Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH2:4].[CH2:5](Br)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[CH2:5]([NH:4][CH2:3][CH2:2][OH:1])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: BrCc1ccccc1
Reactant: NCCO
Product: OCCNCc1ccccc1

Procedure:
2-Hydroxyethylamine was reacted with benzyl bromide according to Method B2a to give N-benzyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-benzyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2,4-dichlorophenyl isothiocyanate to give 2-(2,4-dichlorophenylimino)-3-benzyl-1,3-thiazolidine.
Reaction SMILES: CC1(C)[O:6][C:5](=[O:7])[CH:4]([CH:8]([CH2:12][CH2:13][CH2:14][CH3:15])[C:9]([OH:11])=O)[O:3]1.[NH:17]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:18]1>>[OH:3][C@@H:4]([C@H:8]([C:9]([N:17]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:18]1)=[O:11])[CH2:12][CH2:13][CH2:14][CH3:15])[C:5]([OH:6])=[O:7]
Reactant: CCCCC(C(=O)O)C1OC(C)(C)OC1=O
Reactant: c1ccc(C2CCNC2)nc1
Product: CCCC[C@@H](C(=O)N1CCC(c2ccccn2)C1)[C@H](O)C(=O)O

Procedure:
The title compound is prepared from 2-(2,2-dimethyl-4-oxo-1,3-dioxolan-5-yl)hexanoic acid B-5 and commercially available 2-pyrrolidin-3-yl-pyridine A-5 according to General Procedure B.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]4[CH2:23][CH2:22]4)[CH:20]=3)=[CH:14][CH:13]=[C:12]3[C:7]=2[CH2:8][CH2:9][C@H:10]([CH3:27])[N:11]3[C:24](=[O:26])[CH3:25])[CH2:2]1.[CH:28](=O)[CH3:29]>>[CH:21]1([N:19]2[CH:20]=[C:16]([C:15]3[C:6]([O:5][CH:3]4[CH2:2][N:1]([CH2:28][CH3:29])[CH2:4]4)=[C:7]4[C:12](=[CH:13][CH:14]=3)[N:11]([C:24](=[O:26])[CH3:25])[C@@H:10]([CH3:27])[CH2:9][CH2:8]4)[CH:17]=[N:18]2)[CH2:23][CH2:22]1
Reactant: CC=O
Reactant: CC(=O)N1c2ccc(-c3cnn(C4CC4)c3)c(OC3CNC3)c2CC[C@@H]1C
Product: CCN1CC(Oc2c(-c3cnn(C4CC4)c3)ccc3c2CC[C@H](C)N3C(C)=O)C1

Procedure:
(S)-1-(6-(1-Cyclopropyl-1H-pyrazol-4-yl)-5-(1-ethylazetidin-3-yloxy)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone was synthesized from (S)-1-(5-(azetidin-3-yloxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone and acetaldehyde according to the procedure outlined above for Example 40. 1H NMR (400 MHz, CD3OD) δ ppm 0.97 (t, J=7.20 Hz, 3H), 1.05-1.18 (m, 7H), 1.10-1.35 (m, 1H), 2.16 (s, 3H), 2.20-2.40 (m, 2H), 2.51 (q, J=7.20 Hz, 2H), 2.88-2.98 (m, 1H), 3.07 (t, J=7.20 Hz, 1H), 3.15 (t, J=7.20 Hz, 1H), 3.41-3.55 (m, 2H), 3.68-3.75 (m, 1H), 4.25-4.32 (m, 1H), 4.65-4.80 (m, 1H), 7.01-7.12 (m, 1H), 7.37 (d, J=8.00 Hz, 1H), 7.81 (s, 1H), 8.02 (s, 1H). MS (ESI, pos. ion) m/z 395 [M+H]+.
Reaction SMILES: [CH2:1]([N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([OH:17])=[C:9]([C:18]([O:20]CC)=O)[C:8]1=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:24][C:25]1[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=1>C1(C)C=CC=CC=1>[CH2:1]([N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([OH:17])=[C:9]([C:18]([NH:24][C:25]2[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])=[CH:27][CH:26]=2)=[O:20])[C:8]1=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: CCCCCCn1c(=O)c(C(=O)OCC)c(O)c2ccccc21
Solvent: Cc1ccccc1
Product: CCCCCCn1c(=O)c(C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(O)c2ccccc21

Procedure:
Ethyl 1-hexyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate (159 mg, 0.5 mmol) and tert-butyl 4-aminobenzoate (193 mg, 1 mmol) are suspended in anhydrous toluene (4 ml) and are microwave-heated with the container open (the parameters are the following: power=200 W, temperature=120° C., execution time=7 min, hold time=10 min).
Reaction SMILES: [CH:1]1([CH:7]=[CH:8][C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:14])=O>ClCCl.CN(C=O)C>[CH:1]1([CH:7]=[CH:8][C:9]([Cl:14])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C=CC1CCCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C=CC1CCCCC1
Yield: 100.1 %

Procedure:
4.22 g (27.3 mmol) of 3-cylcohexyl-2-propenoic acid are suspended in dichloromethane (30 ml), 5 drops of DMF are added and at RT 1.9 ml (164 mmol) of thionyl chloride are slowly added dropwise. The reaction mixture is heated to reflux for 2 h, cooled and concentrated to dryness on a rotary evaporator. The oily residue is taken up twice using toluene, concentrated to dryness and dried in vacuo. 4.72 g of product are obtained, which is directly reacted further.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([I:12])[CH:6]=1.C1(C)C=CC(S(O[CH2:23][CH2:24][Cl:25])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CN(C=O)C>[Cl:25][CH2:24][CH2:23][O:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][CH2:3][CH2:2][OH:1])=[CH:6][C:7]=1[I:12]
Reactant: OCCCc1ccc(O)c(I)c1
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: OCCCc1ccc(OCCCl)c(I)c1
Temperature: 50 °C

Procedure:
A mixture of 4-(3-hydroxypropyl)-2-iodophenol (Step A) (2.94 g, 10.57 mmol), 2-chloroethyl p-toluenesulfonate (2.88 ml, 15.86 mmol), and potassium carbonate (3.65 g, 26.4 mmol) in DMF (11 ml) was heated at 50° C. under nitrogen overnight. EtOAc was added and the mixture was washed 2 times with water, followed by brine. The organic layer was dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc in hexanes to afford the title compound. 1H NMR (500 MHz, CD3OD): δ 7.62 (d, J=2.1 Hz, 1H); 7.18-7.13 (m, 1H); 6.85 (d, J=8.3 Hz, 1H); 4.24 (t, J=5.5 Hz, 2H); 3.86 (t, J=5.5 Hz, 2H); 3.54 (t, J=6.4 Hz, 2H); 2.59 (t, J=7.7 Hz, 2H); 1.77 (p, J=7.2 Hz, 2H).
Reaction SMILES: CS([C:5]1[O:6][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:17][CH:16]=[C:15]([C:18]4[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=4)[C:14]=3[CH:29]=2)=[N:8][N:9]=1)(=O)=O.[CH3:30][NH2:31].O1CCCC1>>[CH3:30][NH:31][C:5]1[O:6][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:17][CH:16]=[C:15]([C:18]4[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=4)[C:14]=3[CH:29]=2)=[N:8][N:9]=1
Reactant: CN
Reactant: CS(=O)(=O)c1nnc(-c2ccc3occ(-c4ccc(OC(F)(F)F)cc4)c3c2)o1
Solvent: C1CCOC1
Product: CNc1nnc(-c2ccc3occ(-c4ccc(OC(F)(F)F)cc4)c3c2)o1
Yield: 33 %

Procedure:
In the same manner as in Example 110 and using 2-(methylsulfonyl)-5-[3-[4-(trifluoromethoxy)phenyl]-1-benzofuran-5-yl]-1,3,4-oxadiazole instead of 2-(2,3-dihydro-1-benzofuran-5-yl)-5-(methylsulfonyl)-1,3,4-oxadiazole and using 2M methylamine-tetrahydrofuran solution instead of 3-fluorobenzylalcohol, the title compound (yield 33%) was obtained as colorless crystals.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[C:7]([CH3:14])[CH:6]=1)(=[O:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>CN(C=O)C.ClCCl>[C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:11])=[C:7]([CH3:14])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: C1CCNC1
Reactant: CC(=O)Nc1ccc(C(=O)O)c(C)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(C(=O)N2CCCC2)c(C)c1
Temperature: 50 °C

Procedure:
25.0 g (124 mmol) N-acetyl-4-amino-2-methyl-benzoic acid are combined with 3 drops DMF in 1000 ml dichloromethane and a solution of 21.0 ml (30.56 g, 241 mmol) oxalyl chloride in 100 ml TEA is added dropwise with stirring and cooling in the ice bath. Then the mixture is heated to 50° C. for 4.5 hours. The reaction mixture is filtered and the filtrate is evaporated down completely i. vac. The residue is taken up in 100 ml dichloromethane and this solution is added dropwise to a mixture of 10.4 ml (8.86 g, 125 mmol) pyrrolidine and 34.4 ml (25.0 g, 247 mmol) TEA in 500 ml dichloromethane with stirring and cooling in the ice bath. The mixture is stirred for 16 hours at ambient temperature. After filtering the filtrate is washed with 1-molar hydrochloric acid and sat. sodium chloride solution, combined with activated charcoal and dried over sodium sulphate. After evaporation i. vac. the residue is purified by chromatography on silica gel.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](O)[C:8]([CH3:13])=[N:7]2.P(Cl)(Cl)([Cl:16])=O>[NH4+].[OH-]>[Cl:16][C:9]1[C:8]([CH3:13])=[N:7][C:6]2[C:11]([N:10]=1)=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=2
Reactant: Cc1nc2cccc(Cl)c2nc1O
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Product: Cc1nc2cccc(Cl)c2nc1Cl
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of 8-chloro-3-methylquinoxalin-2-ol (1.0765 g, 5.5314 mmol) and phosphorous oxychloride (10.127 mL, 110.63 mmol) was stirred at 100° C. After 3 h, the mixture was cooled to room temperature. The mixture was poured into ice (˜100 mL) with stirring and neutralized with NH4OH (30 mL) and ice with stirring. The resulting precipitate was collected by filtration, rinsed with water (200 mL), and dried to give 3,5-dichloro-2-methylquinoxaline as a pink solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 7.98-8.07 (2H, m), 7.84 (1H, dd, J=8.3, 7.7 Hz), 2.79 (3H, s); LC-MS (ESI) m/z 213.0 [M+H]+. The pink solid was carried on crude without purification for the next step.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:17]2[CH:22]=[C:21]([N:23]=[N+]=[N-])[CH:20]=[CH:19][C:18]=2[F:26])([CH:14]([F:16])[F:15])[N:13]=1)([CH3:4])([CH3:3])[CH3:2]>CCO.C1COCC1.[Pd]>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:17]2[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:18]=2[F:26])([CH:14]([F:16])[F:15])[N:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1=NC(c2cc(N=[N+]=[N-])ccc2F)(C(F)F)COC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1=NC(c2cc(N)ccc2F)(C(F)F)COC1

Procedure:
A solution of 4.89 g (12.69 mmol) [5-(5-azido-2-fluoro-phenyl)-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester in 64 ml EtOH and 17 ml THF was treated with 1.1 g 10% Pd—C and stirred under an atmosphere of hydrogen until the starting material had been consumed. The mixture was diluted with DCM and filtered over celite. The product was purified by chromatography on silica gel (hexane/25-50% EtOAc) to give the desired product as colorless foam.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]([C:23]5[CH:28]=[CH:27][C:26]([CH2:29][NH:30][CH3:31])=[CH:25][CH:24]=5)[C:19]([CH3:22])=[CH:20][CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].CCN(CC)CC>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]([C:23]5[CH:24]=[CH:25][C:26]([CH2:29][N:30]([CH3:31])[S:33]([CH3:32])(=[O:35])=[O:34])=[CH:27][CH:28]=5)[C:19]([CH3:22])=[CH:20][CH:21]=4)=[O:14])[CH2:11][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CNCc1ccc(-c2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2C)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(CN(C)S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.8 %

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-4′-((methylamino)-methyl)biphenyl-3-yl)cyclopropane carboxamide (30 mg, 0.070 mmol), methanesulfonyl chloride (7.8 μL, 0.14 mmol) and Et3N (30 μL, 0.22 mmol) were dissolved in N,N-dimethylformamide (1.0 mL) and allowed to stir at 25° C. for 16 hours. The crude reaction was purified by reverse phase HPLC to afford 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-4′-((N-methylmethylsulfonamido)methyl)biphenyl-3-yl)cyclopropanecarboxamide (22 mg, 64%). ESI-MS m/z calc. 492.2, found 493.3 (M+1)+; retention time 3.45 minutes.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([N:11]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:12]2[CH:24]=[CH:23][C:22]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]([CH2:27][CH3:28])([CH2:25][CH3:26])[C:14]=3[CH:13]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Br:35][CH2:36][C:37](Br)=[O:38]>ClCCCl>[Br:35][CH2:36][C:37]([C:18]1[CH:17]=[C:16]2[C:21]([C:22]3[CH:23]=[CH:24][C:12]([N:11]([C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:13][C:14]=3[C:15]2([CH2:27][CH3:28])[CH2:25][CH3:26])=[CH:20][CH:19]=1)=[O:38]
Reactant: CCC1(CC)c2ccccc2-c2ccc(N(c3ccccc3)c3ccccc3)cc21
Reactant: O=C(Br)CBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCC1(CC)c2cc(C(=O)CBr)ccc2-c2ccc(N(c3ccccc3)c3ccccc3)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.3 %

Procedure:
To a suspension of aluminium chloride (0.375 g, 2.82 mmol) in 1,2-dichloroethane (15 ml) at 0° C. was added a solution of 2-diphenylamino-9,9-diethylfluorene (1.0 g, 2.57 mmol) in 1,2-dichloroethane (15 ml). Bromoacetyl bromide (0.269 ml, 3.08 mmol) was added over a period of 10 min to maintain a steady reaction temperature between 0–10° C. under an ice-bath. At the end of addition, the mixture was warmed to ambient temperature, stirred for another 4 h, and quenched by a slow addition of water (50 ml) to maintain the mixture temperature below 45° C. Organic layer was washed subsequently with dil. HCl (1.0 N, 50 ml) and water (50 ml, twice). It was concentrated in vacuuo to give crystalline yellow solids. These crude products were purified by column chromatography (silica gel, hexane-toluene/3:2 as eluent, Rf=0.3 on thin layer chromatography using the same solvent mixture as eluent) to afford 7-bromoacetyl-9,9-diethyl-2-diphenylaminofluorene (0.87 g) as yellow crystalline solids in a yield of 66%
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:11][NH:12][O:13][CH3:14].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:12]([O:13][CH3:14])[CH3:11])=[O:5]
Reactant: O=C(Cl)c1ccccc1F
Reactant: CNOC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.5 %

Procedure:
To a solution of 2-fluorobenzoyl chloride (50 g, 0.31 mol) in CH2Cl2 (200 mL) was added N,O-dimethylhydroxylamine (46 g, 0.47 mol), and a solution of triethylamine (127 g, 1.26 mol) in CH2Cl2 (100 mL) at 0° C. The reaction mixture was warmed slowly to rt, and stirred for 3 h. The mixture was quenched with iced water and extracted with CH2Cl2 (200 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to afford 2-fluoro-N-methoxy-N-methylbenzamide (48 g, yield: 84.6%).
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:9]1[C@@:13]2([CH3:28])[CH2:14][CH2:15][CH2:16]/[C:17](=[CH:18]\[CH:19]=[C:20]3\[CH2:21][C@@H:22]([OH:27])[CH2:23][CH2:24][C:25]\3=[CH2:26])/[C@@H:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].[CH3:29]C(CC(C1C(=O)OC2C=CC=CC=2C=1O)C1C=CC=CC=1)=O>>[CH3:1][C@@H:2]([C@@H:9]1[C@@:13]2([CH3:28])[CH2:14][CH2:15][CH2:16]/[C:17](=[CH:18]\[CH:19]=[C:20]3\[CH2:21][C@@H:22]([OH:27])[CH2:23][CH2:24][C:25]\3=[CH2:26])/[C@@H:12]2[CH2:11][CH2:10]1)/[CH:3]=[CH:4]/[C@@H:5]([CH:6]([CH3:7])[CH3:8])[CH3:29]
Reactant: C=C1CC[C@H](O)C/C1=C/C=C1\CCC[C@]2(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@@H]12
Reactant: CC(=O)CC(c1ccccc1)c1c(O)c2ccccc2oc1=O
Product: C=C1CC[C@H](O)C/C1=C/C=C1\CCC[C@]2(C)[C@@H]([C@H](C)/C=C/[C@H](C)C(C)C)CC[C@@H]12

Procedure:
The present invention thus provides a highly effective rodenticide preparation. The rodenticide is readily and economically prepared in a five-step sequence which does not require purification of intermediates. The preparation of this rodenticide in about 50% yield from vitamin D combined with its much higher rodenticidal activity (i.e., at least 20-30 times more potent than vitamin D3) make it a preferred agent for rodent control. The preparation should be particularly effective for the control of rats resistant to commercial rodenticides (e.g., warfarin) and is also advantageously used for the control of other rodents (e.g., mice) or other vertebrate pests (e.g., birds). The high potency of the material combined with its delayed onset of action should overcome problems of bait-avoidance or taste rejection encountered with previously known rodenticies.
Reaction SMILES: CN([CH:4]([CH3:15])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[F:14])=O)C.[NH2:16]/[C:17](/[CH3:24])=[CH:18]\[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[F:14][C:8]1[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=1[C:5]1[CH:4]=[CH:15][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:17]([CH3:24])[N:16]=1
Reactant: CC(C(=O)c1ccc(F)cc1F)N(C)C
Reactant: CCOC(=O)/C=C(/C)N
Product: CCOC(=O)c1ccc(-c2ccc(F)cc2F)nc1C

Procedure:
The title compound was prepared from dimethylamino-(2,4-difluorophenyl)-propan-1-one and ethyl 3-aminocrotonate using the general procedure outlined in D18. 1H NMR (250 MHz, CDCl3) δ (ppm): 8.25 (d, 1H), 8.13 (dt, 1H), 7.67 (dd, 1H), 6.86-7.05 (m, 2H), 4.40 (q, 2H), 2.90 (s, 3H), 1.41 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH2:7][C@H:6]2[C@H:8]3[C@:18]([F:22])([C@@H:19]([OH:21])[CH2:20][C@:4]2([CH3:5])[C:3]=1[S:24][CH2:25][CH3:26])[C@:16]1([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH:14]=[CH:15]1)[CH2:10][CH2:9]3.ClC1C=CC=C(C(OO)=[O:35])C=1>ClCCl>[Cl:1][C:2]1[CH2:7][C@H:6]2[C@H:8]3[C@:18]([F:22])([C@@H:19]([OH:21])[CH2:20][C@:4]2([CH3:5])[C:3]=1[S:24]([CH2:25][CH3:26])=[O:35])[C@:16]1([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH:14]=[CH:15]1)[CH2:10][CH2:9]3
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCSC1=C(Cl)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C
Solvent: ClCCl
Product: CCS(=O)C1=C(Cl)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C

Procedure:
To (11β)-16-chloro-17-(ethylthio)-9-fluoro-11-hydroxyandrosta-1,4,16-trien-3-one (100 mg; see Example 1A) in dichloromethane (15 ml) is added a solution of 85% m-chloroperbenzoic acid (56 mg) in dichloromethane (5.0 ml) over a period of 2 minutes. After 1 hour the solution is washed with a dilute sodium carbonate solution and water, dried (anhydrous MgSO4) and evaporated to yield the title compound.
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][Br:8].[P:9](Cl)([Cl:12])([Cl:11])=[O:10]>C(Cl)Cl>[Br:2][CH2:3][CH2:4][N:5]([CH2:6][CH2:7][Br:8])[P:9]([Cl:12])([Cl:11])=[O:10]
Reactant: BrCCNCCBr
Reactant: O=P(Cl)(Cl)Cl
Agent: Br
Solvent: ClCCl
Product: O=P(Cl)(Cl)N(CCBr)CCBr
Reaction time: 8 h
Yield: 34.7 %

Procedure:
TEA (7.12 g, 70 mmol) was added dropwise to a stirred solution of bis(2-bromoethyl)amine hydrobromide (10.00 g, 32 mmol) and phosphorus oxychloride (4.91 g, 32 mmol) in CH2Cl2 (50 ml) at 0° C. under N2. The mixture was allowed to stir overnight and then poured over ice. The layers were separated, and the aqueous layer was extracted with CH2Cl2 (3×50 ml). The organic layers were combined and dried (MgSO4). The filtrate was concentrated under reduced pressure and the residue purified by chromatography (1:4 EtOAc: hexanes) to give 29 as an oil (3.86 g, 35%); 1H NMR (CDCl3) 3.70 (t, 4H, 6.73 Hz), 3.55 (t, 4H, 6.75 Hz)ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[N+:9]([C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15])([O-:11])=[O:10]>>[N+:9]([C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:15])([O-:11])=[O:10]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: Nc1ccc(Cl)cc1
Product: O=C(Nc1ccc(Cl)cc1)c1ccccc1[N+](=O)[O-]
Yield: 63.4 %

Procedure:
Using the procedure described in Example 93, Part A, 4-chloroaniline (11.8 mmol) and 2-nitrobenzoyl chloride (12.9 mmol) yielded 2.07 g (64%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([N+:25]([O-])=O)[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[S:13][C:6]=12.[BH4-].[Na+]>CO.C1COCC1>[NH2:25][C:23]1[CH:22]=[CH:21][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]3[CH:11]=[C:12]([C:14]([N:16]4[CH2:17][CH2:18][CH2:19][CH2:20]4)=[O:15])[S:13][C:6]=23)=[C:2]([F:1])[CH:24]=1
Reactant: O=C(c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1)N1CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccnc3cc(C(=O)N4CCCC4)sc23)c(F)c1
Reaction time: 1 h
Yield: 91.4 %

Procedure:
To a solution of 22 (3.23 g, 8.33 mmol) and NiCl2.6H2O (3.96 g, 16.66 mmol) in MeOH/THF (100/100 mL) was added NaBH4 (1.24 g, 33.32 mmol). The reaction mixture was stirred for 1 hr, concentrated to dryness and the resultant solid was dissolved in 10% HCl. The aqueous solution was then made basic with concentrated. NH4OH solution and extracted with EtOAc. The organic phase was collected, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 23 as a black solid (2.72 g, 91% yield). MS (m/z): 358.2 (M+H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].Cl[C:13]1[CH:18]=[C:17]([CH3:19])[N:16]=[C:15]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]3)=[C:23]([O:33][CH3:34])[CH:22]=2)[N:14]=1.C1(O)C=CC=CC=1.[H-].[Na+]>>[CH3:34][O:33][C:23]1[CH:22]=[C:21]([NH:20][C:15]2[N:16]=[C:17]([CH3:19])[CH:18]=[C:13]([O:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:2]([F:10])([F:11])[F:1])[N:14]=2)[CH:26]=[CH:25][C:24]=1[N:27]1[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]1
Reactant: COc1cc(Nc2nc(C)cc(Cl)n2)ccc1-n1cnc(C)c1
Reactant: Oc1ccccc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: Oc1ccccc1
Product: COc1cc(Nc2nc(C)cc(Oc3ccccc3C(F)(F)F)n2)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared in analogous manners as described in example 9 from 2-trifluoromethyl-phenol and (4-chloro-6-methyl-pyrimidin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine. The reaction was heated for 3.5 h to 200° C. in a microwave oven. Several times the phenol (overall 4.4 equivalents) and additional sodium hydride had to be added in order to obtain complete conversion. The title compound was obtained, after purification by column chromatography on silica gel using dichloromethane/methanol (19:1 v/v) as eluent, as a white solid in 15% yield.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:18]2[C:5](=[C:6]3[C:15](=[CH:16][CH:17]=2)[C:14]2[CH:13]=[CH:12][C:11]([OH:19])=[CH:10][C:9]=2[CH2:8][CH2:7]3)[CH2:4][CH2:3]1.C1(C)C=CC=CC=1.[H-].[Na+].Br[C:31]([CH3:36])([CH3:35])[C:32]([OH:34])=[O:33]>O>[CH3:35][C:31]([O:19][C:11]1[CH:12]=[CH:13][C:14]2[C:15]3[C:6]([CH2:7][CH2:8][C:9]=2[CH:10]=1)=[C:5]1[C:18]([C:2]([CH3:20])([CH3:1])[CH2:3][CH2:4]1)=[CH:17][CH:16]=3)([CH3:36])[C:32]([OH:34])=[O:33]
Reactant: CC(C)(Br)C(=O)O
Reactant: CC1(C)CCc2c1ccc1c2CCc2cc(O)ccc2-1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(Oc1ccc2c(c1)CCc1c-2ccc2c1CCC2(C)C)C(=O)O

Procedure:
To a solution of 19 parts of 7,15,16,17-tetrahydro-17,17-dimethyl-6H-cyclopenta[ a]phenanthren-3-ol in 800 parts of toluene is added 13 parts of a 50% dispersion of sodium hydride in mineral oil. The resultant mixture is stirred and heated at the boiling point under reflux in an atmosphere of nitrogen for 1 hour, then cooled, whereupon approximately 13 parts 2-bromo-2-methylpropanoic acid is introduced. The mixture thus obtained is stirred and heated at the boiling point under reflux in a nitrogen atmosphere for 4 hours, at which point heating is discontinued. The mixture is stirred 18 hours longer at ambient temperatures, then approximately 250 parts of water is cautiously introduced. The mixture so produced is extracted with benzene. The benzene extract is washed with water, dried over anhydrous sodium sulfate, and stripped of solvent by vacuum distillation. Crystallization of the residue from a mixture of ether and hexane affords 2-methyl-2-[(7,15,16,17-tetrahydro-17,17-dimethyl-6H-cyclopenta[a]phenanthren-3-yl)oxy]propanoic acid melting at 167°-170°, and having the formula ##STR7##