Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6](=[N:16][NH2:17])[C:7]2[CH:12]=[CH:11][C:10]([CH2:13][S:14][CH3:15])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[C:20](Cl)(=[O:26])[O:21][CH2:22][CH:23]([CH3:25])[CH3:24]>CN(C1C=CN=CC=1)C.ClCCl>[CH2:22]([O:21][C:20]([NH:17][N:16]=[C:6]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][S:14][CH3:15])=[CH:9][CH:8]=1)[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:19][CH:18]=1)=[O:26])[CH:23]([CH3:25])[CH3:24]
Reactant: CSCc1ccc(C(=NN)c2ccc(Cl)cc2)cc1
Reactant: CC(C)COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CSCc1ccc(C(=NNC(=O)OCC(C)C)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 24.8 %

Procedure:
To a dichloromethane solution (30 ml) of 4-chloro-4'-methylmercaptomethylbenzophenone hydrazone (1.5 g) and 4-(N,N-dimethylamino)pyridine (1.2 g), isobutyl chlorocarbonate (0.8 g) was dropwise added under cooling with ice and subsequently stirred at a room temperature for 20 hours. The reaction mixture was then successively washed with 2N hydrochloric acid, water and an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. After distilling off the solvent, the crude product was purified by silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:4) to obtain 4-chloro-4'-methylmercaptomethylbenzophenone isobutoxycarbonyl hydrazone (0.5 g) as an isomer mixture.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[C:7]([NH2:9])=[O:8].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:10]([NH:9][C:7]([C@@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6][NH:1]1)=[O:8])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: NC(=O)[C@@H]1CCCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCc1ccccc1)[C@@H]1CCCCN1
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.6 %

Procedure:
To a suspension of 9.0 g (70.2 mmol) of (S)-piperidine-2-carboxamide (prepared by the method of Geotz Hardtmann, William Houlihan and Rudolf Giger, U.S. Pat. No. 4,760,065) in 100 mL of methylene chloride was added 24.0 g (140.4 mmol) of benzyl bromide and 7.2 g (70.2 mmol) of triethylamine. The mixture was stirred at room temperature for 24 h and washed with 1N aqueous sodium hydroxide. The organic layer was dried over anhydrous sodium sulfate and solvent was removed at reduced pressure. The residue was purified by silica gel chromatography using hexane:ethyl acetate (1:1) as eluent to give (S)-N-benzyl-piperidine-2-carboxamide (12.2 g, 80%), mp 103°-104° C., specific rotation=-90.7° (c=2.5, ethanol).
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][C:17]=2[NH:22][C:23]([C:25]2[N:26]=[C:27](Br)[S:28][C:29]=2[NH:30]C(=O)OC(C)(C)C)=[O:24])[CH2:12][CH2:11]1)=O)CCC.[CH2:39]([C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][CH:46]=1)[CH3:40]>>[NH2:30][C:29]1[S:28][C:27]([C:45]2[CH:44]=[CH:43][CH:42]=[C:41]([CH2:39][CH3:40])[CH:46]=2)=[N:26][C:25]=1[C:23]([NH:22][C:17]1[CH:18]=[N:19][N:20]([CH3:21])[C:16]=1[N:13]1[CH2:14][CH2:15][CH:10]([CH2:9][NH2:8])[CH2:11][CH2:12]1)=[O:24]
Reactant: CCCCOC(=O)NCC1CCN(c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC1
Reactant: CCc1cccc(B(O)O)c1
Product: CCc1cccc(-c2nc(C(=O)Nc3cnn(C)c3N3CCC(CN)CC3)c(N)s2)c1
Yield: 29 %

Procedure:
Following Example 278, Suzuki coupling of tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamate and 3-ethylphenyl boronic acid gave 267 as an off-white solid (25 mg, 29% over two steps). 1H NMR (400 MHz, d6-DMSO) δ 8.89 (s, 1H), 7.71 (s, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.43-7.33 (m, 4H), 7.26 (d, J=7.8 Hz, 1H), 3.64 (s, 3H), 3.14-2.98 (m, 4H), 2.67 (q, J=7.6 Hz, 2H), 2.46 (d, J=5.7 Hz, 2H), 1.77 (d, J=11.7 Hz, 2H), 1.32-1.19 (m, 6H). Alkyl NH2 not seen. LCMS (ES+) m/z 440 (M+1)
Reaction SMILES: I[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][C:13]([C:15]([O:17]C)=[O:16])=[CH:14][C:9]=3[O:8][CH2:7][CH2:6][N:5]2[CH:19]=1.[CH:20]([N:23]1[C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=[N:24]1)([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+].C(#N)C>CCOC(C)=O.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>[CH:20]([N:23]1[C:27]([C:2]2[N:3]=[C:4]3[C:10]4[CH:11]=[CH:12][C:13]([C:15]([OH:17])=[O:16])=[CH:14][C:9]=4[O:8][CH2:7][CH2:6][N:5]3[CH:19]=2)=[CH:26][CH:25]=[N:24]1)([CH3:22])[CH3:21]
Reactant: COC(=O)c1ccc2c(c1)OCCn1cc(I)nc1-2
Reactant: CC(C)n1nccc1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)n1nccc1-c1cn2c(n1)-c1ccc(C(=O)O)cc1OCC2
Yield: 185.9 %

Procedure:
Methyl 2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate (0.6 g, 2.0 mmol), prepared according to Example 40, 1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.477 mmol, 2.02 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.059 g, 0.084 mmol) were combined in a 35-mL microwaveable vessel. Subsequently, potassium carbonate (1.0 M in water, 5 mL) and acetonitrile (5 mL) were added. The reaction vessel was then subjected to microwave irradiation at 140° C. for 20 min. The mixture was diluted further with EtOAc and the product was isolated via acid-base extraction to provide 0.3 g (50% yield) of 2-(1-isopropyl-1H-pyrazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylic acid.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[C:7](/[CH:14]=[CH:15]/[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:8]=[CH:9][C:10]=1[N+:11]([O-])=O)=[O:4]>C(O)C.[Pd]>[NH2:11][C:10]1[CH:9]=[CH:8][C:7]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:6][C:5]=1[C:3](=[O:4])[NH:2][CH3:1]
Reactant: CCOC(=O)/C=C/c1ccc([N+](=O)[O-])c(C(=O)NC)c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(N)c(C(=O)NC)c1
Yield: 56.4 %

Procedure:
To a stirred solution of (E)-ethyl 3-(3-(methylcarbamoyl)-4-nitrophenyl)acrylate (345 mg, 1.24 mmol) in ethanol (10 ml) at r.t. under an argon atmosphere was added 10% Pd/C (52.8 mg, 496 μmol). The black suspension was hydrogenated at normal pressure and r.t. overnight. The catalyst was removed by filtration. The filtrate was concentrated. The crude product was purified by silica gel chromatography using a methylenchloride/MeOH gradient to give the title compound (175 mg, 57%) as white solid.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:42][CH2:41][CH:40]([OH:43])[CH2:39]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:38]3[CH2:42][CH2:41][CH:40]([OH:43])[CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: OC1CCNC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(O)C1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with pyrrolidin-3-ol (Aldrich) to give the title compound as a mixture of diastereomers. HR-MS (ES, m/z) calculated for C33H39Cl2N4O3 [(M+H)+] 609.2394, observed 609.2393.
Reaction SMILES: C[O:2][C:3]1[C:19]([C:20]#[N:21])=[C:7]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=3)[O:10][C:6]2=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1.Cl>C(OCC)(=O)C>[OH:2][C:3]1[C:19]([C:20]#[N:21])=[C:7]2[CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=3)[O:10][C:6]2=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc3c(C#N)c(OC)ccc3o2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: N#Cc1c(O)ccc2oc(-c3ccc(O)cc3)cc12
Temperature: 200 °C
Yield: 84.7 %

Procedure:
5-Methoxy-2-(4-methoxyphenyl)-benzofuran-4-carbonitrile 134 (0.088 g, 0.31 mmol) was placed in a sealed tube along with pyridine hydrochloride (enough to fill the volume of the tube by one-half) and heated at 200° C. for 2.5 hours. The reaction was dissolved into a mixture of ethyl acetate and 1N HCl. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×). The combined organics was washed with 1N HCl (1×), water (1×) and then dried over magnesium sulfate, filtered and concentrated. The resulting material was purified by column chromatography, using 40% ethyl acetate in hexanes as the eluent to yield the desired product 135 (0.066 g, 84.7%) as a light brown solid: Mp>230° C.; 1H NMR (DMSO-d6) δ 10.89 (s, 1 H), 10.03 (s, 1 H), 7.82 (d, 2 H, J=8.6 Hz), 7.72 (d, 1 H, J=8.9 Hz), 7.27 (s, 1 H), 6.90 (d, 2 H, J=8.6 Hz), 6.88 (d, 1 H, J=8.9 Hz).
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:11][OH:12])[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=1.I[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>C1COCC1>[CH2:14]([O:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:11][OH:12])=[CH:4][CH:5]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: OCc1ccc(CO)cc1
Reactant: CCCCCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCOCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.8 %

Procedure:
Sodium hydride (0.17 g, 7.20 mmol) was added to a solution of 1,4-benzene dimethanol (1.00 g, 7.20 mmol) in THF at 0° C. The reaction was stirred for 1 h. 1-iodooctane (1.73 g; 7.20 mmol) was added and the reaction mixture was warmed to rt for 4 h and then heated at 50° C. for 2 days. The reaction was cooled and filtered. Silica gel chromatography eluting with 15% ethyl acetate/hexane gave 0.14 g of product: 1H NMR (500 MHz) δ 7.34-7.40 (m, 4H), 4.68-4.72 (m, 2H, 4.51 (s, 2H), 3.46-3.50 (m, 2H), 1.61-1.68 (m, 2H), 1.24-1.40 (m, 10H), 0.88-0.92 (m, 3H).
Reaction SMILES: C([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1)(=O)C.N(C(C)(C)C#N)=NC(C)(C)C#N.CCCCCC.[OH-].[Na+]>C(OCCCC)(=O)C.O.Cl>[CH:10]#[C:9][C:8]1[CH:11]=[CH:12][C:5]([OH:4])=[CH:6][CH:7]=1
Reactant: C=Cc1ccc(OC(C)=O)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCCCOC(C)=O
Solvent: CCCCCC
Product: C#Cc1ccc(O)cc1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
In 120 ml of butyl acetate was dissolved 32.4 g (0.2 mol) of p-acetoxystyrene. Three 0.033 g portions of azobisisobutyronitrile (AIBN) were added at an interval of 2.5 hours to the solution with stirring at 80° C. in a nitrogen stream and stirring was thereafter continued for 5 hours, whereby polymerization reaction was conducted. The resultant reaction mixture was poured into 1,200 ml of hexane to precipitate a white resin. The resin obtained was dried and then dissolved in 150 ml of methanol. Thereto was added an aqueous solution prepared by dissolving 7.7 g (0.19 mol) of sodium hydroxide in 50 ml of water. This mixture was heated with refluxing for 3 hours to hydrolyze the resin. Thereafter, the reaction mixture was diluted with 200 ml of water and neutralized with hydrochloric acid to precipitate a white resin. This resin was taken out by filtration, washed with water, dried, and then dissolved in 200 ml of tetrahydrofuran to give a solution, which was added dropwise to 5 L of ultrapure water with vigorous agitation to conduct reprecipitation. This reprecipitation operation was repeated three times. The resin thus obtained was dried in a vacuum dryer at 120° C. for 12 hours to obtain poly(p-hydroxystyrene) as alkali-soluble resin A-1.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CO.C([O:12][CH2:13][C:14]([N:16]1[CH2:20][CH2:19][CH2:18][CH:17]1[C:21]1[C:22]([O:36][C:37]2[CH:42]=[CH:41][C:40]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=3[F:49])=[CH:39][CH:38]=2)=[CH:23][C:24]2[N:28]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[NH:26][C:25]=2[CH:35]=1)=[O:15])(=O)C>C(Cl)(Cl)Cl>[F:49][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=1[C:40]1[CH:39]=[CH:38][C:37]([O:36][C:22]2[C:21]([CH:17]3[CH2:18][CH2:19][CH2:20][N:16]3[CH:14]([OH:15])[CH:13]=[O:12])=[CH:35][C:25]3[NH:26][C:27]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)=[N:28][C:24]=3[CH:23]=2)=[CH:42][CH:41]=1
Reactant: CC(=O)OCC(=O)N1CCCC1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(-c2ccccc2F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=CC(O)N1CCCC1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(-c2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
10 mg of potassium carbonate was added to a methanol (0.5 ml) solution of 11 mg of 2-(2-(5-((2′-fluorobiphenyl-4-yl)oxy)-2-pyridin-2-yl-1H-benzimidazol-6-yl)pyrrolidin-1-yl)-2-oxoethyl acetate obtained in Example 513, and the reaction liquid was stirred at room temperature for 1 day. The reaction liquid was diluted with chloroform, washed with water and saturated saline in order, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=10/1) to obtain the entitled compound as a white solid.
Reaction SMILES: [CH2:1](Cl)/[CH:2]=[CH:3]/[CH2:4]Cl.[C:7]([O:13][CH3:14])(=[O:12])[CH2:8][C:9]([CH3:11])=[O:10].[Na]CC(=O)CC(OC)=O.[Na]>CO>[C:9]([C:8]1([C:7]([O:13][CH3:14])=[O:12])[CH2:4][CH:3]1[CH:2]=[CH2:1])(=[O:10])[CH3:11]
Reactant: COC(=O)CC(C)=O
Reactant: ClC/C=C/CCl
Agent: COC(=O)CC(=O)C[Na]
Agent: [Na]
Solvent: CO
Product: C=CC1CC1(C(C)=O)C(=O)OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methyl 1-acetyl-2-vinylcyclopropane-1-carboxylate was prepared by the reaction of 1,4-dichlorobutene-2 and methyl acetoacetate using the classical condensation procedure. For the reaction, methyl sodioacetoacetate was prepared by first reacting 36.6 grams sodium metal with 500 mls anhydrous methanol and then adding 185.6 grams of the methyl acetoacetic ester. The resulting solution was then added dropwise, at a rate sufficient to maintain reflux, to 100 grams 1,4-dichlorobutene-2 in 200 mls methanol under a nitrogen atmosphere. After addition was complete, refluxing was continued for 3 hours followed by stirring overnight at ambient temperature. The resulting reaction product (IA) was then stripped under reduced pressure after filtering to remove insoluble salts. Fractional distillation yielded 55 percent yield of a product (IB) consisting predominantly of the desired vinylcyclopropane product (boiling point 83.5° C.-85.0° C. at 4.5 mm Hg; nD22° 1.4705). Nuclear magnetic resonance spectroscopy and gas chromatographic analysis of IB showed the product to consist of 85.7 percent methyl 1-acetyl-2-vinylcyclopropane-1-carboxylate and 14.3 percent 4-carbomethoxy-5-methyl-2-vinyl-2,3-dihydrofuran.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([NH2:12])[C:9]([NH2:13])=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:7]2.[C:21](O)(=[O:25])[C:22](O)=[O:23]>Cl>[Br:1][C:2]1[C:3]2[CH2:4][CH2:5][N:6]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:7][C:8]=2[C:9]2[NH:13][C:21](=[O:25])[C:22](=[O:23])[NH:12][C:10]=2[CH:11]=1
Reactant: Nc1cc(Br)c2c(c1N)CN(Cc1ccccc1)CC2
Reactant: O=C(O)C(=O)O
Agent: Cl
Product: O=c1[nH]c2cc(Br)c3c(c2[nH]c1=O)CN(Cc1ccccc1)CC3
Temperature: 25 °C
Yield: 76.5 %

Procedure:
A solution of the product from Example 7 (0.64 g, 1.93 mmol) in 3N HCl (25 mL) was treated with oxalic acid (0.37 g, 2.9 mmol) and refluxed for four hours. When cool to room temperature the precipitate was filtered, suspended in water (70 mL) and basifyed to pH 10. The solids were filtered, and dried to give the title compound (0.57 g, 89%) as a light brown solid, mp=297-302° C.
Reaction SMILES: C(NC(C)C)(C)C.[CH2:8]([Li])[CH2:9][CH2:10][CH3:11].[CH:13]1([C:18]([O:20][CH3:21])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1.BrCCC=C.[Cl-].[NH4+]>C1COCC1>[CH3:21][O:20][C:18]([C:13]1([CH2:11][CH2:10][CH:9]=[CH2:8])[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:19]
Reactant: [Li]CCCC
Reactant: COC(=O)C1CCCC1
Agent: C=CCCBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C=CCCC1(C(=O)OC)CCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50.4 %

Procedure:
To a solution of diisopropylamine (225 mmol, 31.6 mL) in THF (150 mL) was added dropwise a solution of n-butyl lithium (217.5 mmol, 87 mL, 2.5M) in hexanes at −10° C. while maintaining the temperature below 0° C. After addition, the solution was stirred for 30 min at 0° C. To this, a solution of methyl cyclopentane carboxylate (150 mmol, 19.23 g) in THF (30 mL) was added dropwise at −70° C. maintaining the internal temperature between −60 to −70° C. After addition, the reaction mixture was stirred for 1 h at −50 to −60° C. Then, a solution of 4-bromo-1-butene (142.2 mmol, 19.2 g) in THF (30 mL) was added dropwise and the light brown suspension was stirred for 1 h at −60 to −70° C. Then, it was allowed to warm to room temperature and stirred overnight. The reaction mixture was poured into a saturated solution of ammonium chloride (250 mL) and the mixture was extracted with ether (2×150 mL). The combined extracts were washed with a saturated solution of sodium chloride (150 mL) and dried over anhydrous magnesium sulfate. After filtration of the drying agent, the solution was concentrated under vacuum and the residue was distilled at 63-67° C./2.5 mm Hg to give 13.77 g (53%) of a colorless oil. HR MS (C11H16O2): Obs mass, 182.1311. Calcd mass, 182.1307 (M+).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:15]=[CH:16][C:17]([NH2:20])=[N:18][CH:19]=3)[CH:10]=[CH:9][N:8]=2)[CH:4]=[N:3]1.N1C=CC=CC=1.[O:27]=[C:28]1[N:32]([CH:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[CH2:31][CH2:30][N:29]1[C:39](Cl)=[O:40]>C(Cl)Cl.O>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:15]=[CH:16][C:17]([NH:20][C:39]([N:29]4[CH2:30][CH2:31][N:32]([CH:33]5[CH2:38][CH2:37][O:36][CH2:35][CH2:34]5)[C:28]4=[O:27])=[O:40])=[N:18][CH:19]=3)[CH:10]=[CH:9][N:8]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cc(Oc3ccc(N)nc3)ccn2)cn1
Reactant: O=C(Cl)N1CCN(C2CCOCC2)C1=O
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cn1cc(-c2cc(Oc3ccc(NC(=O)N4CCN(C5CCOCC5)C4=O)nc3)ccn2)cn1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 80.5 %

Procedure:
A 0° C. solution of Example A2 (6.4 g, 23.94 mmol) and pyridine (6 mL, 74.2 mmol) in DCM (150 mL) was treated with a solution of Example B2 (8.36 g, 35.9 mmol) in DCM (10 mL), stirred at 0° C. for 5 min, warmed to RT and stirred for 1.5 h. The mixture was diluted with water, stirred for 15 min, and the layers separated. The organic layer was washed with water and the combined aqueous layers were extracted with DCM (4×). The combined organics were dried over Na2SO4, concentrated to dryness, treated with MeOH and concentrated again to dryness. The residue was dissolved in DCM, sonicated, treated with MTBE, sonicated and the resulting solid collected via filtration. The solid was treated with Et2O, sonicated and again collected via filtration to afford N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide (8.93 g, 80%). 1H NMR (400 MHz, DMSO-d6): δ 10.96 (s, 1 H), 8.36 (d, J=5.7 Hz, 1 H), 8.25 (s, 1 H), 8.23 (d, J=2.9 Hz, 1 H), 8.07 (dd, J=9.0, 0.7 Hz, 1 H), 7.96 (d, J=0.7 Hz, 1 H), 7.72 (dd, J=9.0, 2.9 Hz, 1 H), 7.22 (d, J=2.4 Hz, 1 H), 6.69 (dd, J=5.7, 2.5 Hz, 1 H), 3.93-3.87 (m, 3 H), 3.84 (s, 3 H), 3.83-3.77 (m, 2 H), 3.49-3.43 (m, 2 H) 3.42-3.34 (m, 2 H), 1.78-1.64 (m, 2 H), 1.59 (m, 2 H); MS (ESI) m/z: 464.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.FC(F)(F)C(O)=O.[CH2:50]([O:57][C:58]([N:60]1[CH2:65][CH2:64][NH:63][CH2:62][C:61]1([CH3:67])[CH3:66])=[O:59])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>C(Cl)Cl>[CH2:50]([O:57][C:58]([N:60]1[CH2:65][CH2:64][N:63]([C:9]([C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=2)=[O:11])[CH2:62][C:61]1([CH3:67])[CH3:66])=[O:59])[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: CC1(C)CNCCN1C(=O)OCc1ccccc1
Reactant: COc1cccc(C(=O)O)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(C(=O)N2CCN(C(=O)OCc3ccccc3)C(C)(C)C2)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
510 mg (3.31 mmol) 6-methoxy-2-pyridinecarboxylic acid was stirred with 1.17 g (3.31 mmol) TBTU and 1.50 mL (8.72 mmol) DIPEA in 10 mL DCM at RT. After 10 min, 1.20 g (3.31 mmol) 2,2-dimethyl-piperazine-1-carboxylic acid benzyl ester trifluoroacetate was added and the reaction mixture was stirred at RT for 2 h. Then the reaction mixture was washed with saturated aqueous NaHCO3 solution. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (PE/EtOAc=9/1→1/2).
Reaction SMILES: [CH3:1][C:2]1(CCCCC(OCC)=O)[C:14]2[N:13]3[CH:15]=[CH:16][N:17]=[C:12]3[C:11](=[O:18])[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.CC1C2N3C=CN=C3[C:38](=[O:45])NC=2C2C=CC=CC1=2.[H-].[Na+].C[Si](Cl)(C)C.O1CCCOO1>CN(C)C=O>[OH:45][CH2:38][C:2]1([CH3:1])[C:14]2[N:13]3[CH:15]=[CH:16][N:17]=[C:12]3[C:11](=[O:18])[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)CCCCC1(C)c2ccccc2-c2[nH]c(=O)c3nccn3c21
Reactant: CC1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Agent: C1COOOC1
Agent: C[Si](C)(C)Cl
Agent: [H-]
Solvent: CN(C)C=O
Product: CC1(CO)c2ccccc2-c2[nH]c(=O)c3nccn3c21

Procedure:
The process is performed as in Example 50 for the preparation of ethyl 5-(10-methyl-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-10-yl)-valerate but starting with 0.48 g of 10-methyl-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one, 25 ml of dimethylformamide, 0.33 g of sodium hydride, 0.28 ml of trimethylsilyl chloride and 0.1 g of trioxane. 0.27 g of 10-hydroxymethyl-10-methyl-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one is obtained in the form of a pale yellow solid melting above 260° C. (Analysis, % calculated C: 67.41, H: 4.90, N: 15.72, O: 11.97, % found C: 67.4, H: 4.9, N: 15.7).
Reaction SMILES: CO[C:3](=[O:37])[CH:4]([CH2:31][C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)[NH:5][C:6](=[O:30])[C@H:7]([CH2:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)[NH:8][C:9]([O:11][CH2:12]C1C=CC=CC=1)=[O:10].O.[NH2:39][NH2:40]>CN(C)C=O>[CH2:12]([O:11][C:9]([NH:8][C@H:7]([C:6]([NH:5][CH:4]([C:3]([NH:39][NH2:40])=[O:37])[CH2:31][C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)=[O:30])[CH2:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)=[O:10])[C:20]1[CH:29]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)C(Cc1cccs1)NC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)OCc1ccccc1
Reactant: NN
Solvent: CN(C)C=O
Solvent: O
Product: NNC(=O)C(Cc1cccs1)NC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 967.8 %

Procedure:
A mixed solution of 1.0 g (194 mmole) of N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanyl-3-(2-thienyl)-DL-alanine methyl ester and 0.64 g (0.2 mmole) of 80% hydrazine hydrate in 10 ml of dimethylformamide was stirred for 2 hours at room temperature and then left standing overnight at room temperature. Dimethylformamide was removed by evaporation under reduced pressure. Water was added to the residue, and the mixture was stirred to form a powdery precipitate, which was collected by filtration, washed with a mixture of diethyl ether and hexane and dried to yield 1.0 g (100%) of N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanyl-3-(2-thienyl)-DL-alanine hydrazide melting at 163°-164° C.