Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C@H:6]1[C@@H:11]([N:12]([CH2:33][CH2:34][CH:35]2[CH2:37][CH2:36]2)[C:13](=[O:32])[CH2:14][C:15]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:24][C:18]=3[S:17](=[O:31])(=[O:30])[N:16]=2)[C@H:10]2[CH2:38][C@@H:7]1[CH2:8][CH2:9]2)=O)C.[O-]CC.[Na+].Cl>C(O)C>[CH:35]1([CH2:34][CH2:33][N:12]2[C:13](=[O:32])[C:14]([C:15]3[NH:20][C:19]4[CH:21]=[CH:22][C:23]([NH:25][S:26]([CH3:29])(=[O:27])=[O:28])=[CH:24][C:18]=4[S:17](=[O:30])(=[O:31])[N:16]=3)=[C:4]([OH:3])[C@H:6]3[C@@H:11]2[C@H:10]2[CH2:38][C@@H:7]3[CH2:8][CH2:9]2)[CH2:36][CH2:37]1
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1N(CCC1CC1)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@@H]3[C@H]4CC[C@H](C4)[C@@H]3N(CCC3CC3)C1=O)N2
Temperature: 25 °C
Reaction time: 23 h
Yield: 22.9 %

Procedure:
To a solution of the crude (1S,2R,3S,4R)-3-{(2-cyclopropyl-ethyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester in absolute ethanol (11 mL) was added a 21 wt. % solution of sodium ethoxide in ethanol (2.4 mL, 7.41 mmol). After shaking at 25° C. for 23 h, additional 21 wt. % solution of sodium ethoxide in ethanol (1.0 mL, 3.09 mmol) was added. After shaking at 25° C. for 6 h, additional 21 wt. % solution of sodium ethoxide in ethanol (1.0 mL, 3.09 mmol) was added and the mixture was shaken for another 24 h. The mixture was then acidified with 1.0 M aqueous hydrochloric acid solution (22 mL) and was extracted with ethyl acetate (3×60 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude mixture was purified by prep-HPLC [Column Luna 5μ C18 (2) 100 Å AXIA 150×21.2 mm, 5 micron, 30%-95% in 7 min @ 30 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water] to afford the desired product, N-{3-[(1R,2S,7R,8S)-3-(2-cyclopropyl-ethyl)-6-hydroxy-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (160.7 mg, 0.309 mmol, 22.9% over two steps), as a solid. 1H NMR (400 MHz, CDCl3) δ: 0.09-0.15 (2H, m), 0.49-0.54 (2H, m), 0.64-0.73 (1H, m), 1.27-1.31 (2H, m), 1.48-1.78 (6H, m), 2.55-2.56 (1H, m), 2.74-2.80 (1H, m), 2.85 (1H, d, J=9.2 Hz), 3.06 (3H, s), 3.10-3.17 (1H, m), 3.57 (1H, d, J=9.2 Hz), 3.80-3.87 (1H, m), 6.99 (1H, s), 7.22-7.25 (1H, m), 7.62-7.68 (2H, m). LC-MS (ESI) calcd for C23H28N4O6S2 520.15. found 521.4 [M+H+].
Reaction SMILES: [C:1]1([CH:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]3C(=O)C4=CC=CC=C4C3=O)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN>C(O)C>[C:1]1([CH:7]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH2:11][CH2:10]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Yield: 68.2 %

Procedure:
3.70 g of potassium phthalimide was dissolved in 20 ml of N,N-dimethylformamide; 5.4 ml of 1,5-dichloropentane was added, followed by stirring at room temperature for 15 hours. Ice water was added to the reaction mixture, followed by extraction with ethyl acetate; the extract was washed with saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (4:1). The desired fraction was collected to yield 4.68 g of N-(5-bromopentyl)phthalimide as an oily substance. 4.68 g of N-(5-bromopentyl)phthalimide and 4.25 g of 4-(diphenylmethoxy)piperidine were dissolved in 30 ml of N,N-dimethylformamide; 2.42 g of potassium carbonate was added, followed by stirring at room temperature for 15 hours. Ice water was added to the reaction mixture, followed by extraction with ethyl acetate; the extract was washed with saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate-triethylamine (50:50:1). The desired fraction was collected to yield 6.67 g of N-[5-[4-(diphenylmethoxy)piperidino]pentyl]phthalimide as an oily substance. 6.6 g of N-[5-[4-(diphenylmethoxy)piperidino]pentyl]phthalimide was dissolved in 30 ml of ethanol; 0.694 ml of hydrazine monohydrate was added, followed by thermal refluxing for 3 hours. After cooling, the mixture was concentrated under reduced pressure; ethyl acetate was added to the residue; the crystal precipitated was collected, dissolved in 15 ml of a 1 N aqueous solution of sodium hydroxide and 20 ml of water and extracted with ethyl acetate; the extract was washed with saline and dried with sodium sulfate. The dry product was concentrated under reduced pressure; the crystal obtained was collected to yield 3.29 g of the title compound.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]=[C:14]=[O:15])([CH3:3])[CH3:2].[CH3:16][CH:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]([CH3:27])[CH3:26])[C:20]=1[NH:28][C:29](=[O:44])[CH2:30][NH:31][CH2:32][C:33]1([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:37][CH2:36][CH2:35][CH2:34]1)[CH3:18]>C(OCC)(=O)C>[CH3:18][CH:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]([CH3:26])[CH3:27])[C:20]=1[NH:28][C:29](=[O:44])[CH2:30][N:31]([C:14]([NH:13][C:5]1[C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][CH:8]=[CH:7][C:6]=1[CH:10]([CH3:12])[CH3:11])=[O:15])[CH2:32][C:33]1([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:37][CH2:36][CH2:35][CH2:34]1)[CH3:16]
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CNCC1(c2ccccc2)CCCC1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Solvent: CCOC(C)=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CN(CC1(c2ccccc2)CCCC1)C(=O)Nc1c(C(C)C)cccc1C(C)C
Temperature: 25 °C

Procedure:
2,6-Diisopropylphenylisocyanate (0.24 g) and the product of Example 6 (0.45 g) were mixed and then diluted with a few mL of ethyl acetate. The solution was heated on the steambath and then concentrated to an oil which was heated on the steambath. Upon cooling to room temperature the oil partially solidified. Addition of hexane/EtoAc, 1/1 caused crystallization of the product which was collected by filtration. 0.30 g (44%). NMR (CDCl3) δ 1.08 (12H ,d), δ 1.17 (12H, d), δ 1.60-2.13 (8H, m), δ 2.65 (2H, m), δ 3.04 (2H, m), δ 3.71 (2H, s), δ 4.04 (2H, bs), δ 5.24 (1H, bs), δ 7.04-7.48 (11H, m), δ 7.94 (1H, bs). IR (KBr) 3025, 2965, 2871, 1682, 1637, 1519, 1364, 1230, 958, 801, 700 cm-1.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:15][CH2:14][C@H:13]3[C@@H:8]([CH2:9][CH2:10][CH2:11][N:12]3[C:16](=[O:19])[CH2:17][CH3:18])[C:7]=2[CH:20]=1.B(Br)(Br)Br.C(O)C>C(Cl)(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:15][CH2:14][C@H:13]3[C@@H:8]([CH2:9][CH2:10][CH2:11][N:12]3[C:16](=[O:19])[CH2:17][CH3:18])[C:7]=2[CH:20]=1
Reactant: CCC(=O)N1CCC[C@H]2c3cc(OC)ccc3CC[C@@H]21
Agent: BrB(Br)Br
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCC(=O)N1CCC[C@H]2c3cc(O)ccc3CC[C@@H]21

Procedure:
A solution of 6.8 g of the compound obtained in Step D in 72 ml of chloroform is cooled to 0° C., then 5.3 ml of boron tribromide are added dropwise thereto. The whole is stirred for 18 hours at room temperature before the addition of 20 ml of ethanol. The resulting precipitate is filtered and washed with water, and 5.1 g of the expected compound are thereby isolated.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:18])=[CH:11][CH:10]=1.CCN(CC)CC.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[O:18]=[C:17]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:16][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:1](=[O:3])[CH3:2])=[CH:14][CH:13]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(CCC(=O)c2ccccc2)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc(CCC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetic anhydride (2.45 mL, 26 mmol) was added to a solution of 3-(4-amino-phenyl)-1-phenyl-propan-1-one from Example X (4.5 g, 20 mmol), NEt3 (3.1 mL, 22.2 mmol), and a crystal of DMAP in CH2Cl2 (50 mL). The reaction mixture was stirred overnight at room temperature, then poured onto 1N HCl. The product was partitioned between CH2Cl2 and H2O, and the organic phase was dried (MgSO4) and concentrated to give the title compound. 1H NMR (CDCl3) δ 2.16 (s, 3 H), 3.03 (t, 2 H), 3.28 (t, 2 H), 7.20 (d, 2 H), 7.37-7.60 (m, 6 H), 7.94 (d, 2 H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][CH:10]([N:29]1[N:33]=[N:32][C:31]([CH3:34])=[N:30]1)[CH2:11][S: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][CH2:25][CH2:26][CH2:27][CH3:28])(=[O:7])=[O:6].C(SCC(OC)CNS(CCC[I:62])(=O)=O)CCCCCCCCCCCCCCC>>[CH2:13]([S:12][CH2:11][CH:10]([N:29]1[N:33]=[N:32][C:31]([CH3:34])=[N:30]1)[CH2:9][NH:8][S:5]([CH2:4][CH2:3][CH2:2][I:62])(=[O:7])=[O:6])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)OC
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)n1nnc(C)n1
Product: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)n1nnc(C)n1

Procedure:
3-(3-Chloropropylsulfonylamino)-1-hexadecylthio-2-(5-methyl-2H-tetrazol-2-yl)propane IIIh1 is allowed to react and worked up by the same procedure as described in (5). m.p. 50°-51° C. The summary of the experimental condition and the physical data of the product are listed in Table 8.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[C:6]3[C:12](=O)[CH2:13][CH2:14][C:5]=3[C:4]=2[CH:3]=1.[NH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>C(#N)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:11][N:7]1[C:8]2[CH:9]=[CH:10][C:2]([OH:1])=[CH:3][C:4]=2[C:5]2[CH2:14][CH2:13][C:12](=[N:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:6]1=2
Reactant: Cn1c2c(c3cc(O)ccc31)CCC2=O
Reactant: NCCN1CCOCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CC#N
Product: Cn1c2c(c3cc(O)ccc31)CCC2=NCCN1CCOCC1
Reaction time: 2 h
Yield: 9.6 %

Procedure:
To a stirred solution of 7-hydroxy-4-methyl-1,4-dihydrocyclopent[b]indol-3-one (8.00 g) in acetonitrile (125 ml) under nitrogen were added 4-(2-aminoethyl)morpholine (10.35 g) and titanium isopropoxide (22.60 g). The reaction was monitored by TLC and after two hours additional equivalents of 4-(2-aminoethyl)morpholine (5.17 g) and titanium isopropoxide (11.30 g) were added. Fourteen hours later the reaction was quenched with water (200 ml). EtOAc (200 ml) was added and the mixture stirred for fifteen minutes and filtered. The layers were separated, the aqueous layer was extracted with ethyl acetate, and the combined organics were dried (Na2SO4) and concentrated in vacuo. The resulting yellow solid was dried yielding 6.65 g. of product. A 2 g sample of the solid was further purified by crystallization from CH2Cl2 /hexane to afford 1.2 g of 4-methyl-3-[2-(4-morpholinyl)ethyl]imino-1,2,3,4-tetrahydrocyclopent[b]indol-7-ol.
Reaction SMILES: [O:1]=[C:2]([N:19]1[C:27]2[C:22](=[C:23]([C:34]3[O:35][C:36](=[S:39])[NH:37][N:38]=3)[CH:24]=[C:25]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[CH:26]=2)[CH2:21][CH2:20]1)[C@@H:3]([NH:11]C(=O)OC(C)(C)C)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:11][C@@H:3]([CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:2]([N:19]1[C:27]2[C:22](=[C:23]([C:34]3[O:35][C:36](=[S:39])[NH:37][N:38]=3)[CH:24]=[C:25]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[CH:26]=2)[CH2:21][CH2:20]1)=[O:1]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCc2c(-c3n[nH]c(=S)o3)cc(-c3ccncc3)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](Cc1ccccc1)C(=O)N1CCc2c(-c3n[nH]c(=S)o3)cc(-c3ccncc3)cc21
Yield: 62.8 %

Procedure:
To (S)-tert-butyl 1-oxo-3-phenyl-1-(6-(pyridin-4-yl)-4-(5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)indolin-1-yl)propan-2-ylcarbamate 58.0 (80 mg) was added 3 mL dichloromethane and 1.5 mL trifluoroacetic acid. Stirring was continued for a few hours until deprotection was complete. Reaction was concentrated, basified with NaHCO3 and extracted with 30% isopropanol in chloroform six times to afford 41 mg (63%) 58.D.
Reaction SMILES: [H-].[Na+].C([C:10]1[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:11]=1[OH:12])C1C=CC=CC=1.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C(COC)OC>[CH2:19]([O:12][C:11]1[CH:10]=[CH:16][C:15]([OH:17])=[CH:14][CH:13]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: Oc1ccc(O)c(Cc2ccccc2)c1
Reactant: CCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCCCCCOc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.2 %

Procedure:
Sodium hydride (2.4 g, 0.1 mol) was suspended in 150 mL dry glyme. Monobenzylhydroquinone (20.0 g, 0.1 mol) was dissolved in 250 mL dry glyme and added dropwise to the sodium hydride suspension with stirring under nitrogen at room temperature. 1-Bromohexane (16.5 g, 0.1 mol) was added dropwise and the reaction mixture was refluxed for 1 day. The reaction product was cooled and the glyme removed under reduced pressure. The residue was dissolved in 300 mL 1:1 ethanol-ethyl acetate and catalytically hydrogenated using 2 g 10% Pd on C and a hydrogen pressure of 500 kPa at room temperature for 4 hours. The catalyst was removed by filtration and the solvent was removed from the filtrate under reduced pressure. The crude product residue was recrystallized from aqueous ethanol to yield 15 g 4-hexyloxyphenol.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:14])[C:5]1([C:11]([NH2:13])=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:19]Cl>CN(C)C=O.Cl.CCOCC>[CH3:3][N:4]([CH3:14])[C:5]1([C:11]([NH:13][C:17]2[C:16]([Cl:15])=[C:23]([Cl:24])[CH:22]=[CH:21][C:18]=2[CH3:19])=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: CN(C)C1(C(N)=O)CCCCC1
Reactant: ClCc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1ccc(Cl)c(Cl)c1NC(=O)C1(N(C)C)CCCCC1
Reaction time: 2 h

Procedure:
Sodium hydride (0.8 g., 50% dispersion in oil) was added to a solution of 1-dimethylaminocyclohexane carboxamide (2 g.) in dimethylformamide (40 ml.) and the mixture stirred for 2 hrs. A solution of 3,4-dichlorobenzyl chloride (2.4 g.) in dimethylformamide (10 ml.) was added dropwise and the resulting mixture stirred overnight. The mixture was filtered and the filtrate evaporated to dryness. Petrol (80/100) was added, the mixture boiled, and the solid filtered off. The filtrate was decolourised with activated charcoal and evaporated to dryness to leave a colourless oil. The oil was dissolved in 2N hydrochloric acid and washed with benzene (4 × 200 ml.). The aqueous phase was basified (2N NaOH) and extracted with benzene (4 × 200 ml.). The benzene extracts were washed with water, (4 × 200 ml.) dried (Na2SO4) and evaporated to leave a colourless oil (2.1 g.), shown by T.L.C. (silica/ether) to consist of three components. The oil was dissolved in the minimum of ether and chromatographed on a column of silica (50 × 2.0 cms.) eluting with ether (11 × 100 ml. fractions). Fractions 3-11 were combined, evaporated to dryness and rechromatographed as above. Combination and evaporation of the appropriate fractions afforded a white crystalline solid (1.315 g., 35%). Recrystallisation from 40/60 petrol afforded 1-dimethylamino-N-[3,4-dichlorotolyl]-cyclohexane carboxamide as white needles (0.846 g.) m.p. 82°-83° C. A second crop (0.091 g.) melted at 78°-83° C.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[C:14]2[S:15][CH:16]([CH3:18])[CH2:17][C:13]=2[CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH3:24][O:25][CH2:26]Br.Cl>O1CCCC1.CCCCCC>[C:1]([NH:5][S:6]([C:9]1[C:14]2[S:15][CH:16]([CH3:18])[CH2:17][C:13]=2[CH:12]=[CH:11][C:10]=1[CH2:24][O:25][CH3:26])(=[O:7])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1Cc2cccc(S(=O)(=O)NC(C)(C)C)c2S1
Reactant: COCBr
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCc1ccc2c(c1S(=O)(=O)NC(C)(C)C)SC(C)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 7.14 g of N-t-butyl-2,3-dihydro-2-methylbenzo[b]thiophene-7-sulfonamide in 175 ml of dry tetrahydrofuran was added 34 ml of a 1.6M hexane solution of n-butyl lithium at -40° C. to -30° C. under an inert atmosphere. The mixture was allowed to warm and was stirred at room temperature for 30 minutes. It was recooled to -30° C. and was contacted with 2.2 ml of bromomethyl methyl ether. The mixture was allowed to come to room temperature overnight and was acidified with 10 ml of 6N hydrochloric acid. The organic layer was separated, was dried over magnesium sulfate, and was concentrated to give 7.4 g of the title compound as a brown oil.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.[OH:9][CH:10]([CH:15]=[CH2:16])[C:11]([O:13][CH3:14])=[O:12]>>[CH3:8][C:4]1[CH:3]=[C:2]([CH2:16][CH2:15][C:10](=[O:9])[C:11]([O:13][CH3:14])=[O:12])[CH:7]=[CH:6][CH:5]=1
Reactant: C=CC(O)C(=O)OC
Reactant: Cc1cccc(I)c1
Product: COC(=O)C(=O)CCc1cccc(C)c1

Procedure:
Methyl 4-(3-methylphenyl)-2-oxobutyrate was prepared as a pale yellow oil from 3-iodotoluene and methyl 2-hydroxy-3-butenoate.
Reaction SMILES: [C:1]([C:7]1[C:14]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:13][C:10]([CH:11]=O)=[CH:9][C:8]=1[C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[C:23]([NH:27][OH:28])([CH3:26])([CH3:25])[CH3:24].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[C:1]([C:7]1[C:14]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:13][C:10]([CH:11]=[N+:27]([C:23]([CH3:26])([CH3:25])[CH3:24])[O-:28])=[CH:9][C:8]=1[C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(=O)c1c(C(C)(C)C)cc(C=O)cc1C(C)(C)C
Reactant: CC(C)(C)NO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCCCC(=O)c1c(C(C)(C)C)cc(C=[N+]([O-])C(C)(C)C)cc1C(C)(C)C
Yield: 56.5 %

Procedure:
To a solution of 4-pentanoyl-3,5-di-ter-butylbenzaldehyde (17.48 g, 0.050 mol) in benzene (250 mL) was added tert-butylhydroxylamine (4.57 g, 0.0510 mol) and p-toluenesulfonic acid (0.080 g). Using a Dcan-Stark trap, the resulting mixture was refluxed until no more aldehyde was detected by TLC (Rf=0.43 for product using 1:1 hexanes/EtOAc). The solvent was removed in vacuo and the residue was thoroughly washed with hexanes. The title compound was isolated (56.50% yield) as a white solid, m.p. 195.5-204.8° C.
Reaction SMILES: Cl.[C:2]1([S:8]([CH2:11][C:12]2[C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([CH2:22][CH2:23][CH2:24][NH:25]C(OC(C)(C)C)=O)[C:15]([C:33]3[CH:37]=[CH:36][O:35][CH:34]=3)=[CH:14][CH:13]=2)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCOCC1.O>[NH2:25][CH2:24][CH2:23][CH2:22][C:16]1[C:15]([C:33]2[CH:37]=[CH:36][O:35][CH:34]=2)=[CH:14][CH:13]=[C:12]([CH2:11][S:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)(=[O:10])=[O:9])[C:17]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1CCCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1CCCN
Reaction time: 0.5 h

Procedure:
Concentrated hydrochloric acid was added to a solution of methyl 6-(benzenesulphonylmethyl)-2-(3-t-butoxycarbonylaminopropyl)-3-(furan-3-yl)benzoate (Intermediate 131) in 1,4-dioxane (8 ml) and water (2 ml) and the mixture was stirred for 30 minutes. This was evaporated to dryness and the residue was purified by chromatography on silica eluting with a mixture of DCM:MeOH:AcOH:water (120:15:3:2) to give methyl 2-(3-aminopropyl)-6-(benzenesulphonylmethyl)-3-(furan-3-yl)benzoate as a colourless gum. This material was dissolved in a mixture of dioxane and water (3:1) and lithium hydroxide monohydrate (0.188 g) was added. The reaction was heated in the microwave at 150° C. for one hour. After cooling, concentrated hydrochloric acid was added and the mixture was evaporated to dryness. The residue was purified by chromatography on silica eluting with a mixture of DCM:MeOH:AcOH:water (240:20:3:2), then again with DCM:MeOH:AcOH:water (120:15:3:2). The volume of the product containing fractions was reduced to 5 ml by evaporation and concentrated hydrochloric acid (1 ml) was added to the mixture. The mixture was evaporated to dryness and the residue was triturated with diethyl ether and the solid was collected by filtration and dried under vacuum at 60° C. to give 2-(3-aminopropyl)-6-(benzenesulphonylmethyl)-3-(furan-3-yl)benzoic acid hydrochloride (0.045 g), as a white solid.
Reaction SMILES: Br[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].O.[NH2:11][NH2:12]>C1COCC1>[C:4]1([CH:2]([NH:11][NH2:12])[CH3:3])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(Br)c1ccccc1
Reactant: NN
Solvent: C1CCOC1
Solvent: O
Product: CC(NN)c1ccccc1

Procedure:
1-bromoethylbenzene Compound 3a (8.0 mL, 58.0 mMol) was added to a solution of hydrazine hydrate Compound 3b (20 mL) in THF (80 mL) which was then heated to reflux for 8 hrs. The solvent was removed in vacito and Et2O (100 mL) was added. The organic layer was washed with brine, separated and dried over Na2SO4. The solvent was removed in vacuo to yield (1-phenyl-ethyl)-hydrazine Compound 3c as a pale yellow oil (5.8 g), used in the next step without purification. MS m/z 137 (M+H, 70%), 105 (M-NHNH2, 100%).
Reaction SMILES: COC(=O)C(N1C=CC=C1)[CH2:5][C:6]#[C:7][CH2:8][CH2:9][CH2:10][C:11]1[N:12]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][C:15]=1[CH3:16].[CH3:29][CH2:30][O:31][C:32]([CH2:34][C:35]1[S:39][CH:38]=[CH:37][CH:36]=1)=[O:33]>>[CH2:30]([O:31][C:32](=[O:33])[CH:34]([C:35]1[S:39][CH:38]=[CH:37][CH:36]=1)[CH2:5][C:6]#[C:7][CH2:8][CH2:9][CH2:10][C:11]1[N:12]=[C:13]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[O:14][C:15]=1[CH3:16])[CH3:29]
Reactant: CCOC(=O)Cc1cccs1
Reactant: COC(=O)C(CC#CCCCc1nc(-c2ccccc2)oc1C)n1cccc1
Product: CCOC(=O)C(CC#CCCCc1nc(-c2ccccc2)oc1C)c1cccs1
Yield: 38 %

Procedure:
Prepared in a manner similar to ester 1-10 with the exception that Ethyl 2-thiophene acetate was used instead of Methyl 2-pyrrolo-acetate. Chromatography gave 206 mg of the ethyl ester 1-12 (38% yield) as a yellow oil. NMR CDCl3 (δ): 7.99 (2H, m); 7.43 (3H, m); 7.21 (1H, dd, J=1.0, 5.1 Hz); 6.98 (1H, m); 6.94 (1H, m); 4.22 (2H, m); 4.03 (1H, t, J=7.0, 8.0 Hz), 2.92 (1H, m); 2.71 (1H, m); 2.54 (2H, t, J=7.3, 7.3 Hz); 2.31 (3H, s); 2.14 (2H, m); 1.81 (2H, m); 1.25 (3H, t, J=7.1, 7.1 Hz). M+1=408.2.
Reaction SMILES: O.Cl[C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=4)[N:18]=3)=[O:16])[CH2:11][CH2:10]2)[CH:6]=[CH:5][N:4]=1>[Pd].CO>[CH3:32][O:31][C:25]1[CH:24]=[C:23]([C:19]2[N:18]=[C:17]([C:15]([N:12]3[CH2:13][CH2:14][N:9]([C:7]4[CH:6]=[CH:5][N:4]=[CH:3][N:8]=4)[CH2:10][CH2:11]3)=[O:16])[CH:22]=[CH:21][CH:20]=2)[CH:28]=[CH:27][C:26]=1[O:29][CH3:30]
Reactant: COc1ccc(-c2cccc(C(=O)N3CCN(c4ccnc(Cl)n4)CC3)n2)cc1OC
Agent: [Pd]
Solvent: O
Solvent: CO
Product: COc1ccc(-c2cccc(C(=O)N3CCN(c4ccncn4)CC3)n2)cc1OC
Temperature: 25 °C
Reaction time: 23 h
Yield: 20.4 %

Procedure:
To a methanol (20 ml) solution of 460 mg of 2-chloro-4-{4-[6-(3,4-dimethoxyphenyl) pyridine-2-carbonyl]piperazin-1-yl}pyrimidine monohydrate was added 150 mg of 10% palladium/carbon, followed by 23 hours of stirring at room temperature under a hydrogen atmosphere of normal pressure. Insoluble matter was removed by filtration and the residue obtained by evaporation of the solvent was purified by silica gel column chromatography (chloroform-methanol) and further, recrystallization was carried out from acetonitrile-diisopropyl ether to obtain 83 mg of 4-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl}pyrimidine as colorless crystals.