CH:29]=2)[CH2:33][CH2:34]1)=[O:39])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48]
Reactant: [H][H]
Reactant: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(OCc4ccccc4)c4c3CCC(=O)N4)cc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)c4c3CCC(=O)N4)cc2)CC1
Yield: 36 %

Procedure:
4-(4-{2-[((2S)-3-{[8-(Benzyloxy)-2-oxo-1,2,3,4-tetrahydro-5-quinolinyl]oxy}-2-hydroxypropyl)amino]ethyl}anilino)-N-octyl-1-piperidinecarboxamide (0.16 g, 0.228 mmol) was dissolved in ethanol and 10% palladium on carbon (0.07 g) added. The solution was shaken in a Parr apparatus at 50 psi hydrogen atmosphere for 4 hours, filtered through a Celite pad and the solvent removed in vacuo. The residue was purified by flash silica gel chromatography on silica gel Merck-60 to yield the title compound (0.05 g, 0.082 mmol).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([F:18])[C:10]=1[F:19])C1C=CC=CC=1>CO.[Pd]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([F:19])[C:11]=1[F:18]
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)c(F)c1F
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(O)c(F)c1F
Reaction time: 2 h
Yield: 91.4 %

Procedure:
A mixture of 1-benzyloxy-2,3-difluoro-4-nitrobenzene (14 g, 52.8 mmol) and Pd/C (10%, 1.4 g) in MeOH (200 mL) was stirred under a hydrogen atmosphere (30 psi) for 2 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to afford 4-amino-2,3-difluoro-phenol (7 g, 92% yield). 1H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 6.45 (t, J=8.8 Hz, 1H), 6.34 (t, J=9.2 Hz, 1H), 4.67 (s, 2H).
Reaction SMILES: [C:1]1([C:7]2[N:8]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br)[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:32]([O-:35])([O-:34])=[O:33].[Na+:36].[Na+]>C(O)C.O>[C:1]1([C:7]2[N:8]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][S:32]([O-:35])(=[O:34])=[O:33])[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+:36]
Reactant: BrCCCCCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=S(=O)([O-])CCCCCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Yield: 32.1 %

Procedure:
2,4,5-Triphenyl-1-(7-bromoheptyl)imidazole (0.95 g) was dissolved in hot ethanol (10 ml) and a solution of sodium sulphite (0.38 g) in hot water (5 ml) was added. The white suspension was heated at reflux temperature for 20 hours then evaporated to dryness. The mixture was taken up in dichloromethane, filtered and the filtrate evaporated to an oil which was chromatographed on silica gel (dichloromethane/methanol). The resulting oil was dissolved in methanol and excess ether added giving an oil which slowly solidified to give sodium 7-(2,4,5-tri-phenylimidazol-1-yl)heptane-sulphonate (0.32 g; 32%) as a white solid, m.p. 310° C.
Reaction SMILES: [H-].[Na+].C1C=CC=CC=1.[OH:9][CH:10]1[CH2:15][O:14][CH:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=2)[O:12][CH2:11]1.[CH2:23](Cl)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C(C)=CC=CC=1>[CH2:23]([O:9][CH:10]1[CH2:11][O:12][CH:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=2)[O:14][CH2:15]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1cccc(C2OCC(O)CO2)c1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: Cc1ccccc1C
Product: Cc1cccc(C2OCC(OCc3ccccc3)CO2)c1
Reaction time: 1 h
Yield: 91.9 %

Procedure:
A slurry of sodium hydride (2.1 g. 0.08 mole in 100 ml of xylene and 100 ml of benzene was stirred at ambient temperature while 5-hydroxy-2-(3-methylphenyl)-1,3-dioxane (15.9 g, 0.08 mole) was added dropwise during 1 hour. Stirring was continued for one hour and to the mixture was added benzyl chloride (10.4 g, 0.08 mole) during 0.5 hour. This mixture was heated under reflux for 22 hours, cooled, filtered and the filtrate washed with water (2 × 250 ml). The washed solution was dried over magnesium sulfate and concentrated under reduced pressure to give 20.9 g of oil which distilled at 2 × 10-4 mm. to give three fractions distilling respectively at 102°-133° C (cut 1); 133°-141° C (cut 2); and 141° C (cut 3). Analysis of the various cuts indicated that cut 3 was essentially pure cis-5 -benzyloxy-2-(3-methylphenyl)-1,3-dioxane, 2.1 g, m.p. 68°-70° C and this cut was used in further studies.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].C([Li])CCC.CCCCCC.[CH3:17][C:18]1([CH3:32])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]1[C:27](OCC)=[O:28]>C1(C)C=CC=CC=1>[CH2:1]([NH:5][C:27]([CH:19]1[C:18]([CH3:32])([CH3:17])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20]1)=[O:28])[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)C1Nc2ccccc2C1(C)C
Reactant: CCCCN
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCCCNC(=O)C1Nc2ccccc2C1(C)C
Reaction time: 3 h

Procedure:
Butylamine (15 ml) in toluene (40 ml) was cooled to −78° C. and a 2.5M solution of butyllithium in hexane (12.91 ml, 31.5 mmol) was added dropwise. After half an hour, ethyl 3,3-dimethylindoline-2(R/S)-carboxylate (4.600 g, 21 mmol) was added to the solution and this mixture was stirred under nitrogen for three hours. The mixture was then poured into a water/ice mixture (50 ml) and extracted with ethyl acetate; the extracts were dried over magnesium sulphate and the solvent was removed to give a brown oil. This was purified by chromatography on a column of silica gel, using a 7/3 petroleum ether/ethyl acetate mixture as eluent in order to give a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[O:17]1[CH2:22][CH2:21][CH2:20][CH:19]([NH2:23])[CH2:18]1>>[O:17]1[CH2:22][CH2:21][CH2:20][CH:19]([NH:23][C:14]([C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:13]=2)=[O:16])[CH2:18]1
Reactant: NC1CCCOC1
Reactant: O=C(O)c1cccc(-c2cccc(Cl)c2)n1
Product: O=C(NC1CCCOC1)c1cccc(-c2cccc(Cl)c2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chlorophenyl)-2-pyridinecarboxylic acid (CAN 863704-38-5) and tetrahydro-2H-pyran-3-amine (CAN 120811-32-7) as starting materials, MS (LC/MS): 317.1 (M+H).
Reaction SMILES: [C:1]1([N:7]2[C:14](=[O:15])[CH:13]([CH2:16][CH:17]=[CH:18][CH3:19])[C:11](=[O:12])[NH:10][C:8]2=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20](Cl)(=[O:23])[CH2:21][CH3:22]>N1C=CC=CC=1>[C:1]1([N:7]2[C:14](=[O:15])[C:13]([CH2:16][CH:17]=[CH:18][CH3:19])([C:20](=[O:23])[CH2:21][CH3:22])[C:11](=[O:12])[NH:10][C:8]2=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCC(=O)Cl
Reactant: CC=CCC1C(=O)NC(=O)N(c2ccccc2)C1=O
Solvent: c1ccncc1
Product: CC=CCC1(C(=O)CC)C(=O)NC(=O)N(c2ccccc2)C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A quantity of 1.29 g of 1-phenyl-3-methylallyl-barbituric acid prepared as described in Example Ia) is dissolved in 10 ml of pyridine. 0.52 ml of propionyl chloride is added dropwise to this solution which is cooled at 0° C. The reaction mixture is stirred at approximately 0° C. for 30 minutes and then at room temperature for 3 hours, and is then poured on 50 ml of ice water. After stirring with active carbon and filtering, the filtrate is acidified with conc. hydrochloric acid and extracted with methylene chloride. The organic layer is separated, washed with water, dried and evaporated. The final product is purified by means of column chromatography: silica gel/methylene chloride. The title compound is obtained in a yield of 0.65 g; melting-point 76°-80° C.