Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[OH:13])[CH:10]=2)[N:5]=[C:4]([O:20][CH3:21])[C:3]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1.CCN(CC)CC.[C:40](OC(=O)C)(=[O:42])[CH3:41]>C(Cl)Cl>[C:40]([N:17]1[CH2:18][CH2:19][CH:14]([CH:12]([C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[N:5]=[C:4]([O:20][CH3:21])[C:3]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:32])[F:31])=[CH:27][CH:28]=2)=[C:2]3[Cl:1])[OH:13])[CH2:15][CH2:16]1)(=[O:42])[CH3:41]
Reactant: CC(=O)OC(C)=O
Reactant: COc1nc2ccc(C(O)C3CCNCC3)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1nc2ccc(C(O)C3CCN(C(C)=O)CC3)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(piperidin-4-yl)methanol (74 mg, 0.16 mmol, Intermediate 11: step b) in DCM (3 mL) was added Et3N (24 L, 0.18 mmol) and the resulting solution cooled to 0° C. Then acetic anhydride (16 μL, 0.17 mmol) was added dropwise and the reaction stirred at 0° C. for 30 minutes. The mixture was diluted with DCM and washed with saturated aqueous NaHCO3. The organic layer was dried (MgSO4), filtered, concentrated to dryness and purified by reverse-phase HPLC (acetonitrile/water+ TFA). The acidic fractions were neutralized by diluting with EtOAc and washing with saturated aqueous NaHCO3. The organics were concentrated to dryness, dissolved in 1/1 acetonitrile/water and lyophilized to provide the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.02-7.99 (m, 1H), 7.84-7.80 (m, 1H), 7.72-7.68 (m, 1H), 7.64 (d, J=8.0 Hz, 2H), 7.43 (d, J=7.9 Hz, 2H), 5.49 (s, 1H), 4.57-4.50 (m, 1H), 4.43-4.30 (m, 3H), 4.01 (s, 3H), 3.83-3.71 (m, 1H), 2.94-2.84 (m, 1H), 2.40-2.33 (m, 1H), 1.94 (d, J=8.2 Hz, 3H), 1.84-1.72 (m, 2H), 1.32-1.19 (m, 2H), 1.16-1.03 (m, 1H). MS (ESI): mass calcd. for C26H26ClF3N2O3, 506.2; m/z found, 507.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:12]=[O:13].[CH3:14]C1(C=O)C2C(=CC=CC=2)NC1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:14])[CH:7]=[C:6]2[CH:12]=[O:13]
Reactant: CC1(C=O)CNc2ccccc21
Reactant: COc1ccc2[nH]cc(C=O)c2c1
Product: COc1ccc2c(c1)c(C=O)cn2C
Yield: 92 %

Procedure:
According to the procedure of Preparation 13 (a), except substituting 5-methoxy-1H-indole-3-carboxaldehyde for the 3-methyl-1H-indole-3-carboxaldehyde, the title compound (0.86 g, 92%) was obtained as a light tan solid: MS (ES) m/e 190.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2](=[CH2:5])[CH2:3][OH:4].[H-].[Na+].[F:8][C:9]([F:20])([F:19])[O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Br)=[CH:13][CH:12]=1>CN(C=O)C>[CH3:5][C:2](=[CH2:1])[CH2:3][O:4][CH2:15][C:14]1[CH:17]=[CH:18][C:11]([O:10][C:9]([F:8])([F:19])[F:20])=[CH:12][CH:13]=1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: C=C(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(C)COCc1ccc(OC(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
A solution of 2-methyl-2-propen-1-ol (120) (2.34 mL, 27.8 mmol) in anhydrous DMF (10 mL, then 2×2 mL to rinse) was added to a suspension of 60% NaH (1.32 g, 33.1 mmol) in anhydrous DMF (10 mL) under N2 at 0° C. and the mixture was stirred at 0° C. for 30 min. 4-(Trifluoromethoxy)benzyl bromide (5.1 mL, 31.9 mmol) was added and the mixture was stirred at room temperature for 21 h. The resulting mixture was added to ice/aqueous NaHCO3 (200 mL) and extracted with 25% EtOAc/petroleum ether (2×200 mL) and 50% EtOAc/petroleum ether (3×200 mL). The extracts were washed with water (200 mL), the volatile solvents were removed, and the residual oil was chromatographed on silica gel. Elution with petroleum ether firstly gave foreruns, then further elution with 0-15% CH2Cl2/petroleum ether gave 1-{[(2-methyl-2-propenyl)oxy]methyl}-4-(trifluoromethoxy)benzene (121) (6.57 g, 96%) as an oil that was used directly in the next step; 1H NMR (CDCl3) δ 7.37 (dt, J=8.7, 2.3 Hz, 2H), 7.19 (br d, J=8.0 Hz, 2H), 5.00 (m, 1H), 4.94 (m, 1H), 4.48 (s, 2H), 3.94 (s, 2H), 1.77 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[NH:11][C:10]3([CH2:15][CH2:14][CH2:13][CH2:12]3)[CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.CC#N.C(=O)([O-])[O-].[Cs+].[Cs+].CC1C=CC(S(O[CH2:36][CH2:37][O:38][CH3:39])(=O)=O)=CC=1>C(OCC)(=O)C.O>[Cl:1][C:2]1[N:3]=[C:4]2[N:11]([CH2:36][CH2:37][O:38][CH3:39])[C:10]3([CH2:15][CH2:14][CH2:13][CH2:12]3)[CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1
Reactant: COCCOS(=O)(=O)c1ccc(C)cc1
Reactant: O=c1cc(Cl)nc2n1CC1(CCCC1)N2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: COCCN1c2nc(Cl)cc(=O)n2CC12CCCC2
Temperature: 65 °C
Yield: 63.6 %

Procedure:
0.200 g of 7′-chlorospiro[cyclopentane-1,2′-imidazo[1,2-a]pyrimidin]-5′-one are suspended in 7 mL de CH3CN, 0.62 g of cesium carbonate and 0.49 g of 2-methoxyethyl 4-methylbenzenesulfonate are added. The mixture is heated to 65° C. for 36 h. Water, ethyl acetate are added and then after decantation the organic phase is dried with magnesium sulfate and then evaporated. The crude is purified by flash chromatography on silica gel (CH2CL2/MeOH, 99/1). 0.16 g (yield=41%) of 7′-chloro-1′-(2-methoxyethyl)-spiro[cyclopentane-1,2′-imidazo[1,2-a]pyrimidin]-5′-one are obtained as a brown powder and including the following characteristics:
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][O:9][C:10]2[CH:23]=[C:22]([CH:24]=[O:25])[C:13]3[C:14]([CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:15][S:16][C:12]=3[CH:11]=2)=[CH:6][CH:5]=[C:4]([CH3:26])[N:3]=1.[BH4-].[Na+]>CO>[CH3:21][O:20][C:18](=[O:19])[CH2:17][C:14]1[C:13]2[C:22]([CH2:24][OH:25])=[CH:23][C:10]([O:9][CH2:8][C:7]3[C:2]([CH3:1])=[N:3][C:4]([CH3:26])=[CH:5][CH:6]=3)=[CH:11][C:12]=2[S:16][CH:15]=1
Reactant: COC(=O)Cc1csc2cc(OCc3ccc(C)nc3C)cc(C=O)c12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1csc2cc(OCc3ccc(C)nc3C)cc(CO)c12
Temperature: 0 °C
Reaction time: 1 h
Yield: 12.2 %

Procedure:
To a solution of methyl 2-(6-((2,6-dimethylpyridin-3-yl)methoxy)-4-formyl-1-benzothiophen-3-yl)acetate (140 mg, 0.38 mmol) in MeOH (3 mL) was added NaBH4 (21.51 mg) at 0° C. After stirring at 0° C. for 1 h, the mixture was quenched with saturated aqueous NH4Cl at room temperature and extracted with EtOAc. The organic layer was separated, washed successively with saturated aqueous NH4Cl and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (17.2 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26].Cl>ClCCl.O>[C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:13][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1ccc(NS(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
Compound 8-1 (1 g) was dissolved in anhydrous dichloromethane and the solution was cooled to 0° C. To the solution was added triethylamine (630 μl) and methanesulfonyl chloride (350 μl) in order and the mixture was stirred at room temperature for 24 hours. After confirming the completion of the reaction using TLC, the resulting mixture was neutralized with hydrochloric acid solution, diluted with water, and then extracted three times with dichloromethane. The extracted organic layer was washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then dried under reduced pressure. The obtained residue was purified by column-chromatography (hexane/ethyl acetate=2/1) to yield the compound 8-2 (1.28 g, 95%) as a white solid.
Reaction SMILES: [Cl:1][Si](C)(C)C.[CH3:6][CH2:7][C:8](=[O:14])[CH2:9][C:10](=[O:13])[CH2:11][CH3:12].CS(C)=O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C.O>[Cl:1][CH:9]([C:8](=[O:14])[CH2:7][CH3:6])[C:10](=[O:13])[CH2:11][CH3:12]
Reactant: CCC(=O)CC(=O)CC
Reactant: C[Si](C)(C)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: O
Solvent: CC#N
Solvent: CS(C)=O
Product: CCC(=O)C(Cl)C(=O)CC
Temperature: 25 °C
Reaction time: 4 h
Yield: 43.4 %

Procedure:
Chlorotrimethylsilane (29.7 ml, 0.234 mol) was added dropwise to a stirred pale yellow solution of tetrabutylammonium bromide (1.26 g, 3.9 mmol) in dry acetonitrile (116 ml) at room temperature under nitrogen. The resulting solution was cooled in ice and 3,5-heptanedione (10.6 ml, 78.0 mmol) and then dry dimethylsulphoxide (16.6 ml, 0.234 mol) were added dropwise over 5 minutes producing a yellow solution which was allowed to warm slowly to room temperature, with stirring, over 4 hours. The mixture was diluted with water (1 litre), stirred for 10 min and then extracted with ether (1×500 ml, 2×250 ml). The combined ether layers were dried over magnesium sulphate, filtered and concentrated under reduced pressure to leave a yellow oil. The crude product was purified by distillation under reduced pressure to afford the title compound (5.5 g) as a pale yellow oil, b.p. 102-105° C./54 mmHg containing ca. 10% 4,4-dichloro-3,5-heptanedione as estimated by microanalysis.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([N:8]([CH2:10][CH2:11]CC)[CH3:9])=[O:7])=[C:4]([S:16]([CH:19]([CH3:21])[CH3:20])(=[O:18])=[O:17])[CH:3]=1.Br[C:23]1C=CC(C(O)=O)=C(S(C(C)C)(=O)=O)C=1.C(NCC)C>>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([N:8]([CH2:9][CH3:23])[CH2:10][CH3:11])=[O:7])=[C:4]([S:16]([CH:19]([CH3:21])[CH3:20])(=[O:18])=[O:17])[CH:3]=1
Reactant: CCCCN(C)C(=O)c1ccc(Br)cc1S(=O)(=O)C(C)C
Reactant: CC(C)S(=O)(=O)c1cc(Br)ccc1C(=O)O
Solvent: CCNCC
Product: CCN(CC)C(=O)c1ccc(Br)cc1S(=O)(=O)C(C)C
Yield: 81 %

Procedure:
Following the general method as outlined in Intermediate 253, starting from 4-bromo-2-(isopropylsulfonyl)benzoic acid (Intermediate 242) and diethylamine, the title compound was obtained as a pink solid in 81% yield.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][C:2]2=[O:8].[Li]CCCC.[C:14]([Si:16]([CH3:19])([CH3:18])[CH3:17])#[CH:15]>C1COCC1>[CH3:17][Si:16]([C:14]#[C:15][C:2]1([OH:8])[CH2:3][CH:4]2[CH2:7][CH:1]1[CH2:6][CH2:5]2)([CH3:19])[CH3:18]
Reactant: O=C1CC2CCC1C2
Reactant: C#C[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#CC1(O)CC2CCC1C2
Reaction time: 3 h
Yield: 76.8 %

Procedure:
Bicyclo[2.2.1]heptan-2-one (1.1 g, 10 mmol) in THF was treated with n-BuLi (6 mL, 2.5 M in n-hexane) at −78° C. for about 30 min. Ethynyltrimethylsilane (1.1 g, 11 mmol) was then added and the reaction mixture was stirred for 3 hr. Purification by gel chromatography afforded the title compound (1.6 g); 1H NMR (400 MHz, DMSO) delta 0.16 (s, 9H), 1.15-1.44 (m, 4H), 1.64-1.67 (m, 1H), 1.88-1.93 (m, 2H), 2.07-2.22 (m, 3H), 3.94 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH2:14][CH3:15])=[C:11]([C:16]([NH:18][CH:19]3[CH2:21][CH2:20]3)=[O:17])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[C:22]1(=[O:28])[O:27][C:25](=[O:26])[CH2:24][CH2:23]1.C(OCC)C>C(Cl)(Cl)Cl>[CH:19]1([NH:18][C:16]([C:11]2[N:10]=[N:9][N:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:22](=[O:28])[CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:3][CH:4]=3)[C:12]=2[CH2:13][CH2:14][CH3:15])=[O:17])[CH2:20][CH2:21]1
Reactant: O=C1CCC(=O)O1
Reactant: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(N)cc1
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(NC(=O)CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 51929.6 %

Procedure:
To a solution of 1-(4-aminophenyl)-N-cyclopropyl-5-propyl-1H-1,2,3-triazole-4-carboxamide (0.14 g) obtained in Example 1d) in chloroform (10 ml) was added succinic anhydride (0.06 mg), and the mixture was stirred at room temperature for 3 days. Diethyl ether was added to the reaction mixture, and the precipitated crystals were collected by filtration and washed with diethyl ether to give the title compound as a pale-brown powder (0.12 g, 63%).
Reaction SMILES: C(OP([CH2:9][C:10]([N:12]1[CH2:33][CH2:32][C:15]2[C:16]3[C:21]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([F:29])=[C:25]([Cl:30])[CH:24]=4)=[N:20][CH:19]=[N:18][C:17]=3[S:31][C:14]=2[CH2:13]1)=[O:11])(=O)OCC)C.[H-].[Na+].CO.[CH2:38]1[CH2:42]O[CH2:40][CH2:39]1>>[Cl:30][C:25]1[CH:24]=[C:23]([NH:22][C:21]2[C:16]3[C:15]4[CH2:32][CH2:33][N:12]([C:10](=[O:11])/[CH:9]=[CH:9]/[CH:10]5[CH2:42][CH2:38][CH2:39][CH2:40][N:12]5[CH3:13])[CH2:13][C:14]=4[S:31][C:17]=3[N:18]=[CH:19][N:20]=2)[CH:28]=[CH:27][C:26]=1[F:29]
Reactant: C1CCOC1
Reactant: CCOP(=O)(CC(=O)N1CCc2c(sc3ncnc(Nc4ccc(F)c(Cl)c4)c23)C1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: CN1CCCCC1/C=C/C(=O)N1CCc2c(sc3ncnc(Nc4ccc(F)c(Cl)c4)c23)C1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 24 %

Procedure:
In a separate flask, diethyl (2-{4-[(3-chloro-4-fluorophenyl)amino]-5,8-dihydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-7(6H)-yl}-2-oxoethyl)phosphonate from Example 13A (400 mg, 0.78 mmol) was dissolved in THF (1.0 mL). The solution was cooled to −78° C., and sodium hydride (60% in mineral oil, 31 mg, 0.78 mmol) was added. The mixture was stirred for 15 min, then solution A was added slowly. The mixture was slowly warmed to rt and stirred overnight. Methanol was added, and the solvents were removed in vacuo. The residue was purified by preparative HPLC to yield 90 mg (24%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].O[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([OH:28])[CH2:25][CH2:26][CH3:27])=[CH:20][CH:19]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]([OH:28])[CH2:25][CH2:26][CH3:27])=[CH:20][CH:19]=2)[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CCc1ccc(O)cc1F
Reactant: CCCC(O)c1ccc(CO)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCCC(O)c1ccc(COc2ccc(CCC(=O)OCC)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 51.5 %

Procedure:
A solution of ethyl 3-(2-fluoro-4-hydroxyphenyl)propanoate (2.12 g, 10.0 mmol), 1-[4-(hydroxymethyl)phenyl]-butane-1-ol (1.80 g, 10.0 mmol) and tributylphosphine (4.04 mL, 20.0 mmol) in toluene (150 mL) was stirred under ice-cooling and 1,1′-(azodicarbonyl)dipiperidine (5.04 g, 20.0 mmol) was added by small portions. The mixture was warmed to room temperature and stirred for 22 hr. Hexane (75 mL) was added to the reaction mixture, and precipitated insoluble material was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=5:95-30:70) to give the title compound as a colorless oil (1.93 g, yield 52%).
Reaction SMILES: O[C@H:2]1[CH2:7][C@H:6]2[CH2:8][C@H:4]([C:5]2([CH3:10])[CH3:9])[C@@H:3]1CCOC1CCCO1.C(N(CC)CC)C.CS(Cl)(=O)=O>ClCCl.CCOCC>[CH3:9][C:5]1([CH3:10])[CH:6]2[CH2:8][CH:4]1[CH2:3][CH2:2][CH2:7]2
Reactant: CC1(C)[C@H]2C[C@H](O)[C@@H](CCOC3CCCO3)[C@@H]1C2
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: CC1(C)C2CCCC1C2
Reaction time: 0.25 h
Yield: 252 %

Procedure:
To a solution of 13 g of (1S,2S,3S,5R)-3-hydroxy-6,6-dimethyl-2-[2-(tetrahydrofuran-2-yloxy)-ethyl]bicyclo[3.1.1]heptane 14 [Jap. Unexamined Pat. Pub. No. 13551/1983] in 130 ml of dichloromethane is added 9.9 ml of triethylamine in a stream of nitrogen and then 6.16 g of methanesulfonyl chloride is dropwise added at -20° C., and the resulting mixture is stirred at the same temperature for 15 minutes. The reaction mixture is diluted with ether, washed with water, a saturated aqueous solution of ammonium chloride and a saturated sodium chloride aqueous solution successively, dried over sodium sulfate, and evaporated under reduced pressure to give 16 g of the titled compound 14a, of which the physical constant is as follows.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18]>>[OH:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][NH:12][S:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)(=[O:10])=[O:9]
Reactant: NCCCCCO
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Product: O=S(=O)(NCCCCCO)c1cccc(Br)c1

Procedure:
Using a method analogous to that described in Example 1, 3-bromophenyl sulphonyl chloride was reacted with 5-aminopentanol, and the title compound obtained as a white solid after recrystallisation from ether/petrol.
Reaction SMILES: C(Cl)(Cl)Cl.[Cl:5][C:6]1[CH:7]=[C:8]([CH:12]2[C:16]([OH:17])=[C:15]([C:18]([CH3:20])=[O:19])[CH2:14][S:13]2)[CH:9]=[CH:10][CH:11]=1.S(Cl)(Cl)(=O)=O>O>[Cl:5][C:6]1[CH:7]=[C:8]([C:12]2[S:13][CH:14]=[C:15]([C:18]([CH3:20])=[O:19])[C:16]=2[OH:17])[CH:9]=[CH:10][CH:11]=1
Reactant: CC(=O)C1=C(O)C(c2cccc(Cl)c2)SC1
Solvent: O=S(=O)(Cl)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(=O)c1csc(-c2cccc(Cl)c2)c1O
Temperature: -15 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
A chloroform (25 mL) solution of 2-(3-chlorophenyl)-3-hydroxy-4-methylcarbonyl-2,5-dihydrothiophene (2.49 g, 8.02 mmol, purity: 82%) was cooled to −43° C., and to this solution, a chloroform (50 mL) solution of sulfuryl chloride (0.77 mL, 1.1 equivalent amounts) was dropwise added over a period of 32 minutes, followed by stirring at −15° C. for 1 hour. The temperature of the solution was raised to 0° C., and water (5 mL) was dropwise added, followed by liquid separation. The obtained chloroform solution was sequentially washed with water, a saturated salt solution, a sodium hydroxide aqueous solution, a saturated sodium thiosulfate aqueous solution and a saturated salt solution, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was distilled off to give the desired product as a yellow solid (2.0 g, yield: 99%).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:11]1C2C3C4C[CH:12]1CC1C4CC(CC12)C3>>[C:11]([C:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2)#[CH:12]
Reactant: C1C2CC3C4CC5CC(C14)C(C2)C3C5
Reactant: C1C2CC3CC1CC(C2)C3
Product: C#CC12CC3CC(CC(C3)C1)C2

Procedure:
The aluminum bromide catalyzed reaction of 1-bromodiamantane (see Gund, T.M.; Schleyer, P.v.R. Tetrahedron Lett. 1971, 1583) with vinyl bromide in methylene chloride followed by dehydrohalogenation of the adduct with potassium t-butoxide in DMSO gave a mixture of five components. This mixture was separated by column chromatography and components were identified as diamantane (5%), 1-(2-bromovinyl)diamantane (8%), 1-ethynyldiamantane (50%), 4-(2-bromovinyl)-9-ethynyldiamantane (9%), and 4,9-diethynyl-diamantane (30%). The formation of 2-bromovinyl compounds results from incomplete dehydrohalogenation, and indicates that the elimination is slower than that observed for the adamantane system. The presence of diamantane and 4,9-diethynyl derivatives indicates the facile disproportionation chemistry in this system. In 1-ethynyldiamantane the ethynyl group is on the girdle, whereas in the case of the 4,9- disubstituted derivative, the ethynyl groups are on the epical positions. Although reaction condition were not found to give pure 1-ethynyldiamantane (similar difficulty was encountered with 1-ethynyladamantane), yields were improved to greater than 55% by the use of ferric chloride as the catalyst and hexane/methylene chloride as the solvent.
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:28]([N:33]([CH3:41])[C:34](=[O:40])[C@H:35]([CH:37]([CH3:39])[CH3:38])[NH2:36])[C@@H:29]([CH3:32])[CH2:30][CH3:31])[CH2:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C@H:12]([O:26][CH3:27])[C@@H:13]([CH3:25])[C:14](=[O:24])[NH:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:6].[CH:42]1[C:54]2[CH:53]([CH2:55][O:56][C:57]([NH:59][CH2:60][C:61]([CH3:66])([CH3:65])[C:62](O)=[O:63])=[O:58])[C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:46]=2[CH:45]=[CH:44][CH:43]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.CN(C)C=O>[CH:51]1[C:52]2[CH:53]([CH2:55][O:56][C:57]([NH:59][CH2:60][C:61]([CH3:66])([CH3:65])[C:62]([NH:36][C@H:35]([C:34]([N:33]([C@@H:28]([C@@H:29]([CH3:32])[CH2:30][CH3:31])[C@H:3]([O:2][CH3:1])[CH2:4][C:5]([N:7]3[CH2:11][CH2:10][CH2:9][C@H:8]3[C@H:12]([O:26][CH3:27])[C@@H:13]([CH3:25])[C:14](=[O:24])[NH:15][CH2:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:6])[CH3:41])=[O:40])[CH:37]([CH3:39])[CH3:38])=[O:63])=[O:58])[C:54]3[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:47]=2[CH:48]=[CH:49][CH:50]=1
Reactant: CC(C)(CNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCc1ccccc1)OC)N(C)C(=O)[C@@H](N)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)CNC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Reaction time: 18 h
Yield: 65.4 %

Procedure:
To #73 (100 mg, 0.174 mmol, 1 eq.) in dichloromethane (4 mL, 0.04 M) and N,N-dimethylformamide (0.5 mL) was added #93 (59.1 mg, 0.174 mmol, 1 eq.), followed by diisopropylethylamine (92 μL, 0.52 mmol, 3 eq.) and HATU (102 mg, 0.260 mmol, 1.5 eq.). The reaction was stirred for 18 hours and then concentrated in vacuo. The residue was taken up in ethyl acetate (6 mL) and was washed with 1 M aqueous hydrochloric acid solution (2×2 mL) and with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by silica gel chromatography (Gradient: 0% to 50% acetone in heptane) provided #96 (102 mg, 65%) as a white solid. LC-MS: m/z 896.7 [M+H+], 918.8 [M+Na+], retention time=1.14 minutes; 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, characteristic product signals: δ 7.88 (d, J=7.4 Hz, 2H), [7.83 (br dd, J=6, 5 Hz) and 8.03 (br dd, J=6, 5 Hz), total 1H], 7.67-7.73 (m, 2H), 7.36-7.48 (m, 3H), 7.22-7.35 (m, 4H), 7.13-7.21 (m, 3H), 6.86-6.96 (m, 1H), [4.44 (dd, J=8.6, 8.6 Hz) and 4.50 (dd, J=8.6, 8.6 Hz), total 1H], 3.18, 3.19, 3.26 and 3.29 (4 s, total 6H), 2.96 and 3.11 (2 br s, total 3H), 0.70-0.77 (m, 3H).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]2[C:4]=1[N:5]=[C:6]([O:18][CH3:19])[C:7]([O:16][CH3:17])=[N:8]2.[NH2:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1>ClCCl.C(#N)C>[Br-:1].[NH2:20][C:21]1[CH:26]=[CH:25][N+:24]([CH2:2][C:3]2[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]3[C:4]=2[N:5]=[C:6]([O:18][CH3:19])[C:7]([O:16][CH3:17])=[N:8]3)=[CH:23][CH:22]=1
Reactant: Nc1ccncc1
Reactant: COc1nc2cc([N+](=O)[O-])cc(CBr)c2nc1OC
Solvent: ClCCl
Solvent: CC#N
Product: COc1nc2cc([N+](=O)[O-])cc(C[n+]3ccc(N)cc3)c2nc1OC
Product: [Br-]
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A solution of 197 mg (0.6 mmol) of 5-bromomethyl-2,3-dimethoxy-7-nitro-quinoxaline in 2 ml of dichloromethane is added at room temperature to a suspension of 282 mg (3 mmol) of 4-aminopyridine in 1 ml of dichloromethane and 3 ml of acetonitrile and the mixture is then stirred for 3.5 hours at room temperature. The resulting precipitate is filtered off and then washed on the filter with a small amount of acetonitrile. The title compound is obtained in the form of a colorless powder.