Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[CH2:3][NH:4][C@H:5]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6]1.[Cl:18][C:19]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:18][C:19]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][N:4]([CH2:3][CH:2]([CH3:17])[CH3:1])[C@H:5]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH2:6]1
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: CC(C)CN[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)CN(Cc1cccc(Cl)c1Cl)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reaction time: 16 h

Procedure:
To a solution of 1,1-dimethylethyl (3S)-3-(2-methylpropyl amino)-pyrrolidine-1-carboxylate (see Example 197(a)) (0.363 g, 1.5 mmol) in 1,2-dichloroethane (10 mL) was added 2,3-dichloro-benzaldehyde (1.05 g, 6.0 mmol), followed by sodium triacetoxyborohydride (0.95 g, 4.5 mmol), and the mixture left to stir for 16 h. The reaction mixture was quenched with water (5 mL) and 2N sodium hydroxide (5 mL), and the organic layer separated by passing through a hydrophobic frit. The organic solution was diluted with methanol (5 mL) and absorbed onto an Isolute™ SCX-2 ion exchange cartridge (5 g), washed with methanol (15 mL) and the product eluted with 2M ammonia in methanol solution (15 mL). The solvent was removed in vacuo to give 1,1-dimethylethyl (3S)-3-{[(2,3-dichlorophenyl)methyl](2-methylpropyl)amino}pyrrolidine-1-carboxylate as a colourless oil. This was taken up in dichloromethane (2 mL), trifluoroacetic acid (1.4 mL, 18.3 mmol) added, and the mixture stirred at room temperature for 16 h. The solvent was removed in vacuo and the residue diluted with methanol (5 mL) and absorbed onto an Isolute™ SCX-2 ion exchange cartridge (5 g). The column was washed with methanol (15 mL) and the product eluted with 2M ammonia in methanol solution (15 mL). The solvent was removed in vacuo and the residue purified by mass guided preparative LCMS. The residue was diluted with methanol (5 mL) and again absorbed onto an Isolute™ SCX-2 ion exchange cartridge (5 g). The column was washed with methanol (15 mL), the product eluted with 2M ammonia in methanol solution (15 mL) and the solvent removed in vacuo. The desired compound product was taken up in cyclohexane (15 mL) and a hot solution of L-tartaric acid (1 equiv.) in isopropanol (1 mL) was added. The solvent was removed in vacuo and the residue taken up in 40% acetonitrile/water and freeze dried to give the tile compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[CH:24]=[CH2:25]>[I-].[K+].CC(C)=O>[CH2:25]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1)[CH:24]=[CH2:23]
Reactant: CCOC(=O)c1ccc2ccc(O)cc2c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc2ccc(C(=O)OCC)cc2c1
Reaction time: 15 h
Yield: 81 %

Procedure:
A mixture of ethyl 7-hydroxynaphthalene-2-carboxylate (37.5 g), anhydrous potassium carbonate (24.0 g), potassium iodide (0.5 g), and allyl bromide (29.0 g) was heated in refluxing acetone (200 ml) with stirring for 15 hours. The mixture was filtered and the filtrate was evaporated. The residue was dissolved in ethyl-acetate, washed with 2% sodium hydroxide solution and water, dried and evaporated to give a solid. Crystallisation from petroleum ether (b.p. 40-60) afforded ethyl 7-allyloxynaphthalene-2-carboxylate (36 g), m.p. 60°-61°.
Reaction SMILES: C([O:4][C:5]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:6]=1[C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[N:14]=1)=[O:8])(=O)C.[OH-].[Na+].Cl>O1CCCC1>[Br:23][C:20]1[CH:21]=[CH:22][C:5]([OH:4])=[C:6]([CH:19]=1)[C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([C:15]([CH3:16])([CH3:17])[CH3:18])[N:14]=1)=[O:8]
Reactant: CC(=O)Oc1ccc(Br)cc1C(=O)Nc1nc(C(C)(C)C)cs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)c1csc(NC(=O)c2cc(Br)ccc2O)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 78.9 %

Procedure:
2-Acetoxy-5-bromo-N-{4-[(1,1-dimethyl)ethyl]thiazol-2-yl}benzamide (100.1 mg, 0.25 mmol) was dissolved in tetrahydrofuran (3 mL). 2N Sodium hydroxide (0.2 ml) was added, and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was crystallized (isopropyl ether/n-hexane) to give the title compound (70.1 mg, 78.9%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7](F)=[CH:6][C:3]=1[C:4]#[N:5].C([O-])([O-])=O.[K+].[K+].[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>CS(C)=O>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N:21]2[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]2)=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(F)ccc1Cl
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN1CCN(c2ccc(Cl)c(C#N)c2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
A mixture of 2-chloro-5-fluoro-benzonitrile (1 g, 6.43 mmol), K2CO3 (2.66 g, 19.3 mmol) and 1-methyl-piperazine (1.02 g, 10.26 mmol) in DMSO (14 ml) was stirred at 100° C. overnight and then further 1-methyl-piperazine (1.02 g, 10.26 mmol) was added. The mixture was stirred at 100° C. overnight and then partitioned between water and Et2O. The organic phase was extracted with 1 M HCl and the aqueous layer was brought to basic conditions with NH4OH and extracted with DCM. The organic phase was dried over Na2SO4 and evaporated in vacuo to give 1 g of 2-chloro-5-(4-methyl-piperazin-1-yl)-benzonitrile.
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:7][CH:8]=[CH2:9])[CH2:4][CH:5]=O.S(O)(O)(=O)=O.[NH2:15][OH:16].C([O-])(=O)C.[Na+].O>C(O)C>[CH3:1][O:2][CH:3]([CH2:7][CH:8]=[CH2:9])[CH2:4][CH:5]=[N:15][OH:16]
Reactant: NO
Reactant: C=CCC(CC=O)OC
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C=CCC(CC=NO)OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 46.2 %

Procedure:
A mixture of 3-methoxy-5-hexenal (3.0 g, contaminated with dichloromethane and triethylamine), hydroxylamine sulfate (990 mg) and sodium acetate (624 mg) in ethanol (6.5 mL)-water (0.65 mL) was stirred at room temperature for 12 hours. The reaction solution was poured into ice water, followed by extraction with ethyl acetate. The extract was washed with a saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography to obtain the title compound (500 mg).
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[N:8]=[CH:9][N:10]2[C:16]3[CH:17]=[CH:18][S:19][C:15]=3[C:14](=[O:20])[N:13]3[CH2:21][CH2:22][C@H:12]3[C:11]=12)=[O:6])[C:2]#[CH:3].IN1C(=O)CCC1=O.[CH2:31]([NH:34][CH2:35][CH2:36][CH3:37])[CH2:32][CH3:33]>C(O)(=O)C>[CH2:31]([N:34]([CH2:3][C:2]1[O:6][C:5]([C:7]2[N:8]=[CH:9][N:10]3[C:16]4[CH:17]=[CH:18][S:19][C:15]=4[C:14](=[O:20])[N:13]4[CH2:21][CH2:22][C@H:12]4[C:11]=23)=[N:4][CH:1]=1)[CH2:35][CH2:36][CH3:37])[CH2:32][CH3:33]
Reactant: C#CCNC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1sccc1-2
Reactant: CCCNCCC
Agent: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: CCCN(CCC)Cc1cnc(-c2ncn3c2[C@@H]2CCN2C(=O)c2sccc2-3)o1
Temperature: 25 °C
Reaction time: 46 h
Yield: 29.2 %

Procedure:
A solution of 2.60 g (0.00832 mol) of (S)-8-oxo-11,11a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]-diazepine-1-carboxylic acid prop-2-ynylamide in 60 ml of acetic acid was treated with 2.8 g (0.0125 mol) of N-iodosuccinimide while gassing with argon. After stirring at room temperature for 46 hrs. the dark suspension obtained was completely freed from the solvents and dried azeotropically several times with toluene. The dark solid residue was suspended in 100 ml of THF, treated with 11.4 ml (0.0832 mol) of dipropylamine and stirred at room temperature for 18 hrs. The suspension obtained was completely freed from the solvents, the residue was partitioned between ethyl acetate and 1N aqueous hydrochloric acid and extracted. The aqueous-acidic phase was made basic and extracted with ethyl acetate. The organic phase was concentrated, the orange-brownish product was chromatographed over basic Alox (grade III) with dichloromethane/ethyl acetate 4:1 as the eluent and recrystallized from hot isopropyl ether. There was obtained 1.0 g (25%) of (S)-1-(5-dipropylaminomethyl-oxazol-2-yl)-11,11a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]-diazepin-8-one as yellowish crystals; m.p. 133°-135° and [α]D20 =-32.3° (CHCl3, c=1%).
Reaction SMILES: [NH2:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][NH:15]3)=[CH:11][CH:10]=2)=[O:7])=[C:4](Cl)[CH:3]=1.[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>O1CCOCC1>[NH2:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][NH:15]3)=[CH:11][CH:10]=2)=[O:7])=[C:4]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:3]=1
Reactant: Nc1cc(Cl)c(C(=O)Nc2ccc3cn[nH]c3c2)cc1[N+](=O)[O-]
Reactant: C1CNCCN1
Solvent: C1COCCO1
Product: Nc1cc(N2CCNCC2)c(C(=O)Nc2ccc3cn[nH]c3c2)cc1[N+](=O)[O-]

Procedure:
4-amino-2-chloro-N-(1H-indazol-6-yl)-5-nitrobenzamide (3 mmol; see Example 48) in dioxane (5 mL) was reacted with piperazine (9 mmol) following the general procedure H to afford 4-amino-N-(1H-indazol-6-yl)-5-nitro-2-piperazin-1-yl-benzamide. The product was dissolved in dry THF (6 mL) and was treated with BOC anhydride (3.6 mmol) and stirred for 4-6 h. The solvent was removed to dryness, and the residue obtained was suspended in ether (50 mL) with stirring. The solid fondled was collected by filtration, washed with ether and dried in vacuo to afford 4-[5-amino-2-(1H-indazol-6-ylcarbamoyl)-4-nitro-phenyl]-piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [C:1]([O-:5])(=[O:4])[CH:2]=[CH2:3].[Na+].[I-].[Na+].[CH2:9](Cl)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(OCCCC)(=O)C=C.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].O>[C:1]([O:5][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)[O-]
Reactant: ClCc1ccccc1
Agent: C=CC(=O)OCCCC
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: O
Product: C=CC(=O)OCc1ccccc1

Procedure:
A mixture consisting of sodium acrylate (1.892 g, 20 millimoles, Aldrich, 97%), sodium iodide (0.298 g, 2 millimoles, Aldrich, 98%), and water (200.35 g) was introduced into a three-necked 500 mL flask. The flask was immersed into a water bath kept at 45° C. and the mixture was stirred mechanically (600 rpm, photo-tachometer). Next, an organic phase comprising benzyl chloride (10.128 g, 80 millimoles, Aldrich, 97%), Aliquat 336 (1.29 g, 3 millimoles, Aldrich), butyl acrylate (GC standard, 0.690 g, 5 millimoles, Aldrich, 99+%), and 2,6-di-t-butyl-4-methylphenol (0.045 g, 0.2 millimoles, Aldrich, 99+%) was added to the reactor and the mixture was stirred for 180 minutes at constant temperature. The organic phase:aqueous phase weight ratio was 1:17. The aliquot of the reaction mixture was centrifuged, the phases were separated and the organic phase was injected into the gas chromatographic column. The yield of benzyl acrylate based on the limiting reactant (sodium acrylate) was 59%. The only byproduct detectable in the reaction mixture was benzyl alcohol (less than 3%).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]3[CH2:21][CH2:20][CH2:19][CH2:18][C:16]=3[S:17][C:11]=2[N:10]=[C:9]1[C:22]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C[NH+]=CC=1.[O-:40][Cr](Cl)(=O)=O>ClCCl>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]3[CH2:21][CH2:20][CH2:19][C:18](=[O:40])[C:16]=3[S:17][C:11]=2[N:10]=[C:9]1[C:22]1[CH:23]=[C:24]([O:32][CH3:33])[C:25]([O:30][CH3:31])=[C:26]([O:28][CH3:29])[CH:27]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[Cr](=O)([O-])Cl
Reactant: COc1cc(-c2nc3sc4c(c3c(=O)n2Cc2ccccc2)CCCC4)cc(OC)c1OC
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COc1cc(-c2nc3sc4c(c3c(=O)n2Cc2ccccc2)CCCC4=O)cc(OC)c1OC

Procedure:
3-Benzyl-2-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one (Compound No. 1) (8.2 g, 17.7 mmol) dissolved in dry dichloromethane (30 ml) was added quickly to a mixture of PCC (19.2 g, 89.0 mmol, 500 mol-%) in dichloromethane (200 ml). During refluxing PCC was added several times until the reaction was completed. The reaction mixture was filtered through Celite with dichloromethane. The crude product was purified by flash chromatography. The yield of the compound No. 2 was 4.1 g (48%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[C:7]3=[CH:11][S:12][C:13]([N:14]4C(=O)C5C(=CC=CC=5)C4=O)=[C:6]3[C:5](=[O:25])[C:4]=2[CH:3]=1.O.NN>C(O)C>[NH2:14][C:13]1[S:12][CH:11]=[C:7]2[C:8]3[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=3[C:5](=[O:25])[C:6]=12
Reactant: Cc1ccc2c(c1)C(=O)c1c-2csc1N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1ccc2c(c1)C(=O)c1c-2csc1N
Temperature: 25 °C

Procedure:
To a suspension of 2-(6-methyl-8-oxo-8H-2-thia-cyclopenta[a]inden-1-yl)-isoindole-1,3-dione (0.45 mmol, Example 11, Part E) in absolute ethanol (5 mL) is added hydrazine hydrate (0.5 mmol). The mixture is heated to reflux for one hour, cooled to room temperature, concentrated in vacuo, and the residue dissolved in methylene chloride. The solution is chilled to 5° C. for one hour, during which time the phthaloyl hydrazide precipitates. The precipitate is removed by filtration, the filtrate concentrated in vacuo, and the residue purified by column chromatography on silica gel, eluting with a 4:1 mixture of petroleum ether and ethyl acetate. Fractions containing the product are collected, evaporated, and the product recrystallized.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH:20]2[C:21](=[O:25])[NH:22][C:23](=[O:24])[CH:19]2[C:18]2[C:17]3[CH:16]=[C:15]([O:26][CH3:27])[CH:14]=[CH:13][C:12]=3[NH:11][C:10]=2[CH2:9]1.[Si](OCCCN1C2CC(C3C=CC=CC=3OC)C3C(=O)NC(=O)C3C=2C2C=C(OC)C=CC1=2)(C(C)(C)C)(C)C>O1CCOCC1.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:21](=[O:25])[NH:22][C:23](=[O:24])[C:19]=2[C:18]2[C:17]3[CH:16]=[C:15]([O:26][CH3:27])[CH:14]=[CH:13][C:12]=3[NH:11][C:10]=2[CH:9]=1
Reactant: COc1ccc2[nH]c3c(c2c1)C1C(=O)NC(=O)C1C(c1ccccc1Cl)C3
Agent: [Mn+4]
Agent: COc1ccc2c(c1)c1c(n2CCCO[Si](C)(C)C(C)(C)C)CC(c2ccccc2OC)C2C(=O)NC(=O)C12
Agent: [O-2]
Solvent: C1COCCO1
Product: COc1ccc2[nH]c3cc(-c4ccccc4Cl)c4c(c3c2c1)C(=O)NC4=O
Reaction time: 16 h

Procedure:
Manganese dioxide (12.0 g) was added to a solution of 4-(2-Chlorophenyl)-9-methoxy-4,5,6,10c-tetrahydropyrrolo[3,4-c]carbazole-1,3(2H,3aH)-dione (IV; Ar=2-chlorophenyl, R10═H (32) prepared as described in example 68 (2.1 g, 5.51 mmol) in dioxane (100 mL) and the mixture was refluxed with stirring for 16 h. The mixture was filtered hot through a plug of Celite, washing through with more dioxane and then 10% methanol/dioxane. The combined filtrate and washings were concentrated to dryness and the residue was adsorbed onto silica and chromatographed. Elution with ethyl acetate/petroleum ether (3:7) gave 4-(2-Chlorophenyl)-9-methoxypyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (V; Ar=2-chlorophenyl, R10═H (33) in a yield of 1.66 g, 79% which crystallised from THF/petroleum ether as a yellow powder, mp 170–175° C. (dec). 1H NMR δ [(CD3)2SO 11.96 (br s, 1H), 11.08 (br s, 1H), 8.46 (d, J=2.6 Hz, 1H), 7.60–7.55 (m, 3H), 7.51–7.42 (m, 3H), 7.24 (dd, J=8.9, 2.6 Hz, 1H), 3.89 (s, 3H). Found: C, 65.64; H, 3.63; N, 7.12. C21H13ClN2O3.1/2H2O requires C, 65.37; H, 3.66; N, 7.26.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5](O)=[O:6].[C:27]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:29])[CH3:28]>>[C:27]([N:30]1[CH2:35][CH2:34][N:33]([C:5]([C:4]2[CH:8]=[CH:9][C:10]([C:11]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[CH:14]=3)=[O:26])=[C:2]([Cl:1])[CH:3]=2)=[O:6])[CH2:32][CH2:31]1)(=[O:29])[CH3:28]
Reactant: CC(=O)N1CCNCC1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Product: CC(=O)N1CCN(C(=O)c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)c(Cl)c2)CC1

Procedure:
50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 1-acetylpiperazine via Procedure G. The product was purified on reverse phase HPLC to yield 4-(4-acetylpiperazine-1-carbonyl)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. MS (Q1) 497 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:9]2[CH2:12][C:11](=[CH:13][S:14]([CH2:17][C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])(=[O:16])=[O:15])[CH2:10]2)=[CH:4][CH:3]=1.[NH2:34][CH2:35][CH2:36][N:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1>>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:9]2[CH2:12][C:11](=[CH:13][S:14]([CH2:17][C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:34][CH2:35][CH2:36][N:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)=[O:22])(=[O:16])=[O:15])[CH2:10]2)=[CH:28][CH:29]=1
Reactant: NCCN1CCCC1
Reactant: O=C(O)c1cccc(CS(=O)(=O)C=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1
Product: O=C(NCCN1CCCC1)c1cccc(CS(=O)(=O)C=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1

Procedure:
The operation is carried out under the conditions described in Example 124 starting with 150 mg of activated 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP resin (165 μM) and 0.0333 cm3 of 1-(aminoethyl)pyrrolidine. 39 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(2-pyrrolidin-1-ylethyl)benzamide are thus obtained in the form of a pale yelow powder [1H NMR spectrum (300 MHz, (CD3)2SO-d6 with addition of a few drops of CD3COOD-d4, δ in ppm): from 1.80 to 2.00 (mt, 4H), 2.97 (s, 3H), 3.20 (mt, 6H), 3.57 (t, J=6.5 Hz, 2H), 3.80 (mt, 2H), 4.23 (mt, 2H), 4.77 (s, 1H), 7.35 (d, J=8.5 Hz, 4H), 7.45 (d, J=8.5 Hz, 4H), from 7.50 to 7.65 (mt, 2H), 7.87 (broad s, 1H), 7.90 (broad d, J=7.5 Hz, 1H)].
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]#[N:10])=[C:4]([CH2:11][CH2:12][CH3:13])[CH:3]=1>CO.N.[Ni]>[NH2:10][CH2:9][C:5]1[C:6](=[O:8])[NH:7][C:2]([CH3:1])=[CH:3][C:4]=1[CH2:11][CH2:12][CH3:13]
Reactant: CCCc1cc(C)[nH]c(=O)c1C#N
Agent: [Ni]
Agent: N
Solvent: CO
Product: CCCc1cc(C)[nH]c(=O)c1CN
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.2 %

Procedure:
To a solution of 6-methyl-2-oxo-4-propyl-1,2-dihydropyridine-3-carbonitrile (1.3 g, 7.38 mmol) in methanol and aq. ammonia solution (50 mL, 9:1), catalytic amount of Raney Nickel was added. Reaction mass was stirred at room temperature under hydrogen pressure (balloon pressure) for 5 h. On completion of reaction, it was filtered through celite bed and filtrate was concentrated under reduce pressure to afford the title compound (1.2 g, 92%).
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:19]O>>[I:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:19])=[O:5]
Reactant: CO
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1I
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc([N+](=O)[O-])cc1I
Temperature: 0 °C
Yield: 62 %

Procedure:
A solution of 2-iodo-4-nitrobenzoic acid (9 g, 30.7 mmol), methanol (88 mL) and sulfuric acid (0.82 mL, 15.4 mmol) was heated to reflux overnight. The reaction solution was cooled down to 0° C. for 30 minutes. The solid was filtered to give the desired product (5.90 g, 62%). LCMS calculated for C8H71NO4(M+H)+: m/z=308.0.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[Br:11]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([C:5]#[N:6])[C:3]=1[CH2:10][Br:11]
Reactant: Cc1c(Cl)cccc1C#N
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: N#Cc1cccc(Cl)c1CBr
Yield: 46 %

Procedure:
To a refluxing solution of 3-chloro-2-methylbenzonitrile (2.0 g,13.2 mmol) in 20 mL of CCl4 was added 2.6 g (14.4 mmol, 1.1 eq) of N-bromosuccinimide and 0.2 g of AIBN. The solution was refluxed for 3 hours and then cooled, diluted with 500 mL of CH2Cl2 and washed with 200 mL of H2O and 200 mL of brine. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The resultant oil was flash chromatographed with 5:1 hexane/ethyl acetate to yield the titled compound (1.4 g, 46%) as a yellow oil.
Reaction SMILES: COC[N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N:13]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH:6]=[C:5]1[C:28]1[S:29][CH:30]=[CH:31][N:32]=1.Cl.C(=O)(O)[O-].[Na+]>C(O)C>[S:29]1[CH:30]=[CH:31][N:32]=[C:28]1[C:5]1[NH:4][C:12]2[C:7]([CH:6]=1)=[CH:8][CH:9]=[CH:10][C:11]=2[N:13]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[S:14]([C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)(=[O:15])=[O:16]
Reactant: CCOC(=O)CN(c1cccc2cc(-c3nccs3)n(COC)c12)S(=O)(=O)c1cccs1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CN(c1cccc2cc(-c3nccs3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 70 °C
Reaction time: 6 h
Yield: 60.2 %

Procedure:
A mixture of ethyl N-[1-(methoxymethyl)-2-(1,3-thiazol-2-yl)-1H-indol-7-yl]-N-(2-thienylsulfonyl)aminoacetate (0.31 g), concentrated hydrochloric acid (0.5 mL) and ethanol (6 mL) was stirred at 70° C. for 6 hr. The reaction mixture was neutralized with aqueous sodium bicarbonate, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography and the title compound (0.17 g, yield 60%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point 135-137° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1.C(Cl)(=O)C(Cl)=O.[C:21]1([O:27][CH3:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Al+3].[Cl-].[Cl-].[Cl-].Cl>C(Cl)Cl.CN(C=O)C>[CH3:28][O:27][C:21]1[CH:26]=[CH:25][C:24]([C:9]([C:8]2[CH:7]=[CH:6][C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:14])=[CH:13][CH:12]=2)=[O:11])=[CH:23][CH:22]=1
Reactant: COC(=O)Cc1ccc(C(=O)O)cc1
Reactant: COc1ccccc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(C(=O)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.3 %

Procedure:
4-[2-(Methyloxy)-2-oxoethyl]benzoic acid (150) (1.0 g, 5.15 mmol) was dissolved in CH2Cl2 (25 mL). Oxalyl chloride (0.92 mL, 10.3 mmol) was added dropwise, followed by addition of two drops of DMF. The reaction mixture was stirred at room temperature for 2 h. CH2Cl2 and the excess of oxalyl chloride were removed under vacuum. The residue was dissolved in CH2Cl2 (15 mL) with anisole (0.74 mL, 6.70 mmol). Cooled in an ice bath, AlCl3 (1.04 g, 7.73 mmol) was added in portions. The mixture was stirred at 0° C. for 4 h, then stirred at room temperature for 20 minutes. Poured into 1 N HCl (25 mL) with ice, the mixture was extracted with CH2Cl2 (2×60 mL). The combined CH2Cl2 extract was washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give yellow oil. The crude product was purified by chromatography on a silica gel column eluted with hexanes:EtOAc (5:1) to give 1.00 g (68%) of compound 151 as colorless oil. 1H NMR (400 MHz, CDCl3): δ 3.71 (s, 2H), 3.72 (s, 3H), 3.88 (s, 3H), 6.96 (d, J=8.8 Hz, 2H), 7.38 (d, J=8.0 Hz, 2H), 7.72 (d, J=8.1 Hz, 2H), 7.82 (d, J=8.8 Hz, 2H). LCMS (ESI): m/z, 285 (M+H)+, 283 (M−H)−.