Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[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:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:47][C:48]1[CH:49]=[C:50]([CH:52]=[CH:53][C:54]=1[CH3:55])[NH2:51]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([NH:51][C:50]4[CH:52]=[CH:53][C:54]([CH3:55])=[C:48]([F:47])[CH:49]=4)=[O:42])[CH2:36][CH2:35]3)=[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:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[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)N1CCC(CC(=O)O)CC1
Reactant: Cc1ccc(N)cc1F
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)Nc2ccc(C)c(F)c2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(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]-piperidin-4-yl}-acetic acid was reacted with 3-fluoro-4-methylaniline (Aldrich) to give the title product. LC-MS (ES+) 772 [(M+H)+].
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[C:24]([CH3:30])=[N:25][N:26]([CH3:29])[C:27]=4[Cl:28])=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:31].[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=2)[CH2:35][CH2:34]1>C1COCC1>[CH3:32][N:33]1[CH2:34][CH2:35][N:36]([C:39]2[CH:44]=[CH:43][C:42]([NH:45][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21]([C:23]6[C:24]([CH3:30])=[N:25][N:26]([CH3:29])[C:27]=6[Cl:28])=[O:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:31])=[CH:41][CH:40]=2)[CH2:37][CH2:38]1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: Cc1nn(C)c(Cl)c1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Solvent: C1CCOC1
Product: Cc1nn(C)c(Cl)c1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CNc2ccc(N3CCN(C)CC3)cc2)c1
Temperature: 65 °C
Reaction time: 24 h
Yield: 44.7 %

Procedure:
A small screw cap test tube was charged with 5-Chloro-1,3-dimethyl-1H-pyrazole-4-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (prepared below, 100 mg, 0.244 mmol) and THF (2 mL). To the resulting solution was added 4-(4-Methyl-piperazin-1-yl)-phenylamine (46.7 mg, 0.244 mmol), and the mixture was stirred for 24 h at 65° C. The reaction mixture was cooled to room temperature and concentrated in vacuo. The crude mixture was redissolved into ˜2 mL of EtOAc and then Hexanes were added to causing a precipitate to form. The precipitate was then filtered yielding 45% (0.067 g, 0.109 mmol) of the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.N1C=CC=CC=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>ClCCl.C(OCC)(=O)C>[C:18]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1)(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: O=Cc1c[nH]c2ccccc12
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)n1cc(C=O)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.6 %

Procedure:
To a solution of 1H-indole-3-carboxaldehyde (300 mg, 2.07 mmol) in 6.2 mL of dry dichloromethane were added pyridine (0.34 mL, 4.2 mmol), acetic anhydride (0.59 mL, 6.2 mmol), and N,N-dimethylaminopyridine (20 mg, 0.16 mmol) at room temperature, successively. After being stirred at room temperature for 2 h, the reaction mixture was diluted with ethyl acetate. The solution was washed with 1N HCl, saturated NaHCO3 aqueous solution, brine, dried over MgSO4, filtered, and concentrated in vacuo. The resulting solid was rinsed with diethyl ether/hexane to obtain the title compound as a white powder (235 mg, 77%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[C:11]=2[O:18][CH3:19])=[O:9])=[CH:6][N:5]=[C:4](S(CC)=O)[N:3]=1.FC(F)(F)C(O)=O.[CH3:31][S:32]([N:35]1[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]1)(=[O:34])=[O:33]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[C:11]=2[O:18][CH3:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:41][CH:38]2[CH2:39][CH2:40][N:35]([S:32]([CH3:31])(=[O:34])=[O:33])[CH2:36][CH2:37]2)[N:3]=1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: CCS(=O)c1ncc(C(=O)c2cc(F)cc(F)c2OC)c(N)n1
Solvent: O=C(O)C(F)(F)F
Product: COc1c(F)cc(F)cc1C(=O)c1cnc(NC2CCN(S(C)(=O)=O)CC2)nc1N

Procedure:
The same procedure as described in Example 326 was used, starting with (4-amino-2-ethanesulfinyl-pyrimidin-5-yl)-(3,5-difluoro-2-methoxy-phenyl)-methanone (Example 380) and 1-methanesulfonyl-piperidin-4-ylamine; compound with trifluoroacetic acid (Example 162) to give [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(3,5-difluoro-2-methoxy-phenyl)-methanone as a white solid. MS (M+H)+, 442.
Reaction SMILES: ClCCl.C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:14][CH2:15][CH2:16][N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]([F:30])([F:29])[F:28])[CH:25]=2)[C:20]([O:31][CH3:32])=[CH:19][C:18]1=[O:33]>O.C(N(CC)CC)C>[CH3:32][O:31][C:20]1[C:21]2[C:26](=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:23][CH:22]=2)[N:17]([CH2:16][CH:15]=[O:14])[C:18](=[O:33])[CH:19]=1
Reactant: COc1cc(=O)n(CCO)c2cc(C(F)(F)F)ccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: O
Solvent: ClCCl
Product: COc1cc(=O)n(CC=O)c2cc(C(F)(F)F)ccc12
Reaction time: 0.22 h

Procedure:
To 2 mL of a dichloromethane solution containing 30 μL of oxalyl chloride, 50 μL of dimethylsulfoxide was added dropwise under nitrogen atmosphere at −60° C., and stirred for 13 min. 6 mL of a dichloromethane solution containing 0.08 g of 1-(2-hydroxyethyl)-4-methoxy-7-trifluoromethylquinolin-2(1H)-one was added dropwise at the same temperature, and stirred for 10 min. After 0.16 mL of triethylamine was added at the same temperature, it was stirred at room temperature for 1 hour, and water was added. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give (4-methoxy-7-trifluoromethyl-2-oxoquinolin-1(2H)-yl)acetaldehyde as a pale yellow solid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([C:11]2[CH:12]=[CH:13][C:14]([CH:19]([C:34]3[CH:39]=[CH:38][C:37]([CH:40]([CH3:42])[CH3:41])=[CH:36][CH:35]=3)[CH2:20][C@H:21]3[CH2:25][CH2:24][C:23](=[O:26])[N:22]3C(OC(C)(C)C)=O)=[N:15][C:16]=2[O:17][CH3:18])[CH2:10][CH2:9]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH:8]1([C:11]2[CH:12]=[CH:13][C:14]([CH:19]([C:34]3[CH:39]=[CH:38][C:37]([CH:40]([CH3:42])[CH3:41])=[CH:36][CH:35]=3)[CH2:20][C@@H:21]3[NH:22][C:23](=[O:26])[CH2:24][CH2:25]3)=[N:15][C:16]=2[O:17][CH3:18])[CH2:10][CH2:9]1
Reactant: COc1nc(C(C[C@H]2CCC(=O)N2C(=O)OC(C)(C)C)c2ccc(C(C)C)cc2)ccc1C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1nc(C(C[C@H]2CCC(=O)N2)c2ccc(C(C)C)cc2)ccc1C1CC1
Yield: 105.8 %

Procedure:
Trifluoroacetic acid (1 mL) was added to a solution of tert-butyl (2R)-2-{2-(5-cyclopropyl-6-methoxypyridin-2-yl)-2-[4-(propan-2-yl)phenyl]ethyl}-5-oxopyrrolidine-1-carboxylate (211 mg) in methylene chloride (2 mL) under ice-cooling, and the mixture was stirred under ice-cooling for 75 minutes. Saturated aqueous sodium bicarbonate was added to the reaction solution, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered, after which the solvent was evaporated under reduced pressure to give (5R)-5-{2-(5-cyclopropyl-6-methoxypyridin-2-yl)-2-[4-(propan-2-yl)phenyl]ethyl}pyrrolidin-2-one (176.5 mg, quant.).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[C:11]([CH2:27][CH3:28])=[N:12][CH:13]=[CH:14][C:15]=2[C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[C:18]([O:25][CH3:26])[CH:17]=2)=[CH:4][CH:3]=1.[CH2:29]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[CH3:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O.C(#N)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[C:11]([CH2:27][CH3:28])=[N:12][CH:13]=[CH:14][C:15]=2[C:16]2[CH:24]=[CH:23][C:19]([C:20]([N:34]3[CH2:35][CH2:36][N:31]([CH2:29][CH3:30])[CH2:32][CH2:33]3)=[O:22])=[C:18]([O:25][CH3:26])[CH:17]=2)=[CH:4][CH:3]=1
Reactant: CCN1CCNCC1
Reactant: CCc1nccc(-c2ccc(C(=O)O)c(OC)c2)c1C#Cc1ccc(N)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCc1nccc(-c2ccc(C(=O)N3CCN(CC)CC3)c(OC)c2)c1C#Cc1ccc(N)nc1

Procedure:
The title compound is synthesized according to general procedure GP5 starting from 70 mg (0.19 mmol) 4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-methoxy-benzoic acid (A-42) using 42 mg (0.38 mmoL) N-ethyl piperazine, 71 mg (0.19 mmol) HATU and 35 μL (0.21 mmol) DIPEA in 1.0 mL DMF. After completion of the reaction, the reaction mixture is filtered and the product is isolated from the obtained solution by RP-HPLC using a H2O/ACN-gradient. Yield: 85 mg (97%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][C:16]([O:18]CC2C=CC=CC=2)=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO.C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cc1cccc(OCc2ccccc2)c1)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)Cc1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The crude benzyl 2-(3-(benzyloxy)phenyl)acetate was dissolved in a mixture of MeOH (20 mL) and THF (50 mL). To this solution was added 40 mL of 1N NaOH (40 mmol). The reaction mixture was stirred at room temperature for 2 h. The organic solvent was removed in vacuo. The remaining aqueous solution was extracted with diethyl ether (2×50 mL). The aqueous solution was then acidified with 1N HCl (50 mL) and the title compound precipitated. The solid was collected by filtration (4.35 g, 90% two steps). MS(ESI+) m/z 265 (M+Na)+.
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[C:4]([C:7]([N:9]2[CH2:15][CH2:14][CH2:13][C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10]2)=[O:8])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OC(=O)C[N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1)C>COCCOC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:16][C:12]1([CH3:17])[CH2:13][CH2:14][CH2:15][N:9]([C:7]([C:4]2[CH:3]=[C:2]([C:32]3[CH:33]=[N:29][NH:30][CH:31]=3)[S:6][CH:5]=2)=[O:8])[CH2:10][CH2:11]1
Reactant: CCOC(=O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC1(C)CCCN(C(=O)c2csc(Br)c2)CC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: CC1(C)CCCN(C(=O)c2csc(-c3cn[nH]c3)c2)CC1
Temperature: 140 °C
Yield: 5 %

Procedure:
(5-Bromo-thiophen-3-yl)-(4,4-dimethyl-azepan-1-yl)-methanone (0.31 g, 0.99 mmol), together with caesium carbonate (0.483 g, 1.49 mmol),), [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-acetic acid ethyl ester (0.28 g, 1.0 mmol) and palladium tetrakis(triphenylphosphine) (114 mg, 0.1 mmol) were taken up in DME (9 mL), IMS (2 mL) and water (1 mL) and the vessel was purged with argon. The reaction mixture was heated by microwave irradiation to 140° C. for 20 minutes and then diluted with water then treated with dilute HCl (pH adjusted to 4) and extracted with DCM (×3). The organic solution was dried over sodium sulfate, filtered and the solvent evaporated. The residue was purified by chromatography on a silica II cartridge, eluting with 50 then 100% ethyl acetate in cyclohexane then 5% acetic acid in ethyl acetate. The residue was further purified by HPLC, eluting with 10%-98% acetonitrile in water (0.1% formic acid) and the fractions containing desired product were freeze-dried to give the title compound (0.015 g). LCMS m/z 362.24 [M+H]+ R.T.=8.84 min (Analytical Method 2).
Reaction SMILES: [CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[Fe+2:11].P(=O)(O)(O)[OH:13]>C(OC(=O)C)(=O)C>[C:10]([C-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1)(=[O:13])[CH3:6].[CH-:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[Fe+2:11]
Reactant: O=P(O)(O)O
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)[c-]1cccc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 55.4 %

Procedure:
A mixture of 93.0 g (0.5 mole) of ferrocene, 250 ml of acetic anhydride and 20 ml of 85% strength phosphoric acid was heated to 100° C for 10 minutes, then cooled and poured onto ice. After leaving the mixture to stand overnight, the solid residue was filtered off and washed with water. For further purification the residue was dissolved in cyclohexane, while warming, and animal charcoal/Tonsil were added. The mixture was then filtered and the filtrate was evaporated to dryness under reduced pressure. In this way 64 g (55.4% of theory) of acetylferrocene with a melting point of 84 to 86° C were obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[NH2:40][CH2:41][C@H:42]([N:47]1[CH2:52][CH2:51][N:50]([S:53]([CH3:56])(=[O:55])=[O:54])[CH2:49][CH2:48]1)[C:43]([O:45][CH3:46])=[O:44].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:56][S:53]([N:50]1[CH2:49][CH2:48][N:47]([C@@H:42]([CH2:41][NH:40][C:12](=[O:14])[C:11]2[CH:10]=[CH:9][C:8]([O:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:16][CH:15]=2)[C:43]([O:45][CH3:46])=[O:44])[CH2:52][CH2:51]1)(=[O:54])=[O:55]
Reactant: COC(=O)[C@H](CN)N1CCN(S(C)(=O)=O)CC1
Reactant: COCCOCOc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCOCOc1ccc(C(=O)NC[C@@H](C(=O)OC)N2CCN(S(C)(=O)=O)CC2)cc1
Reaction time: 0.33 h
Yield: 67.6 %

Procedure:
1.1 g (5 mmol) of 4-(2-methoxyethoxymethoxy)benzoic acid are put into solution in 15 ml of dimethylformamide then 0.7 g (5.5 mmol) of 1-hydroxybenzotriazole and 1.1 g (5.5 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride are added. The reaction medium is stirred for 20 minutes before adding a mixture of 1.5 g (5 mmol) of methyl (S)-3-amino-2-(4-methanesulphonylpiperazin-1-yl)propanoate hydrochloride (prepared as described in 2-3) and of 1.4 ml (9.9 mmol) of triethylamine in 15 ml of dimethylformamide. The reaction medium is stirred at 50° C. for 1 h 30 min then at ambient temperature for 18 h. After hydrolysis with a saturated aqueous solution of sodium hydrogen carbonate then extraction with ethyl acetate, the organic phase is washed with an aqueous solution of sodium hydrogen carbonate then with a saturated aqueous solution of sodium chloride, dried over magnesium sulphate, filtered and concentrated. The crude product obtained is purified by chromatography over silica gel eluted with a 9/1 dichloromethane/methanol mixture. 1.6 g (68%) of methyl (S)-2-(4-methanesulphonylpiperazin-1-yl)-3-[4-(2-methoxyethoxymethoxy)benzoylamino]propanoate are obtained in the form of a colourless oil.
Reaction SMILES: [Mg].II.C(Br)C.[C:7]1([C:13]#[CH:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[O:15]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=[O:26])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1.Cl>[O:15]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]([OH:26])[C:14]#[C:13][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: C#Cc1ccccc1
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: CCBr
Solvent: C1CCOC1
Product: OC(C#Cc1ccccc1)c1cccc(Oc2ccccc2)c1
Temperature: 0 °C
Yield: 98.7 %

Procedure:
The alcohol required for the preparation of the pyrethroid is prepared as follows: ##STR12## A reaction vessel is charged with 14.6 g of magnesium filings together with a trace of iodine crystals. 73.6 g of ethyl bromide in 25 ml of tetrahydrofuran are then added dropwise such that the tetrahydrofuran boils gently under reflux. The Grignard solution formed is added dropwise at 0°-5° C. to a solution of 62.1 g of phenylacetylene in 250 ml of tetrahydrofuran and the mixture is stirred until the evolution of gas ceases. The resultant solution is cooled to 0° C. and 99 g of 3-phenoxybenzaldehyde are added dropwise such that the temperature does no exceed +5° C. The reaction mixture is stirred overnight at room temperature and then cooled to a temperature in the range from 0° to +5° C. About 100 g of ice are added, whereupon a precipitate forms which is dissolved in 100 ml of concentrated HCl. The aqueous solution is extracted with three 150 ml portions of ether and the extracts are washed with NaHCO3 solution and then dried over Na2SO4. The ether is distilled off by rotary evaporation, affording as residue 148 g of 3-phenoxy-α-phenylethynylbenzyl alcohol with a refractive index of nD23 =1.6238 and with an NMR spectrum as shown in FIG. 2. The yield is 98.8 % of theory.
Reaction SMILES: [CH2:1]([C:3]1([CH2:13][OH:14])[CH2:7][CH2:6][C:5]2([CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[O:4]1)[CH3:2].Cl.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22]Cl.[H-].[Na+]>>[CH2:1]([C:3]1([CH2:13][O:14][CH2:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=2)[CH2:7][CH2:6][C:5]2([CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[O:4]1)[CH3:2]
Reactant: CCC1(CO)CCC2(CCOCC2)O1
Reactant: ClCc1ccccn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CCC1(COCc2ccccn2)CCC2(CCOCC2)O1
Yield: 62.5 %

Procedure:
Following procedures similar to Embodiments XVII-XIX, 1.10 g of 2-ethyl-1,8-dioxaspiro[4.5]decane-2-methanol was treated with 1.35 g of 2-picolinyl chloride hydrochloride in the presence of sodium hydride to yield 1.00 g of the desired product as pale yellow liquid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=O)[C:11]([C:17]([CH3:21])([CH3:20])[CH:18]=[O:19])=[CH:10][C:9]2=[O:22])[CH2:2][CH2:3][CH3:4].[NH2:23][OH:24]>CO.O>[CH2:1]([O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:12]3[C:11]([C:17]([CH3:21])([CH3:20])[CH:18]([OH:19])[N+:23]=3[O-:24])=[CH:10][C:9](=[O:22])[C:8]=2[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc2c(c1)C(=O)C=C(C(C)(C)C=O)C2=O
Reactant: NO
Solvent: CO
Solvent: O
Product: CCCCOc1ccc2c(c1)C(=O)C=C1C2=[N+]([O-])C(O)C1(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(6-Butoxy-1,4-dioxo-1,4-dihydro-2-naphthalenyl)-2-methylpropanal (compound 5 prepared in step (I) above) (53 mg, 0.18 mmol) in MeOH (5 mL) and water (0.5 mL), 50% NH2OH in water solution (17 μL, 0.28 mmol) was added. The mixture was stirred 3 h at room temp and the solvent was evaporated. The crude product was fairly pure and was taken into the next step without further purification. Yield: 52 mg (92%). 1H NMR (400 MHz, CDCl3) δ 0.99 (tr., 3H), 1.38 (s, 3H), 1.52 (s, 3 H), 1.55 (m, 2 H), 1.84 (quint., 2H), 4.13 (tr., 2H), 5.31 (s, 1 H), 6.43 (s, 1H), 7.24 (d, 1 H), 7.73 (d, 1 H), 9.07 (d, 1 H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH2:9][CH2:10]Cl)=[C:4](Cl)[N:3]=1.[OH-:13].[Na+].O>C(O)(C)(C)C>[Cl:8][C:6]1[C:5]2[CH2:9][CH2:10][O:13][C:4]=2[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: [OH-]
Reactant: Nc1nc(Cl)c(CCCl)c(Cl)n1
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: Nc1nc(Cl)c2c(n1)OCC2

Procedure:
A suspension of 6.0 g of 2-amino-5-(2-chloroethyl)-4,6-dichloropyrimidine, 29 ml of 2 N aqueous sodium hydroxide solution, 35 ml water and 75 ml of t-butanol was heated to reflux (60°) for 24 hours then cooled. The solid was collected by filtration, rinsed with water and dried to yield 2.4 g of 4-chloro-5,6-dihydrofuro[2,3-d]pyrimidin-2-amine, m.p. 258°-263°. The product showed characteristic triplet absorption bands at 3.40 and 5.10 ppm in the nuclear magnetic resonance spectrum (60 MHz), indicating the title compound.
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH3:17][CH:18]([NH2:20])[CH3:19].CCN(C(C)C)C(C)C>CS(C)=O.O>[O:16]=[C:3]1[C:2]([NH:20][CH:18]([CH3:19])[CH3:17])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=2)[NH:4]1
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Reactant: CC(C)N
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccc2[nH]c(=O)c(NC(C)C)nc2c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 78.4 %

Procedure:
To a solution of methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (500 mg, 2.1 mmol) in DMSO (2 mL) was added propan-2-amine (186 mg, 3.15 mmol) and DIEA (540 mg, 3.15 mmol). After stirring for overnight at 50° C., the reaction mixture was dissolved in water (20 mL), then filtered to afford methyl 2-oxo-3-[(propan-2-yl)amino]-1,2-dihydroquinoxaline-6-carboxylate as a white solid (430 mg, 78%).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19](=[O:29])[CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[NH2:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1>CS(C)=O.C(#N)C>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][CH2:20][C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:32][CH2:33][CH2:34][C:35]4[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:29])=[CH:23][CH:24]=1
Reactant: O=C(COc1ccc(Cl)cc1)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Reactant: NCCc1ccc(O)cc1
Solvent: CS(C)=O
Solvent: CC#N
Product: O=C(NCCc1ccc(O)cc1)c1ccc2n1Cc1ccccc1N(C(=O)COc1ccc(Cl)cc1)C2

Procedure:
A solution of 2,2,2-trichloro-1-{10-[(4-chlorophenoxy)acetyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 67 (0.3 mmol) and tyramine (0.62 mmol) in dimethylsulfoxide (0.2 mL) and acetonitrile (4 mL) was stirred at 80° C. for 18 hours. The solvents were evaporated and the residue was dissolved in dichloromethane, washed with water, dried over anhydrous sodium sulfate and evaporated. The compound was purified by HPLC (normal phase, Luna® CN bonded packing) and crystallized from ethyl acetate/hexane (0.12 g), m.p. 206-207 ° C. MS [(+)ESI, m/z]: 516 [M+H]+ Anal. Calcd for C29H26CIN3O4: C, 67.50; H, 5.08; N, 8.14. Found: C, 67.35; H, 5.07; N, 8.08.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19]CC2C=CC=CC=2)=[O:18])=[C:11]([C:27]2[CH2:31][C:30]([CH2:37][C:38]([O:40][CH3:41])=[O:39])([CH2:32][C:33](=[O:36])[O:34][CH3:35])[O:29][N:28]=2)[CH:10]=1)C1C=CC=CC=1>[Pd].C1COCC1>[CH3:41][O:40][C:38](=[O:39])[CH2:37][C:30]1([CH2:32][C:33](=[O:36])[O:34][CH3:35])[O:29][N:28]=[C:27]([C:11]2[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][C:12]=2[CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:31]1
Reactant: COC(=O)CC1(CC(=O)OC)CC(c2cc(OCc3ccccc3)ccc2/C=C/C(=O)OCc2ccccc2)=NO1
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)CC1(CC(=O)OC)CC(c2cc(O)ccc2CCC(=O)O)=NO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
A mixture of benzyl (2E)-3-(4-(benzyloxy)-2-(5,5-bis(2-methoxy-2-oxoethyl)-4,5-dihydro-1,2-oxazol-3-yl)phenyl)acrylate (2.47 g), 10% Pd/C (containing about 55% water, 250 mg), and THF (25 mL) was stirred at room temperature for 3 hours under a hydrogen atmosphere. The catalyst was filtered off, and then, the filtrate was concentrated under reduced pressure to obtain the title compound (1.680 g).