Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:13]3[CH2:14][C@H:15]([NH:18][C:19](=[O:32])[C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[CH:22][CH:21]=4)[CH2:16][O:17][C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].S(O[CH2:44][CH2:45][O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)(=O)(=O)C>CN(C)C=O>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[C:13]3[CH2:14][C@H:15]([NH:18][C:19](=[O:32])[C:20]4[CH:21]=[CH:22][C:23]([N:26]5[CH2:27][CH2:28][N:29]([CH2:44][CH2:45][O:46][CH2:47][C:48]6[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=6)[CH2:30][CH2:31]5)=[CH:24][CH:25]=4)[CH2:16][O:17][C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CS(=O)(=O)OCCOCc1ccccc1
Reactant: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(N4CCNCC4)cc2)CO3)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(N4CCN(CCOCc5ccccc5)CC4)cc2)CO3)CC1
Temperature: 40 °C
Reaction time: 24 h
Yield: 22.5 %

Procedure:
(S)-N-[5-(4-Methylpiperazin-1-yl)-3,4 dihydro-2H-1-benzopyran-3-yl]-4-(piperazin-1-yl)benzamide (500 mg, 1.2 mmol) was dissolved in N,N-dimethylformamide (5 mL) and potassium carbonate (170 mg, 1.3 mmol) was added. To the mixture was added a solution of 2-benzyloxyethyl mesylate (290 mg, 1.3 mmol) (described in: Beard, C; Edwards, J; Fried, J. U.S. Pat. No. 3,929,824, 1972) in N,N-dimethylformamide (5 mL). The reaction mixture was stirred at 40° C. for 24 h. The solvent was evaporated in vacuo giving 950 mg of a crude product. Purification by column chromatography on silica gel using chloroform/methanol/concentrated ammonia 95:5:0.5 as the eluent afforded 154 mg (24% yield) of the title compound as an oil: EIMS (70 eV) m/z (relative intensity) 569 (3, M+).
Reaction SMILES: Cl[C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.[OH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]([N+:12]([O-:14])=[O:13])=[C:2]([C:20]2[CH:21]=[CH:22][C:17]([CH2:16][OH:15])=[CH:18][CH:19]=2)[CH:7]=1
Reactant: Cc1cc(Cl)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: OCc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccc(CO)cc2)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 170 °C
Yield: 45.1 %

Procedure:
A mixture of 5-chloro-2,4-dinitrotoluene (1.0 g), 4-(hydroxymethyl)phenylboronic acid (0.84 g), bis(triphenylphosphine)palladium(II) chloride (150 mg) and potassium carbonate (2.0 g) in a mixture of 1,4-dioxane and water (10/1, 11 mL) was heated at 170° C. in a microwave reactor for 10 minutes. The reaction mixture was then cooled and diluted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (acetone/DCM, 3/97) to give 0.6 g of (5′-methyl-2′,4′-dinitro-biphenyl-4-yl)-methanol.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CS(O[C@H:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:12]([C:23]([O:25][CH3:26])=[O:24])[CH2:11]1)(=O)=O.O>CN(C=O)C>[N:1]([C@@H:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[C@@H:12]([C:23]([O:25][CH3:26])=[O:24])[CH2:11]1)=[N+:2]=[N-:3]
Reactant: COC(=O)[C@H]1C[C@@H](OS(C)(=O)=O)CCN1C(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@H]1C[C@H](N=[N+]=[N-])CCN1C(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 97.7 %

Procedure:
NaN3 (15.8 g, 243 mmol) was added to a solution of (2R,4S)-1-tert-butyl 2-methyl 4-(methylsulfonyloxy)piperidine-1,2-dicarboxylate (26.7 g, 81 mmol) in dry DMF (100 mL). The mixture was heated at 60° C. for 18 hours. Water (300 mL) was added to the reaction mixture and extracted with ethyl acetate/heptane (2:1) (2×200 mL). The combined organic layer was washed by brine and dried over MgSO4, filtered and concentrated under reduced pressure to give a colorless oil 22.5 g (98%). LC-MS: 285.0 (t=2.5 min).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([C:23]([CH3:25])=[CH2:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([CH2:37][N:38]3[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]3)[CH:34]=2)[CH2:29]1)=[O:27])C1C=CC=CC=1.N#N.C([O-])([O-])=O.[K+].[K+]>C(O)(C)C.O>[OH:8][C:9]1[CH:14]=[C:13]([OH:15])[C:12]([CH:23]([CH3:24])[CH3:25])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([CH2:37][N:38]3[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]3)[CH:34]=2)[CH2:29]1)=[O:27]
Reactant: C=C(C)c1cc(C(=O)N2Cc3ccc(CN4CCN(C)CC4)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: CC(C)c1cc(C(=O)N2Cc3ccc(CN4CCN(C)CC4)cc3C2)c(O)cc1O
Reaction time: 1.08 h
Yield: 93.8 %

Procedure:
The product from Step 11 (0.9 Kg, 1.53 mol) was dissolved in isopropanol (6.8 L) and water (1.04 L) and after purging with N2 10% Pd/C (90 g) and K2CO3 (0.212 Kg, 1.53 mol) were added and the suspension was hydrogenated for 60 to 70 mins under an 3 Barr pressure of H2. The solution was diluted with water (0.5 L) and filtered. To the filtrate was added aqueous HCl (30% hydrochloric acid, 0.85 Kg diluted with water 5.42 Kg) and the solution was concentrated at 60° C. under vacuum (removing 10 L isopropanol). Water (0.45 L) was added to the solution and concentration continued (until a further 10 L isopropanol had been removed). The aqueous phase was washed with EtOAc (4.61 L), diluted with acetonitrile (4.06 L) and netralised to pH 7.5-8.5 by addition of conc ammonia solution (0.35 Kg). The suspension was stirred for 2.5 h and then the solid was removed by filtration. The residue was washed with acetonitrile (2×0.8 L) and dried at 40° C. to constant weight to give the title compound 588 g (94% yield).
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH2:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl.O>CC1C=CC(C)=CC=1>[CH2:12]([C:7]1[CH:8]=[C:2]([C:1]([O:10][CH3:11])=[O:9])[C:3]([NH2:4])=[CH:5][CH:6]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccccc1N
Reactant: OCc1ccccc1
Agent: Cl
Solvent: Cc1ccc(C)cc1
Solvent: O
Product: COC(=O)c1cc(Cc2ccccc2)ccc1N
Reaction time: 3 h
Yield: 4.4 %

Procedure:
Methyl anthranilate (30.9 g; 205 mmols) and benzyl alcohol (4.43 g; 40,9 mmols) were dissolved in 50 mL of p-xylene. Montmorillonite (1.3 g), activated with hydrochloric acid, was added to the reaction mixture, which was then heated to boiling. The water produced during the reaction was collected using a Dean-Starck-apparatus. After three hours the solvent and the excess of methyl anthranilate were distilled off at reduced pressure. Chromatography using silica gel 60 and heptane/ethyl acetate (19/1->9/1) as eluent afforded 430 mg (4.4%) of the desired methyl 5-benzylanthranilate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:15]([CH:16]3[CH2:18][O:17]3)[O:14][CH2:13][CH2:12][N:11]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:26][S-:27].[Na+].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:15]([CH:16]([OH:17])[CH2:18][S:27][CH3:26])[O:14][CH2:13][CH2:12][N:11]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCOC(C2CO2)C(c2ccc(Cl)c(Cl)c2)C1
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSCC(O)C1OCCN(C(=O)OC(C)(C)C)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 27.5 %

Procedure:
To a solution of a mixture (420 mg) of tert-butyl (6RS,7RS)-6-(3,4-dichlorophenyl)-7-[(2RS)-oxiran-2-yl]-1,4-oxazepane-4-carboxylate and tert-butyl (6SR,7SR)-6-(3,4-dichlorophenyl)-7-[(2RS)-oxiran-2-yl]-1,4-oxazepane-4-carboxylate in DMF (2 mL) was added sodium thiomethoxide (114 mg), and the mixture was stirred at room temperature for 10 min. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous potassium carbonate and brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate (0%-50%)) to give the title compound (130 mg) in a less polar fraction as colorless crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].[I:13]N1C(=O)CCC1=O.O.C(OCC)C>CN(C)C=O>[I:13][C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:9][N:8]=1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Reactant: O=C1CCC(=O)N1I
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=[N+]([O-])c1ccc2[nH]nc(I)c2c1
Temperature: 80 °C
Reaction time: 7 h
Yield: 91.3 %

Procedure:
To a solution of 17.0 g of 5-nitroindazole in 100 ml dimethylformamide was added 24.6 g of N-iodosuccinimide at room temperature, and the mixture was stirred at 80° C. for 7 hours. After standing to cool, to the reaction mixture were added 150 ml of water and 200 ml of diethyl ether, and the resulting crystals were collected by filtration. The crystals were sequentially washed with water, isopropanol and diethyl ether, to give 27.5 g of the title compound as colorless crystals.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]=[C:5]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[S:6][C:7]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:20][C:19](=[O:21])[O:18][N:17]=2)=[C:12]([F:22])[CH:11]=1.N1C=CC=CC=1.[C:39](OC(=O)C)(=[O:41])[CH3:40].O>ClCCl>[F:22][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[C:16]1[NH:20][C:19](=[O:21])[O:18][N:17]=1)[O:9][CH2:8][C:7]1[S:6][C:5]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:30])[F:32])=[CH:25][CH:24]=2)=[N:4][C:3]=1[CH2:2][NH:1][C:39](=[O:41])[CH3:40]
Reactant: CC(=O)OC(C)=O
Reactant: NCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(-c2noc(=O)[nH]2)c(F)c1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)NCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(-c2noc(=O)[nH]2)c(F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 10.7 %

Procedure:
To a suspension of 53.3 mg of 3-{4-[4-aminomethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-fluoro-phenyl}-4H-1,2,4-oxadiazol-5-one in 1 mL of dichloromethane was added 27 mg of pyridine and 19 mg of acetic anhydride. The resulting mixture was stirred for 1.5 h at room temperature and then a drop of pyridine and acetic anhydride were added. After stirring for 25 minutes at room temperature, it was poured into water and extracted with dichloromethane. The organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (gradient from dichloromethane 100 to dichloromethane 90/methanol 10/water 1/acetic acid 1) to give 6.2 mg of N-[5-[3-fluoro-4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-phenoxymethyl]-2-(4-trifluoromethyl-phenyl)-thiazol-4-ylmethyl]-acetamide.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=1>CC([O-])=O.CC([O-])=O.[Pd+2].C(O)C>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:9]2[CH2:10][C:11]3[C:16]([CH:8]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:21][CH:20]=1
Reactant: COc1ccc(I)cc1
Reactant: C1=Cc2ccccc2C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(C2=Cc3ccccc3C2)cc1
Temperature: 25 °C
Yield: 50.2 %

Procedure:
20 ml of triethylamine, 2.2 g (20 mmole) of indene, 4.68 g (20 mmole) of para-methoxy iodo-benzene and 0.134 g (0.6 mmole) of Pd(OAc)2 were stirred under reflux for 10 h. After that the mixture was cooled to room temperature and treated with 100 ml of ethanol. The crystalline precipitate was isolated, washed with cold ethanol and dried under vacuum to obtain 2.23 g (50%) of 2-(4-methoxy-phenyl)-indene.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[NH:10][NH2:11].C(Cl)Cl.[OH-].[Na+].C(O[CH:20]=[C:21]([C:24]#[N:25])[C:22]#[N:23])C>CO>[NH2:25][C:24]1[N:10]([C:4]2[C:5]([Cl:9])=[CH:6][CH:7]=[CH:8][C:3]=2[Br:2])[N:11]=[CH:20][C:21]=1[C:22]#[N:23]
Reactant: CCOC=C(C#N)C#N
Reactant: NNc1c(Cl)cccc1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: N#Cc1cnn(-c2c(Cl)cccc2Br)c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
(2-Bromo-6-chlorophenyl)hydrazine hydrochloride (Intermediate AH2) (4.71 g, 18.26 mmol) was partitioned between DCM (300 mL) and 2M NaOH (20 mL). Allowed to Stir for 1 hour. The two phases were separated. The organic phase was reduced under vacuum to give the free base. This was dissolved in MeOH (60 mL), and stirred in a cooling bath at 0° C. (Ethoxymethylene)malononitrile (2.230 g, 18.26 mmol) added portionwise. The reaction mixture was then allowed to warm to ambient temperature and stirred for 1 hour. The mixture was then heated to reflux and stirred for 16 hours. Allowed to cool to ambient temperature. The reaction mixture was concentrated to give a solid, which was triturated under MeOH. A solid was filtered off. This was dried to afford the product (4.59 g, 85%). 1H NMR (400 MHz, DMSO) δ 6.79 (2H, s), 7.54-7.47 (1H, m), 7.70 (1H, dd), 7.79 (1H, s), 7.81 (1H, d). m/z (ES+) (M+H)+=299; HPLC tR=1.70 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([CH2:9]Br)[CH:3]=1.[C-:11]#[N:12].[Na+].CCOC(C)=O.O>CS(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([CH2:9][C:11]#[N:12])[CH:3]=1
Reactant: Fc1ccc(Br)cc1CBr
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: N#CCc1cc(Br)ccc1F
Temperature: 90 °C
Reaction time: 2 h

Procedure:
4-Bromo-2-bromomethyl-1-fluoro-benzene (1.2 g, 3.7 mmol) and sodium cyanide (2.0 g, 4.1 mmol) were combined in DMSO (15 mL) and stirred at 90° C. for 2 hours. Once no starting material was seen by analytical tlc, the mixture was worked-up with EtOAc and H2O to give the title compound.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[F:14].C(O[B:19]1[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]1)(C)C>C1COCC1.O.C(OCC)(=O)C>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([B:19]2[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]2)=[C:9]([F:13])[C:8]=1[F:14]
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Fc1cccc(Cl)c1F
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc(Cl)c(F)c2F)OC1(C)C
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
A 2.5M solution of n-butyllithium (2.69 ml, 6.73 mmol) in hexanes was added dropwise to a solution of 1-chloro-2,3-difluorobenzene (1 g, 6.73 mmol) in THF (25 mL) cooled to −78° C. After 45 min at −78° C., 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.253 g, 6.73 mmol) was added dropwise after which the reaction mixture was allowed to warm to ambient temperature. The reaction mixture was diluted with water and ethyl acetate, and the organic phase was extracted twice with water. The aqueous extracts were combined, acidified with 12N HCl to pH 3, and extracted with ethyl acetate. The organic extract was dried and concentrated under vacuum to yield the title compound as an oil product (0.93 g, 50% yield): 1H NMR (CDCl3) δ 7.42 (m, 1H), 7.17 (m, 1H), 1.37 (s, 12H).
Reaction SMILES: [C:1]([O:6][C:7]1([CH3:20])[CH:14]2[CH2:15][C:10]3([C:17](O)=[O:18])[CH2:11][CH:12]([CH2:16][CH:8]1[CH2:9]3)[CH2:13]2)(=[O:5])[C:2]([CH3:4])=[CH2:3].C(Cl)(=O)C([Cl:24])=O>C1(C)C=CC=CC=1>[C:1]([O:6][C:7]1([CH3:20])[CH:14]2[CH2:15][C:10]3([C:17]([Cl:24])=[O:18])[CH2:11][CH:12]([CH2:16][CH:8]1[CH2:9]3)[CH2:13]2)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OC1(C)C2CC3CC1CC(C(=O)O)(C3)C2
Reactant: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)OC1(C)C2CC3CC1CC(C(=O)Cl)(C3)C2

Procedure:
In toluene solvent, 4-methacryloyloxy-4-methyladamantanecarboxylic acid was reacted with oxalyl chloride into a corresponding carboxylic acid chloride. To 1.8 g (6 mmol) of 4-methacryloyloxy-4-methyladamantanecarboxylic acid chloride thus obtained, 2.5 g (5 mmol) of triphenylsulfonium 2-hydroxy-1,1,3,3,3-pentafluoropropane-1-sulfonate (which was synthesized with reference to JP-A 2007-145803) and 20 g of methylene chloride were added, followed by ice cooling. To the solution, a solution of 0.7 g (7 mmol) of triethylamine and 0.06 g (0.5 mmol) of N,N-dimethylaminopyridine in 5 g of methylene chloride was added at such a rate that the temperature might not exceed 10° C., followed by stirring for 12 hours at room temperature. Thereafter, 10 g of 5% dilute hydrochloric acid solution was added to the reaction solution. The organic layer was taken out and washed with water, whereupon methylene chloride was distilled off in vacuum.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([O:10][C:11](=[O:17])[C:12](=[N+:15]=[N-:16])[CH:13]=O)[CH3:9].CC(O)=O>CCO>[CH2:8]([O:10][C:11]([C:12]1[N:15]=[N:16][N:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:13]=1)=[O:17])[CH3:9]
Reactant: Nc1ccccc1
Reactant: CCOC(=O)C(C=O)=[N+]=[N-]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1cn(-c2ccccc2)nn1
Reaction time: 8 h
Yield: 86.8 %

Procedure:
Oxalyl chloride (4.7 g, 30.1 mL, 37.0 mmol) was added to a cold (0-4° C.) solution of DMF (2.25 g, 2.4 mL, 30.8 mmol) in CHCl3 (20 mL) and stirring was continued for 10 minutes. The reaction mixture was heated at 40° C. for 10 minutes and cooled to −10° C. Diazoacetic acid ethyl ester (3.5 g, 3.5 mL, 30.6 mmol) was then added and stirred at room temperature for 1 hr. The reaction mixture was concentrated ether was then added, the precipite was collected and dissolved in 10% aq Hac (10 mL) and stirring was continued for 1 hr. The reaction mixture was extracted with ether, washed with saturated sodium bicarbonate solution and brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to afford 590 mg (21% Yield) of 2-diazo-3-oxo-propionic acid ethyl ester. 1H NMR (300 MHz, CDCl3): δ 9.7 (s, 1H), 4.4 (q, 2H), 1.4 (t, 3H). Aniline (143 mg, 1.5 mmol) was added to a solution of 2-diazo-3-oxo-propionic acid ethyl ester (200 mg, 1.4 mmol) and HOAc (0.2 mL) in EtOH (0.5 mL) and stirring was at room temperature overnight. The reaction mixture was concentrated and cold water was then added, the solid was collected to afford 264 mg (87.41% Yield) of 1-phenyl-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester. 1H NMR (300 MHz, CDCl3): δ 8.5 (s, 1H), 7.8 (d, 2H), 7.6-7.48 (m, 3H), 4.5 (q, 2H), 1.4 (t, 3H). LiOH.H2O (80 mg, 1.9 mmol) was added to a stirred solution of 1-phenyl-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester (130 mg, 0.6 mmol) in THF:H2O (1:1, 4 mL), and the resulting mixture was stirred at room temperature for 45 min. The reaction mixture was concentrated under reduced pressure. Cold water was then added and it was acidified with 10% aqueous HCl, the solid was collected to afford 40 mg (35.4% yield) of 1-phenyl-1H-[1,2,3]triazole-4-carboxylic acid. 1H NMR (300 MHz, DMSO-d6): δ 13.4 (bs, 1H), 9.4 (s, 1H), 8.0 (d, 2H), 7.7 (t, 2H), 7.6 (t, 1H).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[N:6]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3([C:21]([N:23]4[CH2:27][CH2:26][C@@:25]5([C:31]6[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=6[C:29](=[O:36])[O:28]5)[CH2:24]4)=[O:22])[CH2:20][CH2:19]3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[CH:37](N(CC)C(C)C)(C)C.C(Cl)Cl>>[C:1]([N:9]1[CH2:10][CH2:11][N:6]([C:12]2[CH:13]=[CH:14][C:15]([C:18]3([C:21]([N:23]4[CH2:27][CH2:26][C@@:25]5([C:31]6[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=6[C:29](=[O:36])[O:28]5)[CH2:24]4)=[O:22])[CH2:20][CH2:19]3)=[CH:16][CH:17]=2)[CH2:7][CH2:8]1)(=[O:4])[CH:2]([CH3:37])[CH3:3]
Reactant: CCC(=O)Cl
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(N5CCNCC5)cc4)CC3)C2)c2ccccc21
Solvent: ClCCl
Product: CC(C)C(=O)N1CCN(c2ccc(C3(C(=O)N4CC[C@@]5(C4)OC(=O)c4ccccc45)CC3)cc2)CC1
Reaction time: 1 h

Procedure:
Propanoyl chloride (5.0 μL, 0.000057 mol) was added to a solution of (1R)-1′-{[1-(4-piperazin-1-ylphenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one (20.0 mg, 0.0000478 mol) and N,N-diisopropylethylamine (27 μL, 0.00016 mol) in methylene chloride (1.0 mL, 0.016 mol) and the mixture was stirred for 1 h. The solvent was removed and the crude product was purified by prep-HPLC. LC-MS: 488.2 (M+H)+
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][C@H:5]1[C@H:14]2[CH2:15][CH2:16][N:17]([C:18]([C@H:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]3[NH2:26])=[O:19])[C@H:13]2[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:6]1.C(N(CC)CC)C.[NH:34]1[C:38]2[CH:39]=[CH:40][C:41]([C:43](O)=[O:44])=[CH:42][C:37]=2[N:36]=[N:35]1.CCOC(OC(OCC)=O)=O>C1COCC1.O>[CH3:2][O:3][CH2:4][C@H:5]1[C@H:14]2[CH2:15][CH2:16][N:17]([C:18]([C@H:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]3[NH:26][C:43]([C:41]3[CH:40]=[CH:39][C:38]4[NH:34][N:35]=[N:36][C:37]=4[CH:42]=3)=[O:44])=[O:19])[C@H:13]2[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:6]1
Reactant: O=C(O)c1ccc2[nH]nnc2c1
Reactant: COC[C@@H]1Nc2ccccc2[C@H]2[C@@H]1CCN2C(=O)[C@H]1CCCC[C@H]1N
Agent: CCOC(=O)OC(=O)OCC
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: COC[C@@H]1Nc2ccccc2[C@H]2[C@@H]1CCN2C(=O)[C@H]1CCCC[C@H]1NC(=O)c1ccc2[nH]nnc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
To a solution (5 ml) of (1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinolin-1-yl]carbonyl}cyclohexaneamine hydrochloride (200 mg, 0.480 mmol) in THF were added triethylamine (0.199 ml, 1.44 mmol), 1H-1,2,3-benzotriazole-5-carboxylic acid (78.3 mg, 0.480 mmol) and DEPC (0.079 ml, 0.528 mmol) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous MgSO4, and concentrated under reduced pressure. The obtained residue was subjected to column chromatography using silica gel and eluted with hexane:ethyl acetate (1:1-1:9) to give the title compound (187 mg, 80%) as an amorphous form.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:19])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)[CH2:4][CH2:3]1.[H][H]>CCO.[Pd]>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)=[O:19])[CH2:6][CH2:7]1
Reactant: [H][H]
Reactant: CN1CCN(C(=O)Cc2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CN1CCN(C(=O)Cc2ccc(N)cc2)CC1

Procedure:
A solution of 1-methyl-4-[(4-nitrophenyl)acetyl]piperazine(1.5 g, 5.70 mmol) in EtOH (30 mL) was reduced over palladium/charcoal (10% wt, 50% wet, 150 mg) with hydrogen under atmospheric pressure and RT for 18 h. The catalyst was separated by filtration through Celiteo and the solvent evaporated to the title compound as a brown oil, 1.12 g.