Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]1[C:18]2[C:19]3[CH:6]([CH2:7][C@@H:8]4[C:13]([C:14]=3[C:15]([Br:20])=[CH:16][CH:17]=2)=[CH:12][C@H:11]([NH:21][C:22](=[O:28])[N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[CH2:10][N:9]4[CH3:29])[CH2:5]1)(=O)C.Cl>>[Br:20][C:15]1[C:14]2=[C:19]3[C:18]([NH:4][CH2:5][C@H:6]3[CH2:7][C@@H:8]3[C:13]2=[CH:12][C@H:11]([NH:21][C:22](=[O:28])[N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[CH2:10][N:9]3[CH3:29])=[CH:17][CH:16]=1
Reactant: CCN(CC)C(=O)N[C@H]1C=C2c3c(Br)ccc4c3C(C[C@H]2N(C)C1)CN4C(C)=O
Agent: Cl
Product: CCN(CC)C(=O)N[C@H]1C=C2c3c(Br)ccc4c3[C@@H](CN4)C[C@H]2N(C)C1

Procedure:
This compound is obtained--analogously to Example 7--from 3-(1-acetyl-12-bromo-9,10-didehydro-2,3-dihydro-6-methyl-8α-ergolinyl)-1,1-diethylurea by heating with 1N hydrochloric acid.
Reaction SMILES: [H-].[Na+].[S:3]1[CH:7]=[CH:6][N:5]=[C:4]1[NH:8][C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].[Cl:17][CH:18]([C:22]1[O:27][C:26](=[O:28])[C:25]2[CH:29]=[CH:30][CH:31]=[C:32]([C:33]([F:36])([F:35])[F:34])[C:24]=2[N:23]=1)[CH:19]([CH3:21])[CH3:20].Cl>O1CCCC1>[Cl:17][CH:18]([CH:19]([CH3:21])[CH3:20])[C:22]([NH:23][C:24]1[C:32]([C:33]([F:34])([F:35])[F:36])=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](=[O:28])[CH:10]([C:9]([NH:8][C:4]1[S:3][CH:7]=[CH:6][N:5]=1)=[O:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:27]
Reactant: CCOC(=O)CC(=O)Nc1nccs1
Reactant: CC(C)C(Cl)c1nc2c(C(F)(F)F)cccc2c(=O)o1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)Nc1nccs1)C(=O)c1cccc(C(F)(F)F)c1NC(=O)C(Cl)C(C)C
Reaction time: 0.17 h
Yield: 72.2 %

Procedure:
Under an inert gas, 5.52 g of sodium hydride dispersed at 55% in oil and 173 ml of tetrahydrofuran were mixed together and then a solution of 26.22 g of ethyl 3-(2-thiazolylamino)-3-oxo-propanoate in 690 ml of tetrahydrofuran was added slowly at 20° C. After stirring for 10 minutes, a solution of 34.5 g of 2-(1-chloro-2-methylpropyl)-8-trifluoromethyl-4H-3,1-benzoxazine-4-one [prepared according to the process described in European Pat. No. 0040573] in 210 ml of tetrahydrofuran was added slowly at 20° C. After stirring at 20° C. for 35 minutes, the mixture was poured into 200 ml of 2N hydrochloric acid and was extracted with ether. The ethereal phase was washed with water, dried and the solvent was evaporated. The residue was triturated in ether and dried to obtain 42.35 g of ethyl 2-[(2-chloro-1-oxo-3-methylbutyl)-amino]-β-oxo-α-[(2-thiazolylamino)-carbonyl]-3-trifluoromethyl-benzene-propanoate melting at 160° C. A second lot of 8.2 g of the said product was obtained afterwards melting at 160° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:5]2[N:11]=[C:10]([CH2:12][NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:8][C:6]=2[N:7]=1.[Si]([N:33]1[C:41]2[C:36](=[C:37](B3OC(C)(C)C(C)(C)O3)[C:38]([F:42])=[CH:39][CH:40]=2)[CH:35]=[CH:34]1)(C(C)(C)C)(C)C>>[F:42][C:38]1[C:37]([C:2]2[N:3]=[C:4]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[C:5]3[N:11]=[C:10]([CH2:12][NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:8][C:6]=3[N:7]=2)=[C:36]2[C:41](=[CH:40][CH:39]=1)[NH:33][CH:34]=[CH:35]2
Reactant: CC(C)(C)C(=O)NCc1ccc2nc(Cl)nc(N3CCOCC3)c2n1
Reactant: CC1(C)OB(c2c(F)ccc3c2ccn3[Si](C)(C)C(C)(C)C)OC1(C)C
Product: CC(C)(C)C(=O)NCc1ccc2nc(-c3c(F)ccc4[nH]ccc34)nc(N3CCOCC3)c2n1

Procedure:
N-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)pivalamide (0.13 g) was reacted with 1-(tert-butyldimethylsilyl)-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole via General Procedure A to produce 44 mg of 145 following reverse phase HPLC purification. MS (Q1) 463.2 (M)+
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)[N:8]=[C:7]2[CH:19]=O)([O-:3])=[O:2].[CH3:21][CH:22]1[CH2:27][N:26]([C:28]2[CH:29]=[C:30]([NH2:35])[C:31]([NH2:34])=[CH:32][CH:33]=2)[CH2:25][CH2:24][O:23]1.S(=O)(O)[O-].[Na+]>C1COCC1.Cl.C(OCC)(=O)C>[CH3:21][CH:22]1[O:23][CH2:24][CH2:25][N:26]([C:28]2[CH:33]=[CH:32][C:31]3[NH:34][C:19]([C:7]4[C:6]5[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=5)[N:9]([CH:13]5[CH2:18][CH2:17][CH2:16][CH2:15][O:14]5)[N:8]=4)=[N:35][C:30]=3[CH:29]=2)[CH2:27]1
Reactant: CC1CN(c2ccc(N)c(N)c2)CCO1
Reactant: O=Cc1nn(C2CCCCO2)c2ccc([N+](=O)[O-])cc12
Agent: Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1CN(c2ccc3[nH]c(-c4nn(C5CCCCO5)c5ccc([N+](=O)[O-])cc45)nc3c2)CCO1
Temperature: 70 °C
Yield: 55.5 %

Procedure:
5-Nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (150 mg, 0.545 mmol) and 4-(2-methylmorpholino)benzene-1,2-diamine (113 mg, 0.545 mmol) were dissolved in THF (10 mL) and 2N HCl (1 drop) was added. The solution was heated at a gentle reflux for 30 min. Then, 1N sodium bisulfite (104 mg, 1 mmol; 2 mL of a 1N solution) was added and heated at reflux (70° C.) overnight. The solution was cooled to room temperature, and diluted with ethyl acetate (40 mL). The mixture was washed with water and brine, dried over Na2SO4, and concentrated. Purification by flash chromatography (5% CH3OH/CH2Cl2) afforded the title compound (140 mg). 1H NMR: (400 MHz, CDCl3): δ 9.56 (d, 1H, J=1.6 Hz), 8.28 (m, 1H), 7.74 (d, 1H, J=8.8 Hz), 7.64 (m, 1H), 7.36 (m, 1H), 7.03-6.96 (m, 1H), 5.75 (dd, 1H, J=2.8 and 6.4 Hz), 3.99 (m, 2H), 3.79 (m, 3H), 3.38 (m, 2H), 2.84 (m, 1H), 2.51 (m, 2H), 2.11 (m, 2H), 1.86 (m, 1H), 1.74 (m, 2H), 1.22 (d, 3H, J=6.4 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:12]([NH2:14])[CH3:13]>>[CH2:12]([NH:14][C:4](=[O:5])[C:3]1[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:2]=1[Cl:1])[CH3:13]
Reactant: CCN
Reactant: O=C(Cl)c1cc(Cl)ccc1Cl
Product: CCNC(=O)c1cc(Cl)ccc1Cl
Yield: 84.5 %

Procedure:
2,5-Dichlorobenzoyl chloride (51 mmol) and 70% aq EtNH2 (130 mmol) were combined according to General Method E1 to afford 9.4 g of N-ethyl-2,5-dichlorobenzamide as a beige solid, an 85% yield.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:12]=[C:11]2[C:6]([N:7]=[C:8]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[C:9]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[C:10]2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[N:5]1.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:10]2[C:11]3[C:6](=[N:5][N:4]([CH2:3][CH2:2][NH:1][S:34]([CH3:33])(=[O:36])=[O:35])[CH:12]=3)[N:7]=[C:8]([C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[C:9]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[CH:14][CH:15]=1
Reactant: CS(=O)(=O)Cl
Reactant: NCCn1cc2c(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc2n1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CS(=O)(=O)NCCn1cc2c(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.3 %

Procedure:
To a solution of 2-(2-aminoethyl)-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine (0.06 g, 0.15 mmol, obtained in example 90) and DMAP (0.001 g, 0.0058 mmol) in pyridine (0.6 mL), methanesulfonyl chloride (0.017 mL, 0.22 mmol) was added under argon atmosphere and cooled with an ice bath (0.017 mL, 0.22 mmol). This was stirred overnight at room temperature. The solvent was concentrated. The residue was dissolved in CHCl3 and saturated NaHCO3 was added. The phases were separated. The organic phase was dried over Na2SO4 and concentrated. The crude product obtained was purified by chromatography on silica gel using EtOAc as solvent, and 70 mg of the title compound was obtained (yield: 95%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:17][O:16][C@H:15]([CH3:18])[C@H:14]1[CH2:13][S:12][C:11]([NH:19][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[N:10]2.C(O)(C(F)(F)F)=O.S(=O)(=O)(O)O.C1C(=O)N([Br:47])C(=O)C1.[OH-].[Na+]>>[Br:47][C:5]1[C:6]([F:8])=[CH:7][C:2]([F:1])=[C:3]([C@:9]23[CH2:17][O:16][C@H:15]([CH3:18])[C@H:14]2[CH2:13][S:12][C:11]([NH:19][C:20](=[O:27])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[N:10]3)[CH:4]=1
Reactant: C[C@H]1OC[C@]2(c3ccc(F)cc3F)N=C(NC(=O)c3ccccc3)SC[C@H]12
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1OC[C@]2(c3cc(Br)c(F)cc3F)N=C(NC(=O)c3ccccc3)SC[C@H]12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
N-((4aS*,5R*,7aS*)-7a-(2,4-Difluorophenyl)-5-methyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)benzamide (95 mg, 0.24 mmol) was dissolved in TFA (218 μL, 2.93 mmol) and sulfuric acid (78.2 μl, 1.47 mmol). NBS (39 mg, 0.22 mmol) was added and the reaction was stirred at 60° C. for 1 hour. The reaction mixture was cooled to room temperature, neutralized with 2N NaOH and extracted with EtOAc (×3). The combined organics were dried and concentrated in vacuo. The residue was purified by column chromatography, eluting with 0-30% EtOAc in n-hexane to give the desired compound. (78 mg). 1H NMR (400 MHz, CDCl3) δ ppm: 8.05-8.10 (m, 2H), 7.52-7.62 (m, 2H), 7.44-7.51 (m, 2H), 6.95-7.04 (m, 1H), 4.46-4.53 (m, 2H), 3.95 (dd, J=2.45, 9.41 Hz, 1H), 3.17 (dd, J=3.42, 13.45 Hz, 1H), 2.77-2.83 (m, 1H), 2.70-2.77 (m, 1H), 1.37-1.46 (m, 3H).
Reaction SMILES: [CH2:1]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:9](=O)[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.[CH2:17]([O:19]C=C[Li])[CH3:18]>C1COCC1>[CH:4]1[C:3]2[C:2]3[CH2:1][CH2:16][CH:15]=[CH:14][C:13]=3[CH:12]=[CH:11][C:9](=[CH:18][CH:17]=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: [Li]C=COCC
Reactant: O=C1c2ccccc2CCc2ccccc21
Solvent: C1CCOC1
Product: O=CC=C1C=CC2=C(CCC=C2)c2ccccc21

Procedure:
Dibenzosuberone (5.3 g, 0.026 mol) was reacted with 1-ethoxy-2-lithio ethylene in anhydrous THF in the manner of Preparation 1 to yield present title product as a yellow oily solid, 2.86 g (48% ).
Reaction SMILES: Cl[C:2]([S:4]Cl)=[O:3].[F:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([NH2:11])=[O:10]>C1(C)C=CC=CC=1>[F:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]1[O:10][C:2](=[O:3])[S:4][N:11]=1
Reactant: O=C(Cl)SCl
Reactant: NC(=O)c1ccccc1F
Solvent: Cc1ccccc1
Product: O=c1oc(-c2ccccc2F)ns1
Temperature: 80 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
Chlorocarbonyl sulfenyl chloride (11.24 g, 86 mmol) is added dropwise to a stirred suspension of 2-fluorobenzamide (10.80 g, 78 mmol) in dry toluene. The mixture is heated gradually over a period of 30 minutes to a temperature of about 80° C. (a clear solution is formed with evolution of gas), stirred for approximately 1 h at 80° C., heated to about 98° C., stirred at 98° C. for 5 h, and distilled to remove the toluene and excess chlorocarbonyl sulfenyl chloride. The resultant pot residue is redissolved in toluene, washed sequentially with water, 5% sodium bicarbonate and water, dried over anhydrous magnesium sulfate and concentrated in vacuo to give a residue. This residue is recrystallized from petroleum ether to give 5-(2-fluorophenyl)[1,3,4]oxathiazolin-2-one (13.2 g, 86%) as off-white crystals, mp 50° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[N:8]2[C:9](=[O:21])[C:10]3[NH:11][CH:12]=[N:13][C:14]=3[N:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:7]2=[N:6][N:5]=1.[C:22](O)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[O:21]=[C:9]1[N:8]2[C:4]([CH2:3][NH:2][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:5][N:6]=[C:7]2[N:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:14]2[N:13]=[CH:12][NH:11][C:10]1=2
Reactant: CCCCCn1c2nc[nH]c2c(=O)n2c(CN)nnc12
Reactant: O=C(O)c1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCn1c2nc[nH]c2c(=O)n2c(CNC(=O)c3ccccc3)nnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
The mixture of 3-(aminomethyl)-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one hydrochloride (160 mg, 0.51 mmol), [B] benzoic Acid (0.069 g, 0.56 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.25 g, 0.56 mmol) and triethylamine (0.21 mL, 1.5 mmol) in DMF (10 mL) was stirred at room temperature overnight. The reaction mixture was purified by preparative LCMS to yield the desired product (150 mg, 77%). LCMS calculated for C19H22N7O2 (M+H): 380.2. Found: 380.2.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([N+:11]([O-])=O)[CH:5]=1)[CH2:2][CH3:3].[H][H]>[Pd].C(OCC)(=O)C>[NH2:11][C:6]1[CH:5]=[C:4]([CH2:1][CH2:2][CH3:3])[CH:9]=[CH:8][C:7]=1[OH:10]
Reactant: [H][H]
Reactant: CCCc1ccc(O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1ccc(O)c(N)c1
Yield: 93.2 %

Procedure:
A mixture of 6.65 g of 4-propyl-2-nitrophenol, 55 ml of ethyl acetate and 1.0 g of 5% palladium on carbon was stirred under about one atmosphere of hydrogen at room temperature for two hours. The mixture was filtered through Celite™. The filtrate was concentrated under reduced pressure to give 5.17 g of 2-amino-4-propylphenol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([CH3:8])=[CH:6][CH:7]=1.[CH2:10]([C:12]([CH3:19])([C:16](Cl)=[O:17])[C:13](Cl)=[O:14])[CH3:11].[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([CH3:8])=[C:6]2[C:7]=1[C:16](=[O:17])[C:12]([CH2:10][CH3:11])([CH3:19])[C:13]2=[O:14]
Reactant: CCC(C)(C(=O)Cl)C(=O)Cl
Reactant: Cc1ccc(Cl)cc1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCC1(C)C(=O)c2c(Cl)cc(C)c(C)c2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
To a mixture of 28 ml of 4-chloro-o-xylene and 37.6 g of ethylmethylmalonyl chloride in 300 ml of dry dichloromethane was added slowly 26.7 g of AlCl3 under the current of nitrogen gas at -10° C. The reaction mixture was stirred at room temperature for 2 hours, quenched with 200 g of ice, and separated the organic layer. The aqueous layer was extracted with dichloromethane. The combined organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography to afford 24.67 g of the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([O:23]C)=[O:22])[N:9]=2)=[CH:4][CH:3]=1.[OH-].[K+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([OH:23])=[O:22])[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1nc(-c2ccc(Cl)cc2)n(-c2ccc(Cl)cc2Cl)n1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1nc(-c2ccc(Cl)cc2)n(-c2ccc(Cl)cc2Cl)n1
Yield: 92 %

Procedure:
Part C: To a stirred suspension of methyl 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1H-1,2,4-triazole-3-carboxylate (11.3 gram, 0.0295 mol) in methanol (100 mL) is added KOH (45% aqueous solution, 7.5 mL) and the resulting mixture is heated at reflux temperature for 4 hours. The mixture is concentrated in vacuo and water (150 mL) and concentrated HCl are added. The yellow precipitate is collected by filtration, washed with water and dried in vacuo to give 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1H-1,2,4-triazole-3-carboxylic acid (10.0 gram, 92% yield). Melting point: 141-144° C. (decomposition).
Reaction SMILES: [SH:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)#[N:13]>N1C=CC=CC=1>[CH3:11][C:9]1[CH:8]=[CH:7][C:3]2[C:4](=[O:6])[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[S:1][C:2]=2[CH:10]=1
Reactant: Cc1ccc(C(=O)O)c(S)c1
Reactant: N#Cc1ccccn1
Solvent: c1ccncc1
Product: Cc1ccc2c(=O)nc(-c3ccccn3)sc2c1
Yield: 45.9 %

Procedure:
A mixture of 2-mercapto-4-methylbenzoic acid (2.0 g, 12 mmol), 2-cyanopyridine (1.4 g, 13 mmol) and pyridine (8 ml) was refluxed for 14 hrs as described in Example 9. After cooling, the precipitated crystals were collected by filtration, subjected to a silica gel column chromatography, eluted with ethyl acetate-methanol (5:1, v/v) and recrystallized from hexane-tetrahydrofuran to give the titled compound (1.4 g, 48%).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[S:37](=[O:44])(=[O:43])[NH:38]C(C)(C)C)=[CH:27][C:26]=2[F:45])[C:7](=[O:23])[N:8]([C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=2[C:19]([F:22])([F:21])[F:20])[N:9]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>>[CH2:1]([C:5]1[N:6]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[S:37](=[O:44])(=[O:43])[NH2:38])=[CH:27][C:26]=2[F:45])[C:7](=[O:23])[N:8]([C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=2[C:19]([F:20])([F:22])[F:21])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1F
Yield: 94 %

Procedure:
Reaction of 5-n-butyl-4-[[2'-(N-t-butylsulfamoyl)-3-fluorobiphenyl-4-yl]methyl]-2,4-dihydro-2-[5-nitro-2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (from Step A) with trifluoroacetic acid in the presence of anisole according to the procedure of Example 28, Step G, gave a 94% yield of the title compound as a pale yellow foam, homogeneous by TLC (95:5 CH2Cl2 --MeOH); mass spectrum (FAB) m/e 594 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][C:15]([OH:17])=O)=[CH:4][CH:3]=1.[CH2:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][NH:19]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][C:15]([N:19]2[CH2:20][C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:18]2)=[O:17])=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CC(=O)O
Reactant: c1ccc2c(c1)CNC2
Product: Cc1noc(-c2ccc(Br)cc2)c1CC(=O)N1Cc2ccccc2C1

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-acetic acid and 2,3-dihydro-1H-isoindole.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([N:8]1[C@@H:12]([CH3:13])[CH2:11][CH2:10][CH:9]1[C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]2[CH:28]=[N:27][CH:26]=[CH:25][N:24]=2)=[O:22])=[CH:16][C:15]=1[F:29])(=[O:7])[CH3:6]>C(Cl)(Cl)Cl>[C:5]([N:8]1[C@@H:12]([CH3:13])[CH2:11][CH2:10][C@@H:9]1[C:14]1[C:15]([F:29])=[CH:16][C:17]([NH:20][C:21]([C:23]2[CH:28]=[N:27][CH:26]=[CH:25][N:24]=2)=[O:22])=[C:18]([N+:1]([O-:4])=[O:2])[CH:19]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)N1C(c2ccc(NC(=O)c3cnccn3)cc2F)CC[C@@H]1C
Reactant: O=[N+]([O-])O
Solvent: ClC(Cl)Cl
Product: CC(=O)N1[C@@H](c2cc([N+](=O)[O-])c(NC(=O)c3cnccn3)cc2F)CC[C@@H]1C
Reaction time: 0.5 h

Procedure:
1 ml of fuming nitric acid was added to 59 mg of N-(4-((5S)-1-acetyl-5-methylpyrrolidin-2-yl)-3-fluorophenyl)pyrazine-2-carboxamide at room temperature, and the reaction liquid was stirred at the same temperature for 30 minutes. The reaction liquid was diluted with chloroform, washed with aqueous saturated sodium bicarbonate, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduce pressure, and purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), ethyl acetate) to obtain the entitled compound as a pale yellow oily substance. (Rf: trans form>cis form.)
Reaction SMILES: [CH:1]1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Li]CCCC.[C:25]([N:32]1[C@@H:41]([CH2:42]O)[CH2:40][C:39]2[C:34](=[C:35]3[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][C:36]3=[C:37]3[CH:47]=[C:46]([O:48][CH3:49])[C:45]([O:50][CH3:51])=[CH:44][C:38]3=2)[CH2:33]1)([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].[NH4+].[Cl-]>C1COCC1>[C:28]([O:27][C:25]([N:32]1[C@H:41]([CH:42]=[CH2:1])[CH2:40][C:39]2[C:34](=[C:35]3[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][C:36]3=[C:37]3[CH:47]=[C:46]([O:48][CH3:49])[C:45]([O:50][CH3:51])=[CH:44][C:38]3=2)[CH2:33]1)=[O:26])([CH3:30])([CH3:29])[CH3:31]
Reactant: COc1ccc2c3c(c4cc(OC)c(OC)cc4c2c1)C[C@H](CO)N(C(=O)OC(C)(C)C)C3
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=C[C@@H]1Cc2c(c3ccc(OC)cc3c3cc(OC)c(OC)cc23)CN1C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 76 %

Procedure:
To a solution of Ph3P═CH2Br (1.43 g, 4 mmol) in THF was added n-BuLi (2M in heptanes, 1.95 mL) at 0° C. under N2. The mixture was stirred for 0.5 h before compound 8 (906 mg, 2 mmol) in THF (20 mL) was added dropwise. The mixture was then stirred for 2 h (monitored by TLC). Sat. NH4Cl was added to quench the reaction and THF was removed by evaporation. The residue was dissolved in CH2Cl2 (50 mL), washed with sat. NaHCO3 and brine, and dried over MgSO4. Column chromatography eluting with EtOAc/Hexane gave 9 (684 mg, 76%) as a light yellow foam: mp 177-179° C.; [α]23D=118.2 (c 0.56, CHCl3); 1H NMR (300 MHz, CDCl3): δ 7.92 (s, 1H), 7.91 (d, J=2.4 Hz, 1H), 7.85 (d, J=9.0 Hz, 1H), 7.31 (s, 1H), 7.23 (dd, J=9.0 Hz, J=2.7 Hz, 1H), 5.86-5.75 (m, 1H), 5.29 (m, 1H), 5.26 (d, J=16.8 Hz, 1H), 5.16-5.04 (m, 2H), 4.59 (d, J=17.4 Hz, 1H), 4.11 (s, 3H), 4.06 (s, 3H), 4.01 (s, 3H), 3.36 (dd, J=16.2 Hz, J=6.0 Hz, 1H), 3.29 (t, J=16.5 Hz, 1H), 1.55 (s, 9H); 13C NMR (75 MHz, CDCl3): δ 157.9, 155.3, 149.8, 148.8, 136.5, 130.4, 126.8, 124.4, 124.2, 123.9, 123.6, 123.1, 116.6, 115.2, 105.1, 104.3, 104.1, 80.3, 77.4, 56.3, 56.1, 55.7, 41.1, 29.8, 28.7 (3×C); ESI-HRMS ([M+Na]+) calcd for C27H31NO5Na 472.2100. found 472.2103.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[Cl:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=[O:11].[Cl:16]Cl>>[Cl:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[C:10]([Cl:16])=[O:11]
Reactant: ClCl
Reactant: O=Cc1ccccc1Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: O=C(Cl)c1ccccc1Cl
Temperature: 160 °C

Procedure:
Phosphorus pentachloride (41.5 g, 0.2 mole) was added to 2-chlorobenzaldehyde (289.7 g, 2.0 mole, 97%). After the ensuing exotherm had subsided, the resulting red solution was heated to 160° C. A stream of chlorine was introduced through a sparge tube into the solution for a period of six hours. (Gas chromatography indicated 96.5% conversion.) The solution was then cooled and distilled under reduced pressure giving 325.4 grams of 2-chlorobenzoyl chloride which boiled at 135° to 140° C. at 16 millimeters of mercury. The yield of the desired product was 93% (98.5% pure).
Reaction SMILES: [CH3:1][P:2]1(=[O:7])[CH2:6][CH2:5][CH:4]=[CH:3]1.O=O.[CH3:10][O:11][P:12]([CH3:14])[OH:13]>>[CH3:10][O:11][P:12]([CH:3]1[CH2:4][CH2:5][CH2:6][P:2]1([CH3:1])=[O:7])([CH3:14])=[O:13]
Reactant: COP(C)O
Reactant: CP1(=O)C=CCC1
Agent: O=O
Product: COP(C)(=O)C1CCCP1(C)=O
Reaction time: 1.5 h
Yield: 277.5 %

Procedure:
6 g of t-butyl peroctoate in 30 g of methane phosphonous acid methyl ester and 116 g of 1-methyl-1-oxophospholine are added dropwise to 282 g of oxygen-free methane phosphonous acid methyl ester at 120° C with stirring. The reaction time is 90 minutes. Excess methane phosphonous acid methyl ester and a small quantity of 1-methyl-oxophospholine are distilled off. The residue, consisting of 205 g of 1-methyl-1-oxophospholanylmethyl phosphinic acid methyl ester, is purified by distillation under vacuum (bp 1mm :210° to 220° C) to yield 186 g of pure product which solidifies very slowly to stellate crystals which begin to reliquefy at 70° C. Acid saponification leads to isomeric 1-methyl-1-oxophospholanyl-methyl phosphinic acids of the idealized constitution: ##STR16##
Reaction SMILES: C([O:4][CH2:5]/[CH:6]=[C:7](\[F:16])/[S:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:9])(=O)C.[OH-].[Na+]>CO.O>[F:16]/[C:7](/[S:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:9])=[CH:6]\[CH2:5][OH:4]
Reactant: CCCCCCS(=O)/C(F)=C/COC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCCS(=O)/C(F)=C/CO
Reaction time: 0.5 h

Procedure:
To a solution of (E)-3-fluoro-3-hexylsulfinyl-2propenyl acetate (3.0 g, 12.0 mmol) in 20 ml of methanol under N2 is added aqueous sodium hydroxide (3.0 g, 37.5 mmol). After 30 min. at RT, the solution is diluted with water and extracted with ether. The aqueous phase is diluted with saturated brine and extracted again with ether. The combined ether extracts are dried over Na2SO4 and stripped to give (E)-3-fluoro-3-hexylsulfinyl-2-propenol (cpd. 2, Table A).