Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:8]([C:10]2[C:14](Br)=[CH:13][N:12]([C:16]34[CH2:25][CH:20]5[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]5)[CH2:17]3)[CH2:23]4)[N:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1B(O)O)=[O:33].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C(O)C.O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:16]12([N:12]3[CH:13]=[C:14]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[CH:32]=[O:33])[C:10]([C:8]([N:7]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[O:9])=[N:11]3)[CH2:17][CH:18]3[CH2:19][CH:20]([CH2:21][CH:22]([CH2:24]3)[CH2:23]1)[CH2:25]2
Reactant: O=Cc1ccccc1B(O)O
Reactant: O=C(c1nn(C23CC4CC(CC(C4)C2)C3)cc1Br)N(c1ccccc1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: O=Cc1ccccc1-c1cn(C23CC4CC(CC(C4)C2)C3)nc1C(=O)N(c1ccccc1)c1ccccc1
Temperature: 180 °C

Procedure:
1-Adamantan-1-yl-4-bromo-1H-pyrazole-3-carboxylic acid diphenylamide (47 mg), 2-formylphenylboronic acid (18 mg), sodium carbonate (32 mg), and tetrakis(triphenylphosphine)palladium(0) (7 mg) were combined in dimethoxyethane/ethanol/water 12/3/4 (1 mL) and heated in a CEM Discover microwave reactor at 180° C. for 5 minutes. The reaction was cooled, diluted with water and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. After filtration and concentration, the crude material was purified by column chromatography on silica gel using hexanes/ethyl acetate 4/1.
Reaction SMILES: CN([CH:4]=[O:5])C.[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]2[CH2:17][C@H:16]2[C:18](O)=[O:19])=[CH:11][CH:10]=1)([O-:8])=[O:7].C([O-])([O-])=O.[K+].[K+].CI>O>[N+:6]([C:9]1[CH:10]=[CH:11][C:12]([C@@H:15]2[CH2:17][C@H:16]2[C:18]([O:5][CH3:4])=[O:19])=[CH:13][CH:14]=1)([O-:8])=[O:7]
Reactant: CN(C)C=O
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: COC(=O)[C@@H]1C[C@H]1c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
To a 500 mL RB flask fitted with magnetic stirrer was charged with 120 mL of DMF. To the stirred solvent was added (1R,2R)-2-(4-nitrophenyl)cyclo propane carboxylic acid (15 g, 72 mmol), K2CO3 (29 g, 217 mmol) and methyl iodide (5.5 mL, 86 mmol), stirred at RT for 8 h. The RM was poured into water (100 mL) and extracted with ethyl acetate (150 mL×2). The organic layer was washed with saturated NaHCO3 solution (50 mL), water (50 mL) and saturated brine solution (50 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as pale yellow color liquid (14 g, yield: 87.9%). MS (ESI, 120 eV): m/z=206.1 (M−H)+.
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].[CH3:5][S:6]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:7].S(=O)(=O)(O)O.O>C(Cl)Cl>[N+:14]([C:11]1[CH:10]=[CH:9][C:8]([S:6]([CH3:5])(=[NH:1])=[O:7])=[CH:13][CH:12]=1)([O-:16])=[O:15]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)c1ccc([N+](=O)[O-])cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CS(=N)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 45 °C
Yield: 63 %

Procedure:
0.70 g (10.76 mmol) of sodium azide was added to 1.56 g (8.42 mmol) of 1-(methylsulfinyl)-4-nitrobenzene in 20 ml DCM. 2.3 ml concentrated sulfuric acid was slowly added to the mixture at 0° C. and it was then heated to 45° C. After 16 h the mixture was cooled to room temperature, and after adding water it was extracted with DCM. The aqueous phase was adjusted to pH 11 with 15% sodium hydroxide solution and extracted with DCM (2×). The combined organic phases were dried (Na2SO4), filtered and concentrated by evaporation. 1.08 g (5.39 mmol; yield: 63%) of the product was obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[CH2:19]([N:21]1[C:25]([CH2:26]O)=[CH:24][C:23]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)=[N:22]1)[CH3:20].CN(C)C(N=NC(N(C)C)=O)=O.C(P(CCCC)CCCC)CCC>>[C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:26][C:25]3[N:21]([CH2:19][CH3:20])[N:22]=[C:23]([C:28]4[CH:29]=[CH:30][C:31]([C:34]([F:36])([F:35])[F:37])=[CH:32][CH:33]=4)[CH:24]=3)[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Cn1ccc2ccc(O)cc21
Reactant: CCn1nc(-c2ccc(C(F)(F)F)cc2)cc1CO
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCn1nc(-c2ccc(C(F)(F)F)cc2)cc1COc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1

Procedure:
In analogy to the procedure described for example 3 c], (6-hydroxy-indol-1-yl)-acetic acid tert-butyl ester (example 1 d]) was reacted with [2-ethyl-5-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-yl]-methanol in the presence of N,N,N′,N′-tetramethyl azodicarboxamide and tributylphosphine to give {6-[2-ethyl-5-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-ylmethoxy]-indol-1-yl}-acetic acid tert-butyl ester as colorless oil.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][C:11](=[O:15])[C:12]([CH3:14])=[CH2:13])=[CH:4][C:3]=1[N:16]1[N:20]=[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]2=[N:17]1.[CH3:25][O-:26].[Na+].[CH3:28][OH:29]>C1(C)C(C)=CC=CC=1>[N:17]1[N:16]([C:3]2[C:25]([OH:26])=[C:7]([CH2:2][C:7]3[CH:6]=[C:5]([CH3:8])[CH:4]=[C:3]([N:16]4[N:17]=[C:18]5[CH:24]=[CH:23][CH:22]=[CH:21][C:19]5=[N:20]4)[C:28]=3[OH:29])[CH:6]=[C:5]([CH2:8][CH2:9][O:10][C:11](=[O:15])[C:12]([CH3:14])=[CH2:13])[CH:4]=2)[N:20]=[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=12
Reactant: CO
Reactant: C=C(C)C(=O)OCCc1ccc(O)c(-n2nc3ccccc3n2)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: C=C(C)C(=O)OCCc1cc(Cc2cc(C)cc(-n3nc4ccccc4n3)c2O)c(O)c(-n2nc3ccccc3n2)c1
Temperature: 25 °C
Yield: 70.7 %

Procedure:
Ten grams (30.9 mmols) of crude 2-(3'-N,N-diethylaminomethyl-2'-hydroxy-5'-methylphenyl)-2H-benzotriazole obtained following the procedures of Synthesis Example 1 and 10.0 g (30.9 mmols) of 2-(2'-hydroxy-5'-methacryloyloxyethylphenyl)-2H-benzotriazole were dissolved in 64 ml of xylene, and 1.5 ml of a 28% sodium methylate-methanol solution were added thereto. The mixture was then refluxed in a nitrogen stream for 10 hours. After the completion of the reaction, the reaction mixture was cooled to room temperature. Yellow crystals precipitated at this stage were separated through filtration, and recrystallized from chloroform to obtain 12.4 g of 6-(2H-benzotriazol-2-yl)-4-methacryloyloxyethyl-2-[3'-(2H-benzotriazol-2-yl)-2'-hydroxy-5'-methylphenyl]methylphenol (hereinafter abbreviated as "RUVA-1") as white crystals (yield 70.7%, purity 98.6%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][C:9]=1[N+:17]([O-:19])=[O:18].[NH2:20][C:21](=[N:33]O)[C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]([F:32])[CH:23]=1>C(Cl)Cl.C1(C)C=CC=CC=1>[F:32][C:24]1[CH:23]=[C:22]([C:21]2[N:20]=[C:12]([C:11]3[CH:15]=[CH:16][C:8]([N:3]4[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]4[CH3:1])=[C:9]([N+:17]([O-:19])=[O:18])[CH:10]=3)[O:14][N:33]=2)[CH:31]=[CH:30][C:25]=1[C:26]([O:28][CH3:29])=[O:27]
Reactant: COC(=O)c1ccc(C(N)=NO)cc1F
Reactant: CC1CCCCN1c1ccc(C(=O)O)cc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2noc(-c3ccc(N4CCCCC4C)c([N+](=O)[O-])c3)n2)cc1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Intermediate 11 (12.46 g; 47.13 mmol) was dissolved in DCM (200 mL) and n,n′-dicyclohexylcarbodiimide (11.67 g; 56.56 mmol) was added. Then Intermediate 1 was added (10 g; 47.13 mmol) and the suspension was stirred at RT for 12 hours. The precipitate was filtered off and the solvent evaporated to give a yellow solid. The residue was dissolved in Toluene (300 mL) and Py (150 mL) and the solution was heated to 130° C. for 12 hours. The reaction mixture was concentrated to afford a yellow sticky oil which was precipitated from ACN affording the title compound as a yellow solid. LC/MS (Method B): 441.3 (M+H)+ HPLC: Rt 5.86 min (Purity: 95.1%).
Reaction SMILES: [NH2:1]/[C:2](/[CH2:9][O:10][CH2:11][CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23])=[CH:3]\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:24][C:25]1[CH:39]=[CH:38][CH:37]=[CH:36][C:26]=1[CH:27]=[C:28]([C:33]([CH3:35])=O)[C:29]([O:31][CH3:32])=[O:30]>C(O)C>[Cl:24][C:25]1[CH:39]=[CH:38][CH:37]=[CH:36][C:26]=1[CH:27]1[C:28]([C:29]([O:31][CH3:32])=[O:30])=[C:33]([CH3:35])[NH:1][C:2]([CH2:9][O:10][CH2:11][CH2:12][N:13]2[C:14](=[O:23])[C:15]3=[CH:22][CH:21]=[CH:20][CH:19]=[C:16]3[C:17]2=[O:18])=[C:3]1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: COC(=O)C(=Cc1ccccc1Cl)C(C)=O
Reactant: CCOC(=O)/C=C(\N)COCCN1C(=O)c2ccccc2C1=O
Solvent: CCO
Product: CCOC(=O)C1=C(COCCN2C(=O)c3ccccc3C2=O)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Yield: 34.9 %

Procedure:
24.0 g (75.4 mmoles) of ethyl 3-amino-4-(2-(phthalimido)ethoxy)crotonate and 18.9 g (79.2 mmoles) of methyl 2-(2-chlorobenzylidene)acetoacetate in 64 ml of ethanol were heated under reflux for 20 hours. The reaction mixture was diluted with 56 ml of ethanol and was cooled to crystallise the product. 14.2 g (yield 70%) of 4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2-(2-phthalimidoethoxy)methyl-1,4-dihydropyridine were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9]O)=[CH:7][CH:6]=[CH:5][N:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:31]>C(Cl)Cl>[Br:31][CH2:9][C:8]1[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrC(Br)(Br)Br
Reactant: COc1ncccc1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ncccc1CBr
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.6 %

Procedure:
To a 100-mL round-bottomed flask was added (2-methoxy-3-pyridinyl)methanol (1.12 g, 8.05 mmol), triphenylphosphine (2.32 g, 8.85 mmol, Aldrich, St. Louis, Mo.) and carbon tetrabromide (0.86 mL, 8.85 mmol, Aldrich, St. Louis, Mo.) in DCM (20 mL). The reaction mixture was stirred at room temperature for 3 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with 20% EtOAc/hexanes to give 3-(bromomethyl)-2-methoxypyridine (1.10 g) as a colorless oil.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([CH2:12][C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:14])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:21][CH:22]([CH2:36][CH3:37])[C@@H:23]([C:25]1[O:29][N:28]=[C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:26]=1)[OH:24]>>[CH:1]1([CH2:7][C@H:8]([CH2:12][C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:14])[C:9]([NH:21][C@H:22]([C:23]([C:25]2[O:29][N:28]=[C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:26]=2)=[O:24])[CH2:36][CH3:37])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCC(N)[C@H](O)c1nc(-c2ccccc2)no1
Reactant: O=C(O)[C@@H](CC(=O)N1CCOCC1)CC1CCCCC1
Product: CC[C@H](NC(=O)[C@@H](CC(=O)N1CCOCC1)CC1CCCCC1)C(=O)c1nc(-c2ccccc2)no1

Procedure:
Similarly prepared according to the general procedure given for Example 43 above but using (R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyric acid and (S)-2-amino-1 (3-phenyl-[1,2,4]oxadiazol-5-yl)-butan-1-ol; MS: 497 (MH+).
Reaction SMILES: C(N(C(C)C)CC)(C)C.FC(F)(F)C(O)=O.[CH3:17][O:18][C:19](=[O:38])[CH2:20][C:21]1[CH:30]=[C:29]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:37])[CH:27]=2)[CH:22]=1.[Cl:39][C:40]1[CH:45]=[CH:44][C:43]([S:46](Cl)(=[O:48])=[O:47])=[CH:42][CH:41]=1>O1CCCC1>[CH3:17][O:18][C:19](=[O:38])[CH2:20][C:21]1[CH:30]=[C:29]([CH:31]2[CH2:36][CH2:35][N:34]([S:46]([C:43]3[CH:44]=[CH:45][C:40]([Cl:39])=[CH:41][CH:42]=3)(=[O:48])=[O:47])[CH2:33][CH2:32]2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:37])[CH:27]=2)[CH:22]=1
Reactant: COC(=O)Cc1cc(C2CCNCC2)c2cc(F)ccc2c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cc1cc(C2CCN(S(=O)(=O)c3ccc(Cl)cc3)CC2)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.2 %

Procedure:
Diisopropylethylamine (0.6 mL, 3.4 mmol) was added at 0° C. to a solution of (6-fluoro-4-piperidin-4-yl-naphthalen-2-yl)-acetic acid methyl ester trifluoroacetate salt (which may be prepared as described above; 150 mg, 0.36 mmol) in tetrahydrofuran (5 mL), and the mixture was stirred at room temperature for 30 min. 4-Chlorobenzenesulfonyl chloride (available from Sigma-Aldrich; 114 mg, 0.54 mmol) was added and the mixture was stirred at room temperature for 16 h. The solvent was evaporated under reduced pressure. Ethyl acetate was added and the mixture was washed with aqueous NaHCO3 (5 mL) and water (5 mL). The organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using a Biotage purification system, eluting with 10% ethyl acetate/hexanes, to give {4-[1-(4-chloro-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-naphthalen-2-yl}-acetic acid methyl ester (86 mg, 50%) as a white solid. MS cald. for C24H24ClFNO4S [(M+H)+]: 476, obsd. 476.4.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:16]=[CH:15][C:8]2[NH:9][C:10](=[O:14])[CH:11]([CH3:13])[O:12][C:7]=2[CH:6]=1)=[O:4].[H-].[Na+].[CH2:19](I)[CH3:20].O>CN(C)C=O.C(OCC)(=O)C>[CH2:19]([N:9]1[C:8]2[CH:15]=[CH:16][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][C:7]=2[O:12][CH:11]([CH3:13])[C:10]1=[O:14])[CH3:20]
Reactant: COC(=O)c1ccc2c(c1)OC(C)C(=O)N2
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN1C(=O)C(C)Oc2cc(C(=O)OC)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
To a solution of 7-methoxycarbonyl-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (prepared in Preparation 1) (1.00 g) in dimethylformamide (5 ml) were added 60% sodium hydride (in oil) (0.22 g) and ethyl iodide (0.78 g) and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution and extraction with ethyl acetate was conducted. The solvent was distilled off under reduced pressure to give 4-ethyl-7-methoxycarbonyl-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (0.89 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH3:9])=[C:4]([N+:10]([O-])=O)[CH:3]=1.O.O.[C:15]([OH:20])(=O)[C:16](O)=[O:17]>C(O)C.Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]([CH3:9])[C:16](=[O:17])[C:15](=[O:20])[NH:10]2
Reactant: CNc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: O=C(O)C(=O)O
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cn1c(=O)c(=O)[nH]c2cc(Cl)ccc21
Yield: 23 %

Procedure:
A suspension of 4-chloro-1-methylamino-2-nitrobenzene (1.73 g, 9.3 mmol) in 50 ml of ethanol was hydrogenated at room temperature and 2 atm. pressure in the presence of 5% palladium-on-carbon (0.5 g) until the theoretical amount of hydrogen was absorbed. The catalyst was filtered off, and 50 ml of 1N hydrochloric acid was added to the filtrate. The acidic filtrate was evaporated to dryness and the solid residue was refluxed with oxalic acid dihydrate (1.4 g, 11 mmol) in 100 ml of 4M hydrochloric acid for 90 min. The mixture was cooled and the precipitated product was collected by filtration and washed with water, ethanol and ether to give 0.45 g (23%) of the title compound. M.p. 341.5° C. (N,N-dimethylformamide): IR (KBr): 1700, 1660 cm-1, 1H-NMR (DMSO-d6 : 3.43 (s, 3H, CH3), 6.97-7.40 (m, 3H, ArH), 12.0 (broad s, 1H, NH); MS m/z: 212 (M+ +2, 50%), 210 (M+, 100%).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].CO[CH:7]1[CH2:11][CH2:10][CH:9](OC)O1.[O:14]1CCO[CH2:16][CH2:15]1>C(O)(=O)C>[C:15]([NH:3][CH2:2][CH2:1][N:4]1[CH:9]=[CH:10][CH:11]=[CH:7]1)(=[O:14])[CH3:16]
Reactant: C1COCCO1
Reactant: COC1CCC(OC)O1
Reactant: NCCN
Solvent: CC(=O)O
Product: CC(=O)NCCn1cccc1

Procedure:
A solution of 140 g of ethylenediamine and 300 g of 2,5-dimethoxytetrahydrofuran in 2000 ml of dioxane and 1700 ml of glacial acetic acid is stirred and refluxed for 6 hours. The reaction mixture is then cooled and the solvents evaporated under reduced pressure at 60°. The dark residue is taken up in methylene chloride and ice and basified with 3 N aqueous sodium hydroxide. The organic layer is separated and extracted into 5 N aqueous hydrochloric acid. The acid extract is made basic with cooling and is extracted with methylene chloride. The organic phase is dried over magnesium sulfate, treated with 10 g of charcoal and filtered. The methylene chloride is evaporated under reduced pressure to give an N-acetyl-2-(1-pyrrolyl)-ethylamine as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:13])=[CH:4][C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Na+]>O1CCOCC1.O>[Cl:1][C:2]1[C:3]([CH3:13])=[CH:4][C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Cl)c(C)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(F)c(C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 84 %

Procedure:
To a stirred solution of methyl 5-chloro-2-fluoro-4-methylbenzoate (Preparation 240, 340 mg, 1.68 mmol) in dioxane/water (5:1, 12 mL) was added an aqueous sodium hydroxide solution (5 M, 1.63 mL, 8.39 mmol). The reaction mixture was stirred at room temperature for 18 hours and then evaporated in vacuo. The resulting residue was suspended in water and extracted with diethyl ether (3×20 mL). The aqueous layer was separated, cooled in an ice bath, acidified with aqueous hydrochloric acid (6 M) and then extracted with EtOAc (30 mL). The organic phase was washed with brine (2×20 mL), dried over sodium sulphate, filtered and evaporated in vacuo to yield the title compound as a white solid (266 mg, 84%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].C(O[O:18][C:19]([CH3:22])(C)C)(C)(C)C.[C]=O.[CH2:25]([OH:27])C>>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][C:25]([O:18][CH2:19][CH3:22])=[O:27])=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)OOC(C)(C)C
Reactant: CCO
Reactant: CCCCOc1ccc(C)cc1
Agent: [C]=O
Product: CCCCOc1ccc(CC(=O)OCC)cc1
Temperature: 120 °C
Reaction time: 16 h
Yield: 90.7 %

Procedure:
4-n-butoxytoluene (2.46 g), ethanol (46 mg), di-tert-butyl peroxide (73 mg, 1 equivalent), and Pd(Xantphos)Cl2 (3.8 mg, 1 mol %) were added into a reaction kettle, into which 10 atm carbon monoxide was introduced. The reaction was heated to 120° C., and stirred at this constant temperature for 16 h. After the reaction was completed, carbon monoxide was discharged, and 107 mg ethyl 2-(4-n-butoxyphenyl)acetate was obtained by column chromatography, in a yield of 91%. 1HNMR (400 MHz, CDCl3) δ 0.95 (t, J=7.6 Hz, 3H), 1.23 (t, J=7.2 Hz, 3H), 1.45-1.53 (m, 2H), 1.72-1.79 (m, 2H), 3.54 (s, 2H), 3.92 (t, J=6.4 Hz, 2H), 4.11 (q, J=7.2 Hz, 2H), 6.83-6.86 (m, 2H), 7.17-7.19 (m, 2H); 13CNMR (100 MHz, CDCl3) δ 13.9, 14.2, 19.3, 31.3, 40.6, 60.8, 67.7, 114.6, 126.0, 130.2, 158.3, 171.9; HRMS (ESI) calcd. for C14H20NaO3 [M+Na]: 259.1305. found: 259.1312. The ethyl 2-(4-n-butoxyphenyl)acetate obtained was dissolved in 1,4-dioxane. 6 N sodium hydroxide solution was added, and the reaction was heated to 60° C. After 2 h of reaction, the pH value was adjusted to 1 by adding 2 N hydrochloric acid. After removing the organic solvent under reduced pressure, 91 mg product 2-(4-n-butoxyphenyl)acetic acid was obtained by extraction with ethyl acetate, and the yield of hydrolysis was 96%.
Reaction SMILES: Cl[C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[C:4]([CH:13]=[CH:14][CH:15]=1)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].S(=O)(=O)(O)O.[N+:24]([O-:27])([O-])=[O:25].[Na+].C(Cl)[Cl:30]>>[Cl:30][C:15]1[CH:14]=[CH:13][C:4]([C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:6])=[C:3]([N+:16]([O-:18])=[O:17])[C:2]=1[N+:24]([O-:27])=[O:25]
Reactant: O=[N+]([O-])[O-]
Reactant: O=C(c1ccccc1)c1cccc(Cl)c1[N+](=O)[O-]
Reactant: ClCCl
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(c1ccccc1)c1ccc(Cl)c([N+](=O)[O-])c1[N+](=O)[O-]
Temperature: 0 °C
Yield: 95.5 %

Procedure:
This crude chloronitrobenzophenone was dissolved in 500 ml of methylene chloride and 250 g (2.5 mol) of concentrated sulfuric acid and 93.5 g (1.1 mol) of sodium nitrate were added thereto. The mixture was reacted at a temperature of 35° to 40° C. for 7 hours. After the completion of the reaction, 500 ml of ice water was carefully added thereto. Methylene chloride was removed by heating. The precipitated light brown particulate material was recovered by filtration, washed with water, and dried to give 293 g (over-all yield 95.5%) of crude chlorodinitrobenzophenone.
Reaction SMILES: [CH2:1]([NH2:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[C:14](Cl)=[O:15]>C(OCC)(=O)C.O>[CH2:1]([NH:7][C:14](=[O:15])[C:13]1[CH:12]=[C:11]([Cl:10])[CH:19]=[C:18]([Cl:20])[CH:17]=1)[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccco1
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NCc1ccco1)c1cc(Cl)cc(Cl)c1
Yield: 85.4 %

Procedure:
To a vigorously stirred solution of furfurylamine (2.78 g) in ethyl acetate (40 ml) was added sodium hydroxide (1.15 g) in water (45 ml), followed immediately by the addition of a solution of 3,5-dichlorobenzoyl chloride (6.0 g) in ethyl acetate (20 ml). Following the mild exothermic reaction the ethyl acetate layer was removed, dried (MgSO4), and evaporated. Crystallisation of the residue from cyclohexane gave the product (6.6 g) as colourless needles.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].C(O)(=O)CC.N(OS(=O)(=O)O)=O.[CH:24]([O:26][C:27](=[O:40])[CH:28]([CH3:39])[CH2:29][N:30]([CH2:37][CH3:38])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[CH2:25].S(=O)(=O)(O)[NH2:42]>CO.C(O)(=O)C>[CH:24]([O:26][C:27](=[O:40])[CH:28]([CH3:39])[CH2:29][N:30]([C:31]1[CH:36]=[CH:35][C:34]([N:42]=[N:4][C:3]2[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:2]=2[Cl:1])=[CH:33][CH:32]=1)[CH2:37][CH3:38])=[CH2:25]
Reactant: NS(=O)(=O)O
Reactant: C=COC(=O)C(C)CN(CC)c1ccccc1
Reactant: Nc1ccc([N+](=O)[O-])cc1Cl
Agent: O=NOS(=O)(=O)O
Solvent: CCC(=O)O
Solvent: CO
Solvent: CC(=O)O
Product: C=COC(=O)C(C)CN(CC)c1ccc(N=Nc2ccc([N+](=O)[O-])cc2Cl)cc1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
5.2 parts of 2-chloro-4-nitroaniline, 20 parts of propionic acid and 30 parts of acetic acid were charged and cooled to 5° C. 11.4 parts of 40% (w/w) nitrosyl sulfuric acid were added, whilst the temperature was held below 10° C. The diazotization mixture was stirred for a further 2 hrs at 5-10° C. To a separate vessel were charged 7.0 parts of 3-(ethyl-phenyl-amino)-2-methylpropionic acid vinyl ester, 100 parts of methanol, 1 part sulfamic acid and 100 parts of ice. With stirring, the diazotization mixture was slowly added followed by a further 300 parts of ice. The reaction mixture was stirred over night and the product was isolated by filtration, washed with water and dried to yield 9.4 parts of 3-{[4-(2-chloro-4-nitrophenylazo)-phenyl]-ethyl-amino}-2-methyl-propionic acid vinyl ester. λmax=511 nm (DMF).
Reaction SMILES: Cl.[CH2:2]([O:4][CH:5]([O:11][CH2:12][CH3:13])[C@@H:6]1[CH2:10][CH2:9][CH2:8][NH:7]1)[CH3:3].[CH2:14]([O:21][C:22]([N:24]1[CH2:31][CH2:30][CH2:29][C@@H:25]1[C:26](O)=[O:27])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:12]([O:11][CH:5]([O:4][CH2:2][CH3:3])[C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:26](=[O:27])[C@H:25]1[CH2:29][CH2:30][CH2:31][N:24]1[C:22]([O:21][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:23])[CH3:13]
Reactant: CCOC(OCC)[C@@H]1CCCN1
Reactant: O=C(O)[C@H]1CCCN1C(=O)OCc1ccccc1
Agent: Cl
Product: CCOC(OCC)[C@@H]1CCCN1C(=O)[C@H]1CCCN1C(=O)OCc1ccccc1
Yield: 72.3 %

Procedure:
L-prolinal diethyl acetal hydrochloride (726 mg) and benzyloxycarbonyl-D-proline (801 mg, 3.22 mmol) are used to prepare 942 mg (73%) of the title compound as a pale yellow syrup in a manner similar to that as mentioned in Example 8.