Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([CH:19]1[CH2:24][C:23](=[O:25])O[C:20]1=[O:21])=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH2:26]CCNCCNCCNCCN>O>[CH:1]([CH:19]1[CH2:24][C:23](=[O:25])[NH:26][C:20]1=[O:21])=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCC=CC1CC(=O)OC1=O
Reactant: NCCNCCNCCNCCN
Solvent: O
Product: CCCCCCCCCCCCCCCCC=CC1CC(=O)NC1=O

Procedure:
Into a 189 liter (50 gallon) stainless steel reactor, charge 62.6 kg. (137.8 lbs.) of double-bond isomerized-octadecenyl succinic anhydride (Dixie Chemical Company, Inc.) and 13.1 kg. (28.8 lbs.) of 150 solvent neutral (S150N) mineral oil. Heat the contents of the reactor to 130° C.±10° C. under a nitrogen atmosphere and stir at a speed of 150 rpm. Charge 15 kg. (33 lbs.) of tetraethylene pentamine (Union Carbide "Ultra High Purity" grade) below the surface of the reactor contents and heat the contents to 160° C.±5° C. Strip with nitrogen for approximately 21/2 hours or until water no longer evolves.
Reaction SMILES: CS[CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[NH:5][C:4]1=[O:16]>CC(O)=O.[Zn]>[F:15][C:12]([F:13])([F:14])[C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[NH:5][C:4](=[O:16])[CH2:3]2
Reactant: CSC1C(=O)Nc2ccc(C(F)(F)F)cc21
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C1Cc2cc(C(F)(F)F)ccc2N1
Yield: 89.7 %

Procedure:
A solution of 3-(methylthio)-5-(trifluoromethyl)oxindole (Gassman PG, Cue BW, Luh T-Y, J. Org. Chem. 1977;42:1344-1348) (10 g, 40 mmol) in AcOH (100 mL) was heated under reflux with Zn dust (13.3 g, 0.2 mol) for 1 hour. The mixture was cooled and filtered, and the precipitate was washed with AcOH. The combined filtrates were evaporated under reduced pressure, and the residue was diluted with 1M aqueous ammonia to give 5-trifluoromethyloxindole [VII: R1 =5-CF3, R3 =H] (7.22 g, 90%); mp (aqueous EtOH) 188.5°-191° C. (lit. [Hardtmann GE, U.S. Pat. No. 4,160,032; Chem. Abstr. 1979;91:P107890w]; mp 188°-189° C.).
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][C:4]([CH:7]([CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:8](O)=[O:9])=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][N:58]=1>CN(C)C=O>[C:1]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:2]=[CH:3][C:4]([CH:7]([CH2:11][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16]2)[C:8]([NH:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][N:58]=2)=[O:9])=[CH:5][CH:6]=1
Reactant: Nc1ccccn1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(-c2ccccc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccccn1)C(CC1CCCC1)c1ccc(-c2ccccc2)cc1
Yield: 20.9 %

Procedure:
A solution of 2-biphenyl-4-yl-3-cyclopentylpropionic acid (300 mg, 1.02 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (386 mg, 1.02 mmol), N,N-diisopropylethylamine (220 μL, 1.22 mmol), and 2-aminopyridine (144 mg, 1.53 mmol) in dry N,N-dimethylformamide (5 ml) was stirred at 25° C. under nitrogen for 15 h. The reaction mixture was partitioned between water and ethyl acetate, and the layers were separated. The organic layer was washed with a 1N aqueous hydrochloric acid solution, water, and a saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 2/1 hexanes/ethyl acetate) afforded 2-biphenyl-4-yl-3-cyclopentyl-N-pyridin-2-yl-propionamide (79 mg, 21%) as a white solid: mp 57-59° C.; EI-HRMS m/e calcd for C25H26NO (M+) 370.2045, found 370.2049.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:11][CH:12]=[CH:13][C:14]#[C:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:10])=[CH:4][C:3]=1[CH2:20][CH:21](O)C.P(Cl)(Cl)(Cl)=O.N1C=CC=C[CH:30]=1>>[CH3:19][C:16]([CH3:17])([CH3:18])[C:15]#[C:14]/[CH:13]=[CH:12]/[CH2:11][N:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:20]([CH3:21])=[CH2:30])[CH:4]=1)[CH3:10]
Reactant: c1ccncc1
Reactant: CC(O)Cc1cc(CN(C)CC=CC#CC(C)(C)C)ccc1F
Solvent: O=P(Cl)(Cl)Cl
Product: C=C(C)c1cc(CN(C)C/C=C/C#CC(C)(C)C)ccc1F
Temperature: 110 °C
Reaction time: 3 h
Yield: 32.8 %

Procedure:
Compound 29 (0.55 g; 1.73 mmol) and phosphorus oxychloride (1.33 g; 8.65 mmol) were dissolved in pyridine (25 ml). The solution was stirred for 3 hours at 110° C., and left to cool to room temperature. The mixture was poured into ice+saturated aqueous sodium bicarbonate solution, followed by extraction with diethyl ether (100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution and then with saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1), to thereby yield 0.17 g of the target compound (yield: 32.8%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.F[C:13]1[CH:20]=[CH:19][C:18]([CH:21]=[O:22])=[CH:17][C:14]=1[C:15]#[N:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:21]([C:18]1[CH:19]=[CH:20][C:13]([O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=2)=[C:14]([CH:17]=1)[C:15]#[N:16])=[O:22]
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc(C=O)ccc1Oc1cccc(C(F)(F)F)c1
Temperature: 90 °C
Yield: 106.6 %

Procedure:
To a solution of 3-(trifluoromethyl)phenol (1.435 g, 8.85 mmol) and 2-fluoro-5-formylbenzonitrile (1.2 g, 8.05 mmol) in DMF (25 mL) was added K2CO3 (3.34 g, 24.14 mmol) under argon. The mixture was heated at 90° C. for 0.5 h. After removing the solvent, the residue was diluted with water, extracted with DCM. The organic phase was dried over sodium sulfate, filtered, and concentrated. Recrystallization in EA then afforded the title compound (2.5 g, 8.58 mmol, 107% yield). LCMS: rt=3.34 min, [M+H+]=292
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6]3=[C:7]([S:22][CH2:23][CH2:24][N:5]3[C:4](=[O:25])[CH:3]=1)[CH:8]=[C:9]([C:12]([OH:21])([C:17]([F:20])([F:19])[F:18])[C:13]([F:16])([F:15])[F:14])[CH:10]=2.[H-].[Na+].S(OC)(O[CH3:32])(=O)=O.C(O)C>CN(C)C=O>[CH3:1][C:2]1[C:11]2[C:6]3=[C:7]([S:22][CH2:23][CH2:24][N:5]3[C:4](=[O:25])[CH:3]=1)[CH:8]=[C:9]([C:12]([O:21][CH3:32])([C:13]([F:14])([F:15])[F:16])[C:17]([F:20])([F:18])[F:19])[CH:10]=2
Reactant: COS(=O)(=O)OC
Reactant: Cc1cc(=O)n2c3c(cc(C(O)(C(F)(F)F)C(F)(F)F)cc13)SCC2
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: COC(c1cc2c3c(c1)c(C)cc(=O)n3CCS2)(C(F)(F)F)C(F)(F)F

Procedure:
To a solution of 2,3-dihydro-7-methyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-5H-1,4-thiazino-[2,3,4-ij]-quinolin-5-one in dimethyl formamide can be added sodium hydride and dimethyl sulfate. The mixture can be stirred and heated in a nitrogen atmosphere until the reaction is complete, treated with ethanol and purified to give 2,3-dihydro-7-methyl-9-[2,2,2-trifluoro-1-methoxy-1-(trifluoromethyl)ethyl]-5H-1,4-thiazino-[2,3,4-ij]-quinolin-5-one.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([N:17]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)[C:18]([C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)=[O:19])[CH2:13][CH2:12]1.[CH:32]1([N:38]=[C:39]=[S:40])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>ClCCCl>[CH:32]1([NH:38][C:39](=[S:40])[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][CH:14]([N:17]([C:25]3[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=3)[C:18]([C:20]3[O:21][CH:22]=[CH:23][CH:24]=3)=[O:19])[CH2:15][CH2:16]2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: S=C=NC1CCCCC1
Reactant: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCCc3ccccc3N)CC2)cc1
Solvent: ClCCCl
Product: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCCc3ccccc3NC(=S)NC3CCCCC3)CC2)cc1
Yield: 43.7 %

Procedure:
To a solution of N-[1-[3-(2-aminophenyl)propyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide (0.42 g) dissolved in 1,2-dichloroethane (5 mL) was added cyclohexyl isothiocyanate (0.42 g) at room temperature. The solution was then heated under reflux for 8 hours. The solution was purified by chromatography [silica gel, dichloromethane-methanol-aqueous ammonia (97:3:0.2-95:5:0.3)] to give the title compound (0.2458 g).
Reaction SMILES: [CH2:1]([N:3]([CH:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[F:11])[CH3:2].[Cl:19][C:20]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>O1CCOCC1.CO>[Cl:19][C:20]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:21]=1[C:22]([NH:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N:3]([CH2:1][CH3:2])[CH:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[C:5]=1[F:11])=[O:23]
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Reactant: CCN(c1cccc(N)c1F)C1CCN(C)CC1
Solvent: C1COCCO1
Solvent: CO
Product: CCN(c1cccc(NC(=O)c2ccc(F)cc2Cl)c1F)C1CCN(C)CC1

Procedure:
Heat a mixture of N-ethyl-2-fluoro-N-(1-methyl-piperidin-4-yl)-benzene-1,3-diamine (Preparation 27) and 2-chloro-4-fluorobenzoyl chloride (23 mg) in 1,4-dioxane (5 mL) at reflux for 1 hour. Dilute with methanol (5 mL), load on a SCX column (10 g), wash with methanol, elute the product with 2M NH3 in methanol, evaporate to give the title compound: mass spectrum (electric spray) m/z=408 (M+1). Purify further by HPLC to give the di-trifluoroacetic acid salt.
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][O:20][C:21]1[N:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1>>[CH3:19][O:20][C:21]1[N:26]=[CH:25][C:24]([NH:27][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([S:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)(=[O:8])=[O:9])[CH:11]=2)=[CH:23][CH:22]=1
Reactant: COc1ccc(N)cn1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Product: COc1ccc(NC(=O)c2cccc(S(=O)(=O)N3CCCCC3)c2)cn1

Procedure:
The entitled compound was produced according to the method of Example 92 but using 3-(piperidin-1-ylsulfonyl)benzoic acid and 6-methoxypyridine-3-amine as the starting materials.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[CH:10]=[C:9]([S:11][CH2:12][C:13](=O)[CH3:14])[CH:8]=[N:7]1)[CH3:2].Cl.[Cl:18][C:19]1[C:20]([F:27])=[C:21]([NH:25]N)[CH:22]=[CH:23][CH:24]=1>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[CH:10]=[C:9]([S:11][C:12]2[C:22]3[C:21](=[C:20]([F:27])[C:19]([Cl:18])=[CH:24][CH:23]=3)[NH:25][C:13]=2[CH3:14])[CH:8]=[N:7]1)[CH3:2]
Reactant: NNc1cccc(Cl)c1F
Reactant: CCOC(=O)Cn1cc(SCC(C)=O)cn1
Agent: Cl
Product: CCOC(=O)Cn1cc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)cn1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: [4-(2-oxo-propylsulfanyl)-pyrazol-1-yl]-acetic acid ethyl ester and 3-chloro-2-fluorophenylhydrazine hydrochloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[CH2:13][C:12](=[O:14])[NH:11][C:10]2=[O:15])=[N:6][CH:7]=1.[CH3:16]OC(OC)(N(C)C)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[CH2:13][C:12](=[O:14])[N:11]([CH3:16])[C:10]2=[O:15])=[N:6][CH:7]=1
Reactant: O=C1CN(Cc2ccc(Br)cn2)C(=O)N1
Reactant: COC(C)(OC)N(C)C
Solvent: Cc1ccccc1
Product: CN1C(=O)CN(Cc2ccc(Br)cn2)C1=O
Temperature: 150 °C
Yield: 83.6 %

Procedure:
1-((5-bromopyridin-2-yl)methyl)imidazolidine-2,4-dione (9J3) (0.926 mmol, 250 mg) was mixed with toluene (2.5 ml) and N,N-dimethylacetamide dimethyl acetal (9J4) (3.70 mmol, 490 mg) and heated in the microwave at 150° C. for 15 minutes. The volatile components were removed under high vacuum and the resulting oil purified on silica eluting with 0-100% ethyl acetate/heptane to afford 1-((5-bromopyridin-2-yl)methyl)-3-methylimidazolidine-2,4-dione (9J5) 220 mg (84%); 1H NMR (400 MHz, CDCl3) 8.62 (d, 1H) 7.81 (dd, 1H) 7.20 (d, 1H) 4.63 (s, 2H) 3.98 (s, 2H) 3.05 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([N:15]4[C:19]([CH3:21])([CH3:20])[CH2:18][NH:17][C:16]4=[O:22])[S:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:23]=1.[CH3:24][C:25]([OH:42])([CH3:41])[CH2:26][N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1>>[OH:42][C:25]([CH3:41])([CH3:24])[CH2:26][N:27]1[CH:31]=[C:30]([C:2]2[CH:3]=[CH:4][C:5]3[C:11]4[N:12]=[C:13]([N:15]5[C:19]([CH3:21])([CH3:20])[CH2:18][NH:17][C:16]5=[O:22])[S:14][C:10]=4[CH2:9][CH2:8][O:7][C:6]=3[CH:23]=2)[CH:29]=[N:28]1
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC1(C)CNC(=O)N1c1nc2c(s1)CCOc1cc(Br)ccc1-2
Product: CC(C)(O)Cn1cc(-c2ccc3c(c2)OCCc2sc(N4C(=O)NCC4(C)C)nc2-3)cn1
Yield: 12 %

Procedure:
1-(8-Bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-2-yl)-5,5-dimethylimidazolidin-2-one was coupled with 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol under Suzuki conditions to give 429. Yield 12%. MS(ESI+): 454.1. 1H NMR (400 MHz, DMSO) δ 8.18 (d, J=8.2, 1H), 8.10 (s, 1H), 7.89 (s, 1H), 7.61 (s, 1H), 7.35 (dd, J=8.2, 1.8, 1H), 7.21 (d, J=1.7, 1H), 4.71 (s, 1H), 4.31 (t, J=5.0, 2H), 4.03 (d, J=5.6, 2H), 3.18 (dd, J=9.3, 5.1, 3H), 1.72 (s, 6H), 1.09 (s, 6H)
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=[O:14])[NH:8]2)#N.C(O)=[O:16]>[Ni]>[CH3:13][C:10]1[C:9]2[NH:8][C:7](=[O:14])[CH2:6][CH2:5][C:4]=2[C:3]([CH:1]=[O:16])=[CH:12][CH:11]=1
Reactant: Cc1ccc(C#N)c2c1NC(=O)CC2
Reactant: O=CO
Agent: [Ni]
Product: Cc1ccc(C=O)c2c1NC(=O)CC2
Yield: 62 %

Procedure:
5-Cyano-8-methyl-3,4-dihydro-1H-quinolin-2-one (2.0 g) and Raney nickel (10 g) were suspended in formic acid (40 ml), and the suspension was heated under reflux for 6 hours. The reaction mixture was filtered to remove the insoluble matter, and the filtrate was concentrated. Ethyl acetate and water were added to the residue, and after stirring, the mixture was filtered through Celite. The filtrate was separated into layers, and the organic layer was washed with water and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was recrystallized from an ethyl acetate-diethyl ether mixed solvent to thereby obtain 1.29 g (yield: 62%) of 8-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-5-carboxaldehyde as a light brown powder.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[N:11]=[C:12](Cl)[C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[S:16][C:14]=2[N:15]=1>>[Cl:9][C:10]1[N:11]=[C:12]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:13]2[CH:18]=[C:17]([C:19]([F:21])([F:22])[F:20])[S:16][C:14]=2[N:15]=1
Reactant: FC(F)(F)c1cc2c(Cl)nc(Cl)nc2s1
Reactant: NCc1ccccc1
Product: FC(F)(F)c1cc2c(NCc3ccccc3)nc(Cl)nc2s1

Procedure:
Following the procedure of Example 1, the reaction of benzylamine with 2,4-dichloro-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-chloro-6-trifluoromethyl-4-benzylamino-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]([CH:7]1[C:12](=[O:13])[CH2:11][CH2:10][CH2:9][C:8]1=O)(=O)[CH3:5]>CCO>[CH3:5][C:4]1[C:7]2[C:12](=[O:13])[CH2:11][CH2:10][CH2:9][C:8]=2[NH:3][N:2]=1
Reactant: NN
Reactant: CC(=O)C1C(=O)CCCC1=O
Solvent: CCO
Solvent: O
Product: Cc1n[nH]c2c1C(=O)CCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.2 %

Procedure:
According to Scheme 4 Step 3: Hydrazine monohydrate (7.59 mmol, 0.37 mL) was added to a solution of 2-acetylcyclohexane-1,3-dione (7.59 mmol, 1.17 g) in EtOH (19 mL) at 0° C. and the reaction mixture was stirred at room temperature for 2 hours. After evaporation, the crude residue was purified by flash chromatography over silica gel using DCM/AcOEt (70:30 to 50:50) as eluent to yield 3-methyl-6,7-dihydro-1H-indazol-4(5H)-one (1.76 mmol, 265 mg, 23%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1O[C:4]([CH3:13])=[CH:5][C:6](=[C:8]([C:11]#[N:12])[C:9]#[N:10])[CH:7]=1.[CH2:14]([NH2:28])[CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][CH2:26][NH2:27]>>[C:9]([C:8]([C:11]#[N:12])=[C:6]1[CH:7]=[C:2]([CH3:1])[N:27]([CH2:26][CH2:25][CH2:24][O:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][CH2:14][N:28]2[C:4]([CH3:13])=[CH:5][C:6](=[C:8]([C:9]#[N:10])[C:11]#[N:12])[CH:7]=[C:2]2[CH3:1])[C:4]([CH3:13])=[CH:5]1)#[N:10]
Reactant: NCCCOCCOCCOCCCN
Reactant: CC1=CC(=C(C#N)C#N)C=C(C)O1
Product: CC1=CC(=C(C#N)C#N)C=C(C)N1CCCOCCOCCOCCCN1C(C)=CC(=C(C#N)C#N)C=C1C

Procedure:
A solution of 0.52 g (3 mmol) of (2,6-dimethyl-4H-pyran-4-ylidene)malononitril and 0.3 ml (1.5 mmol) of 4,7,10-trioxa-1,13-tridecanediamine in 6 ml of acetontrile was heated to 90° C. for 70 h under nitrogen. Removal of the acetonitrile left a brown residue which was recrystallized from 25 ml methanol and 10 ml ethyl acetate yielding 0.68 g (43%) of 2-{1-[3-(2-{2-[3-(4-dicyanomethylene-2,6-dimethyl-4H-pyridin-1-yl)-propoxy]-ethoxy}-ethoxy)-propyl]-2,6-dimethyl-1H-pyridin-4-ylidene}-malononitrile.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[CH3:24][C:25]1[N:26]([CH2:34][CH2:35][O:36][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][O:38]2)[CH:27]=[C:28]([Sn](C)(C)C)[N:29]=1>O1CCOCC1.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>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:22]=[CH:23][C:2]([C:28]5[N:29]=[C:25]([CH3:24])[N:26]([CH2:34][CH2:35][O:36][CH:37]6[CH2:42][CH2:41][CH2:40][CH2:39][O:38]6)[CH:27]=5)=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][CH:16]=[N:17]1)([CH3:21])[CH3:20]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reactant: Cc1nc([Sn](C)(C)C)cn1CCOC1CCCCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Cc1nc(-c2ccc3c(c2)OCCn2cc(-c4ncnn4C(C)C)nc2-3)cn1CCOC1CCCCO1
Temperature: 120 °C
Reaction time: 0.58 h
Yield: 32.3 %

Procedure:
A mixture of 9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (300 mg, 0.8 mmol), Pd(PPh3)4 (93 mg, 0.08 mmol), 2-methyl-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(trimethylstannyl)-1H-imidazole (600 mg, 1.6 mmol) in dioxane (2 ml) was bubbled with N2 for about 2 min and then stirred at 120° C. for 35 min under the irradiation of microwave. Filtered, concentrated and purified by pre-TLC (EtOAc) to give 130 mg of 256. Yield=32%. 1H NMR (CDCl3, 400 MHz): δ8.44-8.42 (m, 1 H, ArH), 7.81 (s, 1 H), 7.58 (s, 1 H), 7.48-7.46 (m, 1 H), 7.42 (d, J=1.6 Hz, 1 H), 7.19 (s, 1 H), 4.51-4.95 (m, 1 H), 4.45-4.44 (t, 1 H), 4.39-4.38 (m, 2 H), 4.38-4.37 (m, 2 H), 4.07-4.04 (m, 2 H), 4.00-4.97 (m, 1 H), 3.63-3.54 (m, 2 H), 3.40-3.36 (m, 1 H), 2.49 (s, 3 H), 1.76-1.60 (m, 4 H), 1.48-1.47 (m, 2 H) LC-MS: m/z=504 [M+H+]
Reaction SMILES: [CH2:1]([C:8]1[C:9](Cl)=[N:10][C:11]([NH2:15])=[N:12][C:13]=1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([NH2:22])[CH2:18][CH2:19][CH2:20][CH3:21]>O1CCOCC1>[NH2:15][C:11]1[N:10]=[C:9]([NH:22][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:13]([CH3:14])[N:12]=1
Reactant: Cc1nc(N)nc(Cl)c1Cc1ccccc1
Reactant: CCCCCN
Solvent: C1COCCO1
Product: CCCCCNc1nc(N)nc(C)c1Cc1ccccc1
Reaction time: 19 h
Yield: 89.7 %

Procedure:
A mixture of 5-benzyl-4-chloro-6-methylpyrimidine-2-ylamine (500 mg, 2.14 mmol) , amylamine (1.24 ml ) and dioxane (4 ml ) was kept at 95-100° C. for 19 hours. The reaction mixture was concentrated in vacuo, and the residue was extracted with chloroform and a saturated aqueous NaHCO3 solution. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (2%MeOH/CHCl3) to give the object compound (546 mg, 89.7%).
Reaction SMILES: [C:1]1([P:7]2(=[O:14])[CH2:11][CH2:10][CH2:9][CH:8]2[CH2:12]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(Cl)Cl>[C:1]1([P:7]2(=[O:14])[CH2:11][CH2:10][CH2:9][C:8]2=[CH2:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=P1(c2ccccc2)CCCC1CO
Solvent: ClCCl
Product: C=C1CCCP1(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 71.5 %

Procedure:
In a 100 ml round bottom 2-neck flask charged with a magnetic stirring bar and 20 ml freshly distilled CH2Cl2, 1.6 g 1-phenyl-2-phospholanemethanol-1-oxide (0.008 mol, mixture of diastereoisomers) was dissolved. The reaction flask was flushed with argon and cooled to 0° C. Subsequently 2.1 ml SOCl2 in 10 ml CH2Cl2 was added dropwise. The resulting yellowish mixture was stirred for 5 h at room temperature, then 20 ml water was added. The mixture was extracted twice with 20 ml CH2Cl2, and the combined organic phases were dried over MgSO4 and filtered. To the resulting filtrate containing crude 2-chloromethyl-1-phenylphospholane 1-oxide (mixture of isomers; 31P NMR (200 MHz) δ: 58.2, 60.3) 1.7 ml DBU was added. The mixture was heated and refluxed overnight. Evaporation of the solvent and flash chromatography of the residue with EtOAc/ethanol 20:1 yielded 1.1 g (75%) 1-phenyl-2-methylenephospholane-1-oxide as a colorless oil. 1H NMR (500 MHz) δ: 1.72-1.89 (m, 1H), 1.94-2.16 (m, 3H), 2.48-2.59 (m, 1H), 2.66-2.78 (m, 1H), 5.74 (dt, 1H, J=2.4, J=17.2), 5.88 (dt, 1H, J=2.1, J=36.6), 7.37-7.48 (m, 3H), 7.63-7.70 (m, 2H); −P NMR (200 MHz) δ: 45.0.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([CH:19]=[O:20])=[CH:11][C:12]3[NH:16][CH:15]=[N:14][C:13]=3[C:17]=2[F:18])=[C:4]([Cl:21])[CH:3]=1.C([Sn](CCCC)(CCCC)[CH2:27][O:28][CH2:29][O:30][CH3:31])CCC>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([CH:19]([OH:20])[CH2:27][O:28][CH2:29][O:30][CH3:31])=[CH:11][C:12]3[NH:16][CH:15]=[N:14][C:13]=3[C:17]=2[F:18])=[C:4]([Cl:21])[CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)COCOC
Reactant: O=Cc1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Product: COCOCC(O)c1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl

Procedure:
6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carbaldehyde 10f is treated with tributyl-methoxymethoxymethyl-stannane according to the procedure described in Example 42, Step A to yield compound 101. MS APCI (+) m/z 444, 446 (M+, Br pattern) detected.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)=[O:10].Cl[C:23]1[N:28]=[C:27]([C:29]2[O:30][CH:31]=[CH:32][CH:33]=2)[CH:26]=[CH:25][N:24]=1>>[O:30]1[CH:31]=[CH:32][CH:33]=[C:29]1[C:27]1[CH:26]=[CH:25][N:24]=[C:23]([N:7]2[CH2:8][CH:4]3[CH:5]([CH2:1][N:2]([C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:17]4[S:18][CH:19]=[CH:20][CH:21]=4)=[O:10])[CH2:3]3)[CH2:6]2)[N:28]=1
Reactant: Clc1nccc(-c2ccco2)n1
Reactant: O=C(c1ccccc1-c1cccs1)N1CC2CNCC2C1
Product: O=C(c1ccccc1-c1cccs1)N1CC2CN(c3nccc(-c4ccco4)n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 37 and 2-chloro-4-furan-2-yl-pyrimidine. MS (ESI) mass calcd. for C26H22N4O2S, 442.50; m/z found, 443.2 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[NH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=S)[NH2:15])=[CH:10][CH:9]=2)[CH:4]=[CH:3]1.[CH2:17](N)[CH2:18][NH2:19]>>[NH:19]1[CH2:18][CH2:17][N:15]=[C:14]1[C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH2:4][CH2:3][C:2](=[O:1])[NH:7][N:6]=2)=[CH:9][CH:10]=1
Reactant: NCCN
Reactant: NC(=S)c1ccc(-c2ccc(=O)[nH]n2)cc1
Product: O=C1CCC(c2ccc(C3=NCCN3)cc2)=NN1
Temperature: 0 °C

Procedure:
A slurry of 3 g of 4-(1,6-dihydro-6-oxo-3-pyridazinyl)benzenecarbothioamide in 5 ml of ethylenediamine is heated at 100° C. for 30 minutes when a clear solution is obtained. The solution is poured into 50 ml of ice-water and the solid is filtered, washed with a small volume of ice-water, and air-dried to give 2.5 g of the product, 6-[4-(4,5-dihydro-1H-imidazol-2-yl) phenyl]-4,5-dihydro-3(2H)-pyridazinone, mp 296°-297° dec.