Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:19]=[CH:18][C:6]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[C:5]([N+:20]([O-:22])=[O:21])[CH:4]=1.S(OCC)(O[CH2:27][CH3:28])(=O)=O.[OH-].[Na+]>CN(C=O)C>[Cl:2][C:3]1[CH:19]=[CH:18][C:6]([N:7]([CH2:27][CH3:28])[S:8]([C:11]2[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=2)(=[O:10])=[O:9])=[C:5]([N+:20]([O-:22])=[O:21])[CH:4]=1
Reactant: CCOS(=O)(=O)OCC
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2[N+](=O)[O-])cc1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCN(c1ccc(Cl)cc1[N+](=O)[O-])S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 80.6 %

Procedure:
To a mixture of 4′-chloro-2′-nitro-p-toluenesulfonanilide sodium salt (1046 g (3.00 mol)) and DMF (1100 ml), heated in an oil bath kept at 100° C., was added diethyl sulfate (733.8 g (4.50 mol)) over a period of one hour. The resulting mixture was further stirred for 1.5 hours at the same temperature to complete the reaction, and then left to cool to room temperature. A 1.5% aqueous sodium hydroxide solution was added and the mixture was stirred for one hour. The resulting solid was then filtered, washed with water, dried and recrystallized from 1450 ml of ethyl acetate to give 858 g (81%) of the title compound as pale yellow crystals.
Reaction SMILES: [NH2:1][C:2]1([C:7]#[N:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.C(O[C:13](=O)[CH3:14])(=O)C.[CH:16]([OH:18])=O>>[C:7]([C:2]1([N:1]([C:14]2[CH:13]=[CH:4][CH:3]=[CH:2][CH:6]=2)[CH:16]=[O:18])[CH2:6][CH2:5][CH2:4][CH2:3]1)#[N:8]
Reactant: CC(=O)OC(C)=O
Reactant: O=CO
Reactant: N#CC1(N)CCCC1
Product: N#CC1(N(C=O)c2ccccc2)CCCC1

Procedure:
1-Aminocyclopentanecarbonitrile was added to a solution obtained by heating acetic anhydride and formic acid under stirring and the whole was heated to obtain N-(1-cyanocyclopentyl)-N-phenylformamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14]S(C2C=CC=CC=2)(=O)=O)=[C:6]([CH:13]=1)/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10].Br.Br[CH2:26][C:27]([C:29]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][N:30]=1)=[O:28]>>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:7]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:13]=2)[NH:14][C:26]=1[C:27]([C:29]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][N:30]=1)=[O:28]
Reactant: COC(=O)/C=C/c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Reactant: COc1ccnc(C(=O)CBr)c1
Agent: Br
Product: COC(=O)Cc1c(C(=O)c2cc(OC)ccn2)[nH]c2ccc(Cl)cc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-5-chloro-2-(penylsulfonylamino)cinnamate (Example 36, step 3) and 2-bromoacetyl-4-methoxypyridine hydrobromide (Preparation is described in Example 105).
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH2:11][C:10]([CH3:25])([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]#[C:20][Si](C)(C)C)[CH:14]=2)[CH:9]([CH3:26])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.ClCCl.O>[CH2:1]([N:7]1[CH2:12][CH2:11][C:10]([CH3:25])([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]#[CH:20])[CH:14]=2)[CH:9]([CH3:26])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN1CCC(C)(c2cccc(C#C[Si](C)(C)C)c2)C(C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: C#Cc1cccc(C2(C)CCN(CCCCCC)CC2C)c1
Temperature: 25 °C
Yield: 84 %

Procedure:
A solution of 1-hexyl-3,4-dimethyl-4-{3-[2-(trimethylsilyl)ethynyl]-phenyl}piperidine (Preparation 4, 150 mg, 0.40 mmol) in tetrahydrofuran (2 mL) was cooled to -70° C. and tetrabutylammonium fluoride (1.0 M in THF, 0.41 mL, 0.41 mmol) was added slowly. The reaction mixture was allowed to warm to room temperature gradually before being diluted with dichloromethane (10 mL) and water (10 mL). The phases were separated and the aqueous layer was further extracted with dichloromethane (2×10 mL). The combined organics were dried (Na2SO4) and the solvent evaporated in vacuo. The oily yellow residue was purified by column chromatography on silica gel (10 g) eluted with ethyl acetate:hexane 0.880 ammonia (10:89:1) to give the title compound as an oil (100 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][NH:17][C:18](=[O:47])[CH2:19][N:20]1[C:24](=[O:25])[C:23]([CH3:27])([CH3:26])[N:22]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[CH3:45])=[O:37])=[CH:31][CH:30]=2)[C:21]1=[O:46])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:48](O)(=O)[CH2:49][CH3:50]>C(O)(C)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][NH:17][C:18](=[O:47])[CH2:19][N:20]1[C:24](=[O:25])[C:23]([CH3:27])([CH3:26])[N:22]([CH2:28][C:29]2[CH:30]=[CH:31][C:32]([NH:35][C:36]([NH:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[CH3:45])=[O:37])=[CH:33][CH:34]=2)[C:21]1=[O:46])[C:13]([O:15][CH:49]([CH3:50])[CH3:48])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(=O)O
Reactant: Cc1ccccc1NC(=O)Nc1ccc(CN2C(=O)N(CC(=O)NC[C@H](NC(=O)OCc3ccccc3)C(=O)O)C(=O)C2(C)C)cc1
Solvent: CC(C)O
Product: Cc1ccccc1NC(=O)Nc1ccc(CN2C(=O)N(CC(=O)NC[C@H](NC(=O)OCc3ccccc3)C(=O)OC(C)C)C(=O)C2(C)C)cc1

Procedure:
The compound was prepared from (S)-2-benzyloxycarbonylamino-3-((4,4-dimethyl-3-(4-(3-(2-methylphenyl)ureido)benzyl)-2,5-dioxoimidazolidin-1-yl)acetylamino)propionic acid and isopropanol as described in Examples 95, 96, 98-102 and 104-116. Batch size: 0.465 mmol of the starting propionic acid. Yield: 233 mg.
Reaction SMILES: F[C:2]1[C:3]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:4]([CH3:18])[C:5]([C:16]#[N:17])=[C:6]2[C:10]=1[O:9][C:8]([N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[N:7]2.C(N(CC)CC)C.[CH3:32][N:33]([CH3:39])[C@H:34]1[CH2:38][CH2:37][NH:36][CH2:35]1>CS(C)=O.ClCCl>[CH3:32][N:33]([CH3:39])[C@H:34]1[CH2:38][CH2:37][N:36]([C:2]2[C:3]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:4]([CH3:18])[C:5]([C:16]#[N:17])=[C:6]3[C:10]=2[O:9][C:8]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:7]3)[CH2:35]1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(N3CCCC3)nc2c1C#N
Reactant: CN(C)[C@H]1CCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(N3CCCC3)nc2c1C#N
Temperature: 150 °C
Reaction time: 4 h
Yield: 29.5 %

Procedure:
7-Fluoro-5-methyl-6-phenyl-2-(pyrrolidin-1-yl)-1,3-benzoxazole-4-carbonitrile (I-135) (0.10 g, 0.31 mmol) was suspended in dimethyl sulfoxide (3.5 ml), then triethylamine (90.0 μl, 0.65 mmol) and (3S)-3-(dimethylamino)pyrrolidine (88.0 μl, 0.69 mmol) were added, followed by stirring in a sealed tube at an external temperature of about 150° C. for 4 hours. This was diluted with dichloromethane, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified by preparative thin-layer chromatography (dichloromethane:methanol=20:1), then ether and a small amount of hexane were added, and the insoluble matter was collected by filtration to obtain a beige solid (38 mg, 29%).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][CH2:3][CH:2]1[CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([N:19]2[CH2:23][CH2:22][NH:21][C:20]2=[O:24])[CH2:15][CH2:14]1.I([O-])(=O)(=O)=[O:26].[Na+]>O1CCOCC1.CO.O>[O:26]=[S:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:1][CH:2]([CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][CH:16]([N:19]3[CH2:23][CH2:22][NH:21][C:20]3=[O:24])[CH2:17][CH2:18]2)[CH2:3]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: O=C1NCCN1C1CCN(CCC2CSc3ccccc3O2)CC1
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: O=C1NCCN1C1CCN(CCC2CS(=O)c3ccccc3O2)CC1
Temperature: 25 °C

Procedure:
To the solution of 3.47 g of 1-[1-[2-(1,4-benzoxathian-2-yl)-ethyl]-4-piperidyl]-2-imidazolidinone (Example 5, No. 8) in 10 ml of dioxane and 10 ml of methanol, the solution of 2.8 g of sodium metaperiodate in 20 ml of water is added dropwise while stirring at room temperature. After 2 hours the mixture is evaporated, the residue taken up in water and the mixture extracted with methylene chloride. The extract is washed with saturated aqueous sodium chloride, dried, evaporated and the residue recrystalized from isopropanol, to yield the 1-[1-[2-(4-oxo-1,4-benzooxathian-2-yl)-ethyl]-4-piperidyl]-2-imidazolidinone; m.p. 145°.
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([NH:18][N:19]3[CH2:23][CH2:22][N:21]=[CH:20]3)=[C:16]([CH3:17])[C:11]=2[N:10]=[CH:9]1)=O)(C)(C)C.[BrH:24]>C(O)(=O)C>[BrH:24].[BrH:24].[CH3:17][C:16]1[C:11]2[NH:10][CH:9]=[N:8][C:12]=2[CH:13]=[CH:14][C:15]=1[NH:18][N:19]1[CH2:23][CH2:22][N:21]=[CH:20]1
Reactant: Cc1c(NN2C=NCC2)ccc2c1ncn2C(=O)OC(C)(C)C
Agent: Br
Solvent: CC(=O)O
Product: Cc1c(NN2C=NCC2)ccc2nc[nH]c12
Temperature: 25 °C

Procedure:
To a solution of 1-tert-butoxycarbonyl-4-methyl-5-(2-imidazolinylamino)benzimidazole (2.40 g) in glacial acetic acid (50 mL) is added a solution of hydrobromic acid in glacial acetic acid (30%, 6 mL). The mixture is stirred at room temperature and gas evolution is monitored. After the gas evolution has stopped (about 1 hour), the precipitate is filtered and washed with ether. The solid is recrystallized from methanol/ether and dried in vacuo to afford 4-methyl-5-(2-imidazolinylamino)benzimidazole dihydrobromide as a pale rose solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])=[CH:11][C:10]([C:20]([OH:22])=O)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C([N:46]3[CH2:50][C:49](=[O:51])[NH:48][CH2:47]3)=O)=N2)C=CC=1F>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])=[CH:11][C:10]([C:20]([N:46]3[CH2:50][C:49](=[O:51])[NH:48][CH2:47]3)=[O:22])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccc(F)c(Cl)c3)n2)CN1
Reactant: O=C(O)c1cc(-c2ccccc2F)n(-c2cccc(Cl)c2)n1
Product: O=C1CN(C(=O)c2cc(-c3ccccc3F)n(-c3cccc(Cl)c3)n2)CN1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 86A in analogy to the synthesis of the compound of Example 1. 34 mg (88% of theory) of the title compound are obtained.
Reaction SMILES: [OH:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[H-].[Na+].[CH2:14](I)[CH3:15].CN(C=O)C.[CH2:22]1COC[CH2:23]1>>[CH2:22]([O:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:14][CH3:15])=[O:5])[CH3:23]
Reactant: Cc1cccc(C(=O)O)c1O
Reactant: C1CCOC1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(C)c1OCC
Temperature: 60 °C
Reaction time: 0.67 h

Procedure:
at room temperature, a solution of 100.3 g of 2-hydroxy-3-methylbenzoic acid in 150 ml of DMF/THF (dimethylformamide/tetrahydrofuran, 1:1) is dripped into 43.6 g of sodium hydride (80% strength in white oil) in 350 ml of DMF/THF (1:1). The mixture is stirred for 40 minutes at 60° C. and then 226.5 g of ethyl iodide is dripped in at room temperature. After the addition of a further 250 ml of DMF/THF (1:1) the mixture is stirred for 9 hours at 60°-70° C. The reaction mixture is poured into ice water and extracted with ether. The combined organic phases are washed with water, dried and concentrated. There is obtained 126.3 g of the desired compound.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[CH2:3][C@H:4]([NH:6][C:7]([C:9]1[C:22]2[C:13](=[N:14][C:15]3[C:20]([N:21]=2)=[C:19]2[CH:23]=[CH:24][CH:25]=[C:26]([O:27][CH3:28])[C:18]2=[CH:17][CH:16]=3)[CH:12]=[CH:11][C:10]=1[O:29]C)=[O:8])[CH3:5].[CH3:32][N:33]([CH3:63])[CH2:34][C@H:35]([NH:38][C:39]([C:41]1[C:54]2[C:45](=[N:46][C:47]3[C:52]([N:53]=2)=[C:51]2[CH:55]=[CH:56][CH:57]=[C:58]([O:59][CH3:60])[C:50]2=[CH:49][CH:48]=3)[CH:44]=[CH:43][C:42]=1[O:61]C)=[O:40])[CH2:36][OH:37]>>[CH3:31][N:2]([CH3:1])[CH2:3][C@H:4]([NH:6][C:7]([C:9]1[C:22]2[C:13](=[N:14][C:15]3[C:20]([N:21]=2)=[C:19]2[CH:23]=[CH:24][CH:25]=[C:26]([O:27][CH3:28])[C:18]2=[CH:17][CH:16]=3)[CH:12]=[CH:11][C:10]=1[OH:29])=[O:8])[CH3:5].[CH3:63][N:33]([CH3:32])[CH2:34][C@H:35]([NH:38][C:39]([C:41]1[C:54]2[C:45](=[N:46][C:47]3[C:52]([N:53]=2)=[C:51]2[CH:55]=[CH:56][CH:57]=[C:58]([O:59][CH3:60])[C:50]2=[CH:49][CH:48]=3)[CH:44]=[CH:43][C:42]=1[OH:61])=[O:40])[CH2:36][OH:37]
Reactant: COc1ccc2nc3ccc4c(OC)cccc4c3nc2c1C(=O)N[C@H](CO)CN(C)C
Reactant: COc1ccc2nc3ccc4c(OC)cccc4c3nc2c1C(=O)N[C@H](C)CN(C)C
Product: COc1cccc2c1ccc1nc3ccc(O)c(C(=O)N[C@H](C)CN(C)C)c3nc12
Product: COc1cccc2c1ccc1nc3ccc(O)c(C(=O)N[C@H](CO)CN(C)C)c3nc12

Procedure:
10-Hydroxy-4-methoxy-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-1(R)-methyl-ethyl)-amide was prepared in an analogous manner from 4,10-dimethoxy-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-1(R)-methyl-ethyl)-amide; and 10-Hydroxy-4-methoxy-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-1(S)-hydroxymethyl-ethyl)-amide was prepared in an analogous manner from 4,10-dimethoxy-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-1(S)-hydroxymethyl-ethyl)-amide.
Reaction SMILES: CC([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9]C=2)[C:5]=1[OH:14])=O.C1C2CC(=[O:22])C(C2)C1.N1CCCC1>C1(C)C=CC=CC=1>[O:14]1[C:5]2[C:6](=[CH:11][CH:12]=[CH:13][CH:4]=2)[CH2:7][CH2:8][CH:9]1[OH:22]
Reactant: CC(=O)c1ccc2ccccc2c1O
Reactant: O=C1CC2CCC1C2
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Product: OC1CCc2ccccc2O1
Reaction time: 10 h

Procedure:
A solution was prepared by dissolving 10 g (0.054 mole) of 1-hydroxy-2-acetonaphthone, 6.6 g (0.06 mole) of norcamphor and 8 g (0.113 mole) of pyrrolidine in 300 cc of toluene. The solution was boiled for 10 hours and water was separated. After termination of the reaction, toluene was removed under reduced pressure, and the remaining chromanone compound was crystallized with acetone. Then, the chromanone compound was dissolved in 200 cc of methanol, and sodium boron hydride was gradually added to the solution to form a chromanol compound. Then, 7.47 g of the chromanol compound was heated at 150° to 160° C. together with 4.5 g of anhydrous copper sulfate in a carbon dioxide current for 10 minutes and the obtained viscous liquid was purified by the chromatography on silica gel to obtain 6.3 g of a chromene compound of the following formula: ##STR67##
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:9]1[C:15]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:10]1[CH2:11][NH:12][CH2:13][CH2:14]2.C(N(CC)CC)C>C1C=CC=CC=1>[CH2:1]([N:12]1[CH2:13][CH2:14][C:15]2([O:9][CH:10]2[CH2:11]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(C23CCNCC2O3)cc1
Reactant: BrCc1ccccc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: c1ccc(CN2CCC3(c4ccccc4)OC3C2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
22.5 Ml of benzyl bromide was added dropwise to a stirred solution of 32.3 g of 3,4-epoxy-4-phenylpiperidine and 38.1 ml of triethylamine in 254 ml of benzene. A precipitate appeared during the addition. The whole reaction mixture was then stirred at room temperature for three hours. The residual solid was removed by filtration and the solvent evaporated to give 53.4 g of 1-benzyl-3,4-epoxy-4-phenyl-piperidine.
Reaction SMILES: Cl.[CH2:2]([C@@H:9]1NC(C)(C)N(C)[C:10]1=[O:17])[C:3]1C=CC=CC=1.[C:18]1([C:24]2[O:25][C:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[C:27]3[C:32]=2[CH:31]=[CH:30][CH:29]=[CH:28]3)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CO.C(=O)/C=C/C>CN(C=O)C.CCOCC>[C:18]1([C@@:24]23[O:25][C@@:26]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)([C@@H:9]([CH:10]=[O:17])[C@@H:2]2[CH3:3])[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:32]3=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: c1ccc(-c2oc(-c3ccccc3)c3ccccc23)cc1
Reactant: CN1C(=O)[C@H](Cc2ccccc2)NC1(C)C
Agent: C/C=C/C=O
Agent: Cl
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C[C@H]1[C@H](C=O)[C@]2(c3ccccc3)O[C@@]1(c1ccccc1)c1ccccc12
Temperature: 10 °C
Reaction time: 24 h
Yield: 75 %

Procedure:
To a 10° C. solution of 5 (13 mg, 0.058 mmol), 1,3-diphenylisobenzofuran (162 mg, 0.60 mmol), and MeOH (12 μL, 0.30 mmol) in DMF/1H2O (95/5 v/v, 1.0 M) was added (E)-crotonaldehyde (25 μL, 0.30 mmol). The solution was stirred at 10° C. for 24 h. The reaction mixture was then diluted with Et2O (10 mL) and washed with H2O (10 mL). The aqueous layer was extracted with Et2O (10 mL×2) and the combined organics were dried (Na2SO4), and concentrated. Purification by silica gel chromatography (7% EtOAc/hex) afforded the title compound as a yellow solid in 75% yield (76 mg, 0.22 mmol); 35:1 exo:endo; 96% ee. Product ratios were determined, after reduction to the corresponding alcohol (4 eq NaBH4, EtOH (0.1 M)), by HPLC (Chiralcel OD-H column, 3% EtOAc/hex, 1.0 mL/min) exo isomers tr=14.1 min and 15.3 min, endo isomers tr=16.5 min and 20.8. IR (CH2Cl2) 3066, 3041, 2828, 2729, 1722, 1603, 1499, 1457, 1448, 1381, 1355, 1309 cm−1; 1H NMR (500 MHZ, CDCl3) δ 9.36 (d, J=5.8 Hz, 1H, CHO), 7.73-7.78 (m, 2H, ArH), 7.43-7.57 (m, 7H, ArH), 7.35-7.40 (m, 1H, ArH), 7.16-7.26 (m, 3H, ArH), 7.04-7.08 (m, 1H, ArH), 3.08 (dq, J=6.9, 4.1 Hz, 1H, CHCH3), 2.56 (dd, J=5.8, 4.2 Hz, 1H, CHCHO), 0.96 (d, J=6.9 Hz, 3H, CH3); 13C NMR (125 MHZ) δ 201.9, 147.4, 145.0, 145.0, 136.6, 135.7, 135.5, 128.8, 128.6, 128.0, 127.4, 127.3, 127.0, 126.0, 125.5, 121.7, 118.5, 91.4, 89.2, 66.0, 43.0, 34.2, 30.3, 16.5; HRMS exact mass calcd for (C24H20O2) requires m/z 341.1541, found m/z 341.1542; [α]D=−82.4 Ĉ=1.0, CHCl3).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:20]#[N:21])=[C:18]([OH:19])[C:13]=3[C:12]3[CH:22]=[C:23]([Br:26])[CH:24]=[N:25][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:27][O:28][CH2:29][CH2:30]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>CN(C=O)C.C(OCC)(=O)C>[C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:20]#[N:21])=[C:18]([O:19][CH2:30][CH2:29][O:28][CH3:27])[C:13]=3[C:12]3[CH:22]=[C:23]([Br:26])[CH:24]=[N:25][C:11]2=3)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1ncc2c(c1O)c1cc(Br)cnc1n2S(=O)(=O)c1ccccc1
Reactant: COCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCOc1c(C#N)ncc2c1c1cc(Br)cnc1n2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 9 h
Yield: 36.6 %

Procedure:
A solution of 9-benzenesulfonyl-3-bromo-5-hydroxy-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (120 mg, 0.28 mmol), 2-methoxyethanol (128 μL, 1.60 mmol) and triphenylphosphine (315 mg, 1.60 mmol) in anhydrous DMF (1.25 mL) was treated dropwise with diethyl azodicarboxylate (252 μL, 1.60 mmol) and the mixture stirred at ambient temperature for 9 h. The mixture was diluted with ethyl acetate (15 mL) and washed with brine (3×10 mL), dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The crude material was purified by column chromatography (silica, 5 g column, Si-SPE, 30-50% DCM in pentane) to afford the title compound (50 mg, 37%). 1H NMR (CDCl3, 400 MHz): 9.58 (s, 1H), 8.97 (d, J=2.3 Hz, 1H), 8.76 (d, J=2.3 Hz, 1H), 8.24-8.22 (m, 1H), 8.22-8.00 (m, 1H), 7.66-7.60 (m, 1H), 7.54-7.48 (m, 2H), 4.74-4.69 (m, 2H), 3.87-3.83 (m, 2H), 3.48 (s, 3H). LCMS (Method B): RT=4.25 min, M+H+=487/489.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH:5]([NH:9][C:10](=[O:19])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:6]([OH:8])=O.[C:21](OC(=O)C)(=O)C>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH:5]([NH:9][C:10](=[O:19])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:6](=[O:8])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)CC(NC(=O)CCc1ccccc1)C(=O)O
Solvent: c1ccncc1
Product: COC(=O)CC(NC(=O)CCc1ccccc1)C(C)=O
Temperature: 90 °C

Procedure:
2-(3-Phenyl-propionylamino)-succinic acid 4-methyl ester (10 g, 36 mmol), pyridine (50 mL) and acetic anhydride (45 mL) were combined in a 500 mL flask. The reaction mixture was heated at 90° C. for 2 h and then cooled to ambient temperature. After concentrating the reaction mixture under reduced pressure, DI water was added (100 mL). (Potential exotherm!). The reaction mixture was partitioned between water and CH2Cl2. The organic phase was washed with 1N HCl and then dried (MgSO4), filtered and concentrated under reduced pressure. The material was used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.31-7.20 (m, 5H), 6.79 (br d, J=7.6 Hz, 1H), 4.72 (X of ABX, 1H), 3.65 (s, 3H), 3.01-2.93 (m, 3H), 2.71-2.62 (m, 3H), 2.11 (s, 3H); MS (EI) 278.1 (M+H).
Reaction SMILES: [Mg].C(O[CH:5]([O:15]CC)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]Cl)C.Cl[CH:19]([CH2:22][CH3:23])[CH:20]=[CH2:21].ClCC=CCC.Cl>O1CCCC1.CC(C)=O.C(Cl)CCC>[CH:5](=[O:15])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:21][CH:20]=[CH:19][CH2:22][CH3:23]
Reactant: C=CC(Cl)CC
Reactant: CCOC(CCCCCCCCCl)OCC
Agent: CCC=CCCl
Agent: Cl
Agent: [Mg]
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCl
Product: CCC=CCCCCCCCCCC=O
Temperature: 5 °C
Reaction time: 0.08 h

Procedure:
To 0.48 gm of magnesium in a thoroughly dried flask equipped with condensor and magnetic stirrer was added 2 mls of anhydrous tetrahydrofuran and 0.3 ml of butyl chloride. The mixture was stirred and heated at reflux until reaction initiated (approximately 10 minutes). After 5 minutes, portionwise addition of 3.5 gms of 1,1-diethoxy-9-chloro nonane in 10 ml of tetrahydrofuran was begun. When the addition was complete (15 minutes) the mixture was stirred and heated for 2 hours. It was then cooled to 5° C. in an ice bath and 30 gms of a mixture of 3-chloro-1-pentene (approximately 40%) and 1-chloro-2-pentene (approximately 60%) was added all at once. The mixture was heated slowly and stirred, whereupon it became cloudy. Heating was continued at reflux temperature for 2 hours. The mixture was then cooled, poured into 100 ml of 3 N-hydrochloric acid and diluted with 100 ml of tetrahydrofuran and 150 ml of acetone. The resulting solution was stirred and heated for 30 minutes. It was then concentrated on rotary evaporator and extracted twice with 100 mls of hexane. The organic layer was dried over sodium sulphate, evaporated and distilled. The majority distilled at 110° C. at 0.35 torr and yielded 2.11 gms of 11-tetradecenal.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:6]([CH3:11])=[CH:7][CH:8]=[CH:9][CH:10]=1)=O.[Br:12][C:13]1[CH:20]=[CH:19][C:16](C#N)=[CH:15][CH:14]=1.P(Cl)(Cl)(Cl)=O.[CH2:26]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[CH3:27]>>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([C:1]2[N:2]=[C:3]([N:31]3[CH2:32][CH2:33][N:28]([CH2:26][CH3:27])[CH2:29][CH2:30]3)[C:5]3[C:6]([CH:11]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)=[CH:19][CH:20]=1
Reactant: CCN1CCNCC1
Reactant: N#Cc1ccc(Br)cc1
Reactant: CNC(=O)c1ccccc1C
Solvent: O=P(Cl)(Cl)Cl
Product: CCN1CCN(c2nc(-c3ccc(Br)cc3)cc3ccccc23)CC1
Temperature: 100 °C

Procedure:
To 3-(4-bromophenyl)isoquinolin-1-one (3.86 g) obtained by reacting N-methyl-o-toluamide (7.50 g) and 4-bromobenzonitrile (9.10 g) according to the method of Example 10-1 was added phosphorus oxychloride (38.6 g), and the resulting mixture was heated at 100° C. for 2 hr. The reaction solution was evaporated, and to the resulting residue were added ethyl acetate and purified water. The ethyl acetate layer was washed with water, an aqueous solution of saturated sodium bicarbonate and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting 1-chloro-3-(4-bromophenyl)isoquinoline was reacted as it was with N-ethylpiperazine (30 ml) at 120° C. for 8 hr. The reaction solution was evaporated, and to the resulting residue were added ethyl acetate and purified water. The ethyl acetate layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system), to give 3-(4-bromophenyl)-1(4-ethylpiperazin-1-yl)isoquinoline (1.62 g) as a pale yellow oil.