Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[CH:7][C:6]([OH:9])=[CH:5][N:4]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([F:22])[C:20]=1F)[CH:16]=[O:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([F:22])[C:20]=1[O:9][C:6]1[CH:7]=[N:8][C:3]([C:2]([F:1])([F:10])[F:11])=[N:4][CH:5]=1)[CH:16]=[O:17]
Reactant: Oc1cnc(C(F)(F)F)nc1
Reactant: O=Cc1cc(F)c(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc(F)c(Oc2cnc(C(F)(F)F)nc2)c(F)c1
Temperature: 130 °C
Yield: 98.2 %

Procedure:
To a solution of 2-(trifluoromethyl)pyrimidin-5-ol (1.5 g, 9.14 mmol) and 3,4,5-trifluorobenzaldehyde (1.464 g, 9.14 mmol) in DMF (18 mL), was added K2CO3 (1.642 g, 11.88 mmol). The mixture was heated with a microwave condition at 130° C. for 1 h. After cooling, the reaction mixture was diluted in water, extracted with EA. The organic phase was washed with water and brine, dried over Na2SO4, concentrated to afford the title compound (2.73 g, 8.98 mmol, 98% yield) as brown oil. LCMS: rt=3.16 min, [M+H+]=305
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:14])=[CH:4][C:5]2[S:9][C:8]([N:10]=[C:11]=[O:12])=[N:7][C:6]=2[CH:13]=1.[Br:15][CH2:16][CH2:17][NH:18][CH2:19][CH:20]=[O:21]>C1C=CC=CC=1>[Br:15][CH2:16][CH2:17][N:18]([CH2:19][CH:20]=[O:21])[C:11]([NH:10][C:8]1[S:9][C:5]2[CH:4]=[C:3]([Cl:14])[C:2]([Cl:1])=[CH:13][C:6]=2[N:7]=1)=[O:12]
Reactant: O=C=Nc1nc2cc(Cl)c(Cl)cc2s1
Reactant: O=CCNCCBr
Solvent: c1ccccc1
Product: O=CCN(CCBr)C(=O)Nc1nc2cc(Cl)c(Cl)cc2s1
Reaction time: 1 h

Procedure:
5,6-Dichlorobenzothiazol-2-yl isocyanate dimer (0.1 mole), the dimethyl acetal of 2-β-bromoethylaminoacetaldehyde (0.2 mole) and benzene (100 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is stirred at ambient temperatures for a period of about one hour. After this time the reaction mixture is filtered, and the filtrate is stripped of solvent to yield the desired product the dimethyl acetal of 2-[1-β-bromoethyl-3-(5,6-dichlorobenzothiazol-2-yl)ureido]-acetaldehyde as the residue.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[N:14][NH:13][C:12](=[O:24])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Cl:25][C:26]1[CH:35]=[CH:34][C:29]([CH:30]=[CH:31][CH2:32]Cl)=[CH:28][CH:27]=1>>[Cl:25][C:26]1[CH:35]=[CH:34][C:29]([CH:30]=[CH:31][CH2:32][N:13]2[C:12](=[O:24])[CH:11]=[C:10]([C:4]3[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=3)[C:15]([C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)=[N:14]2)=[CH:28][CH:27]=1
Reactant: COc1ccc(-c2n[nH]c(=O)cc2-c2ccc(OC)c(F)c2)cc1
Reactant: ClCC=Cc1ccc(Cl)cc1
Product: COc1ccc(-c2nn(CC=Cc3ccc(Cl)cc3)c(=O)cc2-c2ccc(OC)c(F)c2)cc1
Yield: 58.7 %

Procedure:
Using 5-(3-fluoro-4-methoxyphenyl)-6-(4-methoxyphenyl)-2H-pyridazin-3-one and 4-chlorocinnamyl chloride as starting materials, the procedures of Example 12 were repeated likewise, whereby the title compound was obtained in a yield of 58.7%.
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:21]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:21]1([NH:27][CH2:17][C:16]2[CH:19]=[CH:20][C:13]([N:10]3[CH2:11][CH2:12][CH:7]([CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:8][CH2:9]3)=[CH:14][CH:15]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: NC1CCCCC1
Reactant: O=Cc1ccc(N2CCC(CN3CCCC3)CC2)cc1
Product: c1cc(N2CCC(CN3CCCC3)CC2)ccc1CNC1CCCCC1

Procedure:
Prepared from the product of Example 9 and cyclohexylamine.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].Cl[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1.O>CN(C=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Clc1ccc2ccccc2n1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Nitrophenol (41 moles, 5.1 g) was dissolved in DMF (500 ml) and treated with sodium hydride (41 mmoles previously washed with hexane). After stirring at room temperature for 1 hr, 2-chloroquinoline (40 moles, 6.5 g) was added dropwise and stirred for 16 hr at room temperature followed by refluxing for 6 hr. Water was added to the cooled solution and the product was extracted with ethyl acetate. The ethyl acetate solution was washed with water, and 5N NaOH, dried over sodium sulfate and concentrated. The product was purified by HPLC over silica gel eluted with ethyl acetate/hexane to yield 2-(4-nitrophenoxy)quinoline. 3.1 mmoles, 8%. Mass Spec (FD) 266. Calcd for C15H10N2O3 : C, 67.45; H, 3.84; N, 10.40. Found: C, 65.84; H, 3.88; N, 8.47.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=1)(=O)[CH3:2].P(Cl)(Cl)(Cl)=[O:19].[Cl-]>>[CH3:2][C:1]1[NH:4][N:5]=[C:6]([CH:11]=[CH:10][NH:9][C:8](=[O:19])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=1
Reactant: CC(=O)NNc1ccnc(-c2ccccc2)n1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Cl-]
Product: Cc1nc(C=CNC(=O)c2ccccc2)n[nH]1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A mixture of 1.0 g. of 1-acetyl-2-(2-phenylpyrimidin-4-yl)hydrazine and 10 ml. of phosphorus oxychloride is heated to the reflux temperature, with stirring, for 7 hours. The mixture is cooled to room temperature, melthylene chloride is added and evaporated under reduced pressure to remove excess phosphorus oxychloride. This is repeated, and the residue is taken up in methylene chloride; the organic layer is washed thoroughly with 5% sodium bicarbonate solution, then with water, dried over anhydrous sodium sulfate and evaporated. The residue is a pale yellow solid which is recrystallized from methylene chloride/hexane. The product of the example, m.p. 140°-145°, is thereby obtained.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:31]1[CH:36]=[CH:35][N:34]=[CH:33][N:32]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[N:28]([CH3:29])[N:27]=[N:26][CH:25]=2)=[CH:12][C:11]=1[F:30])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:30][C:11]1[CH:12]=[C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[N:28]([CH3:29])[N:27]=[N:26][CH:25]=2)[C:14]([F:16])=[CH:15][C:10]=1[S:7]([NH:6][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][N:32]=1)(=[O:9])=[O:8]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3CCCC[C@@H]3c3cnnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nncc1[C@H]1CCCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1F
Yield: 82.9 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-1,2,3-triazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (270 mg, 0.450 mmol) prepared in Example 92b, triethylsilane (0.30 mL), trifluoroacetic acid (3.0 mL) and dichloromethane (3.0 mL), to yield the title compound (168 mg, 83%) as a colorless solid.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH2:9])[CH3:2].[CH3:10][O:11][C:12]1[CH:20]=[C:19]([CH3:21])[C:18]([Cl:22])=[CH:17][C:13]=1[C:14](Cl)=[O:15]>CC(CC)=O>[CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH:9][C:14](=[O:15])[C:13]1[CH:17]=[C:18]([Cl:22])[C:19]([CH3:21])=[CH:20][C:12]=1[O:11][CH3:10])[CH3:2]
Reactant: CCN1CCCC1CN
Reactant: COc1cc(C)c(Cl)cc1C(=O)Cl
Solvent: CCC(C)=O
Product: CCN1CCCC1CNC(=O)c1cc(Cl)c(C)cc1OC
Temperature: 5 °C
Reaction time: 1 h
Yield: 101.9 %

Procedure:
In a 1 liter flask equipped with an agitator, a thermometer and a dropping funnel, there are put 46 g (0.36 mole) of 1-ethyl-2-aminomethylpyrrolidine and 45 ml of methylethylketone. While maintaining the temperature of the mixture at about 5° C, there are added dropwise 79 g (0.36 mole) of 2-methoxy-4-methyl-5-chlorobenzoyl chloride dissolved in 400 ml of methylethylketone. The introduction requires about 1 hour. There is precipitation of N-(1-ethyl-2-pyrrolidylmethyl)-2-methoxy-4-methyl-5-chlorobenzamide hydrochloride which is drained, washed on a filter with methylethylketone and air-dried. There are obtained 114 g (yield 91%) of product in the form of white crystals (m.p. 162°-163° C).
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].C([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[N:18][C:19]([N:29]3[CH2:34][CH2:33][CH:32]([O:35][C:36]4[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][C:37]=4[F:44])[CH2:31][CH2:30]3)=[C:20]([NH:25][CH:26]([CH3:28])[CH3:27])[N:21]=2)[CH2:16]1)C1C=CC=CC=1>C1COCC1.[OH-].[OH-].[Pd+2]>[F:44][C:37]1[CH:38]=[C:39]([O:42][CH3:43])[CH:40]=[CH:41][C:36]=1[O:35][CH:32]1[CH2:31][CH2:30][N:29]([C:19]2[N:18]=[C:17]3[CH2:16][NH:15][CH2:24][CH2:23][C:22]3=[N:21][C:20]=2[NH:25][CH:26]([CH3:28])[CH3:27])[CH2:34][CH2:33]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: COc1ccc(OC2CCN(c3nc4c(nc3NC(C)C)CCN(Cc3ccccc3)C4)CC2)c(F)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: COc1ccc(OC2CCN(c3nc4c(nc3NC(C)C)CCNC4)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 6-benzyl-3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (122 mg, 0.197 mmol) and Pd(OH)2 on carbon (20 wt %, 12 mg, 0.017 mmol) in THF (2.0 mL) was stirred under an atmosphere of hydrogen gas (balloon) at rt. After 2 h, the mixture was purified by HPLC Method A to give the title compound as a TFA salt (83.2 mg, 80%) as a yellow oil. 1H NMR (400 MHz, methanol-d4) δ ppm 1.25 (d, J=6.6 Hz, 6H), 1.88-1.98 (m, 2H), 2.04-2.13 (m, 2H), 2.93-3.03 (m, 4H), 3.35-3.41 (m, 3H), 3.54 (t, J=6.3 Hz, 2H), 3.76 (s, 3H), 4.14-4.18 (m, 2H), 4.18-4.23 (m, 1H), 4.32-4.40 (m, 1H), 6.67 (ddd, J=9.0, 3.0, 1.4 Hz, 1H), 6.74 (dd, J=12.9, 3.0 Hz, 1H), 7.07 (t, J=9.2 Hz, 1H); ESI-MS m/z [M+H]+ 416.3.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[N:22][OH:23])[CH:7]=[C:8]([C:12]3[N:13]=[CH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][CH:18]=[CH:17][CH:16]=4)[O:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:31]1([C:37]#[CH:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[CH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[C:12]([C:8]2[O:9][C:10]3[C:5]([C:6](=[N:22][OH:23])[CH:7]=2)=[CH:4][CH:3]=[C:2]([C:38]#[C:37][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:11]=3)[N:13]=1
Reactant: ON=c1cc(-c2cc3ccccc3cn2)oc2cc(Br)ccc12
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: ON=c1cc(-c2cc3ccccc3cn2)oc2cc(C#Cc3ccccc3)ccc12
Temperature: 90 °C
Yield: 13.2 %

Procedure:
A solution of 7-bromo-2-isoquinolin-3-yl-chromen-4-one oxime (52 mg, 0.142 mmol), trans-dichlorobis(triphenylphosphine)palladium (10 mg, 0.014 mmol), copper iodide (5.3 mg, 0.028 mmol) in dimethylformamide (3 ml) was degassed with argon for 10 min and then treated with triethylamine (30 μl, 0.213 mmol) and phenyl acetylene (19 μl, 0.170 mmol). The solution was warmed to 90° C. for 18 hours and then poured onto a 0.5N aqueous solution of hydrogen chloride, extracted with ethyl acetate and purified by preparative HPLC (gradient 25-10% Water/acetonitrile+0.05% trifluoroacetic acid) to yield 2-isoquinolin-3-yl-7-phenylethynyl-chromen-4-one oxime (7.3 mg, 13%) as a yellow solid and a 80/20 mixture of Z/E oxime isomers.
Reaction SMILES: [CH3:1][NH:2][C:3]([CH2:5][CH:6]=[C:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:8]([OH:10])=[O:9])=[O:4].[CH3:15][C:16](=[CH2:18])[CH3:17]>C(Cl)(Cl)Cl.S(=O)(=O)(O)O>[CH3:1][NH:2][C:3]([CH2:5][CH:6]=[C:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:8]([O:10][C:16]([CH3:18])([CH3:17])[CH3:15])=[O:9])=[O:4]
Reactant: C=C(C)C
Reactant: CNC(=O)CC=C(CC(C)C)C(=O)O
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: CNC(=O)CC=C(CC(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 192 h
Yield: 81 %

Procedure:
A suspension of 4-methylaminocarbonyl-2-(2-methylpropyl)but-2-enoic acid (2.4 g) in chloroform (35 ml) was treated with an excess of isobutylene (30 ml) and concentrated sulphuric acid (3 drops) was added as catalyst. The mixture was stirred at room temperature in a sealed vessel for 8 days. The product was purified by silica gel chromatography [chloroformpentane (1:1) as eluant] to give the title compound (2.5 g, 81%), m.p. 35°-36° C. (pentane).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]([O:15][CH3:16])=[N:13][C:12]2[C:7]1=[N:8][C:9]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])=[N:10][C:11]=2[NH2:17].[CH3:23][O:24][CH2:25][CH2:26][NH2:27]>C(#N)C>[CH2:19]([O:18][C:9]1[N:8]=[C:7]2[C:12]([N:13]=[C:14]([O:15][CH3:16])[N:6]2[CH2:5][CH2:4][CH2:3][CH2:2][NH:27][CH2:26][CH2:25][O:24][CH3:23])=[C:11]([NH2:17])[N:10]=1)[CH2:20][CH2:21][CH3:22]
Reactant: COCCN
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCBr)c2n1
Solvent: CC#N
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCNCCOC)c2n1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
The compound obtained in Example 2-13 step (i) (500 mg) and (2-methoxyethyl)amine (303 mg) were dissolved in acetonitrile (5 ml) and stirred at 80° C. for 1 hour. The reaction mixture was cooled, filtered and purified by RPHPLC to give the titled compound as a white solid. Yield: 270 mg (55%); mp 99-100° C., MS APCI+ve 367 (M+H).
Reaction SMILES: [CH2:1]([N:5]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:6](=[O:10])[O:7][CH2:8]Cl)[CH:2]([CH3:4])[CH3:3].[OH:15][C@@H:16]([C@H:18]1[C:38](=[O:39])[N:20]2[C:21]([C:35]([O-:37])=[O:36])=[C:22]([S:25]/[CH:26]=[CH:27]\[C:28]3[S:32][CH:31]=[N:30][C:29]=3[CH2:33][OH:34])[C@H:23]([CH3:24])[C@H:19]12)[CH3:17].[Na+]>>[OH:15][C@@H:16]([C@H:18]1[C:38](=[O:39])[N:20]2[C:21]([C:35]([O:37][CH2:8][O:7][C:6]([N:5]([CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:1][CH:2]([CH3:4])[CH3:3])=[O:10])=[O:36])=[C:22]([S:25]/[CH:26]=[CH:27]\[C:28]3[S:32][CH:31]=[N:30][C:29]=3[CH2:33][OH:34])[C@H:23]([CH3:24])[C@H:19]12)[CH3:17]
Reactant: CC(C)CN(CC(C)C)C(=O)OCCl
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Agent: [Na+]
Product: CC(C)CN(CC(C)C)C(=O)OCOC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 71.5 %

Procedure:
In the same manner as in step b) in Example 125, 242 mg of the title compound was prepared from 159 mg of chloromethyl N,N-diisobutylcarbamate and 241 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[NH2:17][CH2:18][CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:5]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:3][CH2:2][NH:17][CH2:18][CH2:19][CH:20]2[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][CH2:25]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCN)CC1
Reactant: BrCCC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(CCNCCC(c2ccccc2)c2ccccc2)CC1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
3-bromo-1,1-diphenylpropane (2.6 g, 9 mmol) and tert-butyl 4-(2-aminoethyl)piperidine-1-carboxylate (4.7 g, 21 mmol) were mixed together in acetonitrile (100 ml) and potassium carbonate (1.3 g, 9 mmol) was added. The resulting mixture was heated to 65° C. with stirring under N2 overnight. After that time the mixture was cooled and concentrated under reduced pressure. The residue was partitioned between DCM and water. The DCM layer was washed with water, dried over MgSO4 and concentrated under reduced pressure to give the crude product as a clear oil. The crude product was purified by combiflash (0-10% MeOH/DCM) to give tert-butyl 4-(2-(3,3-diphenylpropylamino)ethyl)piperidine-1-carboxylate 48
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18](F)[C:17]([C:21]#[N:22])=[C:16]([F:23])[CH:15]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[OH:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[C:1]([O:5][C:6](=[O:24])[NH:7][CH:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[C:18]([O:25][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[C:17]([C:21]#[N:22])=[C:16]([F:23])[CH:15]=2)[CH2:12][CH2:13]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cc(F)c(C#N)c(F)c2)CC1
Reactant: OCCN1CCOCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCN(c2cc(F)c(C#N)c(OCCN3CCOCC3)c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.2 %

Procedure:
To a solution of 0.10 g (0.30 mmol) of [1-(4-cyano-3,5-difluoro-phenyl)-piperidin-4-yl]-carbamic acid tert-butyl ester and 0.040 mL (0.33 mmol) of 4-(2-hydroxyethyl)-morpholine in THF (15 mL), cooled to 0° C., was added 0.60 mL (0.60 mmol) of sodium bis(trimethylsilyl)amide as a 1.0 M solution in THF. The reaction was stirred at 0° C. for 30 min then warmed to 60° C. for 6 h. The reaction was cooled to room temperature and excess base was consumed by the addition of a saturated aqueous solution of NH4Cl. The mixture was diluted with H2O and washed with EtOAc. The combined organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude residue was purified by flash silica gel chromatography to provide 0.081 g (61%) of {1-[4-cyano-3-fluoro-5-(2-morpholin-4-yl-ethoxy)-phenyl]-piperidin-4-yl}-carbamic acid tert-butyl ester as a white foam.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH:6]([CH2:8]O)[CH2:5][CH2:4][O:3]1.C(Br)(Br)(Br)[Br:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>ClCCl>[Br:12][CH2:8][CH:6]1[CH2:5][CH2:4][O:3][C:2]([CH3:10])([CH3:1])[CH2:7]1
Reactant: CC1(C)CC(CO)CCO1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: CC1(C)CC(CBr)CCO1
Temperature: 25 °C
Reaction time: 20 h
Yield: 30.6 %

Procedure:
To a solution of (2,2-dimethyltetrahydro-2H-pyran-4-yl)methanol (2.50 g) in dichloromethane (30 mL) were added carbon tetrabromide (6.80 g) and triphenylphosphine (5.40 g), and the mixture was stirred at room temperature for 20 hr. Water was added and the mixture was extracted with diethyl ether. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether) to give the title compound (1.10 g) as a colorless oil.
Reaction SMILES: [CH2:1]([P:3](Cl)([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[Cl:22])[CH:8]=[CH:7][C:6]=1[N+:23]([O-:25])=[O:24])=[O:4])[CH3:2].[CH3:27][C:28]1([CH3:35])[O:34][CH2:33][CH:30]([CH2:31][OH:32])[O:29]1>>[CH2:1]([P:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][C:13]=2[Cl:22])[CH:8]=[CH:7][C:6]=1[N+:23]([O-:25])=[O:24])(=[O:4])[O:32][CH2:31][CH:30]1[O:29][C:28]([CH3:35])([CH3:27])[O:34][CH2:33]1)[CH3:2]
Reactant: CCP(=O)(Cl)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: CC1(C)OCC(CO)O1
Product: CCP(=O)(OCC1COC(C)(C)O1)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
Following the procedure of Example 45, P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinic acid chloride and 2,3-(dimethylmethylenedioxy)-1-propanol are reacted together to yield 2,3-(dimethylmethylenedioxy)propyl P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinate, m/s 523 (M+). ##STR34##
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].[BrH:12].N([O-])=O.[Na+].C(OCC)(=O)C>O>[Br:12][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7]
Reactant: Nc1ccc(C(=O)O)c(O)c1
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1ccc(Br)cc1O
Reaction time: 0.5 h
Yield: 73 %

Procedure:
4-Aminosalicylic acid (15.0 g, 98 mmol) and hydrobromic acid (47%, 100 ml) were mixed with water (100 ml). A solution of sodium nitrite (6.8 g, 98 mmol) in water (50 ml) was added dropwise to the mixture at 0° C., and the mixture was stirred at the same temperature for 30 minutes. A mixture of cuprous bromide (16.9 g, 117 mmol) and hydrobromic acid (47%, 45 ml) was added dropwise to the mixture at 0° C., and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was combined with ethyl acetate and extracted. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the titled compound (15.5 g, 73%) as a gray solid.
Reaction SMILES: [CH2:1]([N:8]=[N+:9]=[N-:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:12](=[CH2:15])[C:13]#[N:14]>O>[CH2:1]([N:8]1[CH:15]=[C:12]([C:13]#[N:14])[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(Cl)C#N
Reactant: [N-]=[N+]=NCc1ccccc1
Solvent: O
Product: N#Cc1cn(Cc2ccccc2)nn1
Temperature: 80 °C
Reaction time: 22 h

Procedure:
A mixture of benzyl azide (1.33 g) and 2-chloroacrylonitrile (1.75 g) in water (5 ml) is stirred at about 80° C. for 22 hours, then excess 2-chloroacrylonitrile is distilled off in vacuo. The mixture is cooled to room temperature and the precipitated product is isolated by filtration and washed with water. After drying, the product is obtained in a yield of 1.66 g=90% of theory m.p. 78-79° C. (recrystallization from toluene/hexane).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.Cl.[C:14]1([C:20]2([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:28]3[CH:24]([CH2:25][NH:26][CH2:27]3)[C:23](=[O:29])[CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>ClCCl>[C:30]1([C:20]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:28]3[CH:24]([CH2:25][N:26]([C:10](=[O:12])[CH2:9][C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[S:2][CH3:1])[CH2:27]3)[C:23](=[O:29])[CH2:22][CH2:21]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Reactant: CSc1ccccc1CC(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSc1ccccc1CC(=O)N1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1
Reaction time: 0.25 h
Yield: 59.5 %

Procedure:
N,N'-Carbonyldiimidazole (0.77 g) is added to a solution of 2-methylthiophenylacetic acid (0.87 g) in dry dichloromethane (30 cc), cooled to +5° C. The mixture is stirred for 15 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (1.56 g) and triethylamine (1.34 cc) in dichloromethane (30 cc) is then added. The reaction mixture is stirred at 20° C. for 3.5 hours, then washed with water (3×100 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.04-0.063 mm, diameter 5 cm, height 50 cm), eluting under a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (60/40 by volume) and collecting 50 cc fractions. Fractions 1 to 14 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is recrystallized from acetonitrile (5 cc) and the crystals are drained, washed with isopropyl ether and dried. (3aRS,7aRS)-7,7-diphenyl-2-[(2-methylthiophenyl)acetyl]-4-perhydroisoindolone (1.29 g) is obtained in the form of pale yellow crystals melting at 188° C.