Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH2:10]([O:12]/[CH:13]=[CH:14]\[Sn](CCCC)(CCCC)CCCC)[CH3:11].CN(C)C=O.[F-].[K+]>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.C(OCC)(=O)C.O>[Br:1][C:2]1[C:3](/[CH:11]=[CH:10]/[O:12][CH2:13][CH3:14])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: CCCC[Sn](/C=C\OCC)(CCCC)CCCC
Reactant: Clc1ncc(Br)c(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCO/C=C/c1nc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
A mixture of 3.11 g of 5-bromo-2,4-dichloropyrimidine, 5.18 g of cis-1-ethoxy-2-tri-n-butylstannylethylene (synthesized according to the method disclosed in J. Am. Chem. Soc., 1977, 99, 7365), 0.479 g of dichlorobis(triphenylphosphine)palladium (II), and 60 mL of N, N-dimethylformamide was stirred for 6 hours at 70° C. After standing to cool, 60 mL of water, 60 mL of ethyl acetate, and 20 g of potassium fluoride were added thereto, and the mixture was stirred overnight at room temperature. The insolubles were filtered through celite and the filtrate was extracted with chloroform. The obtained organic layer was washed with water and saturated brine in that order, and dried over anhydrous sodium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: 10% chloroform-hexane/ethylacetate=100/0-0/100), to obtain 1.15 g of 5-bromo-2-chloro-4-[(E)-2-ethoxyvinyl]pyrimidine [11-1] (hereinafter, referred to as the compound [11-1]) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:5]=[CH:6][C:7]=1[C:8]([O:10]C)=[O:9].O.[OH-].[Li+].CO.Cl>C1COCC1.O>[C:8]([C:7]1[CH:6]=[CH:5][C:4]([CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])=[CH:3][C:2]=1[F:1])([OH:10])=[O:9]
Reactant: COC(=O)c1ccc(C2CCCN2C(=O)OC(C)(C)C)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC1c1ccc(C(=O)O)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of EXAMPLE 50C (5.5 g) and lithium hydroxide monohydrate (1.43 g) in THF (50 mL) and water (50 mL) was titrated with methanol until transparent, stirred at ambient temperature for 2 hours, acidified to pH 2 with 2M HCl, concentrated to about 40 mL and filtered.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[NH:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH3:26])[CH:24]=2)[N:19]=[C:18]([C:27]([O-:29])=O)[N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:30][O:31][CH2:32][CH2:33][NH2:34].C(OC(C)C)(C)C>CO>[CH3:30][O:31][CH2:32][CH2:33][NH:34][C:27]([C:18]1[N:17]=[C:16]([NH:15][C@H:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C@H:9]2[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH3:26])[CH:24]=2)[N:19]=1)=[O:29]
Reactant: Cc1ccc2nc(C(=O)[O-])nc(N[C@H]3CCCC[C@H]3NC(=O)OC(C)(C)C)c2c1
Reactant: COCCN
Solvent: CO
Solvent: CC(C)OC(C)C
Product: COCCNC(=O)c1nc(N[C@H]2CCCC[C@H]2NC(=O)OC(C)(C)C)c2cc(C)ccc2n1
Temperature: 50 °C
Reaction time: 15 h

Procedure:
To a suspension of 15.0 g of ethyl 4-({(1S,2R)-2-[(tert-butoxycarbonyl)amino]cyclohexyl}amino-6-methylquinazolin-2-carboxylate in 15 ml of methanol, 7.89 g of 2-methoxyethylamine was added, and the mixture was stirred at 50° C. for 15 hours. After the reaction solution was cooled to room temperature, 45 ml of diisopropyl ether was added thereto, and the mixture was stirred at 0° C. for 30 minutes. The deposited crystal was collected by filtration, washed with diisopropyl ether and dried under reduced pressure, whereby 12.2 g of a desired compound was obtained as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1([CH2:11][CH2:10][CH:9]([CH3:12])[CH2:8]1)[CH2:6][C:5]2=O.C[Si]([N:22]=[C:23]=[N:24][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1([CH2:11][CH2:10][CH:9]([CH3:12])[CH2:8]1)[CH2:6]/[C:5]/2=[N:24]\[C:23]#[N:22]
Reactant: CC1CCC2(CC(=O)c3cc(Br)ccc3O2)C1
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC1CCC2(C/C(=N\C#N)c3cc(Br)ccc3O2)C1
Temperature: 0 °C
Yield: 96.6 %

Procedure:
To a solution of 6-bromo-3′-methylspiro[chroman-2,1′-cyclopentan]-4-one (216 mg, 0.73 mmol) in anhydrous DCM (5.7 mL) was added TiCl4 (1 M solution in DCM, 1.5 mL, 1.49 mmol) dropwise within 15 min at room temperature. The mixture was stirred forl h after the addition. To this mixture was added bis-trimethylsilylcarbodiimide (300 mg, 0.36 mL, 1.61 mmol) dropwise. The resulting mixture was stirred for another 18 h after the addition. The reaction mixture was poured into ice-water (20 g) and extracted with DCM (3×20 mL). The combined organic phases were dried over anhydrous Na2S O4, filtered, and concentrated to give (E)-N-(6-bromo-3′-methylspiro[chroman-2,1′-cyclopentane]-4-ylidene)cyanamide as light brown solid (225 mg), which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][C:15]=2[F:22])[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].B(Br)(Br)Br>ClCCl>[F:22][C:15]1[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:14]=1[CH2:13][CH2:12][C@H:9]1[CH2:10][CH2:11][C@H:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:7][CH2:8]1
Reactant: CCCCC[C@H]1CC[C@H](CCc2ccc(OC)cc2F)CC1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCCC[C@H]1CC[C@H](CCc2ccc(O)cc2F)CC1
Reaction time: 1 h
Yield: 98.9 %

Procedure:
A solution of the 2-(trans-4-pentylcyclohexyl)-1-(2-fluoro-4-methoxyphenyl)-ethane (9.0 g, 0.0294 mol) obtained according to section (c) in absolute dichloromethane (100 ml) was added dropwise to a solution of boron tribromide (11.0 g, 0.0441 mol) and absolute dichloromethane (100 ml) under virtually anhydrous conditions at 0° C. The mixture thus formed was stirred for 1 hour and then poured onto ice water. The organic phase was separated off, and the aqueous phase was extracted again with dichloromethane (2×50 ml). The combined organic phases were washed with water and dried over magnesium sulfate. The crude product obtained after evaporation was recrystallized from hexane at 0° C. 8.5 g (98% yield) of pure target product were obtained.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1C(N)=[CH:8][C:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:6][N:5]=1.CI.[CH3:20][N:21]([CH:23]=O)[CH3:22]>C(=O)(O)[O-].[Na+]>[Br:3][C:4]1[C:23]([N:21]([CH3:22])[CH3:20])=[CH:8][C:7]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)=[CH:6][N:5]=1
Reactant: Nc1cc(-c2ccc(Cl)cc2)cnc1Br
Reactant: CN(C)C=O
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: CN(C)c1cc(-c2ccc(Cl)cc2)cnc1Br
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
169 mg (3.88 mmol) of sodium hydride (55% suspension) was added batchwise under a nitrogen atmosphere to a solution of 0.50 g (1.76 mmol) of 2-bromo-5-(4-chlorophenyl)pyridin-3-ylamine (Example 16.1c) in 10 mL of DMF and the mixture was stirred for 15 minutes at RT. A solution of 0.22 mL (3.53 mmol) of methyl iodide in 0.5 mL of DMF was added and the mixture was stirred for 16 hours at RT. The reaction mixture was diluted with semisaturated aqueous sodium bicarbonate solution and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with water, dried over magnesium sulfate, and evaporated down in vacuo. Yield: 0.47 g (85% of theoretical); C13H12BrClN2 (M=311.605); calc.: molpeak (M+H)+: 311/313/315 (BrCl); found: molpeak(M+H)+:311/313/315 (BrCl).
Reaction SMILES: C(Cl)(=O)[C:2](Cl)=[O:3].CS(C)=O.[Cl:11][C:12]1[CH:13]=[C:14]([CH:19]([CH2:34][CH2:35][OH:36])[CH2:20][C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28](OC)=[C:27](F)[CH:26]=2)=[O:22])[CH:15]=[CH:16][C:17]=1[Cl:18].[CH3:37]CN(CC)CC>C(Cl)Cl>[Cl:11][C:12]1[CH:13]=[C:14]([CH:19]([CH2:34][CH:35]=[O:36])[CH2:20][C:21]([N:23]([CH3:37])[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:3][CH3:2])[CH:26]=2)=[O:22])[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(CNC(=O)CC(CCO)c2ccc(Cl)c(Cl)c2)cc1F
Reactant: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: COc1cccc(CN(C)C(=O)CC(CC=O)c2ccc(Cl)c(Cl)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 130.1 %

Procedure:
Oxalyl chloride (1.44 g) in CH2Cl2 (100 mL) was cooled to a -78° C. and treated with a solution of DMSO (1.84 g) in CH2Cl2 (20 mL) over 15 mins. This mixture was stirred for 15 minutes whereupon a CH2Cl2 (30 mL) solution of 3,4-Dichloro-beta-(2-hydroxyethyl)-N-[(3-fluoro-4-methoxyphenyl)methyl]benzenepropanamide (3.9 g) was added dropwise. The mixture was stirred for 30 minutes and then treated with a solution of Et3N (2.85 g) in CH2Cl2 (20 mL) and stirred for an additional 30 minutes at -78° C., then allowed to warm to ambient temperature. The reaction mixture was washed with water (100 mL), the organic fraction separated, dried over MgSO4, filtered and concentrated under reduced pressure to yield an oil (5.0 g). Silica gel chromatography eluting with 10% EtOAc/CH2Cl2 gave the title compound (3.6 g).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH2:11](Br)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[OH-].[K+].Cl>O.C(O)C>[CH2:11]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CCCCCCCCCBr
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCOc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
12.7 Grams (0.0917 mol) of p-hydroxybenzoic acid, 28.5 g of n-nonyl bromide and 10.2 g of potassium hydroxide were added to a mixture composed of 1,500 ml (milliliter) of ethanol and 200 ml of water, and the mixture was allowed to react under reflux for 10 hours. Further, 500 ml of water was added thereto, and the mixture was stirred for 3 hours. After the completion of the reaction, a concentrated hydrochloric acid was added to acidify the reaction mixture. Thereafter, the solvent was distilled off, and the remaining product was cooled to room temperature and then filtered to give a colorless solid. The solid was fully washed with water and re-crystallized from chloroform to give an intended product (yield 75%).
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:6]([OH:7])[CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.Cl[C:16]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1>N1C=CC=CC=1>[CH3:32][O:31][C:28]1[CH:27]=[CH:26][C:25]([C:16]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:1][C@@H:2]2[C@@H:6]([OH:7])[CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]2)=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)[C@@H](O)C1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: c1ccncc1
Product: COc1ccc(C(O[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 64.7 %

Procedure:
To a solution of (3S,4S)-tert-butyl 3,4-dihydroxypyrrolidine-1-carboxylate (2.79 g, 13.7 mmol) in anhydrous pyridine (144 mL) was added 4,4′-(chloro(phenyl)methylene)bis(methoxybenzene) (5.43 g 15.2 mmol) and the resulting mixture stirred at ambient temperature for 4 days. The reaction was quenched with methanol (10 mL) and concentrated under reduced pressure. The residue was stirred in diethyl ether (150 mL) and the solid which precipitated was collected by filtration. The filtrate was concentrated under reduced pressure and purified by column chromatography (Biotage, 40M; 1% methanol:dichloromethane) to afford (3S,4S)-tert-butyl 3-(bis(4-methoxyphenyl)(phenyl)methoxy)-4-hydroxypyrrolidine-1-carboxylate (4.48 g, 65%).
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([Cl:27])=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=O)(C)(C)C.C([O:32]C(NC1CCN(S(C2C3C(Br)=CN=CC=3C=CC=2)(=O)=O)C1)=O)(C)(C)C>>[NH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([Cl:27])=[CH:20][N:21]=[C:22]([OH:32])[C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1.[ClH:27]
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(S(=O)(=O)c2cccc3cncc(Cl)c23)C1
Product: Cl
Product: N[C@@H]1CCN(S(=O)(=O)c2cccc3c(O)ncc(Cl)c23)C1

Procedure:
Intermediate 16b is used in the method of Example 6, Step A instead of Intermediate 1, then the resultant is used in the method of Step B in a similar manner, and then the title compound is obtained as hydrochloride according to the method described in Example 7.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH:3]=[CH:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:7])=[O:6].C(OO)(=[O:18])C.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C.O1CCCC1>[C:8]1([S:5]([CH:4]2[CH:3]([C:2]([F:1])([F:14])[F:15])[O:18]2)(=[O:6])=[O:7])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(=O)OO
Reactant: O=S(=O)(C=CC(F)(F)F)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccccc1)C1OC1C(F)(F)F
Temperature: 60 °C
Yield: 90 %

Procedure:
To a solution of 25.4 mmol 3,3,3-trifluoro-1-(phenylsulphonyl)prop-1-ene in 80 ml acetonitrile were added 30.5 mmol peracetic acid (39% solution in acetic acid) and 101 mmol potassium carbonate. The mixture was heated at 60° C. for 4 h. The reaction mixture was then diluted with ethyl acetate/tetrahydrofuran (1:1) and was washed with brine. The organic phase was dried over sodium sulfate and concentrated in vacuo to afford the title compound as a light yellow crystalline solid (yield 90%). EI-MS (m/e): 252.0 (M+, 15%), 125.1 (PhSO+, 100%), 77.2 (Ph+, 37%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][C:13](=[O:15])[CH:12]=[C:11]([OH:16])[CH2:10]1.[C:17](OC(=O)C)(=[O:19])[CH3:18].CCN(CC)CC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:10][C:11](=[O:16])[C:12](=[C:17]([OH:19])[CH3:18])[C:13](=[O:15])[CH2:14]1
Reactant: O=C1C=C(O)CC(c2ccc(F)cc2Br)C1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(O)=C1C(=O)CC(c2ccc(F)cc2Br)CC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 500 mL recovery flask was added 5-(2-bromo-4-fluorophenyl)-3-hydroxycyclohex-2-enone (1D) (14.3 g, 50.1 mmol, 1.0 eq.), CH2Cl2 (200 mL), acetic anhydride (6.65 g, 65.2 mmol, 1.3 eq.), Et3N (15.22 g, 150 mmol, 3.0 eq.), and DMAP (catalytic amount). The reaction mixture was stirred overnight at room temperature. Monitoring by LC/MS judged the reaction to be complete. The reaction mixture was concentrated and purified via column chromatography (gradient 70% CH2Cl2/Hex to 100% CH2Cl2) to yield the product as light yellow foam which later became an oil (3.55 g, 22%). The crude material was used in the next step without further purification. ESI-MS: m/z 327.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[NH:11][C:12]1C=[C:16]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:15]=[CH:14][N:13]=1.O.[NH2:25]N>CO.C(OCC)(=O)C>[CH3:1][C:2]1[C:3]([NH:11][C:12]2[N:25]=[C:16]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:15]=[CH:14][N:13]=2)=[CH:4][C:5]([NH2:8])=[CH:6][CH:7]=1
Reactant: NN
Reactant: Cc1ccc([N+](=O)[O-])cc1Nc1cc(-c2cccnc2)ccn1
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(N)cc1Nc1nccc(-c2cccnc2)n1
Temperature: 80 °C
Yield: 56.4 %

Procedure:
N-(2-methyl-5-nitrophenyl)-4-(pyridine-3-yl)pyridine-2-amine (3.07 g, 10.0 mmol), hydrazine monohydrate (1.54 g of 65% solution in water, 20.0 mmol), FeCl3 (21 mg, 0.13 mmol), and activated carbon (0.2 g) were dissolved in a mixture of methanol (200 mL) and ethyl acetate (100 mL). The reaction mixture was heated to 80° C. with stirring and maintained for 24 hours. The reaction mixture was cooled own to room temperature. The insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate (150 mL) and washed with water (150×2). The organic phase was dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the resulting residue was purified by column chromatography (biotage: DMC/Methanol, 1-8%, 25 CV). The product was obtained (1.57 g, yield: 56.4%) as a yellow solid and 0.53 g starting material of N-(2-methyl-5-nitrophenyl)-4-(pyridine-3-yl)pyridine-2-amine was recovered; 1H NMR (500 MHz, CDCl3) δ 2.28 (s, 3H), 3.68 (s, 2H), 6.45 (d, 1H), 6.95 (s, 1H), 7.02 (d, 1H), 7.18 (d, 1H), 7.45 (m, 1H), 7.35 (d, 1H), 7.65 (s, 1H), 8.37 (d, 1H), 8.52 (d, 1H), 8.74 (d, 1H), 9.28 (s, 1H). LC-MS (m/z) calculated, 277.3. found, 278.2 [M+H]+.
Reaction SMILES: [OH:1][CH:2]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].O[Li:23].O>>[OH:1][CH:2]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O-:15])=[O:14].[Li+:23]
Reactant: [Li]O
Reactant: CCCCCCC(O)CCCCCCCCCCC(=O)O
Solvent: O
Product: CCCCCCC(O)CCCCCCCCCCC(=O)[O-]
Product: [Li+]
Temperature: 204 °C

Procedure:
A simple lithium 12-hydroxystearate thickened base grease is prepared in a Stratco contactor by blending 9.75 parts 12-hydroxy stearic acid (Cenwax A, Union Camp) in 70 parts mineral oil (850 SUS @40° C., Texaco HVI) at 77° C. until the acid is dissolved, whereupon 2.15 parts LiOH.H2O (FMC) are added. The contactor is closed and the pressure increases to 80 PSI. The materials are heated to 204° C., the temperature is maintained for 0.2 hour, then the contactor is depressurized. The temperature is reduced to 177° C., the materials are transferred to a finishing kettle, 14.9 parts additional oil are added and the materials are mixed thoroughly until they are uniform. Dropping point is 203° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:15]([CH3:31])([CH3:30])[CH2:14]2)[N:5]=[C:4]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH:37]2[CH2:42][C:41]([CH3:44])([CH3:43])[N:40]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[C:39]([CH3:55])([CH3:54])[CH2:38]2)[N:3]=1.[CH2:56]1[O:59][CH:57]1[CH3:58]>>[OH:59][CH:57]([CH3:58])[CH2:56][NH:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:15]([CH3:30])([CH3:31])[CH2:14]2)[N:5]=[C:4]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH:37]2[CH2:38][C:39]([CH3:54])([CH3:55])[N:40]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[C:41]([CH3:43])([CH3:44])[CH2:42]2)[N:3]=1
Reactant: CC1CO1
Reactant: CCCCCCCCON1C(C)(C)CC(CCCCNc2nc(N)nc(NCCCCC3CC(C)(C)N(OCCCCCCCC)C(C)(C)C3)n2)CC1(C)C
Product: CCCCCCCCON1C(C)(C)CC(CCCCNc2nc(NCCCCC3CC(C)(C)N(OCCCCCCCC)C(C)(C)C3)nc(NCC(C)O)n2)CC1(C)C

Procedure:
The title compound is prepared from the reaction of the compound prepared in Example 21 with propylene oxide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=1)[N:6]=[CH:5]2.[OH:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1>>[OH:22][CH:23]1[CH2:24][CH2:25][N:26]([C:29]2[CH:37]=[CH:36][C:32]([C:33]([NH:1][C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[N:7]([C:11]3[CH:12]=[CH:13][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:20][CH:21]=3)[N:6]=[CH:5]4)=[O:34])=[CH:31][CH:30]=2)[CH2:27][CH2:28]1
Reactant: CCOC(=O)c1ccc(-n2ncc3cc(N)ccc32)cc1
Reactant: O=C(O)c1ccc(N2CCC(O)CC2)cc1
Product: CCOC(=O)c1ccc(-n2ncc3cc(NC(=O)c4ccc(N5CCC(O)CC5)cc4)ccc32)cc1

Procedure:
Compound 1030 was prepared according to the procedure described in Scheme IV from ethyl 4-(5-amino-1H-indazol-1-yl)benzoate and 4-(4-hydroxypiperidin-1-yl)benzoic acid. [M+H]+ calcd for C28H28N4O4: 485.21; found: 485.09.
Reaction SMILES: [CH:1](=[C:4]1[CH2:8][CH2:7][CH2:6][C:5]1=O)[CH2:2][CH3:3].[Na].C(OC)(=O)[CH2:12][C:13]([CH3:15])=[O:14]>CO>[CH2:2]([CH:1]1[CH:4]2[C:5]([CH2:6][CH2:7][CH2:8]2)=[CH:15][C:13](=[O:14])[CH2:12]1)[CH3:3]
Reactant: CCC=C1CCCC1=O
Reactant: COC(=O)CC(C)=O
Agent: [Na]
Solvent: CO
Product: CCC1CC(=O)C=C2CCCC21
Yield: 53.3 %

Procedure:
The procedure of Example 1 is repeated with 19.5 g (0.16 mol) of propylidene cyclopentanone, 0.46 g (0.02 g-atom) of sodium, 21 g (0.18 mol) of methyl acetoacetate and 100 ml of methanol. Fractional distillation yields 14 g (bp 95°-102° C. at 0.5 mm) of 5-ethylbicyclo [4.3.0] non-1-en-3-one having the structure: ##STR8##
Reaction SMILES: [SnH4].[CH3:2][O:3][C:4](=[O:37])[C@@H:5]([NH:10][C:11](=[O:36])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([S:18](=[O:35])(=[O:34])[NH:19][CH2:20][C@@H:21]2[CH2:25][C@H:24]([S:26]C(OC(C)(C)C)=O)[CH2:23][NH:22]2)[CH:13]=1)[CH2:6][CH2:7][S:8][CH3:9]>O.C(Cl)Cl>[CH3:2][O:3][C:4](=[O:37])[C@@H:5]([NH:10][C:11](=[O:36])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([S:18](=[O:34])(=[O:35])[NH:19][CH2:20][C@@H:21]2[CH2:25][C@H:24]([SH:26])[CH2:23][NH:22]2)[CH:13]=1)[CH2:6][CH2:7][S:8][CH3:9]
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1cccc(S(=O)(=O)NC[C@@H]2C[C@H](SC(=O)OC(C)(C)C)CN2)c1
Agent: [SnH4]
Solvent: ClCCl
Solvent: O
Product: COC(=O)[C@H](CCSC)NC(=O)c1cccc(S(=O)(=O)NC[C@@H]2C[C@H](S)CN2)c1
Reaction time: 0.17 h

Procedure:
Tri-nButyl tin hydride (565 mL, 2.1 mmol) was added to a stirred solution of (15(c)) (1.18 g, 1.8 mmol) and (PPh)3PdCl2 (13 mg, 0.018 mmol) in a mixture of water (0.5 mL) and CH2Cl2 (100 mL). The reaction mixture was left to stir for 10 minutes, dried over MgSO4, filtered and concentrated to a brown oil. This was then purified by flash chromatography on 9385 SiO2, eluting with a gradient of 0-10% EtOAc/i-Hexane to give the desired starting material 15(d) as a white foam: 751 mg (73%).
Reaction SMILES: Br[CH:2]([C:4]1[O:5][C:6](=[O:20])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3].[N:21]1[C:26]2[NH:27][CH:28]=[CH:29][C:25]=2[C:24]([NH2:30])=[N:23][CH:22]=1>>[NH2:30][C:24]1[C:25]2[CH:29]=[CH:28][N:27]([CH:2]([C:4]3[O:5][C:6](=[O:20])[C:7]4[C:12]([C:13]=3[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:11][CH:10]=[CH:9][CH:8]=4)[CH3:3])[C:26]=2[N:21]=[CH:22][N:23]=1
Reactant: CC(Br)c1oc(=O)c2ccccc2c1-c1ccccc1
Reactant: Nc1ncnc2[nH]ccc12
Product: CC(c1oc(=O)c2ccccc2c1-c1ccccc1)n1ccc2c(N)ncnc21
Yield: 27.9 %

Procedure:
The title compound was made in a similar way as that of the compound of example 1 using 3-(1-bromoethyl)-4-phenyl-1H-isochromen-1-one (intermediate C7, 50 mg, 0.15 mmol), 7H-pyrrolo[2,3-d]pyrimidin-4-amine (30.6 mg, 0.23 mmol) to give the title compound (16 mg, 28%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].Cl[CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>CN1C(=O)CCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH:5][CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: ClCCN1CCCC1
Reactant: Nc1cc(F)cc(Br)c1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Fc1cc(Br)cc(NCCN2CCCC2)c1
Yield: 50.5 %

Procedure:
A solution of 3-bromo-5-fluoroaniline (CAS 134168-97-1) (380 mg, 2.0 mmol) and 1-(2-chloroethyl)pyrrolidine (CAS 505041-9) (380 mg, 2.2 mmol) in NMP (20 mL) was heated to 120° C. overnight. The solution was diluted with EtOAc (100 mL) and washed with saturated Na2CO3 aqueous solution (3×40 mL). The combined organic layer were dried over Na2SO4, concentrated and purified by prep-TLC (DCM:MeOH=10:1) to give the titled product (290 mg, 50%). LCMS (0-60 AB), RT=1.076 min, M+H, 289.0