Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:11]([NH:13][C:14]1[CH:31]=[CH:30][C:17]([C:18]([N:20]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=2[OH:29])[CH3:21])=[O:19])=[CH:16][C:15]=1[O:32][CH3:33])=[O:12].Br[CH2:35][CH2:36][CH2:37][CH2:38][N:39]1[C:43](=[O:44])[C:42]2=[CH:45][CH:46]=[CH:47][CH:48]=[C:41]2[C:40]1=[O:49].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:11]([NH:13][C:14]1[CH:31]=[CH:30][C:17]([C:18]([N:20]([CH3:21])[C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=2[O:29][CH2:35][CH2:36][CH2:37][CH2:38][N:39]2[C:43](=[O:44])[C:42]3=[CH:45][CH:46]=[CH:47][CH:48]=[C:41]3[C:40]2=[O:49])=[O:19])=[CH:16][C:15]=1[O:32][CH3:33])=[O:12]
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2O)ccc1NC(=O)c1cccc([N+](=O)[O-])c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCN2C(=O)c3ccccc3C2=O)ccc1NC(=O)c1cccc([N+](=O)[O-])c1N
Temperature: 60 °C
Yield: 89.1 %

Procedure:
A mixture of 4-(2-amino-3-nitrophenyl)carbonylamino-N-(2-hydroxy-4-methylphenyl)-3-methoxy-N-methylbenzamide (520 mg), N-(4-bromobutyl)phthalimide (326 mg) and potassium carbonate (160 mg) in N,N-dimethylformamide (10 ml) was heated at 60° C. for 8 hours. The mixture was diluted with ethyl acetate and the solution was washed with water and brine. The organic phase was dried over magnesium sulfate and the solvent was evaporated in vacuo. The crude oil was purified by silica gel column (1% methanol in chloroform) to give 4-(2-amino-3-nitrophenyl)carbonylamino-3-methoxy-N-methyl-N-[2-(4-phthalimidobut-1-yloxy)-4-methylphenyl]-benzamide (670 mg).
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](O)=[O:27].CN(C)C=O.C(Cl)(=O)C([Cl:40])=O>ClCCl>[O:1]=[C:2]1[C:10]2([C:11]3=[CH:21][C:20]4[CH2:19][CH2:18][O:17][C:16]=4[CH:15]=[C:12]3[O:13][CH2:14]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([Cl:40])=[O:27]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid (2.13 g, 5.1 mmol) and N,N-dimethylformamide (0.001 mL, catalytic amount) in anhydrous dichloromethane (30 mL) was treated with oxalyl chloride (4.50 mL, 5.1 mmol). The reaction mixture was stirred at ambient temperature for 3 h. The crude product was concentrated in vacuo to afford 3-((2′-oxo-5,6-dihydro-2H-spiro[benzofuro[6,5-b]furan-3,3′-indoline]-1′-yl)methyl)benzoyl chloride as a light yellow solid. A solution of 3-((2′-oxo-5,6-dihydro-2H-spiro[benzofuro[6,5-b]furan-3,3′-indoline]-t-yl)methyl)benzoyl chloride (0.27 g, 0.6 mmol), cyclohexanemethylamine (0.17 mL, 1.3 mmol), triethylamine (0.44 mL, 3.2 mmol), and 4-(dimethylamino)pyridine (0.005 g, catalytic amount) in anhydrous dichloromethane (5 mL), was stirred at ambient temperature for 20 h under nitrogen. The reaction mixture was diluted with dichloromethane (10 mL) and aqueous citric acid (10 mL) and the phases were separated. The organic phase was washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography with ethyl acetate in hexanes (0% to 100% gradient) to afford N-(cyclohexylmethyl)-3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide (0.33 g, 65%) as a colourless solid: 1H NMR (300 MHz, CDCl3) δ7.80 (s, 1H), 7.63 (d, J=7.4 Hz, 1H), 7.48-7.37 (m, 2H), 7.23-7.15 (m, 2H), 7.08-7.00 (m, 1H), 6.79 (d, J=7.8 Hz, 1H), 6.50 (s, 1H), 6.43 (s, 1H), 6.19-6.09 (m, 1H), 5.08 (d, J=15.7 Hz, 1H), 4.99 (d, J=9.0 Hz, 1H), 4.91 (d, J=15.7 Hz, 1H), 4.72 (d, J=9.0 Hz, 1H), 4.55 (t, J=8.6 Hz, 2H), 3.33-3.23 (m, 2H), 3.07-2.95 (m, 2H), 1.82-1.64 (m, 5H), 1.34-1.13 (m, 4H), 1.07-0.86 (m, 2H); MS (ES+) m/z 509.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:22])=[C:4]([CH:9]=[C:10](B2OC(C)(C)C(C)(C)O2)[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].COCCOC.Cl[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>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(OCC)(=O)C.O>[Cl:1][C:2]1[C:3]([OH:22])=[C:4]([CH:9]=[C:10]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)c(Cl)c1O
Reactant: COc1ccc(CCl)cc1
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: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COC(=O)c1cc(Cc2ccc(OC)cc2)c(C)c(Cl)c1O
Temperature: 80 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
To a solution of methyl 3-chloro-2-hydroxy-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.90 g), in a mixed solvent of DME (13.5 mL)-water (4.50 mL) were added 1-(chloromethyl)-4-methoxybenzene (0.43 g), tetrakis(triphenylphosphine)palladium(0) (0.16 g) and sodium carbonate (0.58 g), and the mixture was stirred at 80° C. overnight under argon atmosphere. The reaction mixture was allowed to be cooled to room temperature, water and ethyl acetate were added thereto, and the mixture was partitioned. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.37 g).
Reaction SMILES: O[CH2:2][C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[N:6]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[CH2:24][C:23]([CH2:47][C:48]#[N:49])([N:25]4[CH:29]=[C:28]([C:30]5[C:31]6[CH:38]=[CH:37][N:36](COCC[Si](C)(C)C)[C:32]=6[N:33]=[CH:34][N:35]=5)[CH:27]=[N:26]4)[CH2:22]3)[CH2:17][CH2:16]2)=[O:14])[CH:4]=1.[CH2:50]([N:52](CC)[CH2:53][CH3:54])[CH3:51].CS(Cl)(=O)=O.S([O-])(=O)(=O)C.N1CCCC1.FC(F)(F)C(O)=O>C(Cl)Cl.C(N(CC)CC)C>[N:52]1([CH2:2][C:3]2[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[N:6]=[C:5]([C:13]([N:15]3[CH2:16][CH2:17][CH:18]([N:21]4[CH2:24][C:23]([CH2:47][C:48]#[N:49])([N:25]5[CH:29]=[C:28]([C:30]6[C:31]7[CH:38]=[CH:37][NH:36][C:32]=7[N:33]=[CH:34][N:35]=6)[CH:27]=[N:26]5)[CH2:22]4)[CH2:19][CH2:20]3)=[O:14])[CH:4]=2)[CH2:53][CH2:54][CH2:51][CH2:50]1
Reactant: CCN(CC)CC
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5CCN(C(=O)c6cc(CO)nc(C(F)(F)F)n6)CC5)C4)c3)ncnc21
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCNC1
Product: N#CCC1(n2cc(-c3ncnc4[nH]ccc34)cn2)CN(C2CCN(C(=O)c3cc(CN4CCCC4)nc(C(F)(F)F)n3)CC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of {1-(1-{[6-(hydroxymethyl)-2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperidin-4-yl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (0.030 g, 0.043 mmol, from Step E) and triethylamine (0.015 mL, 0.11 mmol) in methylene chloride (1 mL) at 0° C. was added methanesulfonyl chloride (0.006 mL, 0.08 mmol). The reaction was allowed to warm to room temperature immediately after addition of mesyl chloride (MsCl). When mesylate formation was confirmed to be complete, the solution of mesylate was added to a mixture of pyrrolidine (0.017 mL, 0.20 mmol, Aldrich) and a few drops of triethylamine in DCM (0.2 mL). The displacement reaction was heated to 40° C. for 30 minutes. The reaction was cooled to room temperature and trifluoroacetic acid (1 mL) was added. After stirring for 1 hour, the solvents were removed in vacuo and replaced with methanol (1 mL) and ethylenediamine (0.2 mL). After stirring for 30 minutes, the product was purified by preparative HPLC-MS (Waters SunFire C18, 5 um particle size, 30×100 mm, eluting with a gradient of 5-23% MeCN in H2O containing 0.1% TFA over 12 minutes). Yield: 0.012 g (25%); LC-MS: 620.2 (M+H)+. 1H NMR (300 MHz, CD3OD): δ 9.10 (s, 1H), 8.90 (s, 1H), 8.59 (s, 1H), 8.01 (s, 1H), 7.83 (d, 1H), 7.29 (d, 1H), 4.95 (d, 2H), 4.85 (s, 2H), 4.77-4.66 (m, 3H), 4.02 (d, 1H), 3.95-3.15 (m, 8H), 3.12-2.99 (m, 1H), 2.31-2.03 (m, 6H), 1.77-1.51 (m, 2H). 19F NMR (300 MHz, CD3OD): δ −72.21 (s, 3F), −77.61 (s, 12F).
Reaction SMILES: O[CH:2]1[CH2:6][N:5]([CH3:7])[C:4](=[O:8])[C:3]1([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.S(Cl)(Cl)=O.N1C=CC=CC=1.[CH:31](Cl)(Cl)[Cl:32]>>[Cl:32][CH2:31][CH:2]1[CH2:6][N:5]([CH3:7])[C:4](=[O:8])[C:3]1([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CN1CC(O)C(c2ccccc2)(c2ccccc2)C1=O
Reactant: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CN1CC(CCl)C(c2ccccc2)(c2ccccc2)C1=O
Yield: 59 %

Procedure:
To 25.0 g. (0.09 mole) of 4-hydroxy-1-methyl-3,3-diphenyl-2-pyrrolidinone, in 200 ml. of chloroform was added 21.4 g. (0.18 mole) of thionyl chloride. With stirring and ice bath cooling, 18.0 g. (0.23 mole) of pyridine was added dropwise. The solution was refluxed for two hours. After concentrating in vacuo, the residue was dissolved in chloroform and washed successively with dilute hydrochloric acid solution and dilute sodium hydroxide. The chloroform solution was dried, filtered, and concentrated in vacuo. The solid residue was recrystallized from a 50:50 ethyl acetate-isopropyl ether mixture. It weighed 16.0 g. (59% yield) and melted at 120°-122° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:10][Sn:11]([N:14]=[N+:15]=[N-:16])([CH3:13])[CH3:12]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]1[N:14]([Sn:11]([CH3:13])([CH3:12])[CH3:10])[N:15]=[N:16][N:5]=1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: N#Cc1ccccc1Br
Solvent: Cc1ccccc1
Product: C[Sn](C)(C)n1nnnc1-c1ccccc1Br
Temperature: 25 °C

Procedure:
To a solution of 1.50 g of o-bromobenzonitrile in 8.0 ml of toluene is added 1.70 g of trimethyltin azide. The reaction mixture is heated to reflux for 18 hours and then allowed to cool to room temperature. The resulting white precipitate is isolated by filtration and used without purification in the next step.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[CH:10]([NH2:13])([CH3:12])[CH3:11].[OH-].[Na+]>C(OCC)(=O)C>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([NH:13][CH:10]([CH3:12])[CH3:11])[N:7]=1
Reactant: CC(C)N
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)Nc1nc(Cl)nc(Cl)n1
Temperature: -15 °C
Reaction time: 2 h

Procedure:
A suspension of 369 g of cyanuric chloride in 1000 ml of ethyl acetate is cooled to -15° C. With good stirring, 124 g of isopropylamine are first added dropwise at -20° C. to -10° C. in the course of 21/2 hours, followed by 267 g of a 30% aqueous solution of sodium hydroxide in the course of one hour. The reaction mixture is stirred for a further 11/2 hours at the same temperature, then the organic phase is separated, washed with two 100 ml portions of water and dried over sodium sulphate. The solvent is evaporated, to yield an oil from which the 2,4-dichloro-6-isopropylamino-s-triazine precipitates in crystalline form after stirring with petroleum ether at low temperature. Melting point: 46°-47° C.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:6])=[CH:3]\[C:4]#[N:5].[CH2:7]([NH:14]N)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(O)CCCC>[NH2:5][C:4]1[N:14]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:1]=[C:2]([CH3:6])[CH:3]=1
Reactant: NNCc1ccccc1
Reactant: C/C(N)=C/C#N
Solvent: CCCCCO
Product: Cc1cc(N)n(Cc2ccccc2)n1
Yield: 45.4 %

Procedure:
To a solution of 16.4 g (0.2 mol) of 3-aminocrotononitrile in 100 cm3 of n-pentanol were added 26.9 g (0.22 mol) of benzylhydrazine and the mixture was then heated at reflux for 12 hours. The n-pentanol was subsequently distilled off under reduced pressure and a thick oil was obtained, which was purified by chromatography on silica gel. A pale yellow solid was obtained, which was crystallized from isopropyl ether and was then filtered on a sinter funnel. After drying under vacuum at 40° C., 17 g of the expected product were obtained in the form of a pale yellow solid, the melting point of which was from 76 to 78° C.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH2:7]([NH:14][OH:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl[CH2:17][C:18]1[C:23]([CH3:24])=[C:22]([CH2:25]Cl)[C:21]([CH3:27])=[C:20]([CH2:28]Cl)[C:19]=1[CH3:30]>CN(C)C=O>[CH2:7]([N:14]([CH2:17][C:18]1[C:23]([CH3:24])=[C:22]([CH2:25][N:14]([OH:15])[CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:21]([CH3:27])=[C:20]([CH2:28][N:14]([OH:15])[CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:19]=1[CH3:30])[OH:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1c(CCl)c(C)c(CCl)c(C)c1CCl
Reactant: ONCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(CN(O)Cc2ccccc2)c(C)c(CN(O)Cc2ccccc2)c(C)c1CN(O)Cc1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 62.6 %

Procedure:
To a suspension of 3.87 g of sodium carbonate in 30 ml of dry N,N-dimethylformamide is added 4.50 g of N-benzylhydroxylamine followed by 3.23 g of 2,4,6-tris(chloromethyl)mesitylene. After stirring at 80° C. for 8 hours, dimethylformamide is removed under reduced pressure and the residue is partitioned between methylene chloride and water. The combined organic layers are washed with water, brine, dried and evaporated to give a crude product. Recrystallization from ethyl acetate-heptane affords 4.0 g of white solid, mp 193°-195° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:30])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2SC)=[CH:17][C:16]=1[Cl:29])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:32]1C=C(C=CC=1)C(OO)=O.[O-:42][S:43]([O-:46])(=S)=O.[Na+].[Na+]>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:30])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=2[S:43]([CH3:32])(=[O:46])=[O:42])=[CH:17][C:16]=1[Cl:29])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CSc1ccccc1-c1ccc(NC(=O)C2CCCN2C(=O)OC(C)(C)C)c(Cl)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)Nc1ccc(-c2ccccc2S(C)(=O)=O)cc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(3-Chloro-2′-methylsulfanyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (1 g, 2 mmol) was dissolved in 20 mL EtOAc, added m-chloroperoxybenzoic acid (2.6 g, 8.9 mmol) in one portion and stirred at ambient temperature for 3 hours. A 10% aqueous solution (30 mL) of Na2S2O3 was added to the vigorously stirring reaction in order to quench peroxide. After 20 minutes the solution was diluted with 100 mL EtOAc, separated layers, washed organics with sat. NaHCO3 (3×100 mL), brine, dried with MgSO4, filtered and concentrated to yield title compound as a clear oil. (1 g, 100%) APCI (AP−): 477.1, 479.1 (M−H)−.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Br:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([Br:16])[CH:15]=1)[CH:11]=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Br:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH2:1])[CH:13]=[C:14]([Br:16])[CH:15]=1
Reactant: O=Cc1cc(Br)cc(Br)c1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=Cc1cc(Br)cc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.9 %

Procedure:
A solution of methyltriphenylphosphonium bromide (20.30 g, 56.8 mmol) in dry THF (50 mL) is cooled to 0° C. under N2 and then treated with solid potassium tert-butoxide (6.38 g, 56.8 mmol) in portions. The resultant yellow slurry is warmed to rt and stirred for 30 minutes. The mixture is cooled to −78° C., and a solution of 3,5-dibromobenzaldehyde (10.0 g, 37.9 mmol) in THF (50 mL) is added dropwise. The reaction is warmed to rt and stirred for 1 hour. The mixture is poured into ice water containing 1 N HCl (56 mL) and then extracted with Et2O. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using 10/1 hexanes/ethyl acetate to afford 4.56 g (46%) of the title compound. Rf=0.64 (4/1 hexanes/EtOAc). 1H NMR (400 MHz, CDCl3).
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([C:16]([OH:18])=[O:17])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[C:7]([C:19]([OH:21])=[O:20])[CH:8]=2)[CH3:2].[CH3:22][N:23]([CH3:28])[CH2:24][CH2:25][CH2:26][Cl:27]>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1>[ClH:27].[ClH:27].[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([C:16]([O:18][CH2:26][CH2:25][CH2:24][N:23]([CH3:28])[CH3:22])=[O:17])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[C:7]([C:19]([O:21][CH2:6][CH2:5][CH2:4][N:3]([CH3:15])[CH3:1])=[O:20])[CH:8]=2)[CH3:2]
Reactant: CN(C)CCCCl
Reactant: CCn1c2ccc(C(=O)O)cc2c2cc(C(=O)O)ccc21
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Product: CCn1c2ccc(C(=O)OCCCN(C)C)cc2c2cc(C(=O)OCCCN(C)C)ccc21
Product: Cl

Procedure:
By the procedure of Example 2, one equivalent of 9-ethylcarbazole-3,6-dicarboxylic acid is allowed to react with two equivalents of 3-dimethylaminopropyl chloride in the presence of a catalytic amount of benzyltrimethylammonium chloride to give the product.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=1[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:8].[CH2:25](N(CC)CC)C.[CH:32]1([C:37](Cl)=[O:38])[CH2:36][CH2:35]CC1>C(Cl)Cl>[Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=1[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][N:13]([C:37](=[O:38])[CH2:32][CH:36]([CH3:35])[CH3:25])[CH2:12][CH2:11]1)=[O:8]
Reactant: O=C(Cl)C1CCCC1
Reactant: CCN(CC)CC
Reactant: O=C(NC1CCNCC1)c1ccccc1Oc1ccc(Cl)cc1Cl
Solvent: ClCCl
Product: CC(C)CC(=O)N1CCC(NC(=O)c2ccccc2Oc2ccc(Cl)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 80.4 %

Procedure:
To an ice cooled solution of 4-[2-(2,4-dichlorophenoxy)-N-piperidin-4-ylbenzamide (AMR01077, 100 mg, 0.274 mmol) in dry DCM (5 mL) were added triethylamine (0.2 mL, 1.37 mmol) and cyclopentanecarbonyl chloride (0.04 mL, 0.33 mmol). The reaction mixture was stirred at room temperature until completion by TLC (1.5 h), and quenched with saturated NaHCO3. The organic solution was evaporated to dryness and the oil obtained was purified by column chromatography using DCM/MeOH 95:5 as eluent. Further purification was carried out by treating a DCM solution of the obtained compound with trisamine scavenger (100 mg) for 2 h. The scavenger was filtered off, and the solvent evaporated to give 2-(2,4-dichlorophenoxy)-N-[1-(3-methylbutyryl)piperidin-4-yl]benzamide (99 mg, 78%) as a white solid, m.p. 57-60° C. Rf: 0.15 (hexane/AcOEt 4:6) LC/MS (APCI) tr=4.94 min, m/z 463.33 (60), 461.32 (M++H, 100). HPLC tr=2.64 min (98.25%) 1H NMR (270 MHz, CDCl3) δ 1.35 (2H, m, CH2), 1.55 (2H, m, CH2), 1.76 (6H, m, 3CH2), 2.00 (2H, m, CH2), 2.87 (2H, m, CH2), 3.17 (1H, m, ½CH2), 3.87 (1H, br t, % CH2), 4.19 (1H, m, CH), 4.43 (1H, m, ½CH2), 6.79 (1H, d, J=8.6 Hz, ArH), 7.21 (1H, dd, J=8.9, 2.5 Hz, ArH), 7.25 (1H, m ArH), 7.35 (1H, br d, NH), 7.50 (1H, d, J=2.5 Hz, ArH) and 8.17 (1H, dd, J=7.9, 1.7 Hz, ArH). 13C NMR (270 MHz, CDCl3) δ 23.81, 29.36, 32.26, 33.17 (CH2), 39.60 (CH), 40.78 (CH2), 43.70 (CH), 47.79 (CH2), 118.00, 120.65, 124.43, 124.88, 126.21, 128.57, 130.85, 130.87, 132.74, 133.06, 148.97, 153.09 (ArC), 163.63 and 174.71 (C═O).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:22]([OH:24])=O)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:25]=2)=[N:7][CH:6]=[N:5]1.[CH3:28][NH2:29]>C1COCC1>[CH3:28][NH:29][C:22]([C:20]1[CH:19]=[CH:18][C:17]2[C:11]3[N:12]([CH:25]=[C:9]([C:8]4[N:4]([CH2:3][C:2]([F:26])([F:1])[F:27])[N:5]=[CH:6][N:7]=4)[N:10]=3)[CH2:13][CH2:14][O:15][C:16]=2[CH:21]=1)=[O:24]
Reactant: O=C(O)c1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)c1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2

Procedure:
Following the same procedure as for 133, 2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylic acid (60 mg, 0.1 mmol) was reacted with 2M methylamine (0.26 mL) in THF to provide 158. LC/MS (ESI+): m/z 393 (M+H). 1H NMR (400 MHz, DMSO) δ 8.49 (d, J=4.2, 1H), 8.42 (s, 1H), 8.11 (d, J=9.8, 1H), 7.60 (dd, J=8.4, 1.6, 1H), 7.52 (d, J=1.4, 1H), 5.90 (q, J=8.8, 2H), 4.57 (dd, J=11.5, 5.4, 4H), 2.79 (d, J=4.5, 3H).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CS(C)=O.CCN(C(C)C)C(C)C.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25]Cl>O>[N:1]([CH2:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[Cl:18])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: ClCc1ccccc1Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: [N-]=[N+]=NCc1ccccc1Cl

Procedure:
Sodium azide (3.36 g, 51.1 mmol, Eq: 1.05) was charged in the reactor followed by DMSO (35.2 g, 32.0 ml) and Hunig's base (642 mg, 868 μl, 4.87 mmol, Eq: 0.1). The suspension was stirred for 10 Min. at 25° C. Then 1-chloro-2-(chloromethyl)benzene (8 g, 6.29 ml, 48.7 mmol, Eq: 1.00) was added dropwise over 60 min. (Tr=25° C.) and stirred at 25° C. until reaction completion (<2 h). The resulting white suspension was treated with water (1.6 g, 1.6 ml) and stirred for 45 Min. at R.T. The suspension was filtered and the filter cake was washed with DMSO (17.6 g, 16.0 ml) to give a colorless solution of 1-(azidomethyl)-2-chloro-benzene solution.
Reaction SMILES: [C:1]([S:4][CH2:5][CH2:6][C:7]([N:9]1[C@H:13]([C:14]([OH:16])=O)[CH2:12][S:11][C@@H:10]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23])=[O:8])(=[O:3])[CH3:2].CN1CCOCC1.C(Cl)(=O)OCC(C)C.[NH2:39][C@H:40]([C:46]([OH:48])=[O:47])[CH2:41][CH2:42][C:43]([OH:45])=[O:44]>C1COCC1.C(N(CC)CC)C>[C:1]([S:4][CH2:5][CH2:6][C:7]([N:9]1[C@H:13]([C:14]([NH:39][C@H:40]([C:46]([OH:48])=[O:47])[CH2:41][CH2:42][C:43]([OH:45])=[O:44])=[O:16])[CH2:12][S:11][C@@H:10]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23])=[O:8])(=[O:3])[CH3:2]
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Reactant: CC(=O)SCCC(=O)N1[C@@H](c2ccccc2O)SC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)SCCC(=O)N1[C@@H](c2ccccc2O)SC[C@H]1C(=O)N[C@@H](CCC(=O)O)C(=O)O
Yield: 78.3 %

Procedure:
The suspension of mixed anhydride in THF is prepared by using 1.78 g of (2R,4R)-3-(S-acetyl-3-mercaptopropanoyl)-2-(2-hydroxyphenyl)-4-thiazolidinecarboxylic acid, 0.51 g of N-methylmorpholine and 0.68 g of isobutyl chlorocarbonate. The suspension is added to the aqueous solution of 1.5 g of L-glutamic acid and 2.0 g of triethylamine, and treated in the same manner as Example 2 to give 1.9 g (80%) of the titled compound.