Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-][O-].[Mg+2].[CH2:4]([C:6](=[CH2:14])[CH:7]([OH:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:5]>C(Cl)Cl>[CH2:4]([C:6](=[CH2:14])[C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:5]
Reactant: C=C(CC)C(O)C(=O)OCC
Agent: [Mg+2]
Agent: [O-][O-]
Solvent: ClCCl
Product: C=C(CC)C(=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
16 g of magnesium dioxide were added to a solution of 3.2 g of ethyl 3-ethyl-2-hydroxy-3-butenoate in 65 ml of methylene chloride and the mixture was stirred at room temperature for 11/2 hours. and was filtered. The solvent was distilled from the filtrate under reduced pressure to obtain ethyl 3-ethyl-2-oxo-3-butenoate in the form of a colorless liquid soluble in ether and alcohols and slighly soluble in water.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([CH3:15])[CH2:5][C:6]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1Cl)=[O:7].C(N(C(C)C)CC)(C)C>O>[O:7]=[C:6]1[C:8]2[C:13](=[CH:12][CH:11]=[N:10][CH:9]=2)[NH:3][CH:4]([CH3:15])[CH2:5]1
Reactant: CC(N)CC(=O)c1cnccc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC1CC(=O)c2cnccc2N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[Step 3] 64 mg of the crude product of 3-amino-1-(4-chloropyridin-3-yl)butan-1-one dihydrochloride were dissolved in 2 mL of N-dimethylformamide followed by adding 0.18 mL of diisopropylethylamine while cooling with ice and stirring for 1 hour at room temperature. This was followed by additionally stirring overnight at 100° C. Following completion of the reaction, water was added followed by extracting three times with chloroform. After washing with saturated brine and dehydrating with anhydrous sodium sulfate, the solution was concentrated under reduced pressure and the resulting residue was purified using silica gel chromatography (methanol:chloroform=1:10) to obtain 9 mg of 4-oxo-2-methyl-2,3-dihydro-1H-[1,6]naphthyridine in the form of a pale yellow oil (27%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([S:15][CH2:22][C:21]4[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=4)=[N:12][N:11]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: COc1ccc(CCl)cc1
Reactant: Sc1nnc(-c2ccc3c(c2)CCO3)o1
Product: COc1ccc(CSc2nnc(-c3ccc4c(c3)CCO4)o2)cc1
Yield: 56 %

Procedure:
In the same manner as in Example 1 and using 5-(2,3-dihydro-1-benzofuran-5-yl)-1,3,4-oxadiazole-2-thiol instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and 4-methoxybenzyl chloride instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 56%) was obtained as colorless crystals.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[ClH:16].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(=O)([O-])[O-].[K+].[K+].Cl>C(O)C.O.CN(C=O)C>[ClH:16].[ClH:16].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][CH2:4][NH:5][C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:27][CH2:26]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=C(NCCCBr)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1N1CCN(CCCNC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 132.1 %

Procedure:
A mixture of benzyl (3-bromopropyl)aminoformate (495.2 g, 1.82 mol), prepared as in Example 6, 1-(2-methoxyphenyl)piperazine hydrochloride (377.9 g, 1.65 mol) and potassium carbonate (456.8 g, 3.31 mol) in 3L of DMF was stirred at 80° to 81° C. for 3.5 hours. The mixture was allowed to cool to room temperature and then poured into 20L of water. The mixture was extracted with ethyl acetate (3×4L). The combined ethyl acetate extracts were washed with water (2×1L) and saturated aqueous sodium chloride (1×1L), dried (Na2SO4) and treated with silica gel (200 g). The ethyl acetate was filtered and 11L of the filtrate was added slowly to 200 mL of 5.5N hydrochloric acid (2.75 mol) in ethanol at a rate such that the reaction temperature did not exceed 23° C. The mixture was aged at room temperature for 1 hour and filtered. The filtered residue was washed with ethyl acetate (3×500 mL), dried under a stream of air for 17 hours and then dried under reduced pressure at 60° C. to give benzyl 3-[4-(2-methoxyphenyl)piperazin-1-yl]propylaminoformate dihydrochloride (496 g, 1.09 mol), m.p. 174°-176° C.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:38])([CH3:37])[CH:14]([O:29]CC1C=CC=CC=1)[C:15]([O:17][CH2:18][CH2:19][O:20][C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:16])(=[O:10])=[O:9])(=[O:3])[CH3:2]>[Pd].C(O)C>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:38])([CH3:37])[CH:14]([OH:29])[C:15]([O:17][CH2:18][CH2:19][O:20][C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:16])(=[O:10])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCCS(=O)(=O)OCC(C)(C)C(OCc1ccccc1)C(=O)OCCOC(=O)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)NCCCS(=O)(=O)OCC(C)(C)C(O)C(=O)OCCOC(=O)c1ccccc1
Reaction time: 8 h
Yield: 47 %

Procedure:
Following the general procedure for the hydrogenolysis of benzyl ethers of Description 18, a mixture of benzoyloxyethyl (2R/S)-4-{[3-(acetylamino)propyl]sulfonyloxy}-3,3-dimethyl-2-(phenylmethoxy)butanoate (39c) (1.7 g, 3.1 mmol) and 1.0 g of 10 wt.-% of palladium on activated carbon in 20 mL of ethanol (EtOH) was stirred overnight under a hydrogen atmosphere. After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and methanol (MeOH) (EtOAc/MeOH=9:1) as eluent to provide 0.67 g (47% yield) of the title compound (39) as a colorless oil. The analytical data was consistent with the data obtained for benzoyloxyethyl (2R)-4-{[(3-acetylamino)propyl]sulfonyloxy}-3,3-dimethyl-2-(phenylmethoxy)butanoate (38).
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][NH:9][C@@H:10]([C:13]1[C:14]([F:28])=[C:15]([C:20]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[O:21])[C:16]([Cl:19])=[CH:17][CH:18]=1)[CH2:11][CH3:12])(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C@H:10]([NH:9][CH2:8][CH2:7][OH:6])[CH2:11][CH3:12])=[C:14]([F:28])[C:15]=1[C:20]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)=[O:21]
Reactant: CC[C@@H](NCCO[Si](C)(C)C(C)(C)C)c1ccc(Cl)c(C(=O)c2cccnc2)c1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC[C@@H](NCCO)c1ccc(Cl)c(C(=O)c2cccnc2)c1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
To (3-{(R)-1-[2-(tert-Butyl-dimethyl-silanyloxy)-ethylamino]-propyl}-6-chloro-2-fluoro-phenyl)-pyridin-3-yl-methanone (0.176 g, 0.39 mmol) in THF (3 ml) at 0° C. added TBAF [1M] (90.43 ml, 0.43 mmol) dropwise stirred at 0° C. for 1 hour, diluted with water, THF evaporated off and reaction mixture extracted with DCM. The organic phase was separated and dried (Na2SO4), filtered and concentrated, purified by Prep HPLC to give 2-{[(1R)-1-{4-chloro-2-fluoro-3-[(pyridin-3-yl)carbonyl]phenyl}propyl]amino}ethan-1-ol (0.129 g).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)=[C:3]1[C:20]([NH2:22])=[O:21]>[Pd].CO>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)=[C:3]1[C:20]([NH2:22])=[O:21]
Reactant: Cn1c(C(N)=O)c(-c2ccc([N+](=O)[O-])cc2)c2ccccc21
Agent: [Pd]
Solvent: CO
Product: Cn1c(C(N)=O)c(-c2ccc(N)cc2)c2ccccc21
Reaction time: 0.5 h
Yield: 506.4 %

Procedure:
0.2 g of 1-methyl-3-(4-nitrophenyl)-1H-indole-2-carboxamide and 0.14 g of 10% palladium-on-charcoal are added to 8 ml of methanol and the reaction mixture is hydrogenated under 5 bar for 4 hours and 30 minutes at 25° C. The reaction mixture is then filtered over a thin layer of silica gel and the filtrate is concentrated under reduced pressure, to give 0.91 g of 1-methyl-3-(4-aminophenyl)-1H-indole-2-carboxamide, the characteristics of which are as follows:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14](O)=[O:15])[C@H:10]([CH2:12][CH3:13])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>CCOCC>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH:14]=[O:15])[C@H:10]([CH2:12][CH3:13])[CH3:11])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: CC[C@H](C)[C@@H](C=O)NC(=O)OC(C)(C)C
Temperature: -45 °C
Yield: 95 %

Procedure:
The Weinreb amide of N-t-butoxycarbonylisoleucine, prepared above, (1.98 g, 7.2 mmol) was dissolved in anhydrous ether (10 ml) and cooled to -45° C. Lithium aluminium hydride (10 ml of a 1N solution in ether, 10 mmol) was then added keeping the temperature below -35° C., after addition the solution was then allowed to warm to 5° C. The solution was then cooled to -45° C. and sodium sulfate decahydrate (5.00 g) added and the cooling bath removed. After 1 hour the solution was filtered through celite and the solvent removed under reduced pressure to yield the aldehyde (1.47 g, 95%) as a colourless oil, which was immediately used in the next reaction as it racemises at room temperature.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:8][CH2:7][N:6]1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])=O.[NH3:19]>CO>[CH2:12]([O:11][C:9]([N:6]1[CH2:7][CH2:8][C@H:5]1[C:3](=[O:2])[NH2:19])=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)[C@@H]1CCN1C(=O)OCc1ccccc1
Reactant: N
Solvent: CO
Product: NC(=O)[C@@H]1CCN1C(=O)OCc1ccccc1
Reaction time: 18 h

Procedure:
A mixture of (S)-azetidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester (2.5 g) and 7M ammonia in methanol (10 ml) is stood at room temperature for 18 hours in a sealed vessel. The reaction mixture is then evaporated to give the title compound as a white solid which is used without further purification. MS M+H 235.1 and M−H 233.1.
Reaction SMILES: [CH:1]([S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([CH:20]=[CH2:21])[C:16]([NH2:19])=[N:17][CH:18]=2)=[CH:9][CH:8]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].[OH:22]/[N:23]=[C:24](\Cl)/[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C=O.C(OCC)(=O)C.O>[CH:1]([S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([CH:20]3[O:22][N:23]=[C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:21]3)[C:16]([NH2:19])=[N:17][CH:18]=2)=[CH:9][CH:8]=1)(=[O:5])=[O:6])([CH3:3])[CH3:2]
Reactant: C=Cc1nc(-c2ccc(S(=O)(=O)C(C)C)cc2)cnc1N
Reactant: O/N=C(\Cl)c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(C3CC(c4ccccc4)=NO3)n2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 29 %

Procedure:
To solution of 5-(4-isopropylsulfonylphenyl)-3-vinyl-pyrazin-2-amine (20 mg, 0.06592 mmol) in N,N-dimethylformamide (2 mL) was added (Z)—N-hydroxybenzimidoyl chloride (13.33 mg, 0.08570 mmol) followed by TEA (20.02 mg, 27.58 μL, 0.1978 mmol) added drop wise. The reaction mixture was stirred at ambient temperature for 20 mins followed by heating to 65° C. for 1 hour. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (5 mL) and water (5 mL) and the layers separated. The aqueous layer was extracted further with ethyl acetate (2×5 mL) and the combined organic extracts washed with water (3×10 mL), dried over MgSO4 and concentrated in vacuo to a solid. Purification by fractionlynx yielded 5-(4-(isopropylsulfonyl)phenyl)-3-(3-phenyl-4,5-dihydroisoxazol-5-yl)pyrazin-2-amine Compound I-1. (10.4 mg, 29% Yield). DMSO 1.15 (6H,d), 3.4-3.48 (1H,m) 3.7-3.8 (1H,m), 4.28 (1H,dd), 6.02 (1H,dd), 6.95 (2H,brs), 7.48-7.53 (3H,m), 7.78-7.85 (4H,m), 8.2 (2H,d), 8.75 (1H,s); LC/MS m/z 423.4 [M+H]+.
Reaction SMILES: [N:1]1([C:10]2[N:18]=[C:17](Cl)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH2:20]([NH2:27])[C:21]1C=CC=[CH:23][CH:22]=1>CS(C)=O>[N:1]1([C:10]2[N:18]=[C:17]([NH:27][CH2:20][CH2:21][CH2:22][CH3:23])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Clc1nc(-n2cnc3ccccc32)c2nc[nH]c2n1
Reactant: NCc1ccccc1
Solvent: CS(C)=O
Product: CCCCNc1nc(-n2cnc3ccccc32)c2nc[nH]c2n1
Temperature: 120 °C

Procedure:
200 mg of product obtained in stage 1 above are mixed with 3 ml of DMSO and 0.6 ml (5 equivalents) of benzylamine, and the mixture is then heated at 120° C. for approximately 60 hours. The mixture is allowed to return to ambient temperature. Purification is carried out by chromatography on silica with a CH2Cl2-MeOH—NH4OH: 90-9-1 mixture for eluent. Evaporation is carried out and a paste is formed in methylene chloride. Partial drying and drying under vacuum at 50° C. are carried out. 105 mg of expected product are obtained.
Reaction SMILES: [C:1]([C:4]1[N:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([NH:14][CH2:15][C:16]2[N:17]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][O:29][C:30]4[CH:31]=[CH:32][CH:33]=[C:34]5[C:39]=4[N:38]=[C:37]([CH3:40])[CH:36]=[CH:35]5)[C:22]=3[Cl:41])[CH:18]=[CH:19][CH:20]=2)=[O:13])=[CH:6][CH:5]=1)(O)=[O:2].Cl.CN.[CH2:45]([N:47]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O>[Cl:41][C:22]1[C:23]([CH2:28][O:29][C:30]2[CH:31]=[CH:32][CH:33]=[C:34]3[C:39]=2[N:38]=[C:37]([CH3:40])[CH:36]=[CH:35]3)=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[N:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[CH2:15][NH:14][C:12](=[O:13])/[CH:11]=[CH:10]/[C:7]1[CH:8]=[N:9][C:4]([C:1](=[O:2])[NH:47][CH3:45])=[CH:5][CH:6]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(-n4cccc4CNC(=O)/C=C/c4ccc(C(=O)O)nc4)c3Cl)c2n1
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1ccc(/C=C/C(=O)NCc2cccn2-c2ccc(Cl)c(COc3cccc4ccc(C)nc34)c2Cl)cn1
Reaction time: 24 h
Yield: 94.6 %

Procedure:
To a solution of 2-[(E)-3-(6-carboxypyridin-3-yl)acryloylaminomethyl]-1-[2,4-dichloro-3-(2-methylquinolin-8-yloxymethyl)phenyl]pyrrole (60 mg) and methylamine hydrochloride (7.59 mg) in N,N-dimethylformamide (2 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (19 mg) and 1-hydroxybenzotriazole (20.7 mg) at ambient temperature, and the mixture was allowed to stand for 1 day at the same temperature. The reaction mixture was poured into water and extracted with chloroform. The extract was washed with water and saturated sodium bicarbonate solution, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (chloroform:methanol=10:1, V/V) to give 1-[2,4-dichloro-3-(2-methylquinolin-8-yloxymethyl)phenyl]-2-[(E)-3-[6-(methylcarbamoyl)pyridin-3-yl]acryloylaminomethyl]pyrrole (58 mg) as amorphous powder.
Reaction SMILES: Br[C:2]1[C:6]2=[N:7][CH:8]=[CH:9][C:10]([Cl:11])=[C:5]2[S:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1B(O)O.O1CCOCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Cl:11][C:10]1[CH:9]=[CH:8][N:7]=[C:6]2[C:2]([C:14]3[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=3[Cl:12])=[CH:3][S:4][C:5]=12
Reactant: Clc1ccnc2c(Br)csc12
Reactant: OB(O)c1ccc(F)cc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: Fc1ccc(-c2csc3c(Cl)ccnc23)c(Cl)c1
Temperature: 90 °C
Yield: 80.2 %

Procedure:
A vessel capable of sealing was charged with a mixture of 3-bromo-7-chlorothieno[3,2-b]pyridine (260 mg, 1.046 mmol), 2-chloro-4-fluorophenylboronic acid (274 mg, 1.569 mmol), PdCl2(dppf)-CH2Cl2 adduct (42.7 mg, 0.0.052 mmol), dioxane (8 mL), and a 2.0 M aqueous solution of K3PO4 (1.6 mL, 3.14 mmol) and was purged with nitrogen for 10 min. The vessel was sealed and heated at 90° C. for 3 h. Upon cooling, the reaction mixture was diluted with water and extracted with CH2Cl2. The combined organics were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude material was purified by BIOTAGE® eluting with 60%-100% CH2Cl2/hexanes at 30 mL/min. Concentration of appropriate fractions provided the title compound (250 mg, 80% yield) as a white solid. LC/MS: Example 103A @ 3.58 min (RT) (Condition G). MS (ES): m/z=297.89, [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][CH:11]([CH2:19][N:20]2C(=O)C3=CC=CC=C3C2=O)[CH2:10][C:9]1=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>C(O)C>[NH2:20][CH2:19][CH:11]1[CH2:10][C:9](=[O:31])[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12]1
Reactant: O=C1c2ccccc2C(=O)N1CC1CC(=O)N(Cc2ccccc2)c2ccccc2N1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCC1CC(=O)N(Cc2ccccc2)c2ccccc2N1
Yield: 151.1 %

Procedure:
A suspension of 1-benzyl-4-(phthalimidomethyl)-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (9.82 g, 20 mmol) and hydrazine monohydrate (16 g, 35 mmol) in ethanol (350 ml) was refluxed for 3 hours. The reaction mixture was cooled and subjected to filtration and washed with chloroform. The filtrate was concentrated under reduced pressure. The concentrate was suspended in chloroform, which was again subjected to filtration. The filtrate was concentrated under reduced pressure to afford 8.5 g (yield 86%) of the titled compound as an oily product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:13])[C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[N+:14]([O-])([OH:16])=[O:15]>S(=O)(=O)(O)O>[N+:14]([C:8]1[CH:7]=[C:6]([CH:9]([CH3:13])[C:10]([OH:12])=[O:11])[CH:5]=[CH:4][C:3]=1[O:2][CH3:1])([O-:16])=[O:15]
Reactant: COc1ccc(C(C)C(=O)O)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COc1ccc(C(C)C(=O)O)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 6 h

Procedure:
5.23g of 2-(4-methoxyphenyl)propionic acid was added gradually under cooling in a mixture of 27.5g of nitric acid and 19.9g of sulfuric acid. After the mixture was stirred at -10° C to -5° C for 6 hours, the mixture was poured into ice-water. The thus obtained oily substance was extracted with ethyl acetate. The extract was dried over magnesium sulfate and distilled off. The residue was purified by means of silica gel chromatography to give the object compound having m.p. 89° - 90° C in a yield of 5.0g (76%).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:9]([CH:11]=1)[NH2:10].[CH:20](O)=[O:21].C(OC(=O)C)(=O)C.O>C(Cl)(Cl)Cl>[CH2:13]([O:12][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][NH2:2])=[CH:11][C:9]=1[NH:10][CH:20]=[O:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCCc1ccc(OCc2ccccc2)c(N)c1
Reactant: O=CO
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: NCCc1ccc(OCc2ccccc2)c(NC=O)c1
Reaction time: 0.08 h

Procedure:
2.7 g of 5-(2-aminoethyl)-2-benzyloxyaniline, hydrochloride, in 160 ml of chloroform is combined with 4 ml of a mixture of formic acid and acetic anhydride (3:5). After 5 minutes of agitation at room temperature, a small amount of water is added and the mixture completely evaporated. The residue is chromatographed on silica gel with methylene chloride/methanol 8:2. The thus-purified material is washed in methylene chloride with sodium bicarbonate solution. After evaporation, 1.5 g of 2-(4-benzyloxy-3-formylaminophenyl)ethylamine is obtained as a noncrystalline material.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:10][CH2:11]I)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:21][S-:22].[Na+].O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:10][CH2:11][S:22][CH3:21])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C[S-]
Reactant: CC(C)(C)OC(=O)N[C@H](CCI)c1ccc(Cl)c(Cl)c1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CSCC[C@@H](NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Yield: 60 %

Procedure:
A solution of 366 (810 mg, 1.88 mmol) and sodium methanethiolate (158 mg, 2.26 mmol) in DMSO (4 mL) was stirred at 50° C. overnight. The mixture was poured into water, extracted with EtOAc, washed with brine, dried (MgSO4), and concentrated in vacuo to afford 395 mg (60%) of (R)-tert-butyl 1-(3,4-dichlorophenyl)-3-(methylthio)propylcarbamate (372).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][CH2:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][C:9]=2[C:18]([O:20][CH3:21])=[O:19])=[CH:4][CH:3]=1.O1CCOCC1.CO.[OH-].[Na+]>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=2[C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=1
Reactant: COC(=O)c1ccc(CCc2ccc(F)cc2)c(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)c1cc(C(=O)O)ccc1CCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.2 %

Procedure:
A mixture of methyl 4-(4-fluorophenethyl)-3-methoxycarbonylbenzoate (51.00 g., 161.22 mmol), dioxane (650 ml), methanol (650 ml), sodium hydroxide (7.10 g., 177.35 mmol) and water (100 ml) was stirred at ambient temperature under an inert atmosphere for 16 hours. The reaction was evaporated to dryness, water (500 ml) was added to the residue and the mixture extracted with diethyl ether. The organic extracts were dried and evaporated to dryness to give recovered methyl 4-(4-fluorophenethyl)-3-methoxycarbonylbenzoate (7 g). The aqueous layer was acidified to pH 2 with 2M HCl (300 ml) and extracted with ethyl acetate (300 ml). The organic extracts were dried, filtered and evaporated to dryness to give as a white solid 4-(4-fluorophenethyl)-3-methoxycarbonylbenzoic acid (42.00 g).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]=[CH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[OH:24])=[CH:12][CH:11]=1>CS(C)=O>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][CH:17]2[CH2:4][O:24][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]2=3)=[CH:14][CH:15]=1
Reactant: C[S+](C)(C)=O
Reactant: Oc1ccccc1C=Nc1ccc(Br)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Brc1ccc(NC2COc3ccccc32)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 75.9 %

Procedure:
A 60% dispersion of sodium hydride in mineral oil (0.145 g, 0.00362 mol) was added to a solution of trimethylsulfoxonium iodide (0.8 g, 0.00362 mol) in anhydrous dimethylsulfoxide (10 mL) and the resulting mixture was stirred under an atmosphere of nitrogen for 10 min. A solution of 2-{[(4-bromophenyl)imino]methyl}phenol (0.4 g, 0.00145 mol) in anhydrous dimethylsulfoxide (5 mL) was added dropwise and the resulting mixture was stirred at ambient temperature for 2.5 hours. It was poured into ice-cold water (100 mL) and extracted with diethyl ether (2×50 mL). The combined organic extracts were dried with magnesium sulfate and concentrated under reduced pressure to yield N-(4-bromophenyl)-N-(2,3-dihydrobenzo[b]furan-3-yl)amine (0.321 g, 0.0011 mol) as an off-white solid.