Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][C:4]([NH:7][S:8]([C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][N:12]=2)(=[O:10])=[O:9])=[CH:3][CH:2]=1.Br[CH2:20][C:21]([O:23]C)=[O:22]>>[CH3:17][C:16]1[C:11]([S:8]([N:7]([CH2:20][C:21]([OH:23])=[O:22])[C:4]2[CH:3]=[CH:2][C:1]([CH3:18])=[CH:6][CH:5]=2)(=[O:10])=[O:9])=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)CBr
Reactant: Cc1ccc(NS(=O)(=O)c2ncccc2C)cc1
Product: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ncccc2C)cc1

Procedure:
prepared by reaction of 3-methyl-pyridine-2-sulfonic acid p-tolylamide with methyl bromoacetate
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][C:8]1[CH:9]=[C:10]([OH:17])[CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15].CS(O[CH:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1)(=O)=O>CC(N(C)C)=O>[CH3:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[O:17][CH:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 85.6 %

Procedure:
Cesium carbonate (11.76 g, 26.11 mmoles, 2 equivalents) was added to a stirred solution of 3-methyl-4-nitrophenol (2.76 g, 18.05 mmoles, 1 equivalent) and tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (7.34 g, 19.96 mmoles, 1.1 equivalents) in anhydrous DMA (50 mls). The stirred reaction mixture was then heated to 90° C. (thermostatically controlled heating mantle) for 22 hours. The reaction mixture was then allowed to cool to room temperature and was filtered through a plug of Celite. The reaction flask and the Celite were then washed with ethyl acetate (250 ml). The organic solution was then transferred to a separatory funnel and extracted with additional ethyl acetate (3×200 ml). The combined ethyl acetate solution was then washed with water (2×100 ml), saturated sodium chloride (2×100 ml), dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to give a product. This material was triturated with diethylether to give a crystalline solid which was filtered off, washed with diethylether and dried under reduced pressure to give 5.2 g of tert-butyl 4-(3-methyl-4-nitrophenoxy)piperidine-1-carboxylate (yield=82%). 1H-NMR (400 MHz, DMSO-d6) δ 8.80 (s, 1H), 7.89 (d, 1H), 7.74 (d, 1H), 3.82 (d, 2H), 3.65 (m, 2H), 2.40 (s, 3H), 1.76 (m, 1H), 1.54 (m, 2H), 1.38 (s, 9H), 0.98 (m, 2H). MS (EI): 351 (MH+).
Reaction SMILES: [NH2:1][C:2]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.Cl.[CH3:12]O>>[NH2:1][C:2]1([C:8]([O:10][CH3:12])=[O:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: NC1(C(=O)O)CCOCC1
Reactant: CO
Agent: Cl
Product: COC(=O)C1(N)CCOCC1

Procedure:
A solution 4-aminotetrahydro-2H-pyran-4-carboxylic acid (0.50 g, 3.4 mmol) in MeOH (10 mL) was saturated with HCl gas at 0-5° C., and the mixture was then heated at reflux for 3.5 h. The solvents were evaporated in vacuo, the residue was dissolved in saturated aqueous NaHCO3 and the aqueous solution was extracted with CH2Cl2 (2×50 mL). The combined extracts were dried (MgSO4) and evaporated in vacuo to give methyl 4-aminotetrahydro-2H-pyran-4-carboxylate (410 mg, 2.58 mmol).
Reaction SMILES: N([O-])=O.[Na+].OS(O)(=O)=O.[Br:10][C:11]1[CH:16]=[C:15]([Cl:17])[N:14]=[N:13][C:12]=1N.[OH2:19]>C(O)(=O)C>[Br:10][C:11]1[C:12](=[O:19])[NH:13][N:14]=[C:15]([Cl:17])[CH:16]=1
Reactant: Nc1nnc(Cl)cc1Br
Reactant: O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=c1[nH]nc(Cl)cc1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a cooled solution (0-5° C.) of NaNO2 (2.4 equiv.) in H2SO4 conc. (23 equiv.) was added 4-bromo-6-chloropyridazin-3-amine (1.0 equiv.) in acetic acid (0.25 M). The reaction mixture was stirred at 0° C. for 30 min before warming to room temperature and stirring for 1 hour. Water was added and stirred at room temperature for a further 4 hours. The reaction mixture was then extracted with ethyl acetate, dried over MgSO4 and concentrated in vacuo to yield a brown oil. The oil was further purified by silica gel column chromatography eluting with 100% heptanes to 80% ethyl acetate/heptanes to yield 4-bromo-6-chloropyridazin-3(2H)-one as an off-white solid in 83% yield. LCMS (m/z) (M+H)=208.9/210.9, Rt=0.42 min. 1H NMR (400 MHz, <dmso>) δ ppm 8.08-8.32 (m, 1H) 13.25-13.71 (m, 1H).
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14](CCC(OC(C)(C)C)=O)[C:15]([OH:17])=[O:16])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>>[CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:15]([OH:17])=[O:16])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CC[C@@H](CC[C@H](Cc1ccccc1)C(=O)O)C(=O)O
Reactant: CC(C)(C)OC(=O)CBr
Product: CC(C)(C)OC(=O)C[C@@H](CC[C@H](Cc1ccccc1)C(=O)O)C(=O)O

Procedure:
(2R,5R)-2-Benzyl-5-(2-tert-butoxy-2-oxoethyl)hexanedioic acid (33 mg, 0.094 mmol) was synthesized as described for the preparation of Intermediate 7 using tert-butyl bromoacetate in step A.
Reaction SMILES: Br[CH2:2][CH:3]1[O:7][CH2:6][CH2:5][O:4]1.[CH2:8]([NH2:11])[CH:9]=[CH2:10].[OH-].[Na+]>O>[CH2:8]([NH:11][CH2:2][CH:3]1[O:7][CH2:6][CH2:5][O:4]1)[CH:9]=[CH2:10]
Reactant: C=CCN
Reactant: BrCC1OCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CCNCC1OCCO1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
2-Bromomethyl-1,3-dioxolane (20 grams) and allylamine (70 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture was heated at a temperature of about 100° C. for a period of about 3 hours. After this time sodium hydroxide (10 grams) dissolved in water (100 ml) was added and the resulting mixture was stirred for a period of about 30 minutes. The reaction mixture was then extracted with ether and the ether solution was separated and dried over magnesium sulfate. The dried solution was filtered and stripped of solvent to yield the desired product N-Allyl-N-(1,3-dioxolan-2-ylmethyl)amine as an oil.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][NH:6]1.C(O[CH:16]1[C:29]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:23][C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)(=O)C>C1C=CC=CC=1>[CH:18]1[C:17]2[CH:16]([N:6]3[CH2:7][CH2:8][CH2:9][CH2:10][CH:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH3:11])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[O:23][C:22]=2[CH:21]=[CH:20][CH:19]=1
Reactant: CN(C)CCC1CCCCN1
Reactant: CC(=O)OC1c2ccccc2Oc2ccccc21
Solvent: c1ccccc1
Product: CN(C)CCC1CCCCN1C1c2ccccc2Oc2ccccc21

Procedure:
A solution of 3.12 g. (0.02 mole) of 2-(2-dimethylaminoethyl)piperidine and 4.8 g. (0.02 mole) of 9-acetoxyxanthene in 75 ml. of anhydrous benzene was refluxed for 20 hours. The cooled solution was washed with 100 ml. of a 5 percent aqueous sodium bicarbonate solution, dried over anhydrous potassium carbonate, filtered, and evaporated in vacuo. The residue was taken up in low boiling petroleum ether and filtered to remove dixanthenyl ether. The filtrate was chromatographed on 125 g. of alumina, eluting successively with petroleum ether, petroleum etherbenzene mixtures, benzene, and finally ether. Evaporation of the ether fractions gave 1-(9-xanthenyl)-2-(2-dimethylaminoethyl)piperidine, m.p. 64°-67°C.
Reaction SMILES: [CH2:1]([C:3]1([C:18]#[N:19])[CH2:7][CH2:6][N:5](C(=O)C2C=CC(F)=CC=2)[C:4]1=[O:17])[CH3:2].N>C(O)C.C(OC(C)C)(C)C>[CH2:1]([C:3]1([C:18]#[N:19])[CH2:7][CH2:6][NH:5][C:4]1=[O:17])[CH3:2]
Reactant: CCC1(C#N)CCN(C(=O)c2ccc(F)cc2)C1=O
Agent: N
Solvent: CCO
Solvent: CC(C)OC(C)C
Product: CCC1(C#N)CCNC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 14 %

Procedure:
To a solution of 3-ethyl-1-(4-fluorobenzoyl)-2-oxopyrrolidine-3-carbonitrile (1.1 g) obtained in Step G in ethanol (15 mL) was added dropwise 28% aqueous ammonia solution (5 mL), and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate). The obtained crude crystals were dissolved in diisopropyl ether, and the remaining solid was removed by filtration. The solvent was evaporated under reduced pressure, and the resulting solid was collected by filtration, and washed with diisopropyl ether to give the title compound (82 mg).
Reaction SMILES: [NH2:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][CH:14]2[CH2:21][N:20]3[C:22]4[CH:23]=[C:24]([C:35](O)=[O:36])[CH:25]=[CH:26][C:27]=4[C:28]([CH:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)=[C:19]3[C:18]3[CH:38]=[CH:39][CH:40]=[CH:41][C:17]=3[O:16][CH2:15]2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:29]1([C:28]2[C:27]3[CH:26]=[CH:25][C:24]4=[CH:23][C:22]=3[N:20]3[CH2:21][CH:14]([CH2:15][O:16][C:17]5[C:18]([C:19]=23)=[CH:38][CH:39]=[CH:40][CH:41]=5)[CH2:13][CH2:12][CH2:11][N:8]2[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]2)[S:2](=[O:3])(=[O:4])[NH:1][C:35]4=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: NS(=O)(=O)N1CCN(CCCC2COc3ccccc3-c3c(C4CCCCC4)c4ccc(C(=O)O)cc4n3C2)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C1NS(=O)(=O)N2CCN(CCCC3COc4ccccc4-c4c(C5CCCCC5)c5ccc1cc5n4C3)CC2
Temperature: 50 °C
Reaction time: 2 h
Yield: 19 %

Procedure:
To a solution of 7-{3-[4-(aminosulfonyl)piperazin-1-yl]propyl}-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylic acid (0.04 M) in DCM were added EDC (1.5 eq) and DMAP (3 eq). The mixture was stirred at 50° C. for 2 h before cooling to RT and evaporating all volatiles in vacuo. The residue was purified by RP-HPLC (Waters Sunfire column; MeCN/H2O/0.1% TFA gradient). Fractions containing the pure compound were combined and lyophilized to afford the product as a white powder (19%). 1H NMR (400 MHz, DMSO-d6+TFA, 335 K) 1.16-1.23 (m, 2H), 1.31-1.39 (m, 2H), 1.47-1.50 (m, 1H), 1.69-1.73 (m, 2H), 1.83-2.19 (m, 7H), 2.64-2.66 (m, 1H), 3.29-3.36 (m, 4H), 3.49-3.74 (m, 7H), 3.89-3.93 (m, 2H), 4.28-4.39 (m, 1H), 4.40-4.44 (m, 1H), 7.28-7.32 (m, 2H), 7.35-7.37 (m, 1H), 7.45-7.47 (m, 1H), 7.52-7.56 (m, 1H), 7.90-7.92 (m, 2H); (ES+) m/z 563 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C@H:3]([C:11]([OH:13])=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl.[CH3:16]O>>[CH3:16][O:12][C:11](=[O:13])[C@H:3]([CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[N:2]([CH3:1])[CH3:14]
Reactant: CO
Reactant: CN(C)[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Product: COC(=O)[C@H](Cc1ccccc1)N(C)C

Procedure:
100 ml of methanol and 10 g (0.05 mol) of N,N-dimethylphenylalanine (prepared in accordance with Y. Ikutani, Bull. Chem. Soc. Jpn. 41, 1679 (1968)) are placed in a 350 ml sulfonating flask having an anchor mixer, thermometer, reflux condenser and gas introduction tube and, with stirring, saturated with HCl gas. The solution is stirred at reflux for 8 hours, then cooled, and the solvent is evaporated in a rotary evaporator. The residue is taken up in 250 ml of methylene chloride and washed first with 10% aqueous NaHCO3 solution and then with H2O until neutral. The reaction mixture is then dried over MgSO4, filtered and concentrated by evaporation. The residue is purified by flash chromatography (hexane/ethyl acetate=7:3), yielding 5.0 g of N,N-dimethylphenylalanine methyl ester in the form of a slightly yellow liquid. NMR analysis and IR spectrum agree with the said structure.
Reaction SMILES: [CH2:1]([C:5]1[C:6]([CH3:13])=[C:7]([C:10]([OH:12])=[O:11])[S:8][CH:9]=1)[CH:2]([CH3:4])[CH3:3].[Li][CH2:15]CCC.IC>C1COCC1>[CH2:13]([C:6]1[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:9][S:8][C:7]=1[C:10]([OH:12])=[O:11])[CH3:15]
Reactant: Cc1c(CC(C)C)csc1C(=O)O
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: CCc1c(CC(C)C)csc1C(=O)O
Temperature: -78 °C
Reaction time: 1 h
Yield: 30.6 %

Procedure:
To a solution of 4-isobutyl-3-methyl-thiophene-2-carboxylic acid (991 mg, 5.0 mmol) in THF (30 mL), tert.-BuLi (7.3 mL, 11 mmol, 1.5 M in pentane) is slowly added at −78° C. The mixture is stirred at −78° C. for 1 h, then iodomethane (1.6 mL, 25.7 mmol) is added. The mixture is stirred and is allowed to warm to rt over a period of 15 h before the reaction is quenched with 1 N aq. HCl (50 mL) and extracted with DCM (1×100 mL, 2×50 mL). The combined organic extracts are dried (MgSO4), filtered and evaporated. The residue is purified by CC on silica gel eluting with a gradient of EA in hexane to give 3-ethyl-4-isobutyl-thiophene-2-carboxylic acid (325 mg) as a yellow solid; LC-MS: tR=0.98 min, 1H NMR (CD3OD): δ 7.22 (s, 1H), 2.94 (q, J=7.6 Hz, 2H), 2.42 (d, J=7.0 Hz, 2H), 1.86 (hept, J=7.0 Hz, 1H), 1.11 (t, J=7.6 Hz, 3H), 0.93 (d, J=7.0 Hz, 6H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][OH:7])=[CH:2]1.[H-].[Na+].[Cl:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13](Cl)[N:12]=1>O1CCCC1>[Cl:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([O:7][CH2:6][C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[N:12]=1
Reactant: OCc1ccsc1
Reactant: Cc1cc(Cl)nc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(Cl)nc(OCc2ccsc2)c1

Procedure:
To a solution containing 3-thiophenemethanol (0.78 g, 0.0062×1.1 mol) and sodium hydride (0.26 g, (ca.60% in mineral oil), 0.0062×1.05 mol) in tetrahydrofuran, 2,6-dichloro-4-methylpyridine (1.0 g, 0.0062 mol) was added, and the resultant solution was refluxed for about 1 hour.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].[NH2:21][C:22]1[C:27]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([S:37](=[O:41])(=[O:40])[NH:38][CH3:39])=[CH:33][CH:32]=2)=[O:29])=[C:26](Cl)[N:25]=[CH:24][N:23]=1.CCN(C(C)C)C(C)C.[F-].[Cs+]>C(O)(C)(C)C>[NH2:21][C:22]1[C:27]([C:28]([NH:30][C:31]2[CH:32]=[CH:33][C:34]([S:37](=[O:41])(=[O:40])[NH:38][CH3:39])=[CH:35][CH:36]=2)=[O:29])=[C:26]([NH:1][C@H:2]([C:4]2[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:8](=[O:16])[C:7]3=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]3[N:5]=2)[CH3:3])[N:25]=[CH:24][N:23]=1
Reactant: Cc1ccn2nc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Reactant: CNS(=O)(=O)c1ccc(NC(=O)c2c(N)ncnc2Cl)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: CNS(=O)(=O)c1ccc(NC(=O)c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)cc1
Temperature: 80 °C
Yield: 23 %

Procedure:
(S)-2-(1-Aminoethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.33 mmol), 4-amino-6-chloro-N-(4-(N-methylsulfamoyl)phenyl)pyrimidine-5-carboxamide (123 mg, 0.36 mmol), DIEA (344 μl, 1.97 mmol) and cesium fluoride (150 mg, 0.99 mmol) were suspended in tert-butanol (10 ml) and the mixture was heated at 80° C. in a sealed tube for 24 h. The solvent was evaporated under reduced pressure and the reaction mixture was diluted with ethyl acetate and washed with saturated ammonium chloride solution and brine. After evaporation of the solvent, the residue was purified by reverse phase chromatography using SP1® Purification System to give 47 mg (23% yield) as a solid. Purity 94%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[NH:10][C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2].[OH-].[NH4+:16]>O>[N+:1]([C:4]1[CH:5]=[C:6]([C:11]([NH2:10])=[O:12])[C:7](=[CH:13][CH:14]=1)[C:8]([NH2:16])=[O:9])([O-:3])=[O:2]
Reactant: O=C1NC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Product: NC(=O)c1ccc([N+](=O)[O-])cc1C(N)=O

Procedure:
Commercial 4-nitrophthalimide (500 g; 2.60 moles; mp 196°-200° C) is added quickly to a stirred solution of 15.6 N ammonium hydroxide (3500 ml). With continued stirring, external heating (water bath, 45° C) is applied until frothing ceases (1 hour). The resulting precipitate is collected, washed with ice water (2 × 400ml) then recrystallized with acetone (2 × 400 ml) and dried to yield 440 g of I as pale yellow crystals; yield, 81%, mp 200°-202° C; lit (6) mp 200° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[O:9][CH2:10][CH:11]1[CH2:15][CH2:14][CH2:13][N:12]1[CH3:16].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[N:33]2[C:28]([CH:29]=[N:30][C:31](OS(C(F)(F)F)(=O)=O)=[N:32]2)=[CH:27][CH:26]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:31]2[N:30]=[CH:29][C:28]3=[CH:27][CH:26]=[C:25]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[O:18][CH3:17])[N:33]3[N:32]=2)=[CH:4][C:3]=1[O:9][CH2:10][CH:11]1[CH2:15][CH2:14][CH2:13][N:12]1[CH3:16]
Reactant: CN1CCCC1COc1cc(N)ccc1Cl
Reactant: COc1ccccc1-c1ccc2cnc(OS(=O)(=O)C(F)(F)F)nn12
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc(Cl)c(OCC4CCCN4C)c3)nn12

Procedure:
Prepared by following a procedure analagous to Example 1220c by using 4-Chloro-3-(1-methyl-pyrrolidin-2-ylmethoxy)-phenylamine and Trifluoro-methanesulfonic acid 7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester. 1H-NMR (DMSO) 69.7 (br s, 1H), 9.6 (s, 1H), 8.9 (s, 1H), 7.75 (d, J=7.5 Hz, 1H), 7.5 (m, 2H), 7.35 (d, J=9.1 Hz, 1H), 7.28 (d, J=9.2 Hz 1H), 7.2 (d, J=8.3 Hz, 1H), 7.1 (t, 1H), 7 (s, 2H), 3.97 (d, 1H), 3.85 (m, 2H), 3.77 (s, 3H), 3.6 (m, 1H), 3.1 (m, 1H), 3 (s, 3H), 2.2 (m, 1H), 2.0 (m, 1H), 1.9 (m, 1H), 1.65 (m, 1H); LC/MS (ESI+): 464 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1.[Cl:17][CH2:18][C:19](Cl)=[O:20]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]([C:19](=[O:20])[CH2:18][Cl:17])[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1
Reactant: O=C(Cl)CCl
Reactant: Cc1ccc(Nc2c(C)cccc2Cl)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(N(C(=O)CCl)c2c(C)cccc2Cl)cc1
Temperature: 25 °C
Yield: 77.9 %

Procedure:
The solution of N-(2′-chloro-6′-methylphenyl)-4-methylaniline (1.4 g) in 2.21 g chloroacetylchloride is heated to 90° C. for 4 h. The mixture is diluted with toluene (25 ml), cooled to room temperature and washed with aqu. sodium carbonate. The organic phase is dried, evaporated and the residue is subjected to flash chromatography [57 g silica, toluene and toluene/ethylacetate (98:2)] to afford 1.45 g of N-(2′-Chloro-6′-methylphenyl)-N-chloroacetyl-4-methylaniline which is crystallised from heptane, mp: 113-114° C.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C@H:7]2[CH2:11][O:10][C:9]([CH3:13])([CH3:12])[N:8]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:4][CH:3]=1.[C:23]1([N:29]=[C:30]=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCl>[NH:29]([C:30]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@H:7]2[CH2:11][O:10][C:9]([CH3:12])([CH3:13])[N:8]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:21][CH:22]=1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2ccc(N)cc2)COC1(C)C
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@@H](Cc2ccc(NC(=O)Nc3ccccc3)cc2)COC1(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice-cooled solution of tert-butyl (S)-4-(4-aminobenzyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (1.0 g) in dichloromethane (10 ml) was added dropwise phenyl isocyanate (0.39 ml). The mixture was stirred at the same temperature for 1 hour and partitioned between chloroform and saturated sodium bicarbonate solution. The organic layer was separated, washed with brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate) to give tert-butyl (S)-4-[4-[(anilinocarbonyl)amino]benzyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (1.48 g) as colorless oil.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])=[O:4].[CH3:14][C:15]1[CH:19]=[C:18]([CH2:20]Cl)[O:17][N:16]=1.[H-].[Na+]>CN(C)C=O>[Cl:1][CH2:2][C:3]([N:5]([CH2:20][C:18]1[O:17][N:16]=[C:15]([CH3:14])[CH:19]=1)[C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])=[O:4]
Reactant: Cc1cc(CCl)on1
Reactant: Cc1cccc(C)c1NC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(CN(C(=O)CCl)c2c(C)cccc2C)on1
Yield: 30 %

Procedure:
A mixture of 4.54 g N-chloroacetyl-2,6-dimethylaniline and 3 g 3-methyl-5-chloromethylisoxazole (prepared as in Example 8 above) in 100 ml dry dimethylformamide was treated with 1.33 g sodium hydride as in Example 3 above. After workup, the solid product was purified by column and high-pressure liquid chromatography to yield 2.0 g pure product, m.p. 78°-82° C. This product is shown as Compound 1 in Table I. C15H17ClN2O2 : calc., %C 61.54, %H 5.81, %N 9.57; found, %C,63.37, %H 6.16, %N 9.65.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>C(#N)C>[CH:1]1([NH:7][C:8]([NH:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C=NC1CCCCC1
Reactant: NCCCN1CCCC1
Solvent: CC#N
Product: O=C(NCCCN1CCCC1)NC1CCCCC1

Procedure:
In an argon atmosphere 10 mmol of cyclohexylisocyanate was added slowly to 10 mmol of 1-(3-aminopropyl)pyrrolidine in 10 ml of acetonitrile. The product precipitated instantly as a pure white solid. The solvent was removed under reduced pressure and the product was crystallized with oxalic acid from diethyl ether/ethanol.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:13]([CH2:20][CH2:21][CH:22]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][O:38]C2CCCCO2)=[CH:31][CH:30]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[OH:38][CH2:37][CH2:36][O:35][C:32]1[CH:31]=[CH:30][C:29]([CH2:28][CH:22]([CH2:21][CH2:20][O:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:34][CH:33]=1
Reactant: CCOC(=O)C(CCOc1ccccc1)Cc1ccc(OCCOC2CCCCO2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(CCOc1ccccc1)Cc1ccc(OCCO)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.2 %

Procedure:
p-Toluenesulfonic acid monohydrate (0.40) was added to a solution of ethyl 2-(2-phenoxyethyl)-3-[4-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl]propionate (738 mg), which is the product of Reference example 3(e), in ethanol (10 ml). The mixture was stirred at ambient temperature for 2 hours. At the end of this time the reaction mixture was concentrated. The residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The ethyl acetate layer was separated and dried over anhydrous magnesium sulfate and then concentrated. The residue was purified via chromatography on a silica gel column using hexane/ethyl acetate=7/3-3/2 as the eluant to afford the desired compound (503 mg) as a syrup.
Reaction SMILES: [NH4+].[Cl-].[Br:3][C:4]1[O:12][C:11]2[CH:10]=[CH:9][N:8]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[C:15]([CH3:22])[CH:14]=3)[C:7](=[O:23])[C:6]=2[CH:5]=1>[Fe].CCO.O>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([N:8]2[CH:9]=[CH:10][C:11]3[O:12][C:4]([Br:3])=[CH:5][C:6]=3[C:7]2=[O:23])=[CH:14][C:15]=1[CH3:22]
Reactant: Cc1cc(-n2ccc3oc(Br)cc3c2=O)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cc1cc(-n2ccc3oc(Br)cc3c2=O)ccc1N
Yield: 97.2 %

Procedure:
Fe powder (1.30 g, 23.2 mmol) and NH4Cl (69 mg, 1.3 mmol) were added to a suspension of 2-bromo-5-(3-methyl-4-nitrophenyl)furo[3,2-c]pyridin-4(5H)-one (896 mg, 2.58 mmol) in 4:1 EtOH/H2O (60 mL) and the resulting suspension was heated at reflux for 14 h. The suspension was filtered through Celite, while warm, and the filtrate was concentrated to afford 800 mg of crude 5-(4-amino-3-methylphenyl)-2-bromofuro[3,2-c]pyridin-4(5H)-one as a yellow solid.