Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[CH:6][C:7]=1[NH2:8].[N:10]([C@H:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1)=[C:11]=S>>[CH3:9][C:4]1[CH:5]=[CH:6][C:7]2[N:8]=[C:11]([NH:10][C@H:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:16][CH2:15][CH2:14]3)[NH:1][C:2]=2[CH:3]=1
Reactant: S=C=N[C@@H]1CCCc2ccccc21
Reactant: Cc1ccc(N)c(N)c1
Product: Cc1ccc2nc(N[C@@H]3CCCc4ccccc43)[nH]c2c1

Procedure:
The title compound was prepared from 3,4-diaminotoluene and (R)-1-isothiocyanato-1,2,3,4-tetrahydronaphthalene by Procedure D. The title compound was isolated by column chromatography as the free base (off-white solid, mp 91-93° C.). MS(ES+) m/z 278 ([M+1]+, 100).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:17]([C:18]#[N:19])=[CH:16][O:15][CH:14]3[C:20]4[C:24](=[CH:25][CH:26]=[C:13]23)[N:23]=[CH:22][CH:21]=4)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9].Br[CH2:28][CH3:29].C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:17]([C:18]#[N:19])=[CH:16][O:15][C:14]3[C:20]4[CH:21]=[CH:22][N:23]([CH2:28][CH3:29])[C:24]=4[CH:25]=[CH:26][C:13]2=3)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9]
Reactant: CCBr
Reactant: COc1cc(C2C(C#N)=COC3C4=CC=NC4=CC=C32)cc(Br)c1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCn1ccc2c3c(ccc21)C(c1cc(Br)c(OC)c(OC)c1)C(C#N)=CO3
Temperature: 60 °C
Reaction time: 22 h
Yield: 50.4 %

Procedure:
A mixture of 4-(3-bromo-4,5-dimethoxy-phenyl)-3-cyano-4H-indolo[4,5-b]pyran (50 mg, 0.122 mmol), bromoethane (50 μL, 0.670 mmol) and cesium carbonate (122 mg, 0.375 mmol) in anhydrous THF (2 mL) was stirred at 60° C. in a sealed tube. After 22 h, additional bromoethane (100 μL, 1.34 mmol) was added and the reaction was continued for additional 43 h. The reaction mixture was diluted with EtOAc (20 mL). The insoluble material was filtered, and washed with EtOAc (30 mL). The EtOAc solution were combined, washed with brine (2×5 mL), dried over MgSO4, and evaporated to yield a light yellow solid. The crude product was purified by column chromatography (silica gel, EtOAc:hexanes, 1:3) to yield 27 mg (51%) of the product as an off-white solid. 1H NMR (CDCl3) 7.44 (d, J=0.9 Hz, 1H), 7.14 (d, J=3.3 Hz, 1H), 7.07 (dd, J=0.6, 8.4 Hz, 1H), 6.96 (d, J=1.8 Hz, 1H), 6.77 (d, J=1.8 Hz, 1H), 6.70 (d, J=8.4 Hz, 1H), 6.59 (dd, J=0.9, 3.3 Hz, 1H), 4.81 (s, 1H), 4.15 (q, J=7.2 Hz, 2H), 3.84 (s, 3H), 3.83 (s, 3H), 1.46 (t, J =7.2 Hz, 3H).
Reaction SMILES: [CH:1]1([C:4]2([CH:18]3[CH2:20][CH2:19]3)[C:9]3[CH:10]=[C:11](B(O)O)[CH:12]=[CH:13][C:8]=3[NH:7][C:6](=[O:17])[O:5]2)[CH2:3][CH2:2]1.Br[C:22]1[CH:23]=[C:24]([C:27]#[N:28])[S:25][CH:26]=1>>[CH:1]1([C:4]2([CH:18]3[CH2:20][CH2:19]3)[O:5][C:6](=[O:17])[NH:7][C:8]3[CH:13]=[CH:12][C:11]([C:22]4[CH:23]=[C:24]([C:27]#[N:28])[S:25][CH:26]=4)=[CH:10][C:9]2=3)[CH2:3][CH2:2]1
Reactant: N#Cc1cc(Br)cs1
Reactant: O=C1Nc2ccc(B(O)O)cc2C(C2CC2)(C2CC2)O1
Product: N#Cc1cc(-c2ccc3c(c2)C(C2CC2)(C2CC2)OC(=O)N3)cs1

Procedure:
The title compound was prepared according to Procedure B from (4,4-dicyclopropyl-1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid and 4-bromo-2-thiophene carbonitrile. A white solid: mp 244-245° C.; 1H-NMR (DMSO-d6) δ10.25 (s, 1H), 8.49 (d, 1H, J=0.87 Hz), 8.33 (s, 1H), 7.74 (d, 1H, J=1.44 Hz), 7.67 (dd, 1H, J=8.28, 1.54 Hz), 6.90 (d, 1H, J=8.28 Hz), 1.53 (m, 2H), 0.59-0.41 (m, 6H), 0.31-0.24 (m, 2H); MS (ESI) m/z 335 ([M−H]−, 100%); Anal. Calc. For C19H16N2O2S: C, 67.84, H, 4.79, N, 8.33. Found: C, 64.92, H, 4.66, N, 7.71.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[C:5]([OH:10])=[N:6][CH:7]=[CH:8][CH:9]=1.[O-]S([O-])=O.[Na+].[Na+]>CN(C)C=O.O>[Br:1][C:8]1[CH:9]=[C:4]([F:3])[C:5]([OH:10])=[N:6][CH:7]=1
Reactant: Oc1ncccc1F
Reactant: BrBr
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Oc1ncc(Br)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
32.0 ml (620.0 mmol) of bromine are added dropwise at 0° C. to 63.7 g (563.2 mmol) of 3-fluoro-2-hydroxypyridine in 700 ml of dimethylformamide. After the mixture has been stirred at room temperature for a further two hours, 800 ml of water are added, and 78 g of Na2SO3 in 350 ml of water are added dropwise. The mixture is then extracted three times with 400 ml of dichloromethane in each case, and the organic phase is dried over Na2SO4 and evaporated to dryness, giving 97.6 g of 5-bromo-3-fluoro-2-hydroxypyridine. ##STR21##
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([S:23][CH2:24][C:25]([O:27]CC)=O)=[O:22])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CC(C)([O-])C.[K+].Cl>C1COCC1.CN(C=O)C>[OH:27][C:25]1[CH2:24][S:23][C:21](=[O:22])[C:20]=1[C:17]1[CH:18]=[CH:19][C:14]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:15][CH:16]=1
Reactant: CCCCCCCCCCCCOc1ccc(CC(=O)SCC(=O)OCC)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCOc1ccc(C2=C(O)CSC2=O)cc1
Reaction time: 1 h
Yield: 0.5 %

Procedure:
In a mixture of THF (50 ml) and DMF (10 ml) was dissolved ethyl S-(4-dodecyloxyphenyl)acetylthioglycolate (2.8 g, 6.6 m mol). To the solution was added at room temperature potassium tertiary butoxide (1.1 g, 10 m mol). The solution was stirred for one hour, to which was then added 2N HCl (20 ml), followed by extraction with ethyl acetate. The organic layer was washed with water, dried and concentrated under reduced pressure. The residue was purified by silica gel chromatography (developing solvent: ethyl acetate). The crude crystals obtained were recrystallized from IPE to obtain 2,5-dihydro-4-hydroxy-3-(4-dodecyloxyphenyl)thiophen-2-one (5-h, 13 mg, 0.5%).
Reaction SMILES: [P:1]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]=O)([S:6][CH2:7][CH2:8][CH3:9])([S:3][CH2:4][CH3:5])=[S:2].[N+:19]([C:22]1[CH:31]=[CH:30][C:25]([C:26]([NH:28][NH2:29])=[O:27])=[CH:24][CH:23]=1)([O-:21])=[O:20]>CO.C(Cl)Cl>[P:1]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]=[N:29][NH:28][C:26](=[O:27])[C:25]1[CH:24]=[CH:23][C:22]([N+:19]([O-:21])=[O:20])=[CH:31][CH:30]=1)([S:6][CH2:7][CH2:8][CH3:9])([S:3][CH2:4][CH3:5])=[S:2]
Reactant: NNC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CCCSP(=S)(Oc1ccccc1C=O)SCC
Solvent: CO
Solvent: ClCCl
Product: CCCSP(=S)(Oc1ccccc1C=NNC(=O)c1ccc([N+](=O)[O-])cc1)SCC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of S-ethyl S-propyl O-(2-formylphenyl) trithiophosphate (0.02 mole) in methanol (50 ml) and 4-nitrobenzoylhydrazine (0.02 mole) are charged into a glass reaction vessel and the mixture is stirred at room temperature for a period of about 12 hours. After this time the reaction mixture is stripped of methanol under vacuum and the residue is dissolved in methylene chloride (100 ml) and the resulting solution is washed with water (75 ml), with aqueous sodium hydroxide (75 ml; 0.1 N) and again with water (75 ml). The washed solution is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent to yield the desired product S-ethyl S-propyl O-[2-(4-nitrobenzoylhydrazonomethyl)phenyl] trithiophosphate.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Cl:16])[CH:10]=2)[N:3]=1.C(=O)(O)[O-].[Na+].[F:22][C:23]([F:37])([F:36])[C:24]1[C:25]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[N:26][CH:27]=[CH:28][CH:29]=1>CO>[Cl:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Cl:16])[CH:10]=2)[CH:5]=[C:6]([N:33]2[CH2:34][CH2:35][N:30]([C:25]3[C:24]([C:23]([F:37])([F:22])[F:36])=[CH:29][CH:28]=[CH:27][N:26]=3)[CH2:31][CH2:32]2)[N:7]=1
Reactant: Fc1ccc(-c2cc(Cl)nc(Cl)n2)cc1Cl
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Fc1ccc(-c2cc(N3CCN(c4ncccc4C(F)(F)F)CC3)nc(Cl)n2)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Combine 2,4-dichloro-6-(3-chloro-4-fluoro-phenyl)-pyrimidine (1.6 g, 5.75 mmol), sodium bicarbonate (1.28 g, 15 mmol), MeOH (100 mL) and cool over ice. Drip in a mixture of 1-(3-trifluoromethyl-pyridin-2-yl)-piperazine (1.33 g, 5.75 mmol) in MeOH (50 mL), and let the reaction stir for 16 hours at room temperature. Evaporate the mixture and purify directly using 10:1 hexanes/EtOAc, obtaining 2-chloro-4-(3-chloro-4-fluoro-phenyl)-6-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyrimidine as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](/[N:8]=[C:9]2\[C:10](=[O:24])[N:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[C:17]\2=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:4][CH:3]=1.[S:25]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26]1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:18]1([N:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)/[C:9](=[N:8]/[C:5]3[CH:6]=[CH:7][C:2]([C:27]4[CH:28]=[CH:29][S:25][CH:26]=4)=[CH:3][CH:4]=3)/[C:10]2=[O:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OB(O)c1ccsc1
Reactant: O=C1/C(=N\c2ccc(Br)cc2)c2ccccc2N1c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1/C(=N\c2ccc(-c3ccsc3)cc2)c2ccccc2N1c1ccccc1
Yield: 35.6 %

Procedure:
A mixture of (3Z)-3-[(4-bromophenyl)imino]-1-phenyl-1,3-dihydro-2H-indol-2-one (50.0 mg, 0.133 mmol), thiophene-3-boronic acid (26.0 mg, 0.199 mmol), tetrakis(triphenylphosphine)palladium(0) (31.0 mg, 0.0268 mmol in THF (5 mL), and aqueous Na2CO3 (2M, 100 μL) was heated at 67° C. for 24 h. The crude product was concentrated in vacuo and the residue was extracted with CH2Cl2 (3×1 ml), and concentrated. The crude product was purified by preparative TLC using 10% methanol in CHCl3, giving the desired product (18 mg, 35%).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[C:14](=[O:23])[NH:13][C:12]2=[O:24])[CH2:10][CH2:9]1)=[O:7].Cl[CH2:37][C:38]1[C:39]([CH3:44])=[N:40][O:41][C:42]=1[CH3:43]>>[F:35][C:2]([F:1])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[C:14](=[O:23])[N:13]([CH2:37][C:38]3[C:39]([CH3:44])=[N:40][O:41][C:42]=3[CH3:43])[C:12]2=[O:24])[CH2:10][CH2:9]1)=[O:7]
Reactant: Cc1noc(C)c1CCl
Reactant: Cc1ccccc1N1C(=O)NC(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2
Product: Cc1ccccc1N1C(=O)N(Cc2c(C)noc2C)C(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2

Procedure:
The title compound, MS: m/e=609.0 (M+H+), was prepared in accordance with the general method of example 99 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-o-tolyl-1,3,8-triaza-spiro[4.5]decane-2,4-dione and 4-(chloromethyl)-3,5-dimethylisoxazole.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][C:14]=2[Cl:25])C(=O)C)[C:5]([N+:26]([O-:28])=[O:27])=[CH:4][CH:3]=1.[OH-].[Na+].Cl.O>O1CCOCC1>[Br:1][C:2]1[N:7]=[C:6]([NH:8][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][C:14]=2[Cl:25])[C:5]([N+:26]([O-:28])=[O:27])=[CH:4][CH:3]=1
Reactant: CC(=O)N(Cc1ccc(-c2ccccc2)cc1Cl)c1nc(Br)ccc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(Br)nc1NCc1ccc(-c2ccccc2)cc1Cl
Temperature: 50 °C
Reaction time: 3 h
Yield: 98.6 %

Procedure:
To a solution of 6-bromo-2-[N-(2-chloro-4-phenylbenzyl)acetamido]-3-nitropyridine (15.4 g) in dioxane (150 ml) was added 1N aqueous sodium hydroxide solution (43.5 ml) at room temperature and the mixture was heated to 50° C. The mixture was stirred for 3 hr, ice-cooled, and neutralized with 1N hydrochloric acid. Water (300 ml) was added and the precipitated crystals were collected by filtration and dried under reduced pressure to give 6-bromo-2-[N-(2-chloro-4-phenylbenzyl)amino]-3-nitropyridine (13.8 g) as yellow crystals.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([C:11]1[C:16]2[N:17]=[C:18]([C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[O:19][C:15]=2[C:14]([F:25])=[C:13]([C:26]([O:28]CC)=[CH2:27])[C:12]=1[CH3:31])#[N:10]>O1CCCC1.O>[Br:1][CH2:28][C:26]([C:13]1[C:12]([CH3:31])=[C:11]([C:9]#[N:10])[C:16]2[N:17]=[C:18]([C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[O:19][C:15]=2[C:14]=1[F:25])=[O:27]
Reactant: C=C(OCC)c1c(C)c(C#N)c2nc(C(=O)N(C)C)oc2c1F
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C(=O)CBr)c(F)c2oc(C(=O)N(C)C)nc2c1C#N
Reaction time: 0.33 h

Procedure:
Next, at room temperature, N-bromosuccinimide (2.10 g, 11.8 mmol) was added to a tetrahydrofuran/water (178 ml/11 ml) mixed solution of the obtained 4-cyano-6-[1-(ethoxy)ethenyl]-7-fluoro-N,N,5-trimethyl-1,3-benzoxazole-2-carboxamide (3.56 g, 11.2 mmol), and stirred for 20 minutes. The solvent was evaporated away under reduced pressure, and the resulting residue was dissolved in ethyl acetate, and the solution was washed with water.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:24]=[CH:23][N:13]3[C:14](=[O:22])[C:15]([C:18]([O:20]C)=[O:19])=[CH:16][N:17]=[C:12]3[CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:24]=[CH:23][N:13]3[C:14](=[O:22])[C:15]([C:18]([OH:20])=[O:19])=[CH:16][N:17]=[C:12]3[CH:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cnc2cc(C#Cc3cccc(F)c3)ccn2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cnc2cc(C#Cc3cccc(F)c3)ccn2c1=O
Yield: 43.3 %

Procedure:
A solution of methyl 8-((3-fluorophenyl)ethynyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-3 carboxylate (100 mg, 0.3 mmol, 1 equiv) in 1% NaOH (2.4 mL, 0.6 mmol, 2 equiv) and THF was stirred at room temperature overnight. Then the reaction mixture was adjusted pH to 3 with 10% aq. HCl and filtered to give 40 mg of the desired product. MS (ESI): 309 (MH+).
Reaction SMILES: C([O:8][C:9](=[O:34])[CH:10]([CH2:15][PH:16]([O:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)=[O:17])[CH2:11][CH:12]([CH3:14])[CH3:13])C1C=CC=CC=1.O[CH:36]1[CH2:41][C:40](=[O:42])[NH:39][C:37]1=[O:38].Cl.CN(CCCN=C=NCC)C>CO.CCOCC.[Pd]>[O:42]=[C:40]1[CH2:41][CH2:36][C:37](=[O:38])[N:39]1[O:34][C:9](=[O:8])[CH:10]([CH2:15][PH:16]([O:18][CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:25][CH:26]=1)=[O:17])[CH2:11][CH:12]([CH3:14])[CH3:13]
Reactant: O=C1CC(O)C(=O)N1
Reactant: CC(C)CC(C[PH](=O)OCCc1ccc(Cc2ccccc2)cc1)C(=O)OCc1ccccc1
Agent: [Pd]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CC(C)CC(C[PH](=O)OCCc1ccc(Cc2ccccc2)cc1)C(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 86 %

Procedure:
2-[(4-Benzyl benzyl)methoxyphosphinoylmethyl]-4-methylpentanoic acid benzyl ester (650 mg, 1.36 mmole) was hydrogenated at 45 psi at room temperature in methanol (50 ml) over 5% palladium on barium sulfate (650 mg) for 1 hour. The catalyst was filtered off and washed with methanol. The filtrate was concentrated and traces of methanol removed by twice diluting the sample with methylene chloride and reconcentrating. The intermediate 2-[(4-benzyl benzyl)methoxyphosphinoylmethyl]-4-methylpentanoic acid was dissolved in dry dimethylformamide (14 ml) and hydroxysuccinimide (235 mg, 2.04 mmole) and dimethylaminopropylethylcarbodiimide hydrochloride (391 mg, 2.04 mmol) added. After stirring at room temperature for 20 hours the solution was diluted with ether (50 ml) and washed with 1N hydrochloric acid (50 ml, 2×25 ml) and saturated sodium bicarbonate solution (25 ml) and dried with magnesium sulfate. After filtration and concentration 566 mg (86%) of 2-[(4-Benzylbenzyl) methoxyphosphinoylmethyl]-4-methyl-pentanoic acid 2,5-dioxo-pyrrolidin-1-yl ester was obtained as an oil.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5](S(C2C=CC=CC=2)(=O)=O)=[N:4][CH:3]=1.[F-:19].[K+].C(OCC)(=O)C.O>CS(C)=O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:19][C:5]1[C:6]([C:8]#[N:9])=[N:7][C:2]([F:1])=[CH:3][N:4]=1
Reactant: N#Cc1nc(F)cnc1S(=O)(=O)c1ccccc1
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1nc(F)cnc1F
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 28 %

Procedure:
In 4 mL of dimethyl sulfoxide was dissolved 0.40 g of 6-fluoro-3-(phenylsulfonyl)-2-pyrazinecarbonitrile. After adding 0.44 g of potassium fluoride and 0.10 g of tetra-n-butylammonium bromide successively, the mixture thus obtained was stirred at 60° C. for 1.5 hours. The reaction mixture was poured into a mixture of 20 mL of ethyl acetate and 20 mL of water, and the organic layer was separated. The organic layer was washed successively with water and saturated aqueous solution of sodium chloride and dried on anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography [eluent: n-hexane:ethyl acetate=20:1] to obtain 0.06 g of 3,6-difluoro-2-pyrazinecarbonitrile as a colorless solid product.
Reaction SMILES: Br[C@:2]12[C@@H:19]([OH:20])[CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH2:14][C:15]3=[O:21])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:23])[CH2:4][CH2:5][C:6](=[O:22])[CH:7]=1>C1COCC1>[OH:20][C@H:19]1[CH2:18][C@@:16]2([CH3:17])[C@@H:12]([CH2:13][CH2:14][C:15]2=[O:21])[C@H:11]2[C@H:2]1[C@:3]1([CH3:23])[C:8]([CH2:9][CH2:10]2)=[CH:7][C:6](=[O:22])[CH2:5][CH2:4]1
Reactant: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3CCC(=O)[C@@]3(C)C[C@H](O)[C@@]12Br
Solvent: C1CCOC1
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 2.2 h

Procedure:
9α-Bromo-11β-hydroxyandrost-4-ene-3,17-dione (I, PREPARATION 2, 2.134 g) is dissolved in THF (THF 20ml) and degassed as described in EXAMPLE 1. This solution is added dropwise over 20 min to a freshly degassed slurry of chromic chloride hexahydrate (81 mg), thiovanic acid (0.70 ml) and zinc dust (555 mg) in DMF (4 ml) at 0° THF (about 8 ml) is used for rinse purposes. The slurry is stirred at 0° to 2° for 2.2 hr and then is slowly heated to 50°. The THF is removed by vacuum distillation and the remaining slurry is diluted with ethyl acetate (25 ml) and water (25 ml). The unreacted zinc is removed by filtration and is washed with aqueous ethyl acetate. The combined filtrate and wash is allowed to separate. The organic layer is washed with water (3×25 ml) and finally is concentrated under vacuum to a residue. The residue is recrystallized from 1 part toluene and 2 parts heptane to give the title compound, TLC Rf =0.45 (methanol/methylene chloride, 5/95); HPLC 96.7% (II), 2.9% ∆9(11).
Reaction SMILES: C[O:2][C:3](=[O:23])[CH:4]([CH3:22])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1.[OH-].[Li+:25]>O1CCCC1.O.C(#N)C>[Li+:25].[F:21][C:18]([F:19])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([N:9]2[CH2:10][CH2:11][N:6]([CH2:5][CH:4]([CH3:22])[C:3]([O-:23])=[O:2])[CH2:7][CH2:8]2)=[CH:13][CH:14]=1
Reactant: COC(=O)C(C)CN1CCN(c2ccc(C(F)(F)F)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: C1CCOC1
Product: CC(CN1CCN(c2ccc(C(F)(F)F)cc2)CC1)C(=O)[O-]
Yield: 76.2 %

Procedure:
3-[4-(4-Trifluoromethyl-phenyl)-piperazin-1-yl]-2-methyl-propionic acid methyl ester (623 mg; 1.89 mmol, prepared in accordance with Example 62) and lithium hydroxide (60 mg; 2.50 mmol) are suspended in a mixture of tetrahydrofuran (4 mL) and water (1 mL). The resulting mixture is irradiated in a mono-mode microwave oven for 50 minutes at 100° C. The mixture is then diluted with acetonitrile until precipitation occurs. The solid formed is then filtered and dried under high vacuum to afford the desired product (465 mg; 1.44 mmol).
Reaction SMILES: C[C:2]1[C:7](SC)=[C:6](C)[CH:5]=[C:4]([O:11][C:12]([NH:14][CH3:15])=[O:13])[CH:3]=1.CC(C1C=CC=[CH:23][C:24]=1[O:25][C:26](NC)=[O:27])C.CNC(OC1C=CC=C2C=CC=CC=12)=O.CC1C=CC(OC(NC)=O)=CC=1C.CNC(OC1C(Cl)=CC=CC=1)=O.CCCC(C1C=CC=C(OC(NC)=O)C=1)C.CCC(C1C=CC=C(OC(NC)=O)C=1)CC.CCC(C1C(OC(NC)=O)=CC=CC=1)C.CC1(C)OC2C(=CC=CC=2OC(NC)=O)C1.CC(OC1C=CC=CC=1OC(NC)=O)C.CCSCC1C=CC=CC=1OC(NC)=O.CCCCN(SN(C(OC1C=CC=C2CC(C)(C)OC=12)=O)C)CCCC.CC1(C)OC2C(=CC=CC=2OC(NC)=O)O1.CC1C=C(OC(NC)=O)C=CC=1N(C)C>>[CH3:15][NH:14][C:12]([O:11][C:4]1[C:3]([CH:26]2[O:25][CH2:24][CH2:23][O:27]2)=[CH:2][CH:7]=[CH:6][CH:5]=1)=[O:13]
Reactant: CNC(=O)Oc1ccccc1C(C)C
Reactant: CNC(=O)Oc1cc(C)c(SC)c(C)c1
Agent: CCC(C)c1ccccc1OC(=O)NC
Agent: CCC(CC)c1cccc(OC(=O)NC)c1
Agent: CCCC(C)c1cccc(OC(=O)NC)c1
Product: CNC(=O)Oc1ccccc1C1OCCO1

Procedure:
methiocarb; isoprocarb; carbaryl; xylylcarb; CPMC, bufencarb; BPMC; carbofuran; propoxur, ethiofencarb; carbosulfan; Mydrol®; bendiocarb; aminocarb; chloetocarb and benzofuracarb.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[O:16])=[CH:10][CH:9]=2)[CH2:4]1.C(=O)([O-])[O-].[K+].[K+].[CH2:30]([S:34](Cl)(=[O:36])=[O:35])[CH2:31][CH2:32][CH3:33]>CN1CCCC1=O>[CH3:1][N:2]([CH3:23])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]([CH:17]3[CH2:22][CH2:21][N:20]([S:34]([CH2:30][CH2:31][CH2:32][CH3:33])(=[O:36])=[O:35])[CH2:19][CH2:18]3)=[O:16])=[CH:12][CH:13]=2)[CH2:4]1
Reactant: CN(C)C1CCN(c2ccc(NC(=O)C3CCNCC3)cc2)C1
Reactant: CCCCS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CCCCS(=O)(=O)N1CCC(C(=O)Nc2ccc(N3CCC(N(C)C)C3)cc2)CC1
Reaction time: 12 h

Procedure:
Piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide (70 mg) dissolved in N-methylpyrrolidone (2 ml) was mixed with potassium carbonate (45 mg) and butylsulfonyl chloride (30 mg). After 12 hours, the mixture was filtered and the filtrate was purified by preparative HPLC. This resulted in the product with the molecular weight of 436.62 (C22H36N4O3S); MS (ESI): 437 (M+H+).
Reaction SMILES: [C:1](Cl)(=O)[CH3:2].[N+:5]([C:8]1[C:9]([C:13]([OH:15])=[O:14])=[N:10][NH:11][CH:12]=1)([O-:7])=[O:6]>C(O)C>[N+:5]([C:8]1[C:9]([C:13]([O:15][CH2:1][CH3:2])=[O:14])=[N:10][NH:11][CH:12]=1)([O-:7])=[O:6]
Reactant: CC(=O)Cl
Reactant: O=C(O)c1n[nH]cc1[N+](=O)[O-]
Solvent: CCO
Product: CCOC(=O)c1n[nH]cc1[N+](=O)[O-]

Procedure:
Acetyl chloride (50 mL) was added dropwise to ethanol (450 mL) at 0° C. with stirring. After addition was complete, the ice-bath was removed, and the mixture was stirred at room temperature for 30 minutes. To this mixture was added 4-nitro-1H-pyrazole-3-carboxylic acid (Aldrich) (10 g, 63.65 mmol), and the resulting homogeneous mixture was stirred at room temperature for a total of 48 hours. The reaction was monitored by TLC. The solvent was removed under reduced pressure and then co-evaporated with ethyl acetate four times. The residue was concentrated under high vacuum to give the title compound as a white powder (11.426 g, (M−H)+=184, M.P.=128.0-130.1° C.).