Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[CH:2]1([CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[H-].[Na+].[CH2:38]([O:45][C:46]([N:48]1[CH2:53][CH2:52][CH:51]([CH:54]=O)[CH2:50][CH2:49]1)=[O:47])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.O>CS(C)=O.O1CCCC1>[CH2:38]([O:45][C:46]([N:48]1[CH2:53][CH2:52][CH:51](/[CH:54]=[CH:16]/[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][CH2:8][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2)[CH2:50][CH2:49]1)=[O:47])[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: c1ccc([P+](Cc2ccccc2OCC2CCCCC2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(/C=C/c2ccccc2OCC2CCCCC2)CC1
Temperature: 70 °C
Yield: 39.5 %

Procedure:
1.75 g of [[2-(cyclohexylmethyloxy)phenyl]methyl]triphenylphosphonium chloride was dissolved in 10 ml of dimethyl sulfoxide, 144 mg of 60% sodium hydride was added thereto, and the mixture was stirred at 70° C. After leaving to cool to room temperature, a solution of 800 mg of 1-(benzyloxycarbonyl)-4-piperidinecarboxaldehyde dissolved in 3 ml of tetrahydrofuran was added dropwise thereinto and the mixture was stirred at room temperature for one hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N-hydrochloric acid, an aqueous saturated sodium bicarbonate and brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1), to give 554 mg of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[C:4]([C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:15][CH:14]=2)=[N:3]1.[F:31]C1C=C(C(=O)CC2C=CN=CC=2)C=CC=1OCC1C=CC2C(=CC=CC=2)N=1>>[F:31][C:29]1[CH:30]=[C:13]([C:4]2[C:5]([C:7]3[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=3)=[CH:6][N:2]([CH3:1])[N:3]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1
Reactant: O=C(Cc1ccncc1)c1ccc(OCc2ccc3ccccc3n2)c(F)c1
Product: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)c(F)c2)n1

Procedure:
Following the procedure for the preparation of 2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline but substituting 1-[3-Fluoro-4-(quinolin-2-ylmethoxy)-phenyl]-2-pyridin-4-yl-ethanone provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.47 (d, J=6.2 Hz, 2H), 8.21 (d, J=8.3 Hz, 1H), 8.05 (d, J=8.7 Hz, 1H), 7.83 (d, J=7.9 Hz, 2H), 7.72 (m, 2H), 7.55 (m, 2H), 7.16 (m, 2H), 7.07 (m, 1H), 6.99 (m, 2H), 5.45 (s, 2H), 3.95 (s, 3H); MS: (M+H m/z=411.0).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][CH:12]([CH3:14])[CH3:13])=[C:7]([CH:10]=1)[C:8]#[N:9].S(Cl)([Cl:17])=O>C1(C)C=CC=CC=1>[Cl:17][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][CH:12]([CH3:14])[CH3:13])=[C:7]([CH:10]=1)[C:8]#[N:9]
Reactant: O=S(Cl)Cl
Reactant: CC(C)Oc1ccc(CO)cc1C#N
Solvent: Cc1ccccc1
Product: CC(C)Oc1ccc(CCl)cc1C#N
Temperature: 75 °C
Reaction time: 0.33 h
Yield: 85.6 %

Procedure:
5-(Hydroxymethyl)-2-isopropoxybenzonitrile (5.96 g, 31.2 mmol) was dissolved in toluene (90 mL) and thionyl chloride (13.65 mL, 187 mmol) was added. The reaction mixture was warmed to 75° C. and stirred for 20 min. The reaction mixture was diluted with hexanes and washed with water and saturated aqueous sodium bicarbonate. The hexane solution was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (5.6 g). 1H NMR (400 MHz, CDCl3) δ ppm 1.41 (d, J=6.1 Hz, 6H), 4.52 (s, 2H), 4.66 (septet, J=6.1 Hz, 1H), 6.95 (d, J=8.6 Hz, 1H), 7.51 (dd, J=8.7, 2.4 Hz, 1H), 7.57 (d, J=2.3 Hz, 1H).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:9])[CH2:5][CH2:6][CH2:7][OH:8].F[C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)(=[O:19])=[O:18])=[CH:13][CH:12]=1>O1CCOCC1>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([NH:20][S:17]([C:14]2[CH:15]=[CH:16][C:11]([O:8][CH2:7][CH2:6][CH2:5][N:4]([CH3:9])[CH3:3])=[CH:12][CH:13]=2)(=[O:19])=[O:18])=[CH:26][CH:25]=1
Reactant: CN(C)CCCO
Reactant: O=S(=O)(Nc1ccc(Cl)cc1)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CN(C)CCCOc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspention of NaH (100 mmol, 55-65% in oil) in dry dioxane (140 mL) was added 3-dimethylamino-1-propanol (11.90 mL, 100 mmol). The mixture was stirred 1 h at room temperature. A solution of 4-fluoro-N-(4-chlorophenyl)benzenesulfonamide (9.53 g, 33.35 mmol, preparation described in example 66) in dry dioxane (35 mL) was added. The resulting mixture was heated 24 h at 100° C. Solvents were evaporated. NH4Cl saturated solution in water (75 mL) was added and the desired product was extracted with three portions of ethyl acetate (3×100 mL). Combined organic phases were dried over magnesium sulfate before filtering and removal of solvent. The desired product, e.g. N-(4-chlorophenyl)-4-[3-(dimethylamino)propoxy]benzenesulfonamide was obtained as a colorless oil, in 96% purity by HPLC (MaxPlot detection between 230 and 400 nm). This intermediate was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=1>>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([NH:20][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])[CH:17]=[CH:18][CH:19]=1
Reactant: COc1cccc(N)c1
Reactant: O=C(O)Cc1ccccc1Br
Product: COc1cccc(Nc2ccccc2CC(=O)O)c1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with m-anisidine to yield 2-[(3-methoxyphenyl)amino]phenylacetic acid.
Reaction SMILES: BrC[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[N-:15]=[N+:16]=[N-:17].[Na+].[CH3:19]N(C=O)C>>[N:15]([CH2:19][C:14]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:6]1[CH:5]=[CH:4][CH:3]=[CH:8][CH:7]=1)=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: BrCc1ccc(-c2ccccc2)cc1
Reactant: CN(C)C=O
Agent: [Na+]
Product: [N-]=[N+]=NCc1ccccc1-c1ccccc1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A mixture of 4-(Bromomethyl)-biphenyl (200 mg, 0.6 mmol) and sodium azide (41 mg, 0.6 mmol) in 2 mL DMF was stirred at 90° C. for 1 h. The reaction mixture was concentrated in vacuo and the residue was treated with DCM and extracted with water. The organic layer was dried over MgSO4 and evaporated to give the title compound which was used in the next step without further purification. 1H-NMR (CDCl3, 400 MHz) 7.62-7.66 (m, 4H), 7.39-7.50 (m, 5H), 4.42 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:13]([C:28]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][N:29]=2)[NH:14][C:15](=[O:27])[C:16]2[CH:21]=[CH:20][C:19]([O:22]C)=[C:18]([N+:24]([O-:26])=[O:25])[N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].[Li+].[Cl-].CC1C=CC(S(O)(=O)=O)=CC=1.CCOC(C)=O>CN1C(=O)CCC1.O>[F:1][C:2]1[CH:3]=[C:4]([C@@H:13]([C:28]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][N:29]=2)[NH:14][C:15](=[O:27])[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([N+:24]([O-:26])=[O:25])[N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:10])[F:11]
Reactant: COc1ccc(C(=O)N[C@@H](c2ccc(OC(F)(F)F)c(F)c2)c2ncccc2F)nc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: O=C(N[C@@H](c1ccc(OC(F)(F)F)c(F)c1)c1ncccc1F)c1ccc(O)c([N+](=O)[O-])n1
Temperature: 180 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl) (3-fluoropyridin-2-yl)methyl)-5-methoxy-6-nitropicolinamide (700 mg, 0.0011 mol) in NMP (7.0 mL) was added LiCl (183.79 mg, 0.0043 mol, Sigma Aldrich, India) followed by pTSA (746.63 mg, 0.0043 mol, Sigma Aldrich, India) at room temperature. The reaction mixture was stirred at 180° C. for 2 h. After completion of the reaction (monitored by TLC, 100% EtOAc), the reaction mixture was cooled to room temperature and water (50 mL) was added and the aqueous solution was extracted with EtOAc (25 mL×2). The organic extracts were washed with water (25 mL×2) and brine (25 mL) and dried over anhydrous sodium sulfate and concentrated. The resulting material was purified by silica gel (60-120 mesh) column chromatography eluting with 60-70% EtOAc in petroleum ether to give the title compound as an off-white solid. 1H-NMR (400 MHz, DMSO-d6): δ 12.77 (br. s., 1H), 9.43 (d, J=7.2 Hz, 1H), 8.57 (d, J=4.4 Hz, 1H), 8.24 (d, J=8.4 Hz, 1H), 7.86-7.79 (m, 2H), 7.59-7.54 (m, 3H), 7.37 (d, J=8.4 Hz, 1H), 6.57 (d, J=7.2 Hz, 1H). MS (ESI, positive ion) m/z: 471 (M+H).
Reaction SMILES: [CH3:1][C:2]([O:4][C:5]([CH3:7])=[O:6])=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]2[C@@H:20]([OH:21])[C@H](CO)[C@@H:18]([OH:24])[C@H:17]([OH:25])[C@H:16]2[OH:26])=[CH:11][C:10]=1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH3:35])=[CH:30][CH:29]=1.N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:5]([O:4][CH2:2][C@@H:1]1[C@@H:18]([OH:24])[C@H:17]([OH:25])[C@@H:16]([OH:26])[C@H:15]([C:12]2[CH:13]=[CH:14][C:9]([Cl:8])=[C:10]([CH2:27][C:28]3[CH:29]=[CH:30][C:31]([CH2:34][CH3:35])=[CH:32][CH:33]=3)[CH:11]=2)[C@H:20]1[OH:21])(=[O:6])[CH3:7]
Reactant: CC(=O)OC(C)=O
Reactant: CCc1ccc(Cc2cc([C@H]3[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)[C@@H]3O)ccc2Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCc1ccc(Cc2cc([C@H]3[C@H](O)[C@@H](O)[C@H](O)[C@@H](COC(C)=O)[C@@H]3O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.4 %

Procedure:
Ac2O (377 mg, 1.5 eq) was added dropwised into the solution of (1R,2R,3S,4R,5R,6S)-4-(4-chloro-3-(4-ethylbenzyl)phenyl)-6-(hydroxymethyl)cyclohexane-1,2,3,5-tetraol (5, R=Et, 1 g, 2.46 mmol) and DMAP (cat.) in CH2Cl2 (10 mL) at 0° C. followed by pyridine (292 mg, 1.5 eq), and the mixture was stirred overnight at rt. The reaction mixture was washed with 3N HCl, and the organic layer was combined, dried over Na2SO4, filtered, and the filtrate was evaporated to dryness. The residue was purified by preperative HPLC to give target compound (566 mg, white solid, yield of 50.4%). 1H-NMR (400 MHz, CD3OD): δ 7.32 (1H, d, J=8.4 Hz), 7.06-7.14 (6H, m), 4.37 (2H, ddd, J=2.0, 10.8, 16.8 Hz), 4.04 (2H, s), 3.57 (1H, t, J=10.8 Hz), 3.40-3.47 (1H, m), 2.49-2.60 (3H, m), 2.04 (3H, s), 1.60-1.66 (1H, m), 1.18 (3H, t, J=8.0 Hz); MS (ESI+): 449 [M+H]+, 466 [M+NH4]+, 897 [2M+H]+, (ESI−): 492 [M+HCOO]−, 941 [2M+HCOO]−.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]([S:5][C:6]1[C:11]2=[N:12][CH:13]=[C:14]([C:17]([O:19]CC3C=CC(OC)=CC=3)=[O:18])[C:15](=[O:16])[N:10]2[CH:9]=[CH:8][CH:7]=1)=[O:4].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:17]([C:14]1[C:15](=[O:16])[N:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:5][C:3](=[O:4])[N:2]([CH3:1])[CH3:29])[C:11]2=[N:12][CH:13]=1)([OH:19])=[O:18]
Reactant: COc1ccc(COC(=O)c2cnc3c(SC(=O)N(C)C)cccn3c2=O)cc1
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)Sc1cccn2c(=O)c(C(=O)O)cnc12
Temperature: 0 °C

Procedure:
A mixture of 0.508 g of 9-(dimethylcarbamoyl)thio-3-(4-methoxybenzyloxycarbonyl)-4H-pyrido[1,2-a]pyrimidin-4-one Ib-82, 2,5 g of anisole and 5 ml of dry methylene chloride is cooled with ice water, mixed with 5 ml of trifluoroacetic acid and stirred under cooling with ice water for 3 hours. The reaction mixture is concentrated in vacuo to dryness, and the residue is washed with ether to give 0.32 g of crude product, which is recrystallized from 95% ethanol to give the titled compound Ib-81.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1Cl.[OH:13][C:14]1[CH:29]=[CH:28][C:17]([O:18][CH:19]([CH3:27])[C:20]([N:22]2[CH2:26][CH2:25][CH2:24][O:23]2)=[O:21])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>C1C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:6][C:7]=1[O:13][C:14]1[CH:15]=[CH:16][C:17]([O:18][CH:19]([CH3:27])[C:20]([N:22]2[CH2:26][CH2:25][CH2:24][O:23]2)=[O:21])=[CH:28][CH:29]=1
Reactant: CC(Oc1ccc(O)cc1)C(=O)N1CCCO1
Reactant: FC(F)(F)c1cccc(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: c1ccccc1
Solvent: O
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1)C(=O)N1CCCO1
Temperature: 130 °C
Reaction time: 3 h
Yield: 96.1 %

Procedure:
A mixture of 1,2-dichloro-3-(trifluoromethyl)benzene (21.5 g), N-[(±)-2-(4-hydroxyphenoxy)propionyl]isoxazolidine (23.7 g) which was prepared as in Example 3, anhydrous potassium carbonate (14.5 g) and dimethylsulfoxide (200 ml) was stirred at 130° C. for 3 hours. After the mixture was cooled, water and benzene were added thereto to form two layers. The organic layer thus separated was washed with 1 N aqueous sodium hydroxide solution and then with water and dried over anhydrous sodium sulfate. Removal of the solvent by a distillation in vacuo gave N-[(±)-2-[4-(2-chloro-4-trifluoromethylphenoxy)phenoxy]propionyl]isoxazolidine (39.9 g) as a pale brown crystalline solid. Recrystallization from a mixture of n-hexane and ethyl acetate afforded a white crystalline solid. m.p. 66.5°-67.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][O:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:18]([O-])=O.C(OCC)(=O)C>[Pd].C(O)C>[NH2:18][C:3]1[CH:4]=[C:5]([S:8]([NH:11][O:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)(=[O:9])=[O:10])[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: Nc1ccc(S(=O)(=O)NOC2CCCC2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(S(=O)(=O)NOC2CCCC2)cc1N
Reaction time: 72 h
Yield: 100.7 %

Procedure:
A solution of 4-amino-N-(cyclopentyloxy)-3-nitrobenzenesulfonamide (4.50 g, 14.95 mmol) in 1:1 ethyl acetate : ethanol (150 mL) was combined with 5% Pd on barium sulfate and reduced under a hydrogen atmosphere over 72 hours. The reaction mixture was filtered through a pad of diatomaceous earth and evaporated in vacuo to a residue which crystallized on standing. The solid was slurried in hexane, filtered and dried under high vacuum to provide 3,4-diamino-N-(cyclopentyloxy)benzenesulfonamide (4.086 g, 100%) as a light brown solid H1-NMR (dimethylsulfoxide-D6): 1.61 (m, 8H), 4.37 (m, 1H), 4.90 (b, 2H), 5.38 (b, 2H), 6.57 (d, 1H), 6.88 (m, 1H), 6.96 (d, 1H), 9.64 (s, !H). . MS(ESI): 272(M+H).
Reaction SMILES: [N+:1]([C:4]1[C:5]2[CH2:6][C@H:7]3[CH2:16][S:15][C:14](=[S:17])[N:8]3[CH2:9][C:10]=2[CH:11]=[CH:12][CH:13]=1)([O-:3])=[O:2].[CH3:18][I:19]>>[I-:19].[CH3:18][S:17][C:14]1[S:15][CH2:16][C@@H:7]2[CH2:6][C:5]3[C:4]([N+:1]([O-:3])=[O:2])=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9][N+:8]=12
Reactant: O=[N+]([O-])c1cccc2c1C[C@H]1CSC(=S)N1C2
Reactant: CI
Product: CSC1=[N+]2Cc3cccc([N+](=O)[O-])c3C[C@H]2CS1
Product: [I-]
Reaction time: 48 h

Procedure:
(S)-9-Nitro-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline-3-thione (40 g.) is dissolved in methyl iodide (100 cc.). After 48 hours at a temperature of about 20° C., the crystals which have appeared are filtered off, washed with diethyl ether (2 × 30 cc.) and then dried at 20° C under reduced pressure (1 mm. Hg). (S)-3-Methylthio-9-nitro-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinolinium iodide (6.0 g.) is thus obtained.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]([CH:16]([CH3:18])[CH3:17])[C:8](=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[Br-:19]>>[Br:19][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]([CH:16]([CH3:18])[CH3:17])[C:8](=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: [Br-]
Reactant: CCCCCCC(=O)N(CCCCCO)C(C)C
Product: CCCCCCC(=O)N(CCCCCBr)C(C)C
Yield: 82 %

Procedure:
N-(5-Hydroxypentyl)-N-isopropylheptanamide (0.25 g, 0.97 mmol) was converted to the corresponding bromide as described above to give the title compound (0.25 g. 82%) as a colorless oil. TLC: EtOAc/hexanes (3:7), Rf˜0.40; 1H NMR (300 MHz, 55/45 mixture of rotamers) δ 4.60-4.70 and 3.96-4.10 (m, 1H for two rotamers), 3.46 and 3.36 (t, J=5.8 Hz 2H for two rotamers), 3.02-3.10 (m, 2H), 2.30 and 2.22 (t, J=7.9 Hz, 2H for two rotamers), 1.80-1.97 (m, 2H), 1.40-1.70 (m, 6H), 1.20-1.40 (m, 6H), 1.16 and 1.10, (d, J=7.3 Hz, 6H for two rotamers), 0.86 (t, J=7.3 Hz, 3H); 13C NMR (75 MHz) δ 172.79, 172.39, 48.17, 45.47, 43.32, 40.70, 33.89, 33.87, 33.49, 32.48, 32.30, 31.81, 31.78, 30.78, 29.27, 28.74, 26.05, 25.84, 25.69, 25.54, 22.64, 21.47, 20.62, 14.17. HRMS calcd for C15H31BrNO [M+1]+ 320.1589. found 320.1588.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH3:23][O:24][C:25]1[C:34]([O:35][CH3:36])=[N:33][C:32]2[C:31]([CH:37]=[O:38])=[CH:30][CH:29]=[CH:28][C:27]=2[N:26]=1.[OH-].[Na+]>FC(F)(F)C(O)=O>[CH3:23][O:24][C:25]1[C:34]([O:35][CH3:36])=[N:33][C:32]2[C:31]([CH:37]=[O:38])=[CH:30][C:29]([N+:1]([O-:4])=[O:2])=[CH:28][C:27]=2[N:26]=1
Reactant: COc1nc2cccc(C=O)c2nc1OC
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1nc2cc([N+](=O)[O-])cc(C=O)c2nc1OC
Temperature: 0 °C

Procedure:
44 ml of 100% nitric acid, 44 ml of 97% sulfuric acid and 44 ml of trifluoroacetic anhydride are added in succession to a solution, cooled to 0° C., of 22 g (100.8 mmol) of 2,3-dimethoxy-quinoxaline-5-carbaldehyde in 88 ml of trifluoroacetic acid. The mixture is maintained at 0° C. for 2 hours and is then carefully poured onto a mixture of 4N NaOH and ice. The temperature should not exceed 20° C. The mixture is extracted with ethyl acetate. The organic phase is washed with an aqueous 1 N NaOH solution, water and brine and dried over sodium sulfate. Crystallization of the crude product yields the title compound in the form of light-yellow crystals. M.p.: 147-149° C.; TLC (EtOAc/hexane 1:3): Rf =0.25.
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.C[Si](C)(C)CCOC[N:26]1[CH:30]=[C:29]([C:31]([OH:35])([C:33]#[CH:34])[CH3:32])[N:28]=[CH:27]1>>[F:19][C:3]1[C:2]([C:34]#[C:33][C:31]([OH:35])([C:29]2[N:28]=[CH:27][NH:26][CH:30]=2)[CH3:32])=[CH:18][C:6]2[C:7]3[N:8]([CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: C#CC(C)(O)c1cn(COCC[Si](C)(C)C)cn1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Product: CC(O)(C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2)c1c[nH]cn1

Procedure:
Similar to as described in General Procedure G, 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)but-3-yn-2-ol and following removal of the SEM protecting group (nBu4F, THF) gave the titled compound as an off-white solid. (1.5 mg, 3%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[CH:26]=[C:25]([CH3:27])[S:24][C:15]=2[N:16]=[C:17]([C:19]2[O:23][N:22]=[CH:21][CH:20]=2)[N:18]=1>>[O:23]1[C:19]([C:17]2[N:18]=[C:13]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:14]3[CH:26]=[C:25]([CH3:27])[S:24][C:15]=3[N:16]=2)=[CH:20][CH:21]=[N:22]1
Reactant: Cc1cc2c(Cl)nc(-c3ccno3)nc2s1
Reactant: NCc1cccc([N+](=O)[O-])c1
Product: Cc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(-c3ccno3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(isoxazol-5-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(3-nitrobenzylamino)-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([NH:5][S:6]([C:9]1[CH:10]=[C:11]([C:16](=[O:19])[CH2:17]Cl)[CH:12]=[CH:13][C:14]=1[Cl:15])(=[O:8])=[O:7])[CH2:2][CH2:3][CH3:4].[CH2:20]([NH:22][C:23]([NH:25][CH2:26][CH3:27])=[S:24])[CH3:21]>C(OC(C)C)(C)C>[ClH:15].[CH2:26]([N:25]1[C:16]([C:11]2[CH:12]=[CH:13][C:14]([Cl:15])=[C:9]([S:6](=[O:8])(=[O:7])[NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH:10]=2)([OH:19])[CH2:17][S:24][C:23]1=[N:22][CH2:20][CH3:21])[CH3:27]
Reactant: CCNC(=S)NCC
Reactant: CCCCNS(=O)(=O)c1cc(C(=O)CCl)ccc1Cl
Solvent: CC(C)OC(C)C
Product: CCCCNS(=O)(=O)c1cc(C2(O)CSC(=NCC)N2CC)ccc1Cl
Product: Cl

Procedure:
6.4 g of 3'-n-butylsulfamoyl-2,4'-dichloroacetophenone and 2.7 g of ground 1,3-diethylthiourea were reacted as prescribed in Example 12. With the addition of 200 ml of diisopropyl ether, the oily end product was precipitated and the solvent was decanted. The amorphous residue was dissolved in 100 ml of water and liophylized. Colorless solid body, decomposition beginning at 130° C, γC=N 1620 cm-1.
Reaction SMILES: C[O:2][C:3](=[O:21])[C@H:4]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[NH:5][C:6](=[O:13])[C@H:7]([CH2:9][C:10](=[O:12])[OH:11])[NH2:8].[CH:22](N[C@@H]1C(=O)OC(=O)C1)=[O:23].N[C@H](C(O)=O)CC1C=CC=CC=1>O>[CH:22]([NH:8][C@H:7]([C:6]([NH:5][C@H:4]([C:3]([OH:2])=[O:21])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:13])[CH2:9][C:10](=[O:12])[OH:11])=[O:23]
Reactant: O=CN[C@H]1CC(=O)OC1=O
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(=O)O
Agent: N[C@@H](Cc1ccccc1)C(=O)O
Solvent: O
Product: O=CN[C@@H](CC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
A process for preparing an α-L-aspartyl-L-phenylalanine methyl ester which comprises the steps of reacting formyl-L-aspartic anhydride with L-phenylalanine in the presence of water at a high pH, to produce formyl-α-L-aspartyl-L-phenylalanine; removing the formyl group from the formyl-α-L-aspartyl-L-phenylalanine and esterifying the resultant compound with methanol and hydrogen chloride to produce the hydrogen chloride salt of α-L-aspartyl-L-phenylalanine methyl ester; neutralizing the hydrogen chloride salt of α-L-aspartyl-L-phenylalanine methyl ester; and filtering the neutralized solution to produce α-L-aspartyl-L-phenylalanine methyl ester.
Reaction SMILES: CN1C=CC(C(O)=O)=C1.[NH:10]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:16])=[CH:11]1.C1(N2CCC(OC3C=CC(I)=CC=3)CC2)CCC1.[C:40]([N:44]1[CH2:49][CH2:48][CH:47]([O:50][C:51]2[CH:56]=[CH:55][C:54](I)=[CH:53][CH:52]=2)[CH2:46][CH2:45]1)([CH3:43])([CH3:42])[CH3:41]>>[C:40]([N:44]1[CH2:45][CH2:46][CH:47]([O:50][C:51]2[CH:56]=[CH:55][C:54]([N:10]3[CH:14]=[CH:13][C:12]([C:15]([N:17]4[CH2:21][CH2:20][CH2:19][CH2:18]4)=[O:16])=[CH:11]3)=[CH:53][CH:52]=2)[CH2:48][CH2:49]1)([CH3:43])([CH3:41])[CH3:42]
Reactant: O=C(c1cc[nH]c1)N1CCCC1
Reactant: CC(C)(C)N1CCC(Oc2ccc(I)cc2)CC1
Agent: Cn1ccc(C(=O)O)c1
Agent: Ic1ccc(OC2CCN(C3CCC3)CC2)cc1
Product: CC(C)(C)N1CCC(Oc2ccc(-n3ccc(C(=O)N4CCCC4)c3)cc2)CC1

Procedure:
The titled compound was prepared as a colorless crystal by repeating the procedure of Example 1, except that the methyl 1H-pyrrole-3-carboxylic acid was replaced by (1H-pyrrol-3-yl)(pyrrolidin-1-yl)methanone and the 1-cyclobutyl-4-(4-iodophenoxy)piperidine by 1-tert-butyl-4-(4-iodophenoxy)piperidine (which can be synthesized in accordance with the method described in WO2008072724).
Reaction SMILES: N#N.[O:3]=[C:4]([CH3:17])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[O:10][CH:11]=[C:12]([C:14](O)=[O:15])[N:13]=1.CN(C=O)C.C(Cl)(=O)C([Cl:26])=O>C1(C)C=CC=CC=1>[O:3]=[C:4]([CH3:17])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[O:10][CH:11]=[C:12]([C:14]([Cl:26])=[O:15])[N:13]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(=O)CCCCc1nc(C(=O)O)co1
Agent: N#N
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)CCCCc1nc(C(=O)Cl)co1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a suspension of 2-(5-oxo-hexyl)-oxazole-4-carboxylic acid (403 mg, 1.91 mmol) in toluene (19 mL) was treated at 0° C. with a drop of DMF followed by oxalyl chloride (0.20 mL, 2.29 mmol) and the resulting yellow solution was stirred at rt for 1 h. The solvent was then removed under reduced pressure (coevaporation with toluene) to give 2-(5-oxo-hexyl)-oxazole-4-carbonyl chloride as a brown oil.