Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[CH:10][C:3]=12.Cl.[N+:12]([C:15]1[CH:16]=[C:17]([C:21]2[N:22]=[C:23]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[NH:24][CH:25]=2)[CH:18]=[CH:19][CH:20]=1)([O-:14])=[O:13].C(O)(C)C.C(N(C(C)C)CC)(C)C>>[N+:12]([C:15]1[CH:16]=[C:17]([C:21]2[N:22]=[C:23]([CH:26]3[CH2:31][CH2:30][N:29]([C:2]4[N:7]=[CH:6][N:5]=[C:4]5[NH:8][N:9]=[CH:10][C:3]=45)[CH2:28][CH2:27]3)[NH:24][CH:25]=2)[CH:18]=[CH:19][CH:20]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cccc(-c2c[nH]c(C3CCNCC3)n2)c1
Reactant: Clc1ncnc2[nH]ncc12
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cccc(-c2c[nH]c(C3CCN(c4ncnc5[nH]ncc45)CC3)n2)c1
Temperature: 70 °C

Procedure:
Place 4-Chloro-1H-pyrazolo[3,4-d]pyrimidine (150 mg; 1.16 equiv; 970.50 μmoles; 150.00 mg), and 4-[4-(3-Nitro-phenyl)-1H-imidazol-2-yl]-piperidine hydrochloride salt (258 mg 1.00 equiv; 835.58 μmoles; 258.00 mg) in a microwave vial and dissolve in isopropyl alcohol (3 mL; 39.24 mmoles; 3.00 mL) and add diisopropylethylamine (0.5 mL; 2.87 mmoles; 500.00 μL). Heat the mixture to 70° C. in a Emrys Optimizer microwave for 1 hour while stirring. Filter, and concentrate filtrate to an oil. Combine solid and oil and dissolve in 3% MeOH/DCM. Purify using ISCO chromatography over a biotage 40S column eluting with a gradient of 2.5% MeOH/DCM to 10% MeOH/DCM at a flow rate of 40 mL/min. Collect appropriate fractions, concentrate to an oil. Dissolve oil in 10% MeOH/DCM and wash with a mixture of aqueous sodium bicarbonate/saturated aqueous sodium chloride three times. Wash the combined organic layers with saturated aqueous sodium chloride and dry over sodium sulfate. Concentrate and dry under reduced pressure to obtain the title compound.
Reaction SMILES: [N+:1]([CH2:4][C:5]([CH3:9])=[CH:6][CH2:7][OH:8])([O-:3])=[O:2].[C:10](Cl)(=[O:26])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C1C=CC=CC=1>[CH3:9][C:5]([CH2:4][N+:1]([O-:3])=[O:2])=[CH:6][CH2:7][OH:8].[C:10]([O-:26])(=[O:2])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Agent: CC(=CCO)C[N+](=O)[O-]
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCC(=O)[O-]
Reaction time: 8 h

Procedure:
To 0.1 Mol of 4-nitro-3-methyl-2-butenol in benzene was added 0.1 Mol of palmitoylchloride and stirred overnight. The benzene was evaporated and the residue was taken up in sat. sodiumbicarbonate solution and extracted with ether. The product was crystallized from a 95% ethanol-water solution. Off white crystals, m.p. 30.5°-31.5° C., were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:16](=O)[CH:17]([CH3:19])[CH3:18]>CS(O)(=O)=O.C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]2[CH2:16][C:17]([CH3:19])([CH3:18])[O:15][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(OCc2ccccc2)c1
Reactant: CC(C)C=O
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: CC1(C)Cc2ccc(OCc3ccccc3)cc2O1
Yield: 59.8 %

Procedure:
3-Benzyloxyphenol (5.0 g), 2.0 g of isobutyraldehyde, 0.1 g of methanesulfonic acid and 50 ml of toluene were put into a flask equipped with the Dean-Stark condenser, and stirred under reflux for 4 hours. Low-boiling compounds were evaporated under reduced pressure. The residue was purified by column chromatography to give 3.8 g of 6-benzyloxy-2,3-dihydro-2,2-dimethylbenzofuran as a brown liquid. This product was dissolved in ethanol, and 0.4 g of 5% palladium-carbon was added. The mixture was stirred at room temperature for 8 hours in an atmosphere of hydrogen. The catalyst was separated by filtration, and the filtrate was concentrated. The residue was purified by column chromatography to give 2.0 g (yield 50%) of the desired product as a pale yellow liquid.
Reaction SMILES: [O:1]=[C:2]([N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)[C@@H:3]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[N:14](C(OC(C)(C)C)=O)[CH:15]=[C:16]([C:17]([O:19]C)=[O:18])[C:9]=12)[CH2:4][CH3:5].CO.[OH-].[Na+]>C1COCC1>[O:1]=[C:2]([N:28]1[CH2:29][CH2:30][CH2:31][CH2:32]1)[C@@H:3]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[NH:14][CH:15]=[C:16]([C:17]([OH:19])=[O:18])[C:9]=12)[CH2:4][CH3:5]
Reactant: CC[C@H](NCc1ccnc2c1c(C(=O)OC)cn2C(=O)OC(C)(C)C)C(=O)N1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC[C@H](NCc1ccnc2[nH]cc(C(=O)O)c12)C(=O)N1CCCC1
Temperature: 53 °C
Reaction time: 16 h
Yield: 9.2 %

Procedure:
To a 20 mL round bottom flask with a stirrer was added (S)-1-tert-butyl 3-methyl 4-((1-oxo-1-(pyrrolidin-1-yl)butan-2-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate (88 mg, 0.198 mmol), MeOH (1 mL) and THF (1 mL). Aqueous NaOH (12N, 1 mL) was added and the reaction mixture was stirred at 53° C. for 16 h. The solvent was removed and the resulting residue was further purified via preparative mass trigger LC-MS (AcCN/H2O, 1-50%). The fractions were collected, concentrated, and dried in vacuo to afford the title compound as a yellow oil (6 mg, 9.17%). [M+H] calc'd for C17H22N4O3, 331; found, 331.6.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16]>>[C:1]1([C:7]2[O:16][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#Cc1ccccc1
Reactant: Oc1ccccc1I
Product: c1ccc(-c2cc3ccccc3o2)cc1

Procedure:
The general procedure was used to convert phenylacetylene and 2-iodophenol to the title product. Purification by flash chromatography (hexanes as the eluent) gave the analytically pure product as a white solid (358 mg, 93% yield). 1H NMR (300 MHz, CDCl3) δ 7.86-7.83 (dd, J=6.97, 2H) 7.56-7.49 (m, 2H), 7.41-7.39 (m, 2H), 7.34-7.18 (m, 3H), 6.97 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 155.88, 154.86, 130.44, 129.20, 128.75, 128.51, 124.89, 124.24, 122.91, 120.89, 111.16, 101.28. Anal. Calcd. for C14H10O: C, 86.57; H, 5.19. Found C, 86.41; H, 5.34. m.p.: 120° C. (lit., 3118-120° C.).
Reaction SMILES: [C:1]([C:3]1[CH:14]=[CH:13][C:6]2[CH:7]=[C:8]([C:10]([OH:12])=O)[O:9][C:5]=2[CH:4]=1)#[N:2].Cl.[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([S:27]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:29])=[O:28])[CH:21]=[CH:20]2>>[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([S:27]([N:30]1[CH2:31][CH2:32][N:33]([C:10]([C:8]3[O:9][C:5]4[CH:4]=[C:3]([C:1]#[N:2])[CH:14]=[CH:13][C:6]=4[CH:7]=3)=[O:12])[CH2:34][CH2:35]1)(=[O:28])=[O:29])[CH:21]=[CH:20]2
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Reactant: N#Cc1ccc2cc(C(=O)O)oc2c1
Agent: Cl
Product: N#Cc1ccc2cc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)oc2c1

Procedure:
In a similar manner to Referential Example 12 except for the use of 6-cyanobenzofuran-2-carboxylic acid and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride as the raw materials, the reaction was conducted, whereby the title compound was obtained.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[N:6]2[N:5]=1)=O.[CH3:23][N:24]1[C:28]2[CH:29]=[C:30]([NH2:33])[CH:31]=[CH:32][C:27]=2[N:26]=[CH:25]1>>[CH3:22][S:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:6]3[C:7]([CH:8]=[N:9][C:4]([NH:33][C:30]4[CH:31]=[CH:32][C:27]5[N:26]=[CH:25][N:24]([CH3:23])[C:28]=5[CH:29]=4)=[N:5]3)=[CH:10][CH:11]=2)=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: Cn1cnc2ccc(N)cc21
Reactant: CS(=O)c1ncc2ccc(-c3ccc(S(C)(=O)=O)cc3)n2n1
Product: Cn1cnc2ccc(Nc3ncc4ccc(-c5ccc(S(C)(=O)=O)cc5)n4n3)cc21

Procedure:
Following the synthetic and purification procedures described in Example 1293d, 2-methanesulfinyl-7-(4-methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (75 mg, 0.22 mmol) was coupled with 3-methyl-3H-benzimidazol-5-ylamine (57 mg, 0.38 mmol) at 105° C. for 86 h to afford the title compound. Yield of TFA salt: 12 mg (10%) of brown powder. LC/MS: 419 (M+H); HPLC: 95% pure, RT=2.21 min; mp: lyophilyte; 1H NMR: (DMSO, δ) 10.11 (s, 1H), 9.33 (s, 1H), 9.14 (s, 1H), 8.43 (d, J=8.6, 2H), 8.40 (s, 1H), 8.11 (d, J=8.6, 2H), 7.81 (d, J=9.0, 1H), 7.70 (d, J=9.0, 1H), 7.34 (d, J=4.9, 1H), 7.08 (d, J=4.9, 1H), 3.85 (s, 3H), 3.30 (s, 3H).
Reaction SMILES: CO[CH:3](OC)[C:4]1[CH:5]=[C:6](C=[CH:18][C:19]=1[CH:20]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[F:31])[CH2:21][N+:22]([O-])=O)[O:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.BrC1C(C(OC)OC)=CC(OCCCN2CCCCC2)=[N:39]C=1.[Li]CCCC.FC1C=CC=CC=1C=C[N+]([O-])=O>C1COCC1.C(O)(=O)C>[F:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH:20]1[C:19]2[C:4](=[CH:5][C:6]([O:7][CH2:8][CH2:9][CH2:10][N:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)=[N:39][CH:18]=2)[CH2:3][NH:22][CH2:21]1
Reactant: COC(OC)c1cc(OCCCN2CCCCC2)ccc1C(C[N+](=O)[O-])c1ccccc1F
Reactant: COC(OC)c1cc(OCCCN2CCCCC2)ncc1Br
Agent: O=[N+]([O-])C=Cc1ccccc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Fc1ccccc1C1CNCc2cc(OCCCN3CCCCC3)ncc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 64 %

Procedure:
1-(3-{3-Dimethoxymethyl-4-[1-(2-fluoro-phenyl)-2-nitro-ethyl]-phenoxy}-propyl)-piperidine. A −78° C. solution of 5-bromo-4-dimethoxymethyl-2-(3-piperidin-1-yl-propoxy)-pyridine (359 mg, 0.962 mmol) in THF (8 mL) was treated with n-BuLi (2.5 M in hexanes; 0.4 mL). After 20 min at −78° C., the mixture was treated with a solution of 1-fluoro-2-(2-nitro-vinyl)-benzene (171 mg, 1.02 mmol) in THF (5 mL). After 20 min at −78° C., the mixture was treated with acetic acid (1 mL) and was allowed to warm to 0° C. The mixture was concentrated and the residue was chromatographed (SiO2; 1-10% 2 M NH3 in MeOH/DCM) to give the title compound (285 mg, 64%) as an oil. MS (ESI): mass calcd. for C24H32FN3O5, 461.23; m/z found, 462.5 [M+H]+. 1H NMR (CDCl3): 8.03 (s, 1H), 7.30-7.24 (m, 2H), 7.15-7.03 (m, 2H), 6.95 (s, 1H), 5.55 (t, 8.2, 1H), 5.43 (s, 1H), 5.02-4.92 (m, 2H), 4.34-4.27 (m 2H), 3.35 (s, 3H), 3.27 (s, 3H), 2.55-2.42 (m, 6H), 2.05-1.95 (m, 2H), 1.69-1.60 (m, 4H), 1.49-1.42 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9]([NH2:11])=[O:10])=[CH:4][CH:3]=1.[O:15]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.ClCCl>CCOCC.F[B-](F)(F)F.[Ag+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9](=[NH:11])[O:10][CH2:25][C:24]2[CH:27]=[CH:28][CH:29]=[C:22]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:23]=2)=[CH:6][CH:7]=1
Reactant: BrCc1cccc(Oc2ccccc2)c1
Reactant: CC(C)C(C(N)=O)c1ccc(Cl)cc1
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)C(C(=N)OCc1cccc(Oc2ccccc2)c1)c1ccc(Cl)cc1

Procedure:
To a refluxing solution of 2.72 g (12.9 mmol) of 2-(4-chlorophenyl)-3-methylbutyramide and 2.27 g (8.6 mmol) of 3-phenoxybenzyl bromide in a solution of 15 ml dichloromethane and 3 ml ethyl ether is added a solution of 1.83 g (9.5 mmol) of silver tetrafluoroborate in ether. The mixture is refluxed for 2 hours and then separated by pouring into ice cold aqueous ethyl acetate/sodium bicarbonate. The organic phase is washed with water, dried and stripped of solvent. The residue is triturated with ether and filtered. The filtrate is concentrated and chromatographed on silica gel, eluting with 25% ethyl acetate/hexane, and then on plates using 35% ethyl acetate/hexane, to yield 3-phenoxybenzyl 2-(4-chlorophenyl)-3-methylbutanimidate, MS m/e 393 (M+).
Reaction SMILES: C([O-])(=O)C.[Na+].CCO[C:9]([CH:11]1[C:15](=O)[CH2:14][CH2:13][CH2:12]1)=[O:10].Cl.[C:18]([NH2:26])(=[NH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C(C)=CC=CC=1>[C:19]1([C:18]2[NH:26][C:9](=[O:10])[C:11]3[CH2:12][CH2:13][CH2:14][C:15]=3[N:25]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)C1CCCC1=O
Reactant: N=C(N)c1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: O=c1[nH]c(-c2ccccc2)nc2c1CCC2
Reaction time: 0.5 h
Yield: 36.4 %

Procedure:
A mixture of 15.6 g (190 mmol) of sodium acetate, 25 mL (172.7 mmol) of ethyl cyclopentanone-2-carboxylate, 27.7 g (177 mmol) of benzamidine hydrochloride and 250 mL of xylene was refluxed with a Dean Stark trap for 8 hours. Most of the xylene was distilled off and the hot reaction mixture was poured onto crushed ice. The reaction mixture was left to stand at room temperature for 0.5 hour, then vacuum filtered to remove the product, as a gray solid. The solid was air dried overnight to yield 13.35 g (37.0%) of 2-phenyl-3,5,6,7-tetrahydro-4H-cyclopentapyrimidin-4-one. 1H-NMR (CDCl3)δ2.11 (2H,m), 2.90 (4H,m), 7.5 (3H,m), 8.18 (2H,m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]=[C:5]2[C:18]([NH:20][C:21](=S)[NH:22][NH:23][C:24]([C:26]1[S:27][CH:28]=[CH:29][CH:30]=1)=[O:25])=[O:19].C1(C2C=C(C(NC(=S)NNC(C3SC=CC=3)=O)=O)C3C(=CC=C(OC(F)(F)F)C=3)N=2)C=CC=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]=[C:5]2[C:18]([NH:20][C:21]1[O:25][C:24]([C:26]2[S:27][CH:28]=[CH:29][CH:30]=2)=[N:23][N:22]=1)=[O:19]
Reactant: O=C(NNC(=S)NC(=O)c1cc(-c2ccccc2)nc2ccc(Cl)cc12)c1cccs1
Agent: O=C(NNC(=S)NC(=O)c1cc(-c2ccccc2)nc2ccc(OC(F)(F)F)cc12)c1cccs1
Product: O=C(Nc1nnc(-c2cccs2)o1)c1cc(-c2ccccc2)nc2ccc(Cl)cc12

Procedure:
The title compound was synthesized according to the synthesis method of a compound Ia-122 described later using 4-(6-chloro-2-phenyl-4-quinolinecarbonyl)-1-(2-thiophenecarbonyl)thiosemicarbazide described in Reference Example 37 instead of 4-(2-phenyl-6-trifluoromethoxy-4-quinolinecarbonyl)-1-(2-thiophenecarbonyl)thiosemicarbazide.
Reaction SMILES: [CH3:1][S:2]([CH3:4])=O.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[NH2:20][C:21]1[C:26]([Cl:27])=[N:25][CH:24]=[CH:23][N:22]=1>C(Cl)Cl>[CH3:1][S:2]([CH3:4])=[N:20][C:21]1[C:26]([Cl:27])=[N:25][CH:24]=[CH:23][N:22]=1
Reactant: CS(C)=O
Reactant: Nc1nccnc1Cl
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CS(C)=Nc1nccnc1Cl
Reaction time: 1 h
Yield: 78.4 %

Procedure:
To a mechanically stirred solution of 3.9 g (0.05 mol) dimethyl sulfoxide in 30 ml dry methylene chloride at -78° under nitrogen is added 13.1 g (0.046 mol) trifluoromethanesulfonic anhydride dropwise to afford a white precipitate. To this is added a solution of 5.0 g (0.039 mol) 2-amino-3-chloropyrazine (1) in 30 ml methylene chloride/15 ml dimethyl sulfoxide and the resulting solution is stirred at -78° for 2 hours and at -55° for 1 hour. The reaction mixture is then quenched with 50 ml of 5% aqueous sodium bicarbonate solution and stirred at -5° for 5 minutes. The reaction mixture is diluted with 200 ml methylene chloride and the phases are separated. The aqueous phase is extracted with 250 ml methylene chloride and the combined organic phases are washed with 3×75 ml portions of water and dried over anhydrous sodium sulfate. The solvent is removed from the rotary evaporator to give 5.8 g (79%) of 2 as yellow crystals, m.p. 106°-108°.
Reaction SMILES: [CH:1]1[S:2][CH:3]=[C:4]2[C:10]=1[C:9](=[O:11])[NH:8][C:7]1[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=1[O:5]2.S(Cl)([Cl:19])(=O)=O>C(Cl)Cl>[Cl:19][C:3]1[S:2][CH:1]=[C:10]2[C:9](=[O:11])[NH:8][C:7]3[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=3[O:5][C:4]=12
Reactant: O=S(=O)(Cl)Cl
Reactant: O=C1Nc2ccccc2Oc2cscc21
Solvent: ClCCl
Product: O=C1Nc2ccccc2Oc2c1csc2Cl
Reaction time: 8 h

Procedure:
An 8.0 g. portion of thieno[3,4-b][1,5]benzoxazepin-10(9H)-one is suspended in 364 ml. of methylene chloride. A 3.27 ml. portion of sulfuryl chloride is added dropwise and the mixture is stirred overnight. The solid is collected and washed with methylene chloride, giving 3-chloro-thieno[3,4-b][1,5]benzoxazepin-10(9H)-one.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:11]1([CH:17]2[CH2:21][NH:20][C:19](=[O:22])[CH2:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Br[CH2:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=1[C:35]1[CH:40]=[C:39]([CH:41]([CH3:43])[CH3:42])[CH:38]=[CH:37][C:36]=1[O:44][CH3:45]>C1COCC1>[CH:41]([C:39]1[CH:38]=[CH:37][C:36]([O:44][CH3:45])=[C:35]([C:26]2[CH:27]=[CH:28][C:29]([C:31]([F:34])([F:32])[F:33])=[CH:30][C:25]=2[CH2:24][N:20]2[CH2:21][CH:17]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:18][C:19]2=[O:22])[CH:40]=1)([CH3:43])[CH3:42]
Reactant: O=C1CC(c2ccccc2)CN1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1CC(c2ccccc2)CC1=O
Reaction time: 0.08 h

Procedure:
Sodium bis(trimethylsilyl)amide (114 μL of a 1M solution in THF, 0.114 mmol) was added to a stirred solution of 4-phenylpyrrolidin-2-one (Winans, C. F., Adkins, H., J. Am. Chem. Soc., 1933, 55, 4167-4176) (17 mg, 0.103 mmol) in dry THF (1 mL) at room temperature under N2. The reaction was stirred for 5 min and a solution of 2-(bromomethyl)-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl (20 mg, 0.0516 mmol) in dry THF (2 mL) was added by cannula. The reaction was stirred at room temperature for 3 days. The reaction was quenched with saturated NH4Cl (10 mL) and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine (10 mL), dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 12×160 mm, 0-90% EtOAc in hexanes gradient) to afford 1-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-phenylpyrrolidin-2-one as a colorless oil. Rf=0.11 (20% EtOAc/hexanes). LCMS calc.=468.22; found=468.2 (M+1)+. 1H NMR (600 MHz, benzene-d6, 1:1 mixture of atropisomers) δ 7.79 (s, 0.5H), 7.73 (s, 0.5H), 7.33 (d, J=7.7 Hz, 1H), 7.08-7.04 (m, 4H), 6.99 (m, 1H), 6.92 (s, 0.5H), 6.88 (s, 0.5H), 6.76 (dd, J=16.0, 7.4 Hz, 2H), 6.60 (dd, J=8.5, 3.1 Hz, 1H), 4.58 (d, J=15.4 Hz, 1H), 4.38 (t, J=13.9 Hz, 1H), 3.29 (s, 1.5H), 3.26 (s, 1.5H), 2.85-2.73 (m, 3H), 2.63-2.57 (m, 1H), 2.38-2.28 (m, 1H), 2.21-2.11 (m, 1H), 1.20-1.16 (m, 6H).
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].[CH2:6]([O:8][C:9](=[O:38])[C@H:10]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[NH:11][C:12]([C:14]1([NH:19][C:20](=[O:29])[C@H:21](Br)[CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[CH3:7]>O1CCCC1.C(OCC)(=O)C>[CH2:6]([O:8][C:9](=[O:38])[C@H:10]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[NH:11][C:12]([C:14]1([NH:19][C:20](=[O:29])[C@@H:21]([S:3][C:1](=[O:4])[CH3:2])[CH:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[CH3:7]
Reactant: CCOC(=O)[C@H](CCc1ccccc1)NC(=O)C1(NC(=O)[C@H](Br)C2CCOCC2)CCCC1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](CCc1ccccc1)NC(=O)C1(NC(=O)[C@@H](SC(C)=O)C2CCOCC2)CCCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of potassium thioacetate (1.66 g, 14.6 mmol) and N-[1-[(R)-2-bromo-2-(4-tetrahydropyranyl)acetylamino]-cyclopentanecarbonyl]-L-homophenylalanine ethyl ester (1.84 g, 3.52 mmol) in 50 mL of tetrahydrofuran is stirred at room temperature for 4 hours. The mixture is diluted with ethyl acetate, washed with water, with saturated sodium bicarbonate solution, with brine and then dried over magnesium sulfate. The mixture is filtered and concentrated to dryness in vacuo. The residual oil is chromatographed on silica gel with hexane:ethyl acetate (50:50) to yield the title compound, m.p. 107–111° C.; [αD]−56.27° (c=0.994, methanol).
Reaction SMILES: [C:1]([NH2:4])(=[NH:3])[CH3:2].[N+:5]([C:8]1[CH:19]=[CH:18][C:11]([CH:12]=[CH:13][S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1)([O-:7])=[O:6]>>[N+:5]([C:8]1[CH:9]=[CH:10][C:11]([CH:12]=[CH:13][S:14]([NH:3][C:1](=[NH:4])[CH3:2])(=[O:16])=[O:15])=[CH:18][CH:19]=1)([O-:7])=[O:6]
Reactant: O=[N+]([O-])c1ccc(C=CS(=O)(=O)Cl)cc1
Reactant: CC(=N)N
Product: CC(=N)NS(=O)(=O)C=Cc1ccc([N+](=O)[O-])cc1

Procedure:
Reaction of acetamidine with 4-nitrostyrylsulfonyl chloride according to the above procedure provides N-(4-NITROSTYRYLSULFONYL)ACETAMIDINE, m.p. 203.0°-203.5° C. (dec.)(corr.), crystallized from acetonitrile.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][CH:9]([CH2:12]O)[CH2:10]O.Cl.[NH2:15][C:16]1[NH:20][N:19]=[CH:18][C:17]=1[C:21]([OH:23])=[O:22]>ClCCl.C(N(CC)CC)C.CS(C)=O>[CH3:7][O:8][C:9]1[CH:10]=[N:15][C:16]2[N:20]([N:19]=[CH:18][C:17]=2[C:21]([OH:23])=[O:22])[CH:12]=1
Reactant: Nc1[nH]ncc1C(=O)O
Reactant: COC(CO)CO
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1cnc2c(C(=O)O)cnn2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 17.9 %

Procedure:
To a solution of oxalyl chloride (6.9 mL) in dichloromethane (65 mL), cooled at −78° C., was added, dropwise, a solution of dimethyl sulfoxide (13 mL) in dichloromethane (16 mL) and the resulting mixture was stirred for 10 minutes. A solution of 2-O-methyl-glycerol (3.3 g, 31.5 mmol) in dichloromethane (16 mL) was then added dropwise and the reaction mixture was stirred for 15 minutes. Triethylamine (52 mL) was then added dropwise and the resulting mixture was stirred for 1 hour. The reaction mixture was warmed up to room temperature and an aqueous solution of hydrochloric acid (6 M, 35 mL) was added followed by 5-amino-1H-pyrazole-4-carboxylic acid (4 g, 31.5 mmol) and the resulting mixture was heated to 95° C. over 20 minutes, the temperature was maintained at 95° C. for 20 minutes. The resulting mixture was cooled to room temperature and stored at room temperature for 24 hours and at 4° C. for 62 hours. The solid formed was collected by filtration and dried in a vacuum oven to afford 1.087 g (18% yield) of 6-methoxy-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid.
Reaction SMILES: [Br:1][CH2:2]/[C:3](=[CH:7]/[C:8]([OH:10])=[O:9])/[C:4]([OH:6])=O.[OH-].[Na+].C(O)CCC>O>[Br:1][CH2:2][C:3]1[C:4]([O:10][C:8](=[O:9])[CH:7]=1)=[O:6]
Reactant: O=C(O)/C=C(/CBr)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Solvent: O
Product: O=C1C=C(CBr)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(Bromomethyl)-maleic anhydride (2) is prepared from compound 1 according to the method of Laursen et al. (1971) J. Med. Chem. 14:619-621 with the modification by Greenlee and Woodward (1980) Tetrahedron 36:3367-3375. This material (2 g) is hydrolyzed in water (20 mL) for about 1 hour at room temperature to 2-(bromomethyl)-maleic acid (3) and the solution is neutralized with 1 N NaOH (21.2 mL), degassed and kept under N2. The solution is added to a previously prepared solution of 4-aminothiophenol (1.51 g) that has been dissolved in degassed 1 N NaOH (11.6 mL) with gentle heating under N2 and filtered to remove the insoluble dimer. The filtrate is diluted with degassed water (12 mL) before being added to the above solution of compound 3. The final reaction solution is brought to about pH 11.0 with 1N NaOH and stirred under N2 at room temperature overnight. The solution is then filtered to remove small amounts of bis-(4-aminophenyl)-disulfide, cooled on ice, and acidified with 1N HCl, which gives a yellow precipitate. n-Butanol is added (40 mL) and the mixture is vigorously stirred on ice for 5 minutes. This removes the fumaric acid analog of compound 4. The solid is then collected by filtration, washed successively with 0.1 N HCl and water, and finally dried in a vacuum desiccator over P2O5, to yield the neutral compound 4.