Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:16][NH2:17])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[O:18]1[CH2:23][CH2:22][CH:21]([C:24](O)=[O:25])[CH2:20][CH2:19]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>O.CN(C)C=O>[Cl:1][C:2]1[C:3]([NH:16][NH:17][C:24]([CH:21]2[CH2:22][CH2:23][O:18][CH2:19][CH2:20]2)=[O:25])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2
Reactant: COC(=O)c1ccc2nc(NN)c(Cl)nc2c1
Reactant: O=C(O)C1CCOCC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)c1ccc2nc(NNC(=O)C3CCOCC3)c(Cl)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
To a mixture of 100 mg of methyl 3-chloro-2-hydrazinoquinoxaline-6-carboxylate, 57 mg of tetrahydro-2H-pyran-4-carboxylic acid, 0.16 mL of diisopropylethylamine, and 1.0 mL of N,N-dimethylformamide was added 203 mg of bromo(tripyrrolidin-1-yl)phosphonium hexafluorophosphate, followed by stirring at room temperature overnight. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol) to obtain 144 mg of methyl 3-chloro-2-[2-(tetrahydro-2H-pyran-4-ylcarbonyl)hydrazino]quinoxaline-6-carboxylate.
Reaction SMILES: [Cl-].[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][CH:4]=1.C([Li])CCC.CCCCCC.O=[C:41]1[CH2:46][CH2:45][CH2:44][N:43]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:42]1>O1CCCC1>[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]=[C:45]2[CH2:46][CH2:41][CH2:42][N:43]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:44]2)=[CH:7][CH:8]=1
Reactant: Fc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCCC(=Cc2ccc(F)cc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.4 %

Procedure:
To a stirred solution of (4-fluorophenylmethyl)triphenylphosphonium chloride (17.68 g, 43.5 mmol) in dry tetrahydrofuran (60 mL) at −78° C. was added 2.5 M n-butyllithium in hexane (14.6 mL, 36.5 mmol). The reaction was warmed to 0° C. for 1 hr. After tis time, t-butyl 3-oxo-1-piperidinecarboxylate (3.46 g, 17.4 mmol) in tetrahydrofuran (60 mL) was added. The mixture was stirred at room temperature for 1 hr and then heated to reflux for 16 hr. The reaction was cooled to room temperature and quenched by the addition of saturated aqueous ammonium chloride. The reaction was extracted with ethyl acetate three times (100 mL). The organic layers were combined, washed with brine, dried over magnesium sulfate, and evaporated in vacuo to a pale yellow oil. The oil was purified by flash chromatography (silica gel, hexane:ethyl acetate 9:1) to yield 3.82 g of a mixture of E and Z isomers as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.22-7.14 (m, 2H), 7.04-6.98 (m, 2H), 6.36 (s, 0.33H), 6.28 (s, 0.67H), 4.14 (s, 1.34H), 4.00 (s, 0.66H) 3.50 (t, J=5, 2H), 2.47 (t, J=5, 0.66H), 2.39 (t, J=5, 1.34H), 1.75-1.68 (m, 1.34H), 1.65-1.57 (m, 0.66H), 1.48 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][C:4](=[O:13])[CH:3]=1.[NH:14]1[CH:18]=[CH:17][N:16]=[C:15]1[CH:19]=O.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH2:30][CH2:31][NH:32][C:33](=[O:35])[CH3:34])=[CH:22]1>>[OH:1][C:2]1[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][C:4](=[O:13])[C:3]=1[CH:19]([C:15]1[NH:14][CH:18]=[CH:17][N:16]=1)[C:22]1[NH:21][C:29]2[C:24]([C:23]=1[CH2:30][CH2:31][NH:32][C:33](=[O:35])[CH3:34])=[CH:25][CH:26]=[CH:27][CH:28]=2
Reactant: O=Cc1ncc[nH]1
Reactant: CC(=O)NCCc1c[nH]c2ccccc12
Reactant: O=C1C=C(O)C(c2ccccc2)C1
Product: CC(=O)NCCc1c(C(C2=C(O)C(c3ccccc3)CC2=O)c2ncc[nH]2)[nH]c2ccccc12

Procedure:
Using general procedure C, 3-hydroxy-4-phenyl-cyclopent-2-enone (Lit. 17) was reacted with 1H-imidazole-2-carbaldehyde and N-[2-(1H-indol-3-yl)-ethyl]-acetamide to give the title compound as pale brown solid. MS: 455.0 ([M+H]+).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1(=[O:12])[O:11][C:9](=[O:10])[CH2:8][C:6]1=[CH2:7].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1.Cl>O.ClC1C=CC=CC=1Cl>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:9](=[O:10])[CH2:8][C:6](=[CH2:7])[C:5]([OH:11])=[O:12])=[CH:22][CH:21]=2)=[CH:18][CH:19]=1
Reactant: C=C1CC(=O)OC1=O
Reactant: Clc1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Solvent: O
Product: C=C(CC(=O)c1ccc(-c2ccc(Cl)cc2)cc1)C(=O)O
Temperature: 20 °C
Yield: 70 %

Procedure:
212 g (1.59 mol) of anhydrous aluminum chloride are introduced into 1800 g of o-dichlorobenzene and the mixture is brought to 45° C. with stirring. A solid mixture of 78.5 g (0.7 mol) of itaconic anhydride and 132 g (0.7 mol) of 4-chlorobiphenyl is added in the course of one hour. The reaction mixture is stirred at 45° C. for two hours and then added to an ice-cold mixture of 900 g of water and 100 g of hydrochloric acid (37%). The aqueous phase is separated off. The organic phase is washed three times with a mixture of 1000 g of water and 25 g of hydrochloric acid (37%) in each case. After washing three times, it is allowed to cool to approximately 20° C. and the colorless product is then filtered off with suction. This is then washed twice with 150 g of ethanol/water 90:10 in each case. The product is dried at 80° C. and about 110 mbar until free of solvent and water. 148 g (0.49 mol) of 4-(4′-chlorobiphenyl-4-yl)-4-keto-2-methylenebutyric acid (70%) are obtained as a colorless, finely crystalline powder. By working up the mother liquor, as described in Example 1, the yield is increased to 87%. (HPLC purity 99.3-99.5%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([OH:8])[CH:7]=1.[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1C=O.[C:17]([O-])(=O)C.[Na+].[BH4-].[Na+]>CO>[CH3:9][C:5]1[CH:4]=[CH:3][C:2]([N:1]([C:11]2[S:10][CH:14]=[CH:13][CH:12]=2)[CH3:17])=[CH:7][C:6]=1[OH:8]
Reactant: CC(=O)[O-]
Reactant: O=Cc1cccs1
Reactant: Cc1ccc(N)cc1O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(N(C)c2cccs2)cc1O
Reaction time: 0.25 h
Yield: 32.5 %

Procedure:
To a solution of 5-amino-2-methylphenol (12.30 g, 100 mmole) in methanol (100 mL) at 4° C. was added 2-thiophenecarboxaldehyde (16.82 g, 150 mmole) and sodium acetate (16.41 g, 200 mmole). The reaction mixture was stirred for 15 minutes and sodium borohydride (4.73 g, 125 mmole) was added portionwise over 1 hour at 4° C. After the addition was complete, the reaction was allowed to stir for an additional 1.5 hours. The reaction mixture was poured onto crushed ice slurry (200 g) and the resulting precipitate was collected, washed with cold water three times and air-dried to afford 2-methyl-5-(thiophen-2-yl-methylamino)phenol (7.12 g, 32% yield): mp 130.8-132.6° C.; 1HNMR (400 MHz, DMSO-d6) δ 1.94 (s, 3H), 4.34 (d, 2H, J=6.0 Hz), 5.91 (t, 1H, J=6.1 Hz), 6.00 (dd, 1H, J=2.3, 8.0 Hz), 6.11 (d, 1H, J=2.2 Hz), 6.70 (d, 1H, J=8.1 Hz), 6.95 (dd, 1H, J=3.5, 5.0 Hz), 7.00 (dd, 1H, J=0.8, 3.4 Hz), 7.34 (dd, 1H, J=1.0, 5.0 Hz), 8.79 (s, 1H); MS m/z 219 (M+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([CH2:10][NH:11][CH3:12])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl.[O:14]=[C:15]1[NH:24][C:23]2[N:22]=[CH:21][C:20](/[CH:25]=[CH:26]/[C:27]([OH:29])=O)=[CH:19][C:18]=2[CH2:17][CH2:16]1>>[NH:1]1[C:9]2[C:4](=[C:5]([CH2:10][N:11]([CH3:12])[C:27](=[O:29])[CH:26]=[CH:25][C:20]3[CH:21]=[N:22][C:23]4[NH:24][C:15](=[O:14])[CH2:16][CH2:17][C:18]=4[CH:19]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CNCc1cccc2[nH]ccc12
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: Cl
Product: CN(Cc1cccc2[nH]ccc12)C(=O)C=Cc1cnc2c(c1)CCC(=O)N2
Yield: 73.7 %

Procedure:
According to the procedure of Example 35g, (1H-indol-4-ylmethyl)-methyl-amine (223 mg, 1.39 mmol) and (E)-3-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3yl)acrylic acid hydrochloride (359 mg, 1.41 mmol), were coupled to give crude product. Purification by column chromatography gave the title compound (369 mg, 73%) as a pink solid and a mixture of amide rotomers: 1H NMR (400 MHz, DMSO-d6) δ 11.20-11.14 (m, 1H), 10.65-10.62 (m, 1H), 8.38-8.32 (m, 1H), 8.08-7.99 (m, 1H), 7.59-7.53 (m, 1H), 7.37-7.21 (m, 3H), 7.09-7.03 (m, 1H), 6.89-6.76 (m, 1H), 6.51 (s, 1H), 5.06-4.88 (m, 2H), 3.04-2.83 (m, 5H), 2.56-2.52 (m, 2H); ESI MS m/z 361 [C21H20N4O2+H]+.
Reaction SMILES: [H-].[Na+].[C:3]1(=[O:9])[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.S(C1C=CC(C)=CC=1)(O[CH2:14][C@@H:15]1[CH2:29][C@H:28]2[C@@H:18]([CH2:19][C:20]3[C:30]4[C:23](=[CH:24][CH:25]=[CH:26][C:27]2=4)[NH:22][CH:21]=3)[N:17]([CH3:31])[CH2:16]1)(=O)=O.C>C(O)C.CN(C)C=O>[CH3:31][N:17]1[C@H:18]2[C@@H:28]([C:27]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:30]=3[C:20]([CH2:19]2)=[CH:21][NH:22]4)[CH2:29][C@@H:15]([CH2:14][N:7]2[C:6](=[O:8])[CH2:5][CH2:4][C:3]2=[O:9])[CH2:16]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H]3c4cccc5[nH]cc(c45)C[C@H]3N(C)C2)cc1
Reactant: O=C1CCC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CN1C[C@H](CN2C(=O)CCC2=O)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Reaction time: 0.5 h
Yield: 54.8 %

Procedure:
0.8 g of 50% sodium hydride in an oil was added in small portions to a mixture of 3.4 g of succinimide and 50 ml of dimethylformamide, and the resulting mixture was stirred for 30 minutes. 2.0 g of 6-methylergolin-8β-ylmethyl tosylate was added to the mixture which was then heated on a water bath for 30 minutes. The solvent was distilled off under reduced pressure, and water was added to the residue. The precipitated crystals were separated by filtration, and washed with water. The crystals thus obtained were treated with charcoal in ethanol and recrystallized from ethanol to obtain 0.9 g of the titled compound as colorless needles having a melting point of 233°-238° C. (with decomposition).
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:13]2[CH2:12][CH:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH3:20])[CH2:10][C:9](=O)[C:8]=2[C:7]([CH3:22])=[CH:6]1)(=[O:4])=[O:3].[C:23]([NH:26][NH2:27])([NH2:25])=[NH:24].[ClH:28].Cl.O>C(O)C>[ClH:28].[NH:26]([N:27]=[C:9]1[CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH2:12][C:13]2[N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=[C:7]([CH3:22])[C:8]1=2)[C:23]([NH2:25])=[NH:24]
Reactant: Cc1ccccc1C1CC(=O)c2c(C)cn(S(C)(=O)=O)c2C1
Reactant: N=C(N)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccccc1C1CC(=NNC(=N)N)c2c(C)cn(S(C)(=O)=O)c2C1
Yield: 61.9 %

Procedure:
A mixture of 1-methanesulfonyl-3-methyl-6-(2-methylphenyl)-4,5,6,7-tetrahydroindol-4-one (0.20 g), aminoguanidine hydrochloride (0.073 g), concentrated hydrochloric acid (0.032 ml), water (0.032 ml) and ethanol (20 ml) was refluxed for 30 minutes. Under reduced pressure, the solvent was evaporated, and to the residue was added sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate, and the organic layer was purified with silica gel column chromatography (EtOAc/MeOH). To the resulting crystals was added 1N hydrochloric acid, and the mixture was concentrated. The residue was recrystallized from ethanol-ethyl acetate to give 4-guanidinoimino-1-methanesulfonyl-3-methyl-6-(2-methylphenyl)-4,5,6,7-tetrahydroindole hydrochloride (Compound 15) (0.16 g) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2=[O:12].[CH2:13]=[O:14].N1CCC[C@H]1[C:17]([OH:19])=O.[OH-].[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][C:6]([CH2:17][OH:19])([CH2:13][OH:14])[C:5]2=[O:12]
Reactant: C=O
Reactant: O=C1CCOc2ccc(Br)cc21
Reactant: O=C(O)[C@@H]1CCCN1
Agent: [Na+]
Agent: [OH-]
Product: O=C1c2cc(Br)ccc2OCC1(CO)CO
Temperature: 25 °C
Reaction time: 16 h
Yield: 216.9 %

Procedure:
A mixture of 6-bromo-2,3-dihydro-4H-chromen-4-one (0.3 g, 1.3 mmol), paraformaldehyde (0.48 g), L-proline (61 mg, 0.53 mmol), and 0.2 M aqueous sodium hydroxide (6 mL) was stirred at room temperature for 16 hours. The mixture was extracted with CHCl3 and concentrated in vacuo. The residue was purified with silica-gel column chromatography (CHCl3/MeOH=100:0 to 90:10) to give 6-bromo-3,3-bis(hydroxymethyl)-2,3-dihydro-4H-chromen-4-one (0.33 g).
Reaction SMILES: C([NH:8][C@H:9]([C:11](N)=O)[CH3:10])(OC(C)(C)C)=O.F[B-](F)(F)F.C([O+](CC)CC)C.[F:26][C:27]1[CH:28]=[C:29]([NH:34][C:35]2[CH:36]=[N:37][CH:38]=[C:39]([F:41])[CH:40]=2)[C:30]([NH2:33])=[CH:31][CH:32]=1>C(Cl)Cl.CCO>[F:26][C:27]1[CH:32]=[CH:31][C:30]2[N:33]=[C:10]([C@@H:9]([NH2:8])[CH3:11])[N:34]([C:35]3[CH:36]=[N:37][CH:38]=[C:39]([F:41])[CH:40]=3)[C:29]=2[CH:28]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(N)=O
Reactant: Nc1ccc(F)cc1Nc1cncc(F)c1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: ClCCl
Product: C[C@H](N)c1nc2ccc(F)cc2n1-c1cncc(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.2 %

Procedure:
To a suspension of (S)-Boc-alaninamide (337 mg, 1.79 mmol) in DCM (5 mL) was added triethyloxonium tetrafluoroborate (340 mg, 1.79 mmol) in one portion under a nitrogen atmosphere. The resulting mixture was left to stir at RT for 1 h. The volatiles were removed under reduced pressure and to the resulting residue was added 4-fluoro-N2-(5-fluoropyridin-3-yl)-benzene-1,2-diamine (198 mg, 0.895 mmol) in absolute EtOH (5 mL) and the mixture stirred at 80° C. for 18 h. The volatiles were removed in vacuo and the resulting residue partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic fraction was dried, concentrated in vacuo and the resulting residue taken up in DCM (2 mL) and TFA (1 mL) added. After stirring at RT for 1 h, the reaction mixture was diluted with MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-20% MeOH in DCM) to afford the title compound as a colourless oil (52 mg, 21% over 2 steps). LCMS (Method C): RT 1.76 min [M+H]+ 275.20
Reaction SMILES: [N:1]#[C:2][NH2:3].[Na].Cl[C:6]1[C:11]([O:12][CH3:13])=[CH:10][N:9]=[C:8]([O:14][CH3:15])[N:7]=1.C(O)(=O)C.[Cl-].[Na+]>CN1CCCC1=O>[CH3:15][O:14][C:8]1[N:7]=[C:6]([NH:3][C:2]#[N:1])[C:11]([O:12][CH3:13])=[CH:10][N:9]=1
Reactant: COc1ncc(OC)c(Cl)n1
Reactant: N#CN
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Product: COc1ncc(OC)c(NC#N)n1
Temperature: 25 °C
Reaction time: 0.27 h
Yield: 98.8 %

Procedure:
To a 100 mL three-neck round bottom flask were added sequentially 7.8 g (121.53 mmol)) of sodium hydrogen cyanamide and then 34.2 g of N-methyl-2-pyrrolidinone (NMP) in one portion, and the slurry mixture was cooled in an ambient temperature water bath. To this mixture was added 10.0 g (54.99 mmol) of 96% 4-chloro-2,5-dimethoxypyrimidine (1; CDMP) in one portion. The mixture was allowed to stir at ambient temperature (<20° C.). After 48 hours (h), 3.78 g (62.95 mmol) of glacial acetic acid was added in one portion and the internal pot temperature rose from 19° C. to 23° C. This reaction slurry was poured over 85 g of crushed ice and the ice was allowed to melt. To this mixture was added 10 g of sodium chloride. The mixture was allowed to stand for 16 minutes (min). Once melted, the cold slurry was suction filtered and the filter cake was washed with two 20-mL portions of water and a final 10 mL water wash. The wet cake transferred to a drying dish and allowed to air dry for 48 h to give 6.78 g (98.8% pure by NMR assay using benzyl acetate) of 2,5-dimethoxy-4-cyanoaminopyrimidine (2) as a light yellow solid in 68% yield. 1H and 13C NMR spectra were identical to that reported in Example 1.
Reaction SMILES: [I:1][C:2]1[CH:13]=[C:6]2[C:7](OC(=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8].S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH2:25]([O:32][C:33](=[O:37])[CH2:34][CH2:35][NH2:36])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CN(C1C=CC=CN=1)C>N1C=CC=CC=1>[CH2:25]([O:32][C:33](=[O:37])[CH2:34][CH2:35][NH:36][C:7](=[O:8])[C:6]1[CH:13]=[C:2]([I:1])[CH:3]=[CH:4][C:5]=1[NH2:11])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=c1[nH]c2ccc(I)cc2c(=O)o1
Reactant: NCCC(=O)OCc1ccccc1
Agent: CN(C)c1ccccn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Product: Nc1ccc(I)cc1C(=O)NCCC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 25.2 %

Procedure:
A magnetically stirred solution of 5 grams of 5-iodoisatoic anhydride (0.0173 mol), 5.85 grams of β-alanine benzyl ester tosylate (0.0173 mol), 35 mL pyridine, and 0.5 of dimethylaminopyridine (0.0041 mol) was heated to 80° C. for 2 hrs. The reaction mixture was allowed to cool to room temperature and concentrated in vacuo. The resulting residue was dissolved in 100mL ethyl acetate and washed 2×50 mL of 10% cupric sulfate, 1×50 mL sat. sodium bicarbonate, 1×50 mL brine, dried over sodium sulfate, filtered and concentrated in vacuo. The product was further purified by column chromatography, using silica gel, eluting with a 1:1 mixture of ethyl acetate and hexane (TLC, SIO2, 1:1 EtOAc/hexane, Rf =0.65, υν positive) to yield 1.85 grams (25%) of N-(2-amino-5-iodobenzoyl)-β-alanine benzyl ester. 1H NMR (CDCl3, δTMS) 7.54 (1H, d, 4JHH =2 Hz, Ar--H o--CON), 7.42 (1H, dd, 3JHH =9 Hz, 4JHH =2 Hz, Ar--H p--CON), 7.38-7.32 (5H, s, ArH Ph), 6.65 (1H, bt, 3JHH =6 Hz, CONH), 6.46 (1H, d, 3JHH =9 Hz, Ar--H m--CON), 5.16 (2H, s, OCH2), 3.68 (2H, q, 3JHH =6 Hz, NCH2), 2.69 (2H, t, 3JHH =6 Hz, CH2CO2). 13C NMR (CDCl3,δTMS) 172.4, 167.8, 148.2, 140.6, 135.6, 135.5, 128.7, 128.4, 128.3, 119.3, 118.1, 76.3, 66.7, 35.2, 34.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:16])=[C:13]([CH3:27])[N:12]=[C:11](SC)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:31]1C=CC=C(C(OO)=O)C=1.[S:41](=[O:44])(O)[O-:42].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:16])=[C:13]([CH3:27])[N:12]=[C:11]([S:41]([CH3:31])(=[O:44])=[O:42])[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CSc1nc(C)c(C(=O)NCCCc2ccccc2)c(-c2ccc(Cl)c(Cl)c2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nc(S(C)(=O)=O)nc(-c2ccc(Cl)c(Cl)c2)c1C(=O)NCCCc1ccccc1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
214 mg (0.479 mmol) of 4-(3,4-dichlorophenyl)-6-methyl-2-(methylthio)-N-(3-phenylpropyl)-5-pyrimidinecarboxamide synthesized in Example 7 was dissolved in 10 ml of dichloromethane. 165 mg (0.958 mmol) of mCPBA (m-chloroperbenzoic acid) was added thereto at 0° C. and stirred at the same temperature for 6 hours. 5 ml of saturated aqueous sodium bisulfite solution was added thereto at the same temperature and stirred for 30 minutes heating to room temperature. After the reaction mixture was diluted with dichloromethane, the organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=5/1) to obtain the title compound.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:10][OH:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C>C(Cl)Cl>[Si:1]([O:8][C@@H:9]([CH2:12][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)[CH:10]=[O:11])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H](CO)CC1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@H](C=O)CC1CCCCC1
Reaction time: 0.33 h

Procedure:
(9.32 mmol) of (S)-2-t-butyldimethylsilyloxy-3-cyclohexylpropyl alcohol [prepared as described in step (iii) above] in 12 ml of methylene chloride was added dropwise over a period of 5 minutes. The resulting mixture was then stirred for 20 minutes at the same temperature, after which 6.5 ml (46.6 mmol) of triethylamine were added. The mixture was then allowed to stand for 7 minutes, and the cooling bath was removed. After a further 10 minutes, the reaction was stopped by adding an aqueous solution of ammonium chloride. The reaction mixture was then extracted with diethyl ether. The extract was washed twice with water and once with a saturated aqueous solution of sodium chloride. The organic phase was dried over anhydrous magnesium sulfate, and the solvent was then removed by distillation under reduced pressure, to give 2.55 g (a quantitative yield) of the title aldehyde compound as a colorless oil.
Reaction SMILES: [Cu]C#N.[Cl-].[Li+].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([Mg]Cl)[CH:11]=[C:12]([O:14][CH3:15])[CH:13]=1.[CH2:18](Br)[CH:19]=[CH2:20]>C1COCC1>[CH2:20]([C:10]1[CH:9]=[C:8]([O:7][CH3:6])[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=1)[CH:19]=[CH2:18]
Reactant: C=CCBr
Reactant: COc1cc(OC)cc([Mg]Cl)c1
Agent: N#C[Cu]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCc1cc(OC)cc(OC)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of 1.49 g (16.5 mmol) of copper (I) cyanide and 1.39 g (33 mmol) of lithium chloride in 40 mL of THF was added dropwise 15 mL of a 1 M solution of 3,5-dimethoxyphenylmagnesium chloride in THF at −78° C. After stirring for 5 min, 2.5 mL (3.6 g, 30 mmol) of allyl bromide was added dropwise, and the resulting solution was stirred for 16 h while slowly warming to room temperature. The reaction mixture was quenched by slowly adding saturated NH4Cl(aq) and stirring for 5 min. The layers were separated and the aqueous phase was extracted three times with 50-mL portions ethyl acetate. The combined organic fractions were dried (Na2SO4), filtered through a pad of silica gel (eluted with ethyl acetate) and concentrated in vacuo. The residue was chromatographed over silica gel (eluted with 50:1 hexanes-ethyl acetate) to afford 2.59 g of a pale-yellow oil as a 6:1 mixture of 2:3. The mixture was suitable for further reactions without additional purification: 1H NMR (400 MHz, CDCl3) δ 6.36 (d, J=2.4 Hz, 2H), 6.32 (t, J=2.4 Hz, 1H), 6.81-5.87 (m, 1 H), 5.10 (dd, J=16.8, 1.6 Hz, 1 H), 5.07 (dd, J=9.6, 1.6 Hz, 1H), 3.78 (s, 6H), 3.33 (d, J=6.8 Hz, 2H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][C:23]=2[F:30])[C@@H:13]2[CH2:19][CH2:18][CH2:17][CH2:16][NH:15][C:14]2=[O:20])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH2:31]([OH:33])[CH3:32]>>[ClH:2].[CH2:31]([O:33][C:28](=[NH:29])[C:25]1[CH:26]=[CH:27][C:22]([CH2:21][N:12]([S:9]([C:6]2[CH:7]=[CH:8][C:3]([Cl:2])=[CH:4][CH:5]=2)(=[O:10])=[O:11])[C@@H:13]2[CH2:19][CH2:18][CH2:17][CH2:16][NH:15][C:14]2=[O:20])=[C:23]([F:30])[CH:24]=1)[CH3:32]
Reactant: N#Cc1ccc(CN([C@@H]2CCCCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)c(F)c1
Reactant: CCO
Agent: Cl
Product: CCOC(=N)c1ccc(CN([C@@H]2CCCCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)c(F)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Dry HCl gas was slowly bubbled through a solution of 4-chloro-N-(4-cyano-2-fluoro-benzyl)-N-((R)-2-oxo-azepan-3-yl)-benzenesulfonamide (0.09 g, 0.20 mmol) in dry ethanol (3 ml) for 30 min at 0° C. The reaction mixture wa allowed to stir for a further 20 h at r.t. and then concentrated under reduced pressure. Trituration of the residue in diethyl ether yielded the HCl salt: 0.09 g; MS: m/e=482.2 (MH+).