Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:17][OH:18])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[H-].[Na+].[C:21]1([CH2:27]Br)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[O:1]1[C:5]2([CH2:6][CH2:7][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:17][O:18][CH2:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:9][CH2:10]2)[O:4][CH2:3][CH2:2]1
Reactant: BrCc1ccccc1
Reactant: OCc1ccccc1C1CCC2(CC1)OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: c1ccc(COCc2ccccc2C2CCC3(CC2)OCCO3)cc1

Procedure:
When the bridging group is carbonyl, the Grignard reagent of 8-bromo-1,4-dioxaspiro[4.5]decane is first prepared. The precursor 8-bromo-1,4-dioxaspiro[4.5]decane is prepared by the method of E. I. Snyder (JOC, 36, 403 (1971)). The Grignard reagent is in turn reacted with an appropriately substituted or unsubstituted benzaldehyde, for example, 3-trifluoromethylbenzaldehyde and then treated with aqueous ammonium chloride, yielding [(1,4-dioxaspiro[4.5]decan-8-yl)(phenyl)]methanol. The so-prepared alcohol is treated with sodium hydride in toluene, and then is reacted with phenylmethyl bromide, yielding phenylmethyl [(1,4-dioxaspiro[4.5]decan-8-yl)(phenyl)]methyl ether. The 1,4-dioxaspiro functional group is then cleaved from the so-prepared molecule with acetic acid and water, as previously described, affording the corresponding phenylmethyl [(cyclohexanon-4-yl)(phenyl)]methyl ether. The ether is then reacted with cyanoguanidine, as previously described, yielding the appropriate 2,4-diamino-6-[(phenylmethoxy)(phenyl)methyl]-5,6,7,8-tetrahydroquinazoline. The tetrahydroquinazoline is then cleaved with hydrogen gas in the presence of 5% palladium on charcoal, yielding the corresponding [(2,4-diamino-5,6,7,8-tetrahydroquinazolin-6-yl)(phenyl)]methanol. Using the method of D. Swern (Tetrahedron, 34, 1651-1660 (1978)), the methanol is oxidized with oxalyl chloride and dimethyl sulfoxide in methylene chloride, yielding the targeted 2,4-diamino-6-phenylcarbonyl-5,6,7,8-tetrahydroquinazoline. Example 9 provides a detailed description of how this reaction is conducted.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:21](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[C:4]([O:3][C:1]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=1)[C:18]([O:20][CH3:21])=[O:19])=[O:2])([CH3:5])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(Cl)cc1)C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COC(=O)[C@H](Cc1ccc(Cl)cc1)NC(=O)OC(C)(C)C
Reaction time: 36 h
Yield: 93.4 %

Procedure:
To a 250 mL round bottom flask was added N-Boc-4-chloro-L-phenylalanine (0.971 g, 3.24 mmol), potassium carbonate (0.448 g, 3.24 mmol), a stir bar and 30 ml of acetone. To this was added dimethyl sulfate (0.613 ml, 6.48 mmol) and the reaction was allowed to proceed at ambient temperature for 36 h. The reaction was quenched with water (15 ml), and the product was extracted with ethyl acetate (4×100 ml). The organics were pooled, washed with brine, and dried over sodium sulfate. The organics were filtered and concentrated in vacuo to provide a pale yellow residue. The residue was purified by column chromatography on a Biotage SP1, 40M Biotage silica cartridge, eluting with a linear gradient of hexanes-ethyl acetate to provide the title compound as a pale yellow foam (950 mg). Mass spectrum (ESI) 214.1 (M-Boc). 1H NMR (600 MHz, CDCl3): δ 7.24 (d, J=8.3 Hz, 2H), 7.06 (d, J=8.1 Hz, 1H), 4.96 (d, J=7 Hz, 1H), 4.56 (d, J=6 Hz, 1H), 3.71 (s, 3H), 3.08 (dd, J=5.7, 5.7 Hz, 2H), 3.01 (dd, J=5.9, 6.0 Hz, 1H), 1.42 (s, 9H).
Reaction SMILES: [CH:1]1([NH:5][C:6]2[N:7]=[N:8][C:9]([C:12]#[CH:13])=[CH:10][CH:11]=2)[CH2:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[NH:25][C:24]3[CH:26]=[C:27]([CH2:30][N:31]4[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]4)[CH:28]=[CH:29][C:23]=3[N:22]=2)=[CH:17][C:16]=1I>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[NH:25][C:24]3[CH:26]=[C:27]([CH2:30][N:31]4[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]4)[CH:28]=[CH:29][C:23]=3[N:22]=2)=[CH:17][C:16]=1[C:13]#[C:12][C:9]1[N:8]=[N:7][C:6]([NH:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)=[CH:11][CH:10]=1
Reactant: C#Cc1ccc(NC2CCC2)nn1
Reactant: CN1CCN(Cc2ccc3nc(-c4ccc(Cl)c(I)c4)[nH]c3c2)CC1
Product: CN1CCN(Cc2ccc3nc(-c4ccc(Cl)c(C#Cc5ccc(NC6CCC6)nn5)c4)[nH]c3c2)CC1

Procedure:
The title compound was synthesized from N-cyclobutyl-6-ethynylpyridazin-3-amine and 2-(4-chloro-3-iodophenyl)-6-((4-methylpiperazin-1-yl)methyl)-1H-benzo[d]imidazole in a manner similar to that described for in Example 1. The title compound was obtained as a pale yellow solid. Mp:161-163° C.; 1H NMR (300 MHz, CDCl3) δ: 8.13-8.15 (1 H, d, J=6.0 Hz), 7.95 (1 H, s), 7.62-7.65 (1 H, d, J=9.0 Hz), 7.65 (1 H, s), 7.36-7.39 (1 H, d, J=9.0 Hz), 7.29-7.32 (1 H, d, J=9.0 Hz), 7.18-7.21 (1 H, d, J=9.0 Hz), 6.63-6.66 (1 H, d, J=9.0 Hz), 5.80 (1 H, s), 4.28-4.30 (1 H, m), 3.63 (2 H, s), 2.63 (8 H, brs), 2.40-2.44 (2 H, m) 2.40 (3 H, s), 1.96-2.02 (2 H, m), 1.79-1.81 (2 H, m). HRMS (ESI-TOF+): m/z [M+H]+ calcd for C29H31ClN7: 512.2324. found: 512.2303.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[S:8])[NH:6][CH:7]=1.C(N(CC)CC)C.[CH2:16]([CH:18]1[O:20][CH2:19]1)[Cl:17]>ClCCl>[OH:20][CH:18]([CH2:16][Cl:17])[CH2:19][S:8][C:5]1[N:6]=[CH:7][C:2]([Cl:1])=[CH:3][N:4]=1
Reactant: ClCC1CO1
Reactant: S=c1ncc(Cl)c[nH]1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: OC(CCl)CSc1ncc(Cl)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 30 %

Procedure:
A mixture of 5-chloropyrimidine-2-thione (14 mmol) and triethylamine (14 mmol) was stirred together in dichloromethane (30 ml) for 5 min before epichlorohydrin (15 mmol) was added. The mixture was stirred at room temperature for 3 h, the solvent evaporated, the residue triturated with water, the insoluble material extracted with chloroform, the dried (MgSO4) chloroform solution evaporated and the residue crystallized from chloroform:pet. ether; yield 30%, m.p. 99° C. 1H NMR (acetone-d6): δ3.3-3.8 (2CH2, m) 3.9-4.4 (CH, m), 4.6-4.7 (OH), 8.59 (H-4, H-6).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][CH:3]=1.Cl[CH2:14][CH:15]1[CH2:17][O:16]1.[OH-].[K+]>O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:14][CH:15]2[CH2:17][O:16]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)c2ccccc12
Reactant: ClCC1CO1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Clc1ccc(OCC2CO2)c2ccccc12

Procedure:
To a stirred mixture of 44.5 parts of 4-chloro-1-naphthalenol and 115 parts of 2-(chloromethyl)oxirane are added portionwise 17.1 parts of potassium hydroxide (exothermic reaction). When the exothermic reaction is ceased, the whole is heated to reflux and stirred at reflux temperature for 2 hours. Water is added and the whole is extracted twice with trichloromethane. The combined extracts are washed three times with water, dried and evaporated. The residue is distilled, yielding 45.3 parts of 2-[(4-chloro-1-naphthalenyloxy)methyl]oxirane; bp. 150°-151° C. at 0.2 mm. pressure.
Reaction SMILES: CI.[CH3:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:7]=1[OH:13])=O.[C:14](=O)([O-])[O-].[K+].[K+].NN.[OH-].[K+]>CC(C)=O>[Br:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:4][CH3:3])=[C:7]([O:13][CH3:14])[CH:8]=1
Reactant: CC(=O)c1ccc(Br)cc1O
Reactant: O=C([O-])[O-]
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CI
Product: CCc1ccc(Br)cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 1.4 %

Procedure:
Methyl iodide (3 mL, 47.3 mmol) was added to a solution of 4-bromo-2-hydroxyacetophenone (9.25 g, 43 mmol) and potassium carbonate (6.54 g, 47.3 mmol) in acetone (20 mL) and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo to low volume and diluted with water. The aqueous mixture was extracted with dichloromethane (3×50 mL) and the combined organic solution was washed with water, dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in 1,2-ethanediol (10 mL), hydrazine (19.47 mL, 400 mmol) and potassium hydroxide (7.86 g, 140 mmol) were added and the reaction mixture was heated at 150° C. for 60 hours. The reaction mixture was then quenched with 1M hydrochloric acid and extracted with ethyl acetate (3×20 mL). The combined organic solution was dried over sodium sulfate, concentrated in vacuo and the residue was purified by Kugel Rohr fractional distillation (150° C./0.05 mbar) to provide the title compound as a yellow oil (128 mg).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[N:2]1.O[N:14]=[C:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1.N>>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:12][N:22]=[C:15]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[N:14]=3)=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(O)c1ccc2snnc2c1
Agent: N
Product: c1cncc(-c2noc(-c3ccc4snnc4c3)n2)c1

Procedure:
The title compound was prepared according to Method C using benzo[d][1,2,3]thiadiazole-5-carboxylic acid (Maybridge) and N′-hydroxynicotinimidamide (Tyger). 1H NMR (300 MHz, DMSO-d6) δ 7.69 (ddd, J=8.0, 4.9, 0.7 Hz, 1 H), 8.51 (dt, J=8.2, 1.9, 1.7 Hz, 1 H), 8.57 (dd, J=8.5, 1.7 Hz, 1 H), 8.73 (d, J=7.8 Hz, 1 H), 8.85 (dd, J=4.9, 1.5 Hz, 1 H), 9.32 (dd, J=2.4, 1.0 Hz, 1 H), 9.51 (dd, J=1.7, 0.7 Hz, 1 H) ppm; MS (DCI/NH3) m/z 282 (M+H)+.
Reaction SMILES: [P:1]([O:13][CH2:14][C:15]([CH3:27])([CH3:26])[CH2:16][CH2:17][O:18][Si](C(C)(C)C)(C)C)([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(OCC)(=O)C>[P:1]([O:13][CH2:14][C:15]([CH3:27])([CH3:26])[CH2:16][CH2:17][OH:18])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:2]
Reactant: CC(C)(CCO[Si](C)(C)C(C)(C)C)COP(=O)(OC(C)(C)C)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(CCO)COP(=O)(OC(C)(C)C)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.8 %

Procedure:
To a solution of the product from Example 10B (0.435 g, 1.03 mmol) in THF (3.8 mL) was added a solution of tetrabutylammonium fluoride in THF (1 M, 1.2 mL), and the reaction was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with water and brine, dried over MgSO4, filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with 33% ethyl acetate in hexane, to give the title compound (0.239 g, 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH2:30][CH3:31])([C:27](O)=[O:28])[CH2:25][CH3:26])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1.[NH:42]1[CH2:46][CH2:45][CH2:44][CH2:43]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH2:25][CH3:26])([C:27]([N:42]4[CH2:46][CH2:45][CH2:44][CH2:43]4)=[O:28])[CH2:30][CH3:31])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1
Reactant: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)O
Reactant: C1CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)N1CCCC1
Reaction time: 5 h
Yield: 54.7 %

Procedure:
At room temperature, a mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-ethyl-1-hydroxycarbonyl-propoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (50 mg, 0.084 mmol), pyrrolidine (12 mg, 0.17 mmol), HATU (63.5 mg, 0.17 mmol) and DMAP (40.8 mg, 0.33 mmol) in DMF (2 mL) was stirred for 5 h. Then the mixture was poured into water and extracted with EtOAc thrice. The combined organic layers were washed with saturated NaCl solution twice, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column to give the title compound as a white solid (30 mg).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:9]=[C:8]([S:10](=[O:13])(=[O:12])[NH2:11])[C:7]([Cl:14])=[CH:6][C:4]=1[NH2:5].[C:15](O)(=O)[CH3:16]>>[ClH:14].[Cl:14][C:7]1[C:8]([S:10](=[O:13])(=[O:12])[NH2:11])=[CH:9][C:3]2[NH:2][C:15]([CH3:16])=[N:5][C:4]=2[CH:6]=1
Reactant: Nc1cc(Cl)c(S(N)(=O)=O)cc1N
Reactant: CC(=O)O
Agent: Cl
Product: Cc1nc2cc(Cl)c(S(N)(=O)=O)cc2[nH]1

Procedure:
To 10 ml of 4 N hydrochloric acid containing 0.86 ml of acetic acid was added 2.22 g. of 2-amino-4-chloro-5-sulfamylaniline (VI) and the mixture refluxed for four hours. Concentration in vacuo gave a blue solid which was collected by filtration, dissolved in methanol, treated with charcoal and filtered. The blue solution was concentrated in vacuo and triturated with ether to yield a blue solid. Washing with methanol provided the product as light blue crystals which upon drying gave 1.0 g. of 5(6)-chloro-2-methyl-6(5)-sulfamyl-1(3)H-benzimidazole hydrochloride, m.p. 313°-316° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=1)=[O:4].[N:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.CCOCC>C(#N)C>[N:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:24][CH2:25][N:26]([CH2:2][C:3]([C:5]3[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=3)=[O:4])[CH2:27][CH2:28]2)=[CH:19][CH:18]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: COC(=O)CCc1ccc(C(=O)CBr)cc1
Solvent: CC#N
Solvent: CCOCC
Product: COC(=O)CCc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1
Reaction time: 8 h

Procedure:
A solution of methyl 3-(4-bromoacetylphenyl)propionate (380 mg) in acetonitrile (4 ml) was added dropwise over 15 minutes to a stirred solution of 1-(4-pyridyl)piperazine (450 mg) in acetonitrile (10 ml) and the mixture stirred overnight. The mixture was then filtered and the filtrate concentrated in vacuo to give an oil. Purification by flash chromatography on silica eluting first with dichloromethane then 5% v/v methanol/dichloromethane gave a solid. Trituration with ether gave the title compound, 172 mg, as a solid: m.p. 141°-143° C.; NMR(d6DMSO) δ8.15(2H,d), 7.92(2H,d), 7.37(2H,d), 6.83(2H,d), 3.89(2H,s), 3.59(3H,s), 3.37(4H,t), 2.93(2H,t), 2.69(2H,t), 2.65(4H,t); m/e 368(M+H)+ ; calculated for C21H25N3O3. 0.25H2O: C, 67.8; H, 6.9; N, 11.3. found: C, 67.8; H, 6.9; N,11.1%.
Reaction SMILES: Cl[C:2]1(Cl)[CH:6]2[N:7]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:11])[CH2:8][CH2:9][CH:5]2[CH2:4][C:3]1=[O:20].[Cl-].[NH4+]>CO.[Zn]>[O:20]=[C:3]1[CH2:2][CH:6]2[N:7]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:11])[CH2:8][CH2:9][CH:5]2[CH2:4]1
Reactant: O=C(OCc1ccccc1)N1CCC2CC(=O)C(Cl)(Cl)C21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: O=C1CC2CCN(C(=O)OCc3ccccc3)C2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
Benzyl 6,6-dichloro-5-oxohexahydrocyclopenta[b]pyrrole-1(2H)-carboxylate (3.87 g, 11.8 mmol), prepared as described in Tetrahedron Lett. (1997), 38, 1869–1872, in MeOH (60 mL) at 0° C. was treated with solid ammonium chloride (6.32 g, 118 mmol) followed by zinc duct (Aldrich; 3.09 g, 47.2 mmol). After stirring at room temperature for 1 hour, the reaction mixture was filtered and the filtrate concentrated under reduced pressure. The residue was purified by chromatography (SiO2, 40% EtOAc/hexanes) to provide 2.57 g (84%) of the title compound. MS (DCI/NH3) m/z 260 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]#[C:18][CH3:19])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:2].Cl.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]([CH2:33][CH2:34]Cl)[CH2:30][CH2:31]Cl)[CH:23]=1>>[CH2:16]([O:15][C:12]1[CH:11]=[CH:10][C:9]([S:6]([C:5]2([C:4]([O:3][CH2:1][CH3:2])=[O:20])[CH2:34][CH2:33][N:29]([CH2:28][C:24]3[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=3)[CH2:30][CH2:31]2)(=[O:7])=[O:8])=[CH:14][CH:13]=1)[C:17]#[C:18][CH3:19]
Reactant: ClCCN(CCCl)Cc1cccnc1
Reactant: CC#CCOc1ccc(S(=O)(=O)CC(=O)OCC)cc1
Agent: Cl
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3cccnc3)CC2)cc1
Yield: 5 %

Procedure:
Ethyl 4-{[4-(2-butynyloxy)phenyl]sulfonyl}-1-(3-pyridinylmethyl)-4-piperidine carboxylate was prepared according to the general method as outlined in example 1 (step 6), starting from (4-but-2-ynyloxy-benzenesulfonyl)-acetic acid ethyl ester (4 g, 16.9 mmol) and 3-pyridyl methyl [bis(2-chloroethyl)]amine hydrochloride (4.18 g, 18.6 mmol); 370 mg brown oil. Yield 5%; MS: 457.4 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N+:9]([O-:11])=[O:10].C(O)C.[CH3:15][CH:16]([S-:18])[CH3:17].[Na+]>>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([S:18][CH:16]([CH3:17])[CH3:15])[C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1c(F)cccc1F
Reactant: CC(C)[S-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)Sc1cccc(F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1,3-Difluoro-2-nitro-benzene (5.00 g, 31.4 mmol) was stirred in Ethanol (25 mL, 430 mmol) and treated with sodium 2-propanethiolate (3.08 g, 31.4 mmol) in several portions over 5 min. The reaction mixture was stirred at rt for 30 mins, was concentrated under reduced pressure, diluted with water, and extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to afford a yellow oil.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:12][CH:11]2[C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[CH3:28])[CH2:17][CH2:16]2)=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[Na+].[CH2:31]([N:35]=[C:36]=[O:37])[CH2:32][CH2:33][CH3:34]>>[C:1]1([S:7]([N:10]2[CH2:12][CH:11]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[CH3:28])[CH2:17][CH2:16]3)=[O:14])[N:35]([CH2:31][CH2:32][CH2:33][CH3:34])[C:36]2=[O:37])(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CN3S(=O)(=O)c3ccccc3)CC2)c1
Reactant: CCCCN=C=O
Agent: [I-]
Agent: [Na+]
Product: CCCCN1C(=O)N(S(=O)(=O)c2ccccc2)CC1C(=O)N1CCN(c2cc(C)ccc2C)CC1

Procedure:
In analogy to example 2, (RS)-(1-benzenesulfonyl-aziridin-2-yl)-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-methanone (example 2, step 3) was reacted with sodium iodide and butyl isocyanate to give the title compound as a colorless solid. MS: 499.0 ([M+H]+)
Reaction SMILES: [CH:1]([C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:17]C)=[C:11]([C:14](=[O:16])[CH3:15])[CH:12]=2)[O:7][C:6]([CH3:20])([CH3:19])[CH:5]=1)([CH3:3])[CH3:2].B(Br)(Br)Br>ClCCl>[OH:17][C:10]1[CH:9]=[C:8]2[C:13]([C:4]([CH:1]([CH3:2])[CH3:3])=[CH:5][C:6]([CH3:20])([CH3:19])[O:7]2)=[CH:12][C:11]=1[C:14](=[O:16])[CH3:15]
Reactant: COc1cc2c(cc1C(C)=O)C(C(C)C)=CC(C)(C)O2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(=O)c1cc2c(cc1O)OC(C)(C)C=C2C(C)C

Procedure:
As described in General Procedure J, a solution of 1-(4-isopropyl-7-methoxy-2,2-dimethyl-2H-chromen-6-yl)-ethanone (Compound 54, 752 mg, 2.43 mmol) in dichloromethane was treated with boron tribromide (1M in dichloromethane, 3.64 mL, 3.64 mmol) to afford the title compound as a bright yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH3:46])([CH3:45])[CH2:9][CH:10]=[CH:11][C:12](=[O:44])[N:13]([CH:15]([C:27](=[O:43])[N:28]([CH:30]([C:39](=[O:42])[NH:40][CH3:41])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[F:38])[CH3:29])[CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=1)[CH3:14])(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+].C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl>[F:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[CH2:31][CH:30]([N:28]([CH3:29])[C:27]([CH:15]([N:13]([CH3:14])[C:12](=[O:44])[CH:11]=[CH:10][CH2:9][C:8]([NH2:7])([CH3:46])[CH3:45])[CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=1)=[O:43])[C:39](=[O:42])[NH:40][CH3:41]
Reactant: CNC(=O)C(Cc1ccccc1F)N(C)C(=O)C(Cc1ccc2ccccc2c1)N(C)C(=O)C=CCC(C)(C)NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)C(Cc1ccccc1F)N(C)C(=O)C(Cc1ccc2ccccc2c1)N(C)C(=O)C=CCC(C)(C)N
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 77.8 %

Procedure:
{4-[(1-{[2-(2-Fluorophenyl)-1-methylcarbamoylethyl]methylcarbamoyl}2-(2-naphthyl)ethyl)methylcarbamoyl]-1,1-dimethyl-but-3-enyl}carbamic acid tert-butyl ester (0.36 g; 0.557 mmol) was dissolved in methylene chloride (3 ml). Trifluoro acetic acid (3 ml) was added and the reaction mixture was stirred 5 min at room temperature. Methylene chloride (25 ml), sodium hydrogen carbonate/sodium carbonate (3 ml) and sodium hydrogen carbonate (s) was added until pH=8. The organic phase was dried (magnesium sulfate) and the solvent was removed in vacuo. The residue was lyophylised to afford 0.237 g of the title compound.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C@@H:6]1[CH2:10][C@H:9]([C:11]([CH3:13])=[CH2:12])[C@H:8]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH2:23][CH2:24][CH2:25][O:26][CH3:27])[CH:15]=2)[N:7]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:5]>C1(C)C=CC=CC=1.[Pd]>[CH3:1][CH2:2][O:3][C:4]([C@@H:6]1[CH2:10][C@@H:9]([CH:11]([CH3:13])[CH3:12])[C@H:8]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH2:23][CH2:24][CH2:25][O:26][CH3:27])[CH:15]=2)[N:7]1[C:28]([O:30][C:31]([CH3:34])([CH3:32])[CH3:33])=[O:29])=[O:5]
Reactant: C=C(C)[C@H]1C[C@@H](C(=O)OCC)N(C(=O)OC(C)(C)C)[C@H]1c1ccc(OC)c(OCCCOC)c1
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H]1C[C@@H](C(C)C)[C@H](c2ccc(OC)c(OCCCOC)c2)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (2S,4R,5R)-4-Isopropenyl-5-[4-methoxy-3-(3-methoxy-propoxy)-phenyl]-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester VIIa (0.3 g) in 10 mL of toluene is treated with 50 mg of 5% palladium on carbon. The suspension is stirred under an atmosphere of hydrogen for 2 hours at room temperature and filtered. The solvent is removed in vacuum to give the desired compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:11])[CH3:10].Cl.[C:13]([O:16][CH2:17][CH3:18])(=[O:15])[CH3:14]>O1CCCC1>[OH:11][C:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])([CH3:10])[CH2:14][C:13]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(C)=O
Reactant: COc1ccccc1C(C)=O
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)CC(C)(O)c1ccccc1OC
Reaction time: 4 h
Yield: 96 %

Procedure:
Under argon atmosphere, 20 mL (10.7 mmol, 2 equivalent) of the solution of ethyl bromozincacetate in tetrahydrofuran obtained in Example 43 was added dropwise to a solution of 0.74 mL (5.35 mmol) of o-methoxyacetophenone in 2.75 mL of THF at 7˜10° C. The mixture was stirred at to 4˜6° C. for 4 hours. 10 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 30 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 5 mL (×2) of 1N hydrochloric acid, 5 mL of water, 5 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 5 mL (×2) of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. Concentration under reduced pressure afforded 1.43 g of the desired product (NMR yield 96%; internal standard dioxane).