Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[CH2:6]([O:10][C:11]1[CH:16]=[C:15](/[CH:17]=[C:18](\[O:23][CH3:24])/[C:19]([O:21][CH3:22])=[O:20])[CH:14]=[CH:13][C:12]=1[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]([CH3:44])[C:32]([O:34]C2C=CC([N+]([O-])=O)=CC=2)=O)[CH:26]=1)[CH2:7][CH2:8][CH3:9].O.C(OCC)(=O)C>CN(C)C=O>[CH2:6]([O:10][C:11]1[CH:16]=[C:15](/[CH:17]=[C:18](\[O:23][CH3:24])/[C:19]([O:21][CH3:22])=[O:20])[CH:14]=[CH:13][C:12]=1[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]([CH3:44])[C:32]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:34])[CH:26]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCN
Reactant: CCCCOc1cc(/C=C(\OC)C(=O)OC)ccc1-c1cccc(N(C)C(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OC)C(=O)OC)cc2OCCCC)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 71.1 %

Procedure:
0.075 mL (0.75 mmol) of n-butylamine is added to a solution of 0.4 g (0.6 mmol) of methyl (Z)-3-{2-butoxy-3′-[methyl-(4-nitrophenoxycarbonyl)amino]biphenyl-4-yl}-2-methoxyacrylate in 5 mL of dimethylformamide. The reaction mixture is rapidly placed in an oil bath preheated to 80° C. and then stirred at 80° C. for 3 hours. After cooling, the reaction is stopped by addition of 10 mL of water and extraction with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution and then dried over magnesium sulfate. The solvents are evaporated off. The crude product obtained is purified by chromatography on a column of silica eluted with a 70/30 heptane/ethyl acetate mixture to give 0.2 g (67%) of methyl (Z)-3-[2-butoxy-3′-(3-butyl-1-methylureido)biphenyl-4-yl]-2-methoxyacrylate in the form of a colorless oil.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].C[N:17]1[CH2:22][CH2:21][C:20]2=[C:23]([CH:26]=O)[NH:24][CH:25]=[C:19]2[C:18]1=[O:28].N1CCCCC1>C(O)C>[CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[CH:26][C:23]1[NH:24][CH:25]=[C:19]2[C:20]=1[CH2:21][CH2:22][NH:17][C:18]2=[O:28])(=[O:5])=[O:4]
Reactant: CN1CCc2c(c[nH]c2C=O)C1=O
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Solvent: CCO
Solvent: C1CCNCC1
Product: CNS(=O)(=O)c1ccc2c(c1)C(=Cc1[nH]cc3c1CCNC3=O)C(=O)N2
Temperature: 80 °C

Procedure:
A mixture of 2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid methylamide (45.2 mg, 0.2 mmol), 5-methyl-4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridine-1-carbaldehyde (35.6 mg, 0.2 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated at 80° C. for 4 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[NH:11][C:10]2[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=1.[C:15]([C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19]Br)#[N:16].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[Cl:1][C:2]1[N:11]([CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[C:15]#[N:16])[C:10]2[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=1
Reactant: N#Cc1ccccc1CBr
Reactant: Cn1c(=O)c2[nH]c(Cl)nc2n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(nc(Cl)n2Cc2ccccc2C#N)n(C)c1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
8-Chlorotheophylline (20 g, 93.19 mmol) was dissolved in 800 ml of DMF and 2-cyanobenzyl bromide (18.28 g, 93.19 mmol), potassium carbonate (12.88 g, 93.19 mmol), and potassium iodide (10 mg, 0.06 mmol) were added. The mixture was stirred at room temperature for 20 hours. The solvent was evaporated and the residue was suspended in 900 ml of water and 900 ml of EtOAc, and compound (1A) was collected by filtration of the suspension. The layers in the mother liquor were separated and the aqueous layer was extracted with 3×500 ml of EtOAc. The combined organic layers were washed with 1×500 ml of water, and the solvent was evaporated to give compound (1A) as white crystals. Combined yield: 28.6 g (93%). Mp. 222.5-223.7° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([C@H:12]([CH:17]([CH3:19])C)[C:13]([O:15][CH3:16])=[O:14])[CH2:5]2.Br[C:21]1C=CC(C(OC)=O)=C(CBr)[CH:22]=1.Cl.COC(=O)C(C1C=CC=CC=1)N>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([C:12]1([C:13]([O:15][CH3:16])=[O:14])[CH2:17][CH2:19][CH2:22][CH2:21]1)[CH2:5]2
Reactant: COC(=O)c1ccc(Br)cc1CBr
Reactant: COC(=O)[C@@H](C(C)C)N1Cc2cc(Br)ccc2C1=O
Agent: COC(=O)C(N)c1ccccc1
Agent: Cl
Product: COC(=O)C1(N2Cc3cc(Br)ccc3C2=O)CCCC1

Procedure:
The compound of example 368 was prepared analogous to compound of example 359 by reaction of the compound of example 358 and 2-phenyl glycine methyl ester hydrochloride.
Reaction SMILES: [Na].[CH2:2]([NH:9]/[C:10](=[C:18]1/[C:19]([CH2:31][C:32]([O:34]C)=O)=[N:20][N:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[C:22]/1=[O:23])/[CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl>CC(O)C>[CH2:2]([N:9]1[C:32](=[O:34])[CH:31]=[C:19]2[NH:20][N:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[C:22](=[O:23])[C:18]2=[C:10]1[CH2:11][N:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)CC1=NN(c2ccccc2Cl)C(=O)/C1=C(/CN1CCOCC1)NCc1ccccc1
Agent: Cl
Agent: [Na]
Solvent: CC(C)O
Product: O=c1c2c(CN3CCOCC3)n(Cc3ccccc3)c(=O)cc2[nH]n1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 12 %

Procedure:
An isopropanolic solution of i-PrONa, obtained by dissolving of sodium (0.017 g, 0.75 mmol, 2 equiv) in i-PrOH (2 ml), was treated with methyl [(4Z)-4-[1-(benzylamino)-2-morpholin-4-ylethylidene]-1-(2-chlorophenyl)-5-oxo-4,5-dihydro-1H-pyrazol-3-yl]acetate (Compound of Formula (XIV) (170 mg, 0.75 mmol, 1 equiv.). The reaction mixture was stirred at room temperature for 0.5 h, then cooled and neutralized to pH 6 by addition 1M HCl solution. i-PrOH were removed in vacuo and the crude was purified by flash chromatography to yield 9 mg of pure product 5-benzyl-2-(2-chlorophenyl)-4-(morpholin-4-ylmethyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione. Yield 12%. 1HNMR (500 MHz, DMSO-d6): 2.37-2.41 (m, 4H); 3.94-4.00 (m, 2H); 5.52-5.55 (m, 2H), 5.84 (s, 1H); 7.07-7.09 (m, 2H), 7.22-7.28 (m, 2H); 7.30-7.33 (m, 2H); 7.48-7.51 (m, 2H); 7.59-7.61 (m, 1H); 7.63-7.67 (m, 1H). MS (ESI+): 451.9; MS (ESI−): 449.7.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5]=1[CH3:13].CNCC1C=CC2C(=CC=CC=2)C=1CCC.[ClH:30].[N:31]1([CH2:37][CH2:38][CH2:39][N:40]2[CH2:46][C:45]3[CH:47]=[C:48](/[CH:51]=[CH:52]/[C:53](O)=[O:54])[CH:49]=[N:50][C:44]=3[NH:43][C:42](=[O:56])[CH2:41]2)[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1>>[ClH:30].[CH3:1][N:2]([CH2:3][C:4]1[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5]=1[CH3:13])[C:53](=[O:54])/[CH:52]=[CH:51]/[C:48]1[CH:49]=[N:50][C:44]2[NH:43][C:42](=[O:56])[CH2:41][N:40]([CH2:39][CH2:38][CH2:37][N:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)[CH2:46][C:45]=2[CH:47]=1
Reactant: CNCc1sc2ccccc2c1C
Reactant: O=C(O)/C=C/c1cnc2c(c1)CN(CCCN1CCOCC1)CC(=O)N2
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CN(CCCN2CCOCC2)CC(=O)N3)sc2ccccc12
Yield: 56 %

Procedure:
According to the procedure of Example 1, except substituting methyl-(3-methyl-benzo[b]thiophen-2-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-[4-(3-morpholin-4-yl-propyl)-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl]acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (0.20 g, 56%) was prepared as an off-white powder: 1H NMR (300 MHz, DMSO-d6) δ 10.88 (br s, 1H), 10.48 (br s, 1H), 8.58 (s, 1H), 8.31 (s, 1H), 7.88-7.86 (m, 1H), 7.75-7.72 (m, 1H), 7.60-7.55 (m, 1H), 7.42-7.30 (m, 3H), 5.16-4.89 (m, 2H), 3.98 (br s, 2H), 3.92-3.79 (m, 4H), 3.63 (br s, 2H), 3.37-3.33 (m, 6H), 3.18-3.10 (m, 2H), 2.94 (s, 1H), 2.63 (br s, 2H), 2.42 (s, 3H), 1.92 (br s, 2H); MS (ESI) m/e 534 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([C:11]([NH2:13])=[O:12])[NH:5][N:4]=1)[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+].[CH3:22][O:23][CH2:24][CH2:25]Br>CC(CC)=O.O>[CH2:1]([C:3]1[N:4]([CH2:25][CH2:24][O:23][CH3:22])[N:5]=[C:6]([C:11]([NH2:13])=[O:12])[C:7]=1[N+:8]([O-:10])=[O:9])[CH3:2]
Reactant: COCCBr
Reactant: CCc1n[nH]c(C(N)=O)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CCC(C)=O
Product: CCc1c([N+](=O)[O-])c(C(N)=O)nn1CCOC
Temperature: 25 °C
Reaction time: 70 h
Yield: 73.8 %

Procedure:
A mixture of 3-ethyl-4-nitro-1H-pyrazole-5-carboxamide (25 g, 0.136 Mol), sodium carbonate (18 g, 0.17 Mol) and sodium iodide (20.4 g, 0.136 Mol) were suspended in ethyl methyl ketone (125 mL) at room temperature. 2-bromoethyl methyl ether (12.8 mL, 0.142 Mol) was added and the mixture was heated to reflux and stirred for 70 hours. The mixture was cooled to ambient temperature and water (250 mL) was added. The resultant slurry was warmed to reflux and held at that temperature for 30 min before cooling to room temperature. The resultant precipitate was granulated at room temperature for 3 h, filtered and vacuum dried to afford 5-ethyl-1-(2-methoxyethyl)-4-nitro-1H-pyrazole-3-carboxamide as a yellow crystalline solid 24.3 g, 74%. Data as reported for Example (b)(i).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N+:15]([O-:17])=[O:16])[C:6]([C:12]([OH:14])=O)=[N:7][C:8]=1[O:9][CH2:10][CH3:11])#[N:2].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.Cl.Cl.[N:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[C:50]1[S:51][C:52]([CH2:55][N:56]2[CH2:61][CH2:60][CH:59]([CH2:62][NH2:63])[CH2:58][CH2:57]2)=[CH:53][N:54]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O.O>[C:1]([C:3]1[CH:4]=[C:5]([N+:15]([O-:17])=[O:16])[C:6]([C:12]([NH:63][CH2:62][CH:59]2[CH2:60][CH2:61][N:56]([CH2:55][C:52]3[S:51][C:50]([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][N:44]=4)=[N:54][CH:53]=3)[CH2:57][CH2:58]2)=[O:14])=[N:7][C:8]=1[O:9][CH2:10][CH3:11])#[N:2]
Reactant: CCOc1nc(C(=O)O)c([N+](=O)[O-])cc1C#N
Reactant: NCC1CCN(Cc2cnc(-c3ccccn3)s2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1nc(C(=O)NCC2CCN(Cc3cnc(-c4ccccn4)s3)CC2)c([N+](=O)[O-])cc1C#N
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 47.2 %

Procedure:
To a stirred solution of the compound prepared in Example 447 (94 mg) and 1-hydroxybenzotriazole hydrate (67 mg) in N,N-dimethylformamide (2.5 mL) at ambient temperature was added 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (84 mg). The resulting solution was stirred at ambient temperature for 40 minutes, and then the compound prepared in Example 214 (189 mg) was added, followed immediately by N,N-diisopropylethylamine (0.35 mL). The resulting mixture was stirred at ambient temperature for 1 hr 50 minutes, and then diluted with water (25 mL). After stirring for 30 minutes, the resulting precipitate was collected by filtration, washed with a small amount of water, and dried under vacuum to provide the title compound (95 mg) with the following physical data.
Reaction SMILES: [CH3:1][C:2]1[CH2:9][CH2:8][CH2:7][C:6]([CH3:11])([OH:10])[CH2:5][CH2:4][CH:3]=1.CCCCCCCCCCCCCCCC.O=[Si]=O.[Na]>C1CCCCC1>[CH3:11][C:6]([OH:10])([CH2:7][CH2:8][CH:9]=[C:2]([CH3:3])[CH3:1])[CH:5]=[CH2:4]
Reactant: CC1=CCCC(C)(O)CCC1
Agent: O=[Si]=O
Agent: [Na]
Solvent: C1CCCCC1
Solvent: CCCCCCCCCCCCCCCC
Product: C=CC(C)(O)CCC=C(C)C

Procedure:
A mixture of 1,5-dimethylcyclooct-1-en-5-ol (prepared as in Example II (b) 100, cyclohexane and n-hexadecane in the volume ratio 1:2:1 was passed at a rate of 12 ml/hour together with nitrogen gas at one 1/hour through a 30 cm quartz glass tube filled with 3 mm sodium glass beads at 540° C. It was shown by GLC that under these conditions the conversion of starting material was 39% and the selectivity to the required product was 87%. The alpha-linalool was recovered by distillation b.p. 91°-92° C. at 20 mm Hg.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[CH3:19][O:20][C:21]1[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=1[O:23][CH2:24][CH2:25][NH2:26].[C:31]([OH:39])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CC(O)C>[CH3:19][O:20][C:21]1[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=1[O:23][CH2:24][CH2:25][NH:26][CH2:3][CH:2]([OH:1])[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[NH:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:18]=12.[C:31]([O-:39])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: c1ccc2c(c1)[nH]c1cccc(OCC3CO3)c12
Reactant: O=C(O)c1ccccc1
Reactant: COc1ccccc1OCCN
Solvent: CC(C)O
Product: COc1ccccc1OCCNCC(O)COc1cccc2[nH]c3ccccc3c12
Product: O=C([O-])c1ccccc1
Yield: 66.1 %

Procedure:
A mixture of 4-(oxiran-2-ylmethoxy)-9H-carbazole (II) (25.0 g, 104.60 mmole) and 62.5 ml 2-propanol is heated to 70° C. to 80° C. To this 2-(2-methoxyphenoxy)ethylamine (III) (25.33 g, 151.67 mmole) is added in one lot. The temperature of reaction mass is raised to reflux (80° C. to 85° C.) and maintained at this temperature for 1 hour. After that, this reaction mass was added to the pre-heated (80° C. to 85° C.) solution of benzoic acid (18.5 g) in 2-propanol (287.5 ml) and continued the reflux for next 2-hour, cooled to 50° C. to 55° C. and maintained the same temperature for 1 hr. The product filtered at same temperature followed by three 33.5 ml wash with hot (50° C. to 55° C.) 2-propanol. The wet product dried at 60° C. to 65° C. for 6-8 hours or till constant weight gives 36.5 g of Carvedilol benzoate (Yield=66%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.[OH:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+]>CC#N.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>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:26]3[CH:27]=[CH:28][C:23]([OH:22])=[CH:24][CH:25]=3)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(Br)cnc32)cc1
Reactant: OB(O)c1ccc(O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccc(O)cc3)c3cc(Br)cnc32)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 94.6 %

Procedure:
To a stirred suspension of 5-bromo-3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (0.30 g, 0.62 mmol) and 4-hydroxyphenylboronic acid (0.12 mg, 0.75 mmol) in CH3CN (3 mL) was added 1 M Na2CO3 (3 mL) followed by bis(triphenylphosphine)palladium(II) dichloride (0.004 g, 0.062 mmol). The resulting mixture was stirred overnight at 60° C. After the mixture was evaporated to dryness in vacuo, it was dissolved in DMF (3 mL), absorbed onto Celite, and dried. The residue was purified via silica gel chromatography using CH2Cl2 as the eluent to obtain the title compound (0.26 g, 76%). 1H NMR (CDCl3, 300 MHz): δ 8.48 (d, J=2.1 Hz, 1H), 8.27 (bs, 1H), 8.26 (d, J=2.4 Hz, 1H), 8.08 (d, J=8.1 Hz), 7.85 (s, 1H), 7.81 (m, 1H), 7.50 (d, J=8.7 Hz, 1H), 7.37 (dd, J=1.8, 8.4 Hz), 7.30 (m, 3H), 6.63 (m, 1H), 2.39 (s, 3H); MS ESI (m/z): 443/445 (M+1)+, calc. 443.31.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].N1CCCC1>C(O)C>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH:20]=[C:21]([C:7]2[C:6]3[C:10](=[C:2]([Br:1])[CH:3]=[CH:4][CH:5]=3)[NH:9][CH:8]=2)[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Brc1cccc2cc[nH]c12
Solvent: C1CCNC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3c(Br)cccc23)CC1
Yield: 28.5 %

Procedure:
A stirred solution of 7-bromoindole (390 mg, 2.0 mmol), t-butyl-4-oxo-1-piperidinecarboxylate (438 mg, 2.2 mmol), and pyrrolidine (0.42 mL, 5.0 mmol) in ethanol (10 mL) was heated at reflux for 16 hours. Solvent was evaporated and the residue subjected to chromatography on silica gel with 20% ethyl acetate/hexanes to afford a yellow solid (215 mg, 29%).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH:3]1[CH2:18][CH2:17][C:6]2[O:7][C:8]3[CH:13]=[CH:12][C:11]([C:14](Cl)=[O:15])=[CH:10][C:9]=3[C:5]=2[CH2:4]1.[CH2:20]([NH2:22])[CH3:21]>>[CH2:20]([NH:22][C:14]([C:11]1[CH:12]=[CH:13][C:8]2[O:7][C:6]3[CH2:17][CH2:18][CH:3]([N:2]([CH3:19])[CH3:1])[CH2:4][C:5]=3[C:9]=2[CH:10]=1)=[O:15])[CH3:21]
Reactant: CCN
Reactant: CN(C)C1CCc2oc3ccc(C(=O)Cl)cc3c2C1
Product: CCNC(=O)c1ccc2oc3c(c2c1)CC(N(C)C)CC3
Yield: 32.3 %

Procedure:
Beginning with 0.011 gm (0.04 mMol) 2-dimethylamino-1,2,3,4-tetrahydrodibenzofuran-8-carbonyl chloride and 0.08 mMol ethylamine, 0.0037 gm (33%) of the title compound were recovered.
Reaction SMILES: [C:1](=[N:35]O)([C:8]1[CH:34]=[CH:33][C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24](=[N:31]O)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:20][CH:19]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.N.[Ni]>[NH2:31][CH:24]([C:21]1[CH:22]=[CH:23][C:18]([O:17][CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:8]([CH:1]([NH2:35])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:34][CH:33]=2)=[CH:19][CH:20]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: ON=C(c1ccccc1)c1ccc(OCCCCOc2ccc(C(=NO)c3ccccc3)cc2)cc1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CCO
Product: NC(c1ccccc1)c1ccc(OCCCCOc2ccc(C(N)c3ccccc3)cc2)cc1

Procedure:
The dioxime from Step 2 (6.3 g) is dissolved in ethyl alcohol saturated with ammonia gas (220 ml) and Raney nickel W-6 (2.3 g) added. The mixture is subjected to 650 psi hydrogen pressure and heated to 90° for twenty-two hours. The catalyst is removed by filtration and the solvent is removed by distillation to yield 4.1 g (69% of theory) of colorless crystals mp 120°-3°.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[N:13]1(C(O)C)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[CH2:22]([OH:24])[CH3:23]>>[N+:10]([C:7]1[CH:8]=[CH:9][C:2]([N:13]2[CH2:14][CH2:15][NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][OH:24])=[C:3]([CH:6]=1)[C:4]#[N:5])([O-:12])=[O:11]
Reactant: CC(O)N1CCNCC1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: CCO
Product: N#Cc1cc([N+](=O)[O-])ccc1N1CCNCC1CCO
Reaction time: 1 h

Procedure:
2-Chloro-5-nitrobenzonitrile (15 g) and piperazinoethanol (16 g) were added to ethanol (100 ml) and the mixture was stirred at a refluxing temperature for 1 h. The solvent was evaporated under reduced pressure. To the residue was added aqueous sodium hydroxide solution and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure. To the residue diisopropyl ether was added to allow crystallization. The crystals were recrystallized from hydrous ethanol to give 5-nitro-2-(2-hydroxyethylpiperazin-1-yl)benzonitrile (18.7 g), melting point 100–102° C.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C([Li])CCC.[CH3:12][C:13]([O:16][C:17](=[O:27])[NH:18][CH2:19][CH2:20][C:21](NCOC)=[O:22])([CH3:15])[CH3:14].C(OCC)(=O)C>O1CCCC1.CCCC(C)C>[CH3:15][C:13]([O:16][C:17](=[O:27])[NH:18][CH2:19][CH2:20][C:21](=[O:22])[C:2]1[S:3][CH:4]=[CH:5][N:6]=1)([CH3:12])[CH3:14]
Reactant: Brc1nccs1
Reactant: COCNC(=O)CCNC(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCCC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCC(=O)c1nccs1
Temperature: 0 °C
Yield: 67.1 %

Procedure:
To a solution of 2-bromothiazole (5.035 g, 30.7 mmol) in dry tetrahydrofuran (125 ml) at −78° C. under nitrogen, was added a solution of n-butyllithium in hexanes (1.6M, 17.6 ml, 28.2 mmol) over a period of 30 minutes, followed by a solution of [3-(methoxymethylamino)-3-oxopropyl]carbamic acid 1,1-dimethylethyl ester (2.976 g, 12.8 mmol) in dry tetrahydrofuran (30 ml) added over 30 minutes. The reaction mixture was allowed to warm up to 0° C., then quenched with saturated ammonium chloride and extracted with ethyl acetate (3×100 ml). The combined extracts were washed with water (3×50 ml) and saturated brine solution (1×100 ml), dried (magnesium sulphate) and concentrated in vacuo to leave a crude orange oil. Flash chromatography (silica, 25% ethyl acetate in isohexane) gave a pale yellow oil (2.2 g, 67%).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O.[Br-].[CH3:24][C:25]1[CH:50]=[C:49]([CH3:51])[CH:48]=[C:47]([CH3:52])[C:26]=1[CH2:27][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[CH3:52][C:47]1[CH:48]=[C:49]([CH3:51])[CH:50]=[C:25]([CH3:24])[C:26]=1/[CH:27]=[CH:18]/[C:17]1[CH:16]=[C:15]([CH2:14][CH2:13][CH2:12][N:3]2[C:4](=[O:11])[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]2=[O:1])[CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1
Reactant: Cc1cc(C)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(C)c1
Agent: [Br-]
Product: Cc1cc(C)c(/C=C/c2cccc(CCCN3C(=O)c4ccccc4C3=O)c2)c(C)c1

Procedure:
Phthalimide 29 was coupled with 2,4,6-trimethylbenzyltriphenylphosphonium bromide to give (E)-2-(3-(3-(2,4,6-trimethylstyryl)phenyl)propyl)isoindoline-1,3-dione. Yield (0.2485 g, 46%), trans-/cis-isomer ratio 4:1. Trans-isomer: 1H NMR (400 MHz, CDCl3) δ 7.84-7.87 (m, 2H), 7.72-7.74 (m, 2H), 7.26-7.36 (m, 3H), 7.16 (s, 1H), 7.12 (d, J=16.4 Hz, 1H), 6.94 (s, 2H), 6.57 (d, J=16.8 Hz, 1H), 3.82 (t, J=7.2 Hz, 2H), 2.76 (t, J=7.2 Hz, 2H), 2.39 (s, 6H), 2.33 (s, 3H), 2.10-2.17 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:18][C@@H:19]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:20]([NH2:22])=[O:21]>>[C:20]([C@@H:19]([NH:18][C:8]([C:5]1[CH:4]=[C:3]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])[CH2:23][CH:24]([CH3:26])[CH3:25])(=[O:21])[NH2:22]
Reactant: CC(C)C[C@H](N)C(N)=O
Reactant: O=C(O)c1cc(-c2cccc(Cl)c2)c(Cl)cn1
Product: CC(C)C[C@H](NC(=O)c1cc(-c2cccc(Cl)c2)c(Cl)cn1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-chloro-4-(3-chlorophenyl)-pyridine-2-carboxylic acid and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials and isolated (8 mg, 21%) as colorless oil; MS (ESI, m/z): 380.1, 382.1 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=O.[C:11]1([C:17](=[O:19])[CH3:18])[CH:16]=C[CH:14]=[CH:13][CH:12]=1.[NH:20]1CCCCC1>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1/[CH:4]=[CH:18]/[C:17]([C:11]1[CH:16]=[N:20][CH:14]=[CH:13][CH:12]=1)=[O:19]
Reactant: CC(=O)c1ccccc1
Reactant: O=Cc1c(F)cccc1Cl
Reactant: C1CCNCC1
Product: O=C(/C=C/c1c(F)cccc1Cl)c1cccnc1
Temperature: 100 °C
Yield: 28 %

Procedure:
A mixture of 2-chloro-6-fluorobenzaldehyde (0.599 g, 3.8 mmol) and 1-phenylethanone (0.414 mL, 0.38 mmol) in piperidine (1 mL) was heated at 100° C. for 1 h. The reaction mixture was allowed to cool to rt and was concentrated. The residue was purified by column chromatography to give (2E)-3-(2-chloro-6-fluorophenyl)-1-pyridin-3-ylprop-2-en-1-one (0.28 g, 28%).
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[Br:12]Br.O>C(O)(=O)C>[Br:12][C:7]1[CH:8]=[C:2]([C:1]([O:10][CH3:11])=[O:9])[C:3]([OH:4])=[CH:5][CH:6]=1
Reactant: BrBr
Reactant: COC(=O)c1ccccc1O
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1cc(Br)ccc1O
Temperature: 25 °C
Reaction time: 21 h

Procedure:
Methyl salicylate (149 g) was dissolved in acetic acid (900 mL), and bromine (50 mL) was added thereto. The mixture was stirred at room temperature for 21 hr. Water (10 L) was added to the reaction mixture, and the precipitated solid was collected by filtration, which was then recrystallized from methanol to give methyl 5-bromosalicylate (175 g) as white crystals.