Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][NH2:2].Cl[C:4]1[CH:17]=[CH:16][C:15]2[C:14](=[O:18])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=O)[C:6]=2[CH:5]=1>N1C=CC=CC=1>[N:1]1[NH:2][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:8]=2[C:7]=1[C:6]1[C:15]([C:14]3=[O:18])=[CH:16][CH:17]=[CH:4][CH:5]=1
Reactant: NN
Reactant: O=C1c2ccccc2C(=O)c2cc(Cl)ccc21
Solvent: c1ccncc1
Product: O=C1c2ccccc2-c2n[nH]c3cccc1c23
Temperature: 100 °C

Procedure:
Anhydrous hydrazine is added to a solution of 2-chloroanthraquinone (Aldrich) in 10 mL pyridine, and the mixture heated at 100° C. for 16 hours. The mixture is cooled and the solvent is evaporated in vacuo. The residue is taken in hot 6N HCl, and the solid is collected by filtration. Flash chromatography of the crude material on silica gel affords anthra[1,9cd]pyrazol-6(2H)-one (“Compound 1”) as yellow solids.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[C:17]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[OH:31])[CH:16]=1.O>CS(C)=O>[OH:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:17]1[CH:16]=[C:15]([NH:13][C@H:10]2[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1
Reactant: Oc1ccccc1-c1cc(Cl)c2ccccc2n1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2cc(-c3ccccc3O)nc3ccccc23)C1
Yield: 42.3 %

Procedure:
A solution of (S)-3-aminopyrrolidine-1-carboxylic acid tert-butyl ester (0.218 g, 1.173 mmol) and 2-(4-chloroquinolin-2-yl)phenol (0.100 g, 0.391 mmol) in DMSO (2 mL) was heated under microwave conditions at 155° C. for 1.5 hours. The mixture was added to water (50 mL) and extracted with diethyl ether (2×20 mL). The organic layers were combined, dried (MgSO4) and concentrated. The crude product was purified by silica gel chromatography (30-40% ethyl acetate/hexane) to give the title compound (0.067 g, 42%).
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH:6]([CH3:8])[CH2:5][N:4]([CH2:9][CH2:10][CH2:11][C:12]2[C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[NH:14][C:13]=2[CH:21]=O)[CH2:3]1.[CH3:23][NH:24][S:25]([C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32](=[O:37])[CH2:31]2)(=[O:27])=[O:26]>>[CH3:23][NH:24][S:25]([C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32](=[O:37])/[C:31]/2=[CH:21]\[C:13]1[NH:14][C:15]2[CH2:16][CH2:17][CH2:18][CH2:19][C:20]=2[C:12]=1[CH2:11][CH2:10][CH2:9][N:4]1[CH2:5][CH:6]([CH3:8])[NH:7][CH:2]([CH3:1])[CH2:3]1)(=[O:27])=[O:26]
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: CC1CN(CCCc2c(C=O)[nH]c3c2CCCC3)CC(C)N1
Product: CNS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c3c(c1CCCN1CC(C)NC(C)C1)CCCC3)C(=O)N2
Yield: 60.4 %

Procedure:
3-[3-(3,5-Dimethyl-piperazin-1-yl)-propyl]-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde (67 mg, 0.22 mmol) was condensed with 5-methylaminosulfonyloxindole (50 mg, 0.22 mmol) following the procedure used in Example 1 to provide (68 mg, 60% yield) of the desired compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[CH2:13]([C:15]1[N:19]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:18]2[CH:26]=[CH:27][CH:28]=[CH:29][C:17]=2[N:16]=1)[CH3:14].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:13]([C:15]1[N:19]([CH:20]2[CH2:21][CH2:22][N:23]([CH2:2][CH2:3][CH2:4][S:5][C:6]3[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=3)[CH2:24][CH2:25]2)[C:18]2[CH:26]=[CH:27][CH:28]=[CH:29][C:17]=2[N:16]=1)[CH3:14]
Reactant: Fc1ccc(SCCCBr)cc1
Reactant: CCc1nc2ccccc2n1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nc2ccccc2n1C1CCN(CCCSc2ccc(F)cc2)CC1
Temperature: 100 °C
Yield: 75.2 %

Procedure:
To a stirred solution of 1-(3-bromopropylsulfanyl)-4-fluorobenzene (0.5 g) and 2-ethyl-1-piperidin-4-yl-1H-benzimidazole (0.5 g) in DMF (5 ml) was added K2CO3 (1.0 g) and KI (0.05 g). The mixture was heated at 100° C. for 1 h, and then allowed to cool to rt. Water (50 ml) was added and the mixture extracted with ethyl acetate (80 ml), and the organic layer separated and washed with water. This was further dried and concentrated in vacuo. The oil was purified by flash chromatography (9:1 DCM:MeOH) to yield 0.6 g of the title compound as colourless crystals. Mp. 182-184° C.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([NH2:8])[CH:5]=[N:4]1)[CH3:2].Br[C:10]1[C:11](=[O:18])[N:12]([CH3:17])[CH:13]=[C:14]([Br:16])[N:15]=1>>[Br:16][C:14]1[N:15]=[C:10]([NH:8][C:6]2[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[CH:7]=2)[C:11](=[O:18])[N:12]([CH3:17])[CH:13]=1
Reactant: Cn1cc(Br)nc(Br)c1=O
Reactant: CCn1cc(N)cn1
Product: CCn1cc(Nc2nc(Br)cn(C)c2=O)cn1
Yield: 75.3 %

Procedure:
Using the same general procedure as Example 102k, reaction of 111b (500 mg, 4.50 mmol) and 3,5-dibromo-1-methylpyrazin-2(1H)-one (1.33 g, 4.95 mmol) afforded a 75% yield (1.01 g) of 111c as an off-white solid: mp 237-239° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.02 (s, 1H), 7.73 (s, 1H), 7.20 (s, 1H), 4.11 (q, 2H, J=7.5 Hz), 3.41 (s, 3H), 1.34 (t, 3H, J=7.3 Hz); MS (ESI+) m/z 298.0 (M+H).
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C:6]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:11][C:5]=2[NH:4][C:3]1=[O:36].C(=O)([O-])[O-].[K+].[K+].Br[CH2:44][C:45]#[N:46]>CN(C=O)C.C(OCC)(=O)C>[C:31]([O:30][C:29](=[O:35])[NH:28][C:24]1([C:21]2[CH:22]=[CH:23][C:18]([C:9]3[C:10]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[CH:11][C:5]4[N:4]([CH2:44][C:45]#[N:46])[C:3](=[O:36])[CH:2]([CH3:1])[O:7][C:6]=4[N:8]=3)=[CH:19][CH:20]=2)[CH2:25][CH2:26][CH2:27]1)([CH3:32])([CH3:34])[CH3:33]
Reactant: N#CCBr
Reactant: C[C@H]1Oc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2NC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1Oc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2N(CC#N)C1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 50.9 %

Procedure:
A solution of (R)-tert-butyl 1-(4-(3-methyl-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (100 mg, 0.206 mmol) in DMF (2 ml) was added potassium carbonate (85 mg) and 2-bromoacetonitrile (44 μl, 0.618 mmol). The reaction mixture was stirred at room temperature for 48 h then was diluted with ethyl acetate (20 ml). Washed with water, brine, and dried with Na2SO4, filtered and concentrated to give crude product which was purified by column (biotage, 25 g) eluted with ethyl acetate and cyclohexane to afford product (55 mg). 1H NMR (500 MHz, CDCl3): 7.35 (s, 1H), 7.20-7.32 (m, 9H), 4.98 (q, 1H), 4.87 (dd, 2H), 2.44-2.49 (m, 4H), 2.06 (m, 1H), 1.80 (m, 1H), 1.75 (d, 3H), 1.24-1.36 (br, 9H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([NH2:6])=[O:5].OC1C=CC=CN=1.[CH3:16][C:17]1([CH3:55])[CH2:22][N:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[C:20](=[O:30])[CH2:19][N:18]1[CH2:31][C@H:32]([NH:42][S:43]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[N+:52]([O-:54])=[O:53])(=[O:45])=[O:44])[C@@H:33]1[CH2:37][C@@H:36]([CH:38]([CH3:40])[CH3:39])[C:35](=[O:41])[O:34]1>C(N(CC)CC)C>[C:4]([C:3]([CH3:8])([CH3:7])[CH2:2][NH:1][C:35](=[O:41])[C@H:36]([CH:38]([CH3:39])[CH3:40])[CH2:37][C@H:33]([OH:34])[C@@H:32]([NH:42][S:43]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[N+:52]([O-:54])=[O:53])(=[O:44])=[O:45])[CH2:31][N:18]1[CH2:19][C:20](=[O:30])[N:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[CH2:22][C:17]1([CH3:55])[CH3:16])(=[O:5])[NH2:6]
Reactant: CC(C)(CN)C(N)=O
Reactant: Cc1ccccc1N1CC(C)(C)N(C[C@H](NS(=O)(=O)c2ccccc2[N+](=O)[O-])[C@@H]2C[C@@H](C(C)C)C(=O)O2)CC1=O
Agent: Oc1ccccn1
Solvent: CCN(CC)CC
Product: Cc1ccccc1N1CC(C)(C)N(C[C@H](NS(=O)(=O)c2ccccc2[N+](=O)[O-])[C@@H](O)C[C@H](C(=O)NCC(C)(C)C(N)=O)C(C)C)CC1=O
Temperature: 80 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
223 mg of 3-amino-2,2-di(methyl)propionamide obtained in Reference Example 2 (1.92 mmol) and 61 mg of 2-hydroxypyridine (0.64 mmol) were added to a solution of 367 mg of N-{(S)-2-[2,2-dimethyl-4-(2-methylphenyl)-5-oxopiperazin-1-yl]-1-[(2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl]ethyl}-2-nitrobenzenesulfonamide obtained in the above reaction (0.64 mmol) in triethylamine (6 ml), and the mixture was stirred at 80° C. for one hour. The reaction mixture was cooled and then concentrated under reduced pressure and further stirred at 80° C. for 14 hours. The reaction mixture was cooled and then water was added, followed by extraction with methylene chloride. Then, the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol=20/1) to obtain 345 mg of (2S,4S,5S)-6-[2,2-dimethyl-4-(2-methylphenyl)-5-oxopiperazin-1-yl]-4-hydroxy-2-isopropyl-5-(2-nitrobenzenesulfonylamino)hexanoic acid (2-carbamoyl-2-methylpropyl)amide (yield: 78%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([O:16][CH3:17])=[CH:4][C:3]=1[C:18](=[O:20])[CH3:19].C[O-].[Na+].[CH:24](OCC)=O.Cl>COCCOC.O>[CH2:9]([O:8][C:6]1[CH:7]=[C:2]2[C:3]([C:18]([OH:20])=[CH:19][CH:24]=[N:1]2)=[CH:4][C:5]=1[O:16][CH3:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC=O
Reactant: COc1cc(C(C)=O)c(N)cc1OCc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc2c(O)ccnc2cc1OCc1ccccc1
Reaction time: 0.5 h
Yield: 72.4 %

Procedure:
To a solution of 1-(2-Amino-4-benzyloxy-5-methoxy-phenyl)-ethanone (108 mmol, 29.3 g) in DME (700 ml) was added sodium methoxide (432 mmol, 23.35 g). The mixture was stirred for 30 minutes. Ethyl formate (540 mmol, 44 ml) was added and the mixture was stirred overnight. (Additional sodium methoxide may be needed if reaction is not complete as monitored by LC/MS.) After the reaction was completion, the mixture was diluted with water (40 ml) and acidified to neutral with 1M HCl. The precipitate was filtered and washed with water, dried in vacuo to afford 22 g (72%) of 7-benzyloxy-6-methoxy-quinolin-4-ol. 1H NMR (CDCl3): 10.7 (1H, br), 7.703 (1H, s), 7.493-7.461 (1H, t), 7.431-7.413 (2H, br d), 7.372-7.333 (2H, t), 7.296-7.283 (1H, d), 6.839 (1H, s), 6.212-6.193 (1H, d), 5.212 (2H, s), 3.965 (3H, s). LC/MS (M+l=282).
Reaction SMILES: O.O.O.O.O.O.[NH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[CH:13]1([C:18](Cl)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1>C(O)C>[CH:13]1([C:18]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(Cl)C1CCCC1
Reactant: C1CNCCN1
Solvent: O
Solvent: CCO
Product: O=C(C1CCCC1)N1CCNCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Piperazine hexahydrate (8.55 g, 44.0 mmol) was dissolved in absolute ethanol (50 ml) and then refluxed for 10 min. Cyclopentanecarbonyl chloride (5.83 g, 44 mmol) was added dropwise at 65° C. and the reaction mixture was refluxed for 30 min and then stirred at room temperature for 18 h. The reaction mixture was cooled, filtered and the filtrate was concentrated in vacuo to give ˜20 ml of solution. The concentrate was cooled and then filtered again. Ethanolic hydrogen chloride was added to the mother liquor, and the reaction mixture was concentrated to give a white solid, which was dissolved in water (15 ml). The solution was basified to pH 14 and the product was extracted with dichloromethane (7×50 ml). The extracts were dried, (Na2SO4) and concentrated to give the title compound as a yellowish residue, which was distilled to give the product (1.28 g, 7.0 mmol, 16%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][NH:11][C:12]([CH:14]2[O:19][CH2:18][CH2:17][N:16]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:15]2)=O)=[CH:5][CH:4]=1.FC(F)(F)C([O-])=O.[NH4+:35]>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:35]=[C:12]([CH:14]3[O:19][CH2:18][CH2:17][N:16]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:15]3)[NH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)CNC(=O)C2CN(Cc3ccccc3)CCO2)cc1
Reactant: [NH4+]
Agent: O=C([O-])C(F)(F)F
Solvent: O
Product: COc1ccc(-c2c[nH]c(C3CN(Cc4ccccc4)CCO3)n2)cc1
Temperature: 150 °C
Reaction time: 2.5 h
Yield: 96.9 %

Procedure:
A mixture of N-{2-[4-(methyloxy)phenyl]-2-oxoethyl}-4-(phenylmethyl)-2-morpholinecarboxamide (2.5 g, 6.79 mmol) and ammonium trifluoroacetate (4.45 g, 33.9 mmol) was stirred for 2.5 hours at 150° C. Water (150 mL) was added to the residue, and the aqueous mixture was extracted with EtOAc (3×80 mL). The combined organic phases were dried (Na2SO4), filtered, and concentrated to afford the title compound (2.3 g) as a brown solid. LC-MS (ES) m/z=350 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[CH:8]2)[CH2:3][CH2:2]1.Cl[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[F:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][CH2:19][CH2:18][CH2:17][N:1]2[CH2:2][CH2:3][CH:4]([N:7]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[N:9]=[CH:8]3)[CH2:5][CH2:6]2)=[CH:22][CH:23]=1
Reactant: c1ccc2c(c1)ncn2C1CCNCC1
Reactant: Fc1ccc(OCCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(OCCCN2CCC(n3cnc4ccccc43)CC2)cc1
Temperature: 90 °C
Yield: 66.6 %

Procedure:
To a stirred solution of 1-piperidin-4-yl-1H-benzimidazole (4.02 g) and 1-(3-chloropropoxy)-4-fluorobenzene (4.16 g) in DMF (50 ml) was added K2CO3 (4.1 g) and KI (0.2 g). The mixture was heated at 90° C. for 2 h, and then allowed to cool to rt. Water (100 ml) was added and the mixture extracted with ethyl acetate (2×80 ml), and the organic layer separated and washed with water. This was further dried and concentrated in vacuo. The free base converted to the hydrochloride salt by action of HCl in ethanol. The solid was recrystallised from ethanol-diethylether to yield 4.7 g of the title compound as colourless crystals. MP. 233-235° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[C:19]([Cl:23])[C:20]([Cl:22])=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1.Cl.[CH3:25][N:26]([CH3:30])[CH2:27][CH2:28]Cl.C(=O)([O-])[O-].[K+].[K+].CC(C)=O>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:28][CH2:27][N:26]([CH3:30])[CH3:25])[C:12]3[CH:18]=[C:19]([Cl:23])[C:20]([Cl:22])=[CH:21][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc([C@@H]2Sc3cc(Cl)c(Cl)cc3NC(=O)[C@@H]2O)cc1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc([C@@H]2Sc3cc(Cl)c(Cl)cc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Yield: 66.9 %

Procedure:
A mixture of 1.48 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-7,8-dichloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 0.64 g of 2-(dimethylamino)ethyl chloride hydrochloride, 1.66 g of potassium carbonate, 45 ml of acetone and 0.5 ml of water is refluxed for 22 hours. After the reaction is completed, insoluble materials are removed by filtration. The filtrate is evaporated to remove solvent, and diisopropyl ether is added to the residue. The precipitated crystals are collected by filtration and then recrystallized from ethyl acetate. 1.18 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-7,8-dichloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained.
Reaction SMILES: [Br:1][C:2]1[C:22]([Br:23])=[CH:21][C:20]([Br:24])=[CH:19][C:3]=1[C:4]([C:6]1[N:10]([CH3:11])[C:9]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:8][C:7]=1[CH3:18])=[O:5].Cl[C:26]1C=CC(C(C2N(C)C(CC(OCC)=O)=CC=2C)=O)=CC=1>>[Br:1][C:2]1[C:22]([Br:23])=[CH:21][C:20]([Br:24])=[CH:19][C:3]=1[C:4]([C:6]1[N:10]([CH3:11])[C:9]([CH:12]([CH3:26])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:8][C:7]=1[CH3:18])=[O:5]
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)c2cc(Br)cc(Br)c2Br)n1C
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)c2ccc(Cl)cc2)n1C
Product: CCOC(=O)C(C)c1cc(C)c(C(=O)c2cc(Br)cc(Br)c2Br)n1C

Procedure:
The methylation procedure of Example 77A is repeated, except that an equivalent quantity of ethyl 5-(2',3',5'-tribromobenzoyl)-1,4-dimethylpyrrole-2-acetate (from Example 91) is methylated instead of the ethyl 5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate used in Example 77A, to yield ethyl 5-(2',3',5'-tribromobenzoyl)-1,4,α-trimethylpyrrole-2-acetate.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:14]([OH:22])(=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:14]([C:9]1[CH:8]=[CH:7][C:6]2[C:5]3[C:13](=[CH:1][C:2]([C:14](=[O:22])[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:3][CH:4]=3)[CH2:12][C:11]=2[CH:10]=1)(=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)c1ccccc1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Product: O=C(c1ccccc1)c1ccc2c(c1)Cc1cc(C(=O)c3ccccc3)ccc1-2

Procedure:
The compound 2,7-bis(dimethylphenylcarbyl) fluorene, which is believed to be a new compound, was prepared by reacting benzoic acid with fluorene in hot polyphosphoric acid at about 100° C. to yield 2,7-dibenzoylfluorene which is then reacted with trimethyl aluminum in boiling toluene.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)=[N:4][NH:3]1.[C:23]([O:27][CH3:28])(=[O:26])[CH:24]=[CH2:25].[OH-].C[N+](C)(C)CC1C=CC=CC=1.CO>C(Cl)(Cl)Cl>[CH3:28][O:27][C:23]([CH2:24][CH2:25][N:3]1[C:2](=[O:1])[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)=[N:4]1)=[O:26]
Reactant: O=c1ccc(-c2c(-c3ccccc3)nn3ccccc23)n[nH]1
Reactant: C=CC(=O)OC
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)CCn1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Yield: 66.3 %

Procedure:
A mixture of 3-(3-oxo-2,3-dihydropyridazin-6-yl)-2-phenylpyrazolo[1,5-a]pyridine (0.43 g), methyl acrylate (1.29 g), 40% methanolic trimethylbenzylammonium hydroxide (0.4 ml) and methanol (2 ml) in chloroform (8 ml) was refluxed for 40 minutes and then evaporated in vacuo. To the residue were added methylene chloride (30 ml) and water (30 ml), and the organic layer was separated, dried over magnesium sulfate and evaporated in vacuo. The crystalline residue was recrystallized from a mixture of ethyl acetate and diethyl ether to give 3-[2-(2-methoxycarbonylethyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (0.37 g).
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH3:10][C:11](=[CH2:14])[CH:12]=[O:13].Cl>C(OCC)C.BrCCCCCCC>[CH3:14][C:11]([CH:12]([OH:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[CH2:10]
Reactant: CCCCCCCBr
Reactant: C=C(C)C=O
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: C=C(C)C(O)CCCCCCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 60.8 %

Procedure:
Under an atmosphere of nitrogen the reaction flask is charged with 9.85 g magnesium and 100 ml diethyl ether. The Grignard reaction is started with 3.00 g bromo-heptane. Then a solution of 70.00 g bromo-heptane in 50 ml diethyl ether is added dropwise within 90 minutes, the reaction mixture is kept at mild reflux and subsequently cooled to 0° C. to add now within 30 minutes a solution of 28.70 g 2-methyl-2-propenal in 30 ml diethyl ether. After further stirring for 2 hours at room temperature the reaction mixture is again cooled to 0° C. and 50 ml of diluted hydrochloric acid (3.5%) are carefully added. The organic layer is washed with water, dried with sodium sulfate and subsequently concentrated to give 86.7 g crude material. Distillation over a 10 cm-column (Widmer type) gives 40.5 g 2-methyl-1-decen-3-ol having a boiling point of 75° C. at 0.12 bar.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[S-:11][C:12]#[N:13].[NH4+]>CO>[CH3:8][C:7]1[C:2]([CH3:1])=[C:3]([OH:10])[C:4]([CH3:9])=[CH:5][C:6]=1[S:11][C:12]#[N:13]
Reactant: N#C[S-]
Reactant: Cc1ccc(C)c(O)c1C
Agent: [NH4+]
Solvent: CO
Product: Cc1cc(SC#N)c(C)c(C)c1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
2,3,6-trimethylphenol (1.6 g, 11.8 mmol) was disolved in 50 mL of anhydrous methanol which had been deoxygenated by bubbling with nitrogen. Ammonium thiocyanate (2.2 g, 28,9 mmol) was added to this solution which was then cooled to 0° C. and bubbled with chlorine gas. The initially colorless homogeneous solution becomes pink and then green with the formation of a white precipitate. The solution was stirred for 1 h at 0° C. and then for a further hour at 20° C. The dissolved chlorine was removed by bubbling with nitrogen and the precipitate removed by filtration. Evaporation of the filtrate under reduced pressure followed by drying under high vacuum (0.1 torr) yielded 2.20 g (97%) of 2,3,5-Trimethyl-4-hydroxyphenylthiocyanate in a form pure enough for the next step in the synthesis. An analytical sample was recrystallized from hexanes: white crystals, mp 100.3° C. 1H NMR (CDCl3) δ 7.2 (s, 1H), 5.0 (s, 1H) 2.4 (s, 3H), 2.2 (s, 6H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([CH3:20])[C:7](B3OC(C)(C)C(C)(C)O3)=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:21].Br[C:23]1[CH:24]=[C:25]([CH:29]=[O:30])[CH:26]=[N:27][CH:28]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.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>[OH:30][CH2:29][C:25]1[CH:24]=[C:23]([C:7]2[C:6]([CH3:20])=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:2]([CH3:1])[C:3](=[O:21])[CH2:4]3)[CH:28]=[N:27][CH:26]=1
Reactant: O=Cc1cncc(Br)c1
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)ccc2c1CC(=O)N2C
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: ClCCl
Solvent: COCCOC
Product: Cc1c(-c2cncc(CO)c2)ccc2c1CC(=O)N2C
Temperature: 120 °C

Procedure:
To 1,4-dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one (85 mg, 0.30 mmol) was added (5-bromo-pyridin-3-yl)-methanal (CAS#37669-64-0, 61 mg, 0.33 mmol), 1,2-dimethoxyethane (3.0 mL), and 2 M aqueous sodium carbonate (0.370 mL, 0.74 mmol). The reaction mixture was degassed and placed under an argon atmosphere, at which time resin bound tetrakis(triphenylphosphine)palladium(0), specifically polystyrene triphenylphosphine palladium (0) [PS—PPh3-Pd(0) (Biotage), 0.11 mmol/g loading, (135 mg, 0.015 mmol)] was added. The reaction vessel was sealed and was heated by microwave irradiation at 120° C. for 3 hours. The reaction mixture was then cooled to room temperature, diluted with dichloromethane and filtered through glass wool. The filtrate was further diluted with saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was partially purified by silica gel flash chromatography (ethanol-dichloromethane, 0 to 7.5%). Further purification was accomplished via reverse phase HPLC (10 to 40% acetonitrile/Water w/0.1% NH4OH) to furnish 5-(5-hydroxymethyl-pyridin-3-yl)-1,4-dimethyl-1,3-dihydro-indol-2-one; HRMS: (ESI) m/z 269.1288 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.14 (s, 3H), 3.15 (s, 3H), 3.56 (s, 2H), 4.60 (s, 2H), 5.35 (br. s., 1H), 6.93 (d, J=7.8 Hz, 1H), 7.18 (d, J=8.1 Hz, 1H), 7.65 (t, J=2.1 Hz, 1H), 8.40 (d, J=2.3 Hz, 1H), 8.50 (d, J=2.0 Hz, 1H).