Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:17][C:18]1([OH:24])[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:20]2[CH2:21][CH2:22][CH2:23][C:18]([CH3:17])([OH:24])[CH2:19]2)=[CH:4][CH:3]=1
Reactant: CC1(O)CCCNC1
Reactant: BrCc1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(O)CCCN(Cc2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
A mixture of 4-bromobenzyl bromide (0.50 g, 2.0 mmol), triethylamine (0.42 mL, 3.0 mmol) and 3-methyl-piperidin-3-ol (0.46 g, 4.0 mmol) in THF (20 mL) was stirred at ambient temperature for 16 h. The reaction mixture was evaporated and the resultant residue diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (2×50 mL). The combined organic layer was dried over sodium sulfate, filtered and evaporated to afford the title compound (0.50 g, 88%). 1H NMR (CDCl3, 300 MHz): 7.49-7.43 (m, 2H), 7.23-7.15 (m, 2H), 3.78 (s, 2H), 3.69-3.59 (m, 2H), 2.63-2.51 (m, 2H), 2.14 (br s, 1H), 1.77-1.49 (m, 4H), 1.15 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][C:7]([NH:10][CH2:11][CH2:12][OH:13])=[N:8][CH:9]=1)([O-:3])=[O:2].Cl[Si:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][CH3:17].N1C=CN=C1>CN(C)C=O.C(OCC)(=O)C>[N+:1]([C:4]1[N:5]=[CH:6][C:7]([NH:10][CH2:11][CH2:12][O:13][Si:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][CH3:17])=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cnc(NCCO)cn1
Reactant: CC[Si](Cl)(CC)CC
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)OCCNc1cnc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.5 %

Procedure:
A solution of 2-(5-nitro-pyrazin-2-ylamino)-ethanol (370 mg, 2.01 mmol) in N,N-dimethylformamide (10 mL) at 0° C. was treated with chlorotriethylsilane (371 μL, 2.21 mmol) and imidazole (342 mg, 5.02 mmol). The reaction mixture was then allowed to warm up to 25° C. where it was stirred overnight for 16 h. After this time, the reaction was diluted with ethyl acetate (20 mL) and a saturated aqueous sodium chloride solution (10 mL) and then further extracted with ethyl acetate (2×10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/3 hexanes/ethyl acetate) afforded (5-nitro-pyrazin-2-yl)-(2-triethylsilanyloxy-ethyl)-amine (531 mg, 89%) as a light yellow solid: (ES)+-HRMS m/e calcd for C12H22N4O3Si (M+H)+ 299.1534, found 299.1538.
Reaction SMILES: [CH2:1]([NH:3][C:4]([N:6]=[C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[CH2:10][C:9](=[CH2:22])[S:8]1)=[O:5])[CH3:2].C[O-].[Na+]>CO>[CH2:1]([NH:3][C:4]([N:6]=[C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=2)[CH:10]=[C:9]([CH3:22])[S:8]1)=[O:5])[CH3:2]
Reactant: C=C1CN(c2cccc(C(F)(F)F)c2)C(=NC(=O)NCC)S1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCNC(=O)N=c1sc(C)cn1-c1cccc(C(F)(F)F)c1
Yield: 50 %

Procedure:
A solution of 2-(N-ethylcarbamoylimino)-3-(3-trifluoromethylphenyl)-5-methylenethiazolidine (0.2 g) and sodium methoxide (28% methanolic solution; 0.2 g ) in methanol (30 ml) was refluxed for 10 hours. After removal of the solvent, the residue was extracted with chloroform (100 ml), washed with water and dried over anhydrous magnesium. The solvent was removed under reduced pressure, and the residue was subjected to column chromatography to give 0.1 g of 2-(N-ethylcarbamoylimino)-3-(3-trifluoromethylphenyl)-5-methylthiazoline (Compound No. 44).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:6]([O-:10])(=[O:9])(=[O:8])=[O:7].CS[C:13]1[S:17][CH:16]=[CH:15][S+:14]=1>>[Cl:6]([O-:10])(=[O:9])(=[O:8])=[O:7].[S:14]1[CH:15]=[CH:16][S:17][C:13]1=[N+:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CSc1scc[s+]1
Reactant: C1CCNC1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: c1csc(=[N+]2CCCC2)s1

Procedure:
0.9 ml of pyrrolidine and 2.5 g of 2-methylthio-1,3-dithiolium perchlorate were treated in the same manner as in Example 26, and the product was recrystallized from acetone-ethyl ether, whereby 1.5 g (yield: 55.3%) of 1-(1,3-dithiol-2-ylidene)pyrrolidinium perchlorate (Compound No. 35) was obtained as crystals having a melting point of 216° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17].Br[CH2:19][C:20]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:21]=1[O:22][CH2:23][C:24]#[N:25]>>[CH3:19][C:20]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][O:17][CH2:16][CH2:15][CH2:14][CH2:13][O:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)[C:21]=1[O:22][CH2:23][C:24]#[N:25]
Reactant: OCCCCOCc1ccc2ccccc2n1
Reactant: Cc1cccc(CBr)c1OCC#N
Product: Cc1cccc(COCCCCOCc2ccc3ccccc3n2)c1OCC#N

Procedure:
MS (ESI) 391 (M+H)+. Prepared from 4-(quinolin-2-ylmethoxy)-butan-1-ol (EXAMPLE 34b) and (2-bromomethyl-6-methyl-phenoxy)-acetonitrile
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][OH:7])[N:3]=[N:2]1.N1C=CN=C1.[CH3:13][C:14]([Si:17](Cl)([CH3:19])[CH3:18])([CH3:16])[CH3:15]>C(Cl)Cl>[Si:17]([O:7][CH2:6][C:4]1[N:3]=[N:2][NH:1][CH:5]=1)([C:14]([CH3:16])([CH3:15])[CH3:13])([CH3:19])[CH3:18]
Reactant: OCc1c[nH]nn1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1c[nH]nn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.8 %

Procedure:
To a solution of (1H-1,2,3-triazol-4-yl)methanol (30 g, 200 mmol) in DCM (160 mL) was added imidazole (20.4 g, 300 mmol) followed by TBDMS-Cl (33.3 g, 220 mmol) as a solid in portions. After stirring at rt for 16 h, the reaction mixture was filtered through celite, and the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc (500 mL) and washed with water, brine, dried over Na2SO4, and concentrated in vacuo. The crude residue was purified via silica gel chromatography (EtOAc-hexanes, 5-30%) to afford the title compound (30.2 g, 71%) as a pale yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][CH2:13][C:14]([CH3:17])([CH3:16])[N:15]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CN([CH:26]=[O:27])C>C1COCC1.CCCCCC>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[O:12][CH2:13][C:14]([CH3:17])([CH3:16])[N:15]=2)=[C:9]([CH:10]=1)[CH:26]=[O:27])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)COC(c2ccc(C(C)(C)C)cc2)=N1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1(C)COC(c2ccc(C(C)(C)C)cc2C=O)=N1
Temperature: -20 °C
Reaction time: 4 h
Yield: 62 %

Procedure:
To a solution of 101c (50 g, 0.22 mol) in anhydrous THF (750 mL) was added 2.4 M solution of n-butyllithium in hexane (225 mL) at −78° C. under nitrogen atmosphere. The clear amber solution was warmed to −20° C. and stirred for 4 hr. The reaction mixture became red-amber and cloudy. The mixture was re-cooled to −78° C. and stirred rapidly before 72 mL of DMF was added drop wise at such a rate that the temperature was controlled below −60° C. After the addition, the reaction mixture was stirred at −78° C. for 15 min then stirred at −20° C. for 1 hr and room temperature for 1 hr. The reaction mixture was quenched with 200 mL of 0.5 M aqueous KHSO4. More KHSO4 solution was added in until the pH was adjusted to 4-5. The aqueous phase was extracted with EtOAc (3×500 mL) and the combined organic phases was washed with 400 mL of brine and dried over Na2SO4, filtered and concentrated in vacuo to give 101d (35 g, 62%) as a yellow solid which was used in the next step without further purification. LCMS, ESI, m/z 260 (M+1)+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][C:21]([C:39]1[CH:44]=[CH:43][C:42]([C:45]2[O:49][N:48]=[C:47]([CH2:50]O)[CH:46]=2)=[CH:41][CH:40]=1)([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)=[CH:27][N:26]=1)[CH:22]([CH3:24])[CH3:23].C(Br)(Br)(Br)[Br:53].C(=O)(O)[O-].[Na+]>C1COCC1>[Br:53][CH2:50][C:47]1[CH:46]=[C:45]([C:42]2[CH:43]=[CH:44][C:39]([C:21]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)=[CH:27][N:26]=3)([CH3:20])[CH:22]([CH3:24])[CH3:23])=[CH:40][CH:41]=2)[O:49][N:48]=1
Reactant: CC(C)C(C)(c1ccc(-c2cc(CO)no2)cc1)c1ccc(OCc2ccccn2)cn1
Reactant: BrC(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)C(C)(c1ccc(-c2cc(CBr)no2)cc1)c1ccc(OCc2ccccn2)cn1
Reaction time: 1.5 h

Procedure:
Triphenylphosphine (1.34 g, 5.21 mmol) was added to a stirred solution of 1d (1.49 g, 3.47 mmol) and carbon tetrabromide (1.73 g, 5.21 mmol) in THF (100 mL) at rt. After approximately 1.5 h, the reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted three times with EtOAc. The combined organic extracts were dried (magnesium sulfate), concentrated in vacuo, and the crude residue was purified by flash chromatography on silica gel (gradient elution; 0%-70% EtOAc/hexanes as eluent) to afford the title compound 1e. m/z (ES) 494 (MH)+.
Reaction SMILES: Cl.[N+:2]([CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]#[N:17])[CH:14]=2)[NH:9][CH:8]=1)([O-])=O.[OH-].[Na+]>CO.[Zn]>[C:16]([C:13]1[CH:14]=[C:15]2[C:10]([NH:9][CH:8]=[C:7]2[CH2:6][CH2:5][NH2:2])=[CH:11][CH:12]=1)#[N:17]
Reactant: N#Cc1ccc2[nH]cc(CC[N+](=O)[O-])c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1ccc2[nH]cc(CCN)c2c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Add zinc powder (16.22 g, 248.1 mmol) in four portions to 2N HCl (300.0 ml). Add dropwise 3-(2-nitroethyl)-5-cyano-1H-indole (2.25 g, 10.5 mmol) as a solution in methanol (300.0 ml). Heat to reflux. After 2.5 hours, cool to ambient temperature and adjust the pH to 11 using 5N NaOH, filter through Celite, wash with water, then extract the filtrate with dichloromethane. Combine the organic extracts, wash with brine, dry (Na2SO4), then evaporated to give the title compound: mp 102-105° C., MS (ACPI): m/e 186.1 (M+1). Analysis for C11H11N3: Calcd: C, 71.33; H, 5.99; N, 22.69. found: C, 71.03; H, 5.91; N, 22.64.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Sn](Cl)Cl>Cl>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Cc1ccc([N+](=O)[O-])c2ncccc12
Agent: Cl
Agent: Cl[Sn]Cl
Product: Cc1ccc(N)c2ncccc12
Yield: 118.9 %

Procedure:
In a similar fashion using route 1 general procedure 4, 5-methyl-8-nitroquinoline (Intermediate 32) (950 mg, 5.05 mmol), tin (II) chloride (2.87 g, 15.1 mmol) and 6 N HCl (5 drops) gave the title compound (950 mg, >100% crude) which was used in the next step without purification. The structure was confirmed by 1H NMR.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]1[CH2:14][CH:13]([OH:15])[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[NH2:18][C:19]1[C:24]([N+:25]([O-:27])=[O:26])=[C:23](Cl)[CH:22]=[CH:21][N:20]=1>C1COCC1>[Si:1]([O:8][C@@H:11]1[C@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:14][C@@H:13]([O:15][C:23]2[CH:22]=[CH:21][N:20]=[C:19]([NH2:18])[C:24]=2[N+:25]([O-:27])=[O:26])[CH2:12]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCC1CCC(O)C1
Reactant: Nc1nccc(Cl)c1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2ccnc(N)c2[N+](=O)[O-])C[C@@H]1O[Si](C)(C)C(C)(C)C
Reaction time: 1 h
Yield: 70.5 %

Procedure:
To a solution of (1R,3S,4S)-3-f[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentanol (0.782 g, 0.00217 mol) in THF (30.0 mL) was added NaH (0.156 g, 0.00650 mol) and the mixture was stirred for 1 h. To this was added 2-amino-4-chloro-3-nitropyridine (0.376 g, 0.00217 mol) and the mixture was stirred overnight. The solution was concentrated and the residue was purified by flash chromatography (25% EtOAc/hexanes) to afford the title compound (0.381 g, 35%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9]Br)=[C:4]([F:12])[CH:3]=1.[S-:13][C:14]#[N:15].[NH4+].C(=O)(O)[O-].[Na+]>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][S:13][C:14]#[N:15])=[C:4]([F:12])[CH:3]=1
Reactant: N#C[S-]
Reactant: O=C(CBr)c1ccc(Br)cc1F
Agent: O=C([O-])O
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Product: N#CSCC(=O)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of the above-mentioned 1-(4-bromo-2-fluorophenyl)-2-bromo-1-ethanone, ammonium thiocyanate 2.15 g and acetonitrile 100 mL was stirred at 25° C. for one hour. To the reaction mixtures was added aqueous saturated sodium bicarbonate solution and the mixtures were extracted with ethyl acetate. The organic layers were washed with aqueous saturated sodium bicarbonate solution and were dried over anhydrous sodium sulfate. The resulting mixtures were concentrated under reduced pressure to give 1-(4-bromo-2-fluorophenyl)-2-thiocyanato-1-ethanone.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]#[CH:9])[CH:5]=[CH:4][N:3]=1.[N:10]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)=[N+:11]=[N-:12].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2].O.CC(O)(C)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[N:12]=[N:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: C#Cc1ccnc(Cl)n1
Reactant: COc1ccc(CN=[N+]=[N-])cc1
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: CC(C)(C)O
Solvent: O
Product: COc1ccc(Cn2cc(-c3ccnc(Cl)n3)nn2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.6 %

Procedure:
To a solution of 2-chloro-4-ethynylpyrimidine (200 mg, 1.4 mmol) and 1-(azidomethyl)-4-methoxybenzene (0.5 M in t-butanol, 2.9 mL, 1.44 mmol) in 1:1 water tBuOH (7.2 mL) was added copper(II) sulfate pentahydrate (36 mg, 0.14 mmol) and sodium ascorbate (143 mg, 0.72 mmol) and the reaction was stirred at room temperature for 2 hrs. The reaction was then partitioned between water (50 mL) and EtOAc (50 mL). The layers were separated and the aqueous phase was extracted once with EtOAc (50 mL). The combined organic phases were washed with saturated aqueous sodium chloride (50 mL), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. Purification on silica (30-50% ethyl acetate in hexanes) afforded 2-chloro-4-[1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl]pyrimidine (256 mg, 59%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1>>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([C:10]2[CH:15]=[CH:14][C:13]([C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=3)=[CH:12][CH:11]=2)=[CH:3][CH:4]=1)#[N:7]
Reactant: OB(O)c1ccc(B(O)O)cc1
Reactant: N#Cc1ccc(Br)cc1
Product: N#Cc1ccc(-c2ccc(-c3ccc(C#N)cc3)cc2)cc1
Yield: 73 %

Procedure:
The same procedure described for 1 was used by employing 4-bromobenzonitrile (2 equiv.) and 1,4-phenylenebisboronic acid (1 equiv.) to furnish 17 as a white solid in 73% yield; mp 299-300° C. 1H NMR (DMSO-d6): δ 7.89 (dd, J=8.1, 2.1 Hz, 4H), 7.94-7.96 (m, 8H). MS (ESI) m/e (rel. int.): 280 (M+, 100). Anal. Calc. for C20H12N2: C %, 85.69; H %, 4.31. Found C %, 85.41; H %, 4.52.
Reaction SMILES: NC1C=C(NC(=O)C)C=CC=1.C(Cl)(=O)C=CC1C=CC=CC=1.[C:23]([NH:26][C:27]1[CH:28]=[C:29]([NH:33][C:34](=[O:43])[CH:35]=[CH:36]C2C=CC=CC=2)[CH:30]=[CH:31][CH:32]=1)(=[O:25])[CH3:24].[Cl-].[Al+3].[Cl-].[Cl-]>>[O:43]=[C:34]1[CH:35]=[CH:36][C:30]2[C:29](=[CH:28][C:27]([NH:26][C:23](=[O:25])[CH3:24])=[CH:32][CH:31]=2)[NH:33]1
Reactant: CC(=O)Nc1cccc(NC(=O)C=Cc2ccccc2)c1
Agent: CC(=O)Nc1cccc(N)c1
Agent: O=C(Cl)C=Cc1ccccc1
Agent: [Al+3]
Product: CC(=O)Nc1ccc2ccc(=O)[nH]c2c1

Procedure:
N-(3-Aminophenyl)acetamide was treated with cinnamoyl chloride in the presence of a base and then the resulting N-[3-(acetylamino)phenyl]-3-phenylacrylamide was treated with aluminum chloride to obtain N-(2-oxo-1,2-dihydroquinolin-7-yl)acetamide.
Reaction SMILES: [CH2:1]([C:3]([CH2:11][CH3:12])([CH2:8][CH:9]=[CH2:10])[C:4]([O:6][CH3:7])=[O:5])[CH3:2].B.C1C[O:17]CC1.O>C1COCC1>[CH2:11]([C:3]([CH2:1][CH3:2])([CH2:8][CH2:9][CH2:10][OH:17])[C:4]([O:6][CH3:7])=[O:5])[CH3:12]
Reactant: C1CCOC1
Reactant: C=CCC(CC)(CC)C(=O)OC
Agent: B
Solvent: O
Product: CCC(CC)(CCCO)C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 267.4 %

Procedure:
To a stirred solution of methyl 2,2-diethyl-4-pentenoate (Canney D J, Holland K D, Levine J A, McKeon A C, Ferrendelli J A, Covey D F (1991), supra.)(5.10 g, 30 mmol) in dry THF (10 mL), was added BH3.THF (1M, 12 mL, 12 mmol) slowly over a period of 15 min at 0° C. in a nitrogen atmosphere. After 2 h at 0° C., the reaction mixture was allowed to warm to room temperature (ca. 2 h). The reaction flask was immersed in an ice bath; water (5 mL) was added to destroy residual hydride, and the reaction mixture was oxidized by adding NaOH (3N, 3.2 mL) and then slowly adding 30% hydrogen peroxide (3.2 mL). After stirring for 1.5 h, the solution was poured into water (100 mL), and extracted with ether (3×50 mL). The combined ether extract was washed with 50 mL portions of water and brine, dried over MgSO4, and the solvent removed in vacuo to give 6.04 g of colorless oil. Column chromatography over silica gel (gradient elution, hexanes-EtOAc, 4:1 to 1:1) afforded the pure hydroxyester (2.79 g, 50%) as a colorless liquid.
Reaction SMILES: [C:1]1([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[CH2:15]([O:17][C:18](=[O:23])[CH2:19][CH2:20][CH2:21]Br)[CH3:16]>>[CH2:15]([O:17][C:18](=[O:23])[CH2:19][CH2:20][CH2:21][O:14][C:11]1[CH:10]=[CH:9][C:8]([C:1]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=2)=[CH:13][CH:12]=1)[CH3:16]
Reactant: CCOC(=O)CCCBr
Reactant: Oc1ccc(C2=CCCCCC2)cc1
Product: CCOC(=O)CCCOc1ccc(C2=CCCCCC2)cc1

Procedure:
Analogously to the process described in Example 1, using 13.2 g of p-(1-cycloheptenyl)-phenol and 21.1 g of 4-bromobutyric acid ethyl ester as starting material gives crude 4-[p-(1-cycloheptenyl)-phenoxy]-butyric acid ethyl ester of boiling point 160° C at 0.03 mm Hg, after chromatography on silica gel with methylene chloride as the eluant and subsequent fractional distillation in a high vacuum.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[Cl:21].CN([CH:25]=[O:26])C>C1COCC1.O>[Br:13][C:14]1[C:15]([Cl:21])=[CH:16][CH:17]=[C:18]([F:20])[C:19]=1[CH:25]=[O:26]
Reactant: Fc1ccc(Cl)c(Br)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=Cc1c(F)ccc(Cl)c1Br
Temperature: -75 °C
Reaction time: 0.75 h
Yield: 58.9 %

Procedure:
To a solution of diisopropylamine (5 mL, 35.4 mmol) in THF (30 mL) at 0° C. under argon was added n-butyl lithium (16.5 mL of 1.6 M solution in hexane, 26.4 mmol) slowly over 20 minutes. The mixture was cooled to −75° C. and 2-bromo-1-chloro-4-fluorobenzene (5 g, 23.9 mmol) in THF (20 mL) was added dropwise over 15 mins whilst maintaining the temperature <−70° C. The solution was then stirred at −75° C. for 45 mins and then DMF (2.2 mL, 28.6 mmol) was added over 5 mins. The mixture was stirred at −78° C. for 2 hrs and then allowed to reach room temperature. Water was added and the aqueous layer was extracted with ethyl acetate. The combined extracts were washed with brine and the solvent evaporated. Chromatography (silica gel, ethyl acetate/hexane) gave the title compound (D21) as a yellow solid (3.344 g)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:16]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:24][CH:25]=2)[C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc(C(F)(F)F)cc1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)piperidin-2-one with commercially available 1-(bromomethyl)-4-(trifluoromethyl)benzene. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.79 min.; [M+H]+: 394.17 g/mol.
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][CH2:8][C@H:9]([C@@H:11]1[C@:28]2([CH3:29])[C@H:14]([C@H:15]3[C@H:25]([CH2:26][CH2:27]2)[C@:23]2([CH3:24])[C:18](=[CH:19][C:20](=[O:30])[CH2:21][CH2:22]2)[CH2:17][CH2:16]3)[CH2:13][CH2:12]1)[CH3:10].C([O:34][N+:35]([O-])=[O:36])(C)C.C(O)(=O)C>C(O)(C)(C)C.ClCCl>[OH:7][CH2:8][C@H:9]([C@@H:11]1[C@:28]2([CH3:29])[C@H:14]([C@H:15]3[C@H:25]([CH2:26][CH2:27]2)[C@:23]2([CH3:24])[C:18](=[C:19]([N+:35]([O-:36])=[O:34])[C:20](=[O:30])[CH2:21][CH2:22]2)[CH2:17][CH2:16]3)[CH2:13][CH2:12]1)[CH3:10]
Reactant: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(C)O[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CC(=O)O
Solvent: ClCCl
Product: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC4=C([N+](=O)[O-])C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Potassium tert-butoxide (1.70 g, 15 mM), (20S)-20-hydroxymethylpregn-4-en-3-one (1.65 g, 5 mM) are mixed in tert-butanol and heated at reflux temperature, under argon atmosphere for 90 minutes. The combination is then cooled to room temperature and treated with one continuous portion of isopropylnitrate (0.51 mL, 5 mM). After 18 hours, the contents of the reaction vessel are acidified with 5 ml of acetic acid, and subsequently diluted with dichloromethane. The solids are then removed by filtration and further washed with additional dichloromethane. The filtrate and wash residue are purified as described in Example 1 to give a crystallized (20S)-20-hydroxymethyl-4-nitropregn-4-en-3-one.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:3]=1[C:4]([N:6]([C:15](=[O:24])[C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:23])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13]O)=[CH:9][N:8]=1)=[O:5].C(Br)(Br)(Br)[Br:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:3]=1[C:4]([N:6]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][Br:31])=[CH:9][N:8]=1)[C:15](=[O:24])[C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:23])=[O:5]
Reactant: BrC(Br)(Br)Br
Reactant: O=C(c1c(Cl)cccc1Cl)N(C(=O)c1c(Cl)cccc1Cl)c1ccc(CO)cn1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(c1c(Cl)cccc1Cl)N(C(=O)c1c(Cl)cccc1Cl)c1ccc(CBr)cn1
Reaction time: 2.5 h
Yield: 65.8 %

Procedure:
In 40 ml of dichloromethane was dissolved 855 mg (1.8 mmol) of 2,6-dichloro-N-(2,6-dichlorobenzoyl)-N-(5-hydroxymethylpyrid-2-yl)benzamide (e), and 905 mg (2.7 mmol) of carbon tetrabromide and 573 mg (2.2 mmol) of triphenylphosphine were added. The mixture was stirred for 2.5 hours, and treated with a saturated sodium hydrogen carbonate aqueous solution. The mixture was subjected to extraction with chloroform, and the extract was washed with a saturated sodium chloride aqueous solution. The solvent was evaporated off under vacuum, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate (volume ratio)=3:1-2:1) to give 631 mg (yield 65%) of 2,6-dichloro-N-(5-bromomethylpyrid-2-yl)-N-(2,6-dichlorobenzoyl)benzamide (f).