Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li][CH2:2]CCC.[Br:6][C:7]1[C:8]([O:19][CH3:20])=[CH:9][C:10]([Cl:18])=[C:11]([C:13]([CH3:17])([CH3:16])[CH:14]=O)[CH:12]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Br:6][C:7]1[CH:12]=[C:11]([C:13]([CH3:17])([CH3:16])[CH:14]=[CH2:2])[C:10]([Cl:18])=[CH:9][C:8]=1[O:19][CH3:20]
Reactant: COc1cc(Cl)c(C(C)(C)C=O)cc1Br
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=CC(C)(C)c1cc(Br)c(OC)cc1Cl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A suspension of methyltriphenylphosphonium bromide (11.4 g, 0.032 mol) in dry THF (100 mL) was cooled to 0° C. under argon. n-BuLi (2.5M, 12 mL, 0.030 mol) was added slowly. The suspension became more homogenous. The resulting clear orange solution of the ylide was stirred for another 15 min at 0° C. 2-(5-Bromo-2-chloro-4-methoxy-phenyl)-2-methyl-propionaldehyde (7.8 g, 0.027 mol) was dissolved in dry THF (50 mL) and added to ylide-solution. The mixture was stirred for 3 h/25° C. and the resulting suspension was quenched with MeOH (10 mL). The solvent was removed under reduced pressure and the crude product was purified by flash chromatography using n-heptane as eluent. Yield: 3.92 g (50%). GCMS: >99%
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([O:27][PH:28]([CH:30]([NH:34][C:35](=[O:44])[CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH:31]([CH3:33])[CH3:32])=[O:29])[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I([O-])(=O)(=O)=[O:46].[Na+]>O1CCOCC1.O>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([O:27][P:28]([CH:30]([NH:34][C:35](=[O:44])[CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH:31]([CH3:33])[CH3:32])([OH:46])=[O:29])[C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CC(C)C(NC(=O)CCc1ccccc1)[PH](=O)O[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)C(NC(=O)CCc1ccccc1)P(=O)(O)O[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 84 %

Procedure:
The benzyl (S)-6-(benzyloxycarbonylamino)-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)phosphinoyloxy)hexanoate (117 mg) obtained in the above step (b) was dissolved in a mixed solvent of dioxane (4.5 ml) and water (1.5 ml) and added with sodium periodate (40.4 mg), and then the mixture was stirred at room temperature for 15 hours. The organic substances were extracted with ethyl acetate, and the extract was washed with saturated aqueous sodium thiosulfate and saturated brine, successively, and dried over anhydrous magnesium sulfate. Then the solvent was evaporated to obtain benzyl (S)-6-(benzyloxycarbonylamino)-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoate (100.8 mg, 84%). This compound was subjected to the measurement of molecular weight and then used in the following reaction without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([CH2:7][NH:8][CH2:9][CH2:10][NH2:11])[O:4][N:3]=1.[N+:12]([NH:15][C:16](N)=N)([O-:14])=[O:13]>O>[Br:1][C:2]1[CH:6]=[C:5]([CH2:7][N:8]2[CH2:9][CH2:10][NH:11][C:16]2=[N:15][N+:12]([O-:14])=[O:13])[O:4][N:3]=1
Reactant: NCCNCc1cc(Br)no1
Reactant: N=C(N)N[N+](=O)[O-]
Solvent: O
Product: O=[N+]([O-])N=C1NCCN1Cc1cc(Br)no1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
N-(3-bromo-5-isoxazolylmethyl)ethylene diamine (4 g), prepared as described above, and nitroguanidine (2.5 g), were added to water (50 ml) and the reaction mixture stirred at 80° C. for 1 hour. The reaction mixture was partitioned with trichloromethane and the organic layer was separated, washed and dried. Thin layer chromatography showed a single product and was used to recover the product as a colorless solid (2.1 g). Recrystallization gave the title compound as colorless crystals (m.p. 149° C.).
Reaction SMILES: [O:1]1[C:5]2[C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[S:23](O)(=[O:25])=[O:24].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CS(O)(=O)=O>>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[S:23]([C:8]1[CH:7]=[C:6]([C:10]([O:12][CH3:13])=[O:11])[C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=1)(=[O:24])=[O:25]
Reactant: COc1ccc(C)cc1S(=O)(=O)O
Reactant: COC(=O)c1cccc2c1OCC2
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: COC(=O)c1cc(S(=O)(=O)c2cc(C)ccc2OC)cc2c1OCC2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To methyl 2,3-dihydro-1-benzofuran-7-carboxylate (1 g, 5.6 mmol; Intermediate 65) were 2-methoxy-5-methylbenzenesulfonic acid (1.13 g, 5.6 mmol) and phosphorus pentoxide-methanesulfonic acid solution (1:10; 13.5 mL) added. The mixture was stirred at room temperature for 48 h. Additional 2-methoxy-5-methylbenzenesulfonic acid (0.56 g, 2.8 mmol) was added and the reaction mixture was stirred at 50° C. for 15 h. The mixture was poured onto water/ice and the formed precipitate was filtrated off, dissolved in DCM and evaporated. The crude product was purified using flash chromatography (eluent: isohexane:EtOAc 1:1) yielding the title compound. Yield: 1.07 g (53%). MS (ESI+) for C18H18O6S m/z 363 (M+H)+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:18])([C:14]([F:17])([F:16])[F:15])[C@@H:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[OH:6].[F:19][C:20]([F:26])([F:25])[S:21](Cl)(=[O:23])=[O:22]>C(OCC)C>[F:18][C:4]([F:3])([C:14]([F:15])([F:16])[F:17])[C@H:5]([O:6][S:21]([C:20]([F:26])([F:25])[F:19])(=[O:23])=[O:22])[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1
Reactant: O[C@H](c1ccc(F)cc1)C(F)(F)C(F)(F)F
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: O=S(=O)(O[C@H](c1ccc(F)cc1)C(F)(F)C(F)(F)F)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A 60% suspension of NaH in oil (2.35 g, 58.8 mmol) was washed several times with hexanes and after suspending it in anhydrous ethyl ether (100 mL), (R)-2,2,3,3,3-pentafluoro-1-(4-fluoro-phenyl)propan-1-ol (12.0 g, 49 mmol) in ether (20 mL) was added slowly at room temperature. After stirring for 15 min, the reaction mixture was cooled at 0° C. and trifluoromethylsulfonyl chloride (12.38 g, 73.7 mmol) was added. The reaction mixture was stirred for 1:30 h at 0° C., then concentrated under reduced pressure and the residue was diluted with hexane (100 mL). The reaction mixture was washed with sat. sol. NaHCO3, brine and dried over magnesium sulfate. After removing the solvent on rotovapor, trifluoro-methanesulfonic acid (R)-2,2,3,3,3-pentafluoro-1-(4-fluorophenyl)propyl ester was obtained as a colorless oil (16.0 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[O:8].[O:9]=O>O>[OH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([OH:9])=[O:1]
Reactant: O=O
Reactant: O=CCCCCCO
Solvent: O
Product: O=C(O)CCCCCO
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
5.28 Grams (45 mmols) of 6-hydroxyhexanal was charged to a 100 milliliter Schlenk flask and dissolved in 45 milliliters of deionized water by heating to 85-95° C. in a water bath. The resulting solution was charged to the Parr autoclave, placed under 1500 psi O2 and heated to 120° C. Samples were taken every 30 minutes throughout the reaction. After 1.5 hours, reaction conversion was 92% and 6-hydroxycaproic acid was formed in 92% selectivity.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][C:25]([NH2:27])=[O:26]>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][C:25]([NH2:27])=[O:26])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)CN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 33.1 %

Procedure:
The mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (6.77 g, 30.7 mmol), K2CO3 (5 g, 36.2 mmol) and 2-bromoacetamide (4.46 g, 32.3 mmol) in acetonitrile (250 ml) was heated to reflux for 4 hours. The insolubles were filtered and rinsed with dichloromethane (DCM). The solvents were removed. The residual solid was dissolved in DCM and upon concentration of this solution, 2.3 g of product crystallized out and was collected when the volume was reduced to about 50 ml. The rest of the product in DCM was purified by flash chromatography over a silica gel column (80 gm, SiO2 ; eluted with DCM and 1% CH3OH in DCM). The total product (4.2 g) thus purified was recrystallized from ethanol to yield 2.82 g of white crystals, m.p. 170°-172° C. dec.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[NH:7]1[CH2:12][CH2:11][CH:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8]1>ClCCl>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[N:7]1[CH2:12][CH2:11][CH:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8]1
Reactant: CCOC(=O)C1CCNCC1
Reactant: Brc1nccs1
Solvent: ClCCl
Product: CCOC(=O)C1CCN(c2nccs2)CC1
Temperature: 100 °C
Yield: 62.9 %

Procedure:
A mixture of 2-bromo-1,3-thiazole (522 mg, 3.18 mmol) and ethyl piperidine-4-carboxylate (1 g, 6.36 mmol) was heated to 100° C. neat overnight, then cooled to room temperature. The residue was dissolved in dichloromethane and directly purified by CombiFlash (0-40% ethyl acetate/hexanes) to provide 654 mg (2.7 2 mmol, 86% yield) of ethyl 1-(1,3-thiazol-2-yl)piperidine-4-carboxylate as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1[C:10](=[O:14])/[CH:11]=[CH:12]\[CH3:13].C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC>[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:8])([CH3:9])[C:3]=1[C:10](=[O:14])/[CH:11]=[CH:12]/[CH3:13]
Reactant: C/C=C\C(=O)C1=C(C)CCCC1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: c1ccccc1
Product: C/C=C/C(=O)C1=C(C)CCCC1(C)C
Yield: 90 %

Procedure:
Under an atmosphere of nitrogen, a solution containing 1.16 g. of cis-2,6,6-trimethyl-1-crotonoyl-1-cyclohexene prepared according to Example 18, 12 ml. of dry benzene and 0.023 g. of p-toluenesulfonic acid were stirred 48 hours at room temperature. The solution was diluted with ether, neutralised and washed as usual. The volatile components were removed in vacuo and distillation gave a 90% yield of trans-2,6,6-trimethyl-1-crotonoyl-1-cyclohexene, b.p. 78°-80°/0.001 Torr, the constants of which were found identical with those of the compound described in Example 12.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:12]1[CH:13]=[CH:14][C:15]([N+:27]([O-:29])=[O:28])=[C:16]([N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:17]=1>CN(C)C=O>[CH2:3]([O:10][C:12]1[CH:13]=[CH:14][C:15]([N+:27]([O-:29])=[O:28])=[C:16]([N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[CH:17]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 268.5 %

Procedure:
A mixture of sodium hydride (5.24 g, 55% dispersion in mineral oil), benzyl alcohol (13 g) and anhydrous N,N-dimethylformamide (150 ml) was stirred at room temperature for 30 minutes. To this mixture was added t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (8.7 g) at room temperature and this mixture was stirred for 18 hours. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated. The residue was chromatographed on a silica gel column using hexane: ethyl acetate=10:1 as the eluant to afford the title compound (29.2 g, yellow crystals, mp 108-110° C.).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:26])[C@H:10]([CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[NH:11]C(OC(C)(C)C)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30]>ClCCl>[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[C:1]1([CH2:7][O:8][C:9](=[O:26])[C@H:10]([CH2:19][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[NH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](CC1CCCCC1)C(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
To a stirred solution of 35.3 g (94.5 mmole) of N-[(1,1-dimethylethoxy)carbonyl]-3-cyclohexyl-(L)-alanine phenylmethyl ester in 100 mL of dichloromethane at 17° C. is added 100 mL of trifluoroacetic acid over 15 minutes during which time the reaction mixture temperature rises to 21° C. The reaction mixture is stirred overnight, then is concentrated in vacuo. The residue is azeotroped with dichloromethane, toluene and methyl tert-butyl ether. The resulting oil is subjected to high vacuum to afford 3-cyclohexyl-(L)-alanine phenylmethyl ester trifluoroacetate (32.6 g). MS (ion spray) m/z 262 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)=[O:5].[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([C:4](=[O:5])[CH2:3][CH2:2][N:28]2[CH2:29][CH2:30][CH:25]([C:21]3[CH:20]=[C:19]([NH:18][C:16](=[O:17])[CH:15]([CH3:14])[CH3:31])[CH:24]=[CH:23][CH:22]=3)[CH2:26][CH2:27]2)=[CH:7][CH:8]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: COc1ccc(C(=O)CCCl)cc1
Product: COc1ccc(C(=O)CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)cc1

Procedure:
Procedure K (KI) and Scheme E (K2cO3) using 3-chloro-1-(4-methoxyphenyl)-1-propanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 409.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C:14]23[O:21][CH:18]([CH2:19]C2)[CH:17]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:16][CH2:15]3)[N:6]=1.[CH3:40][O:41][C@@H]1[C@H](NC(=O)OC(C)(C)C)CC[C@@H](C2N(C)N=CC=2[N+]([O-])=O)OC1>>[Br:1][C:2]1[S:3][C:4]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:37])([CH3:38])[CH3:36])=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C@@H:14]2[CH2:15][CH2:16][C@@H:17]([NH:22][C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[C@@H:19]([O:41][CH3:40])[CH2:18][O:21]2)[N:6]=1
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1C12CCC(NC(=O)OC(C)(C)C)C(CC1)O2
Reactant: CO[C@H]1CO[C@H](c2c([N+](=O)[O-])cnn2C)CC[C@H]1NC(=O)OC(C)(C)C
Product: CO[C@H]1CO[C@H](c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC[C@H]1NC(=O)OC(C)(C)C

Procedure:
Following the procedure for Intermediate 65, starting from tert-butyl ((3S,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 93) gave tert-Butyl N-[2-bromo-4-[[5-[(2S,5R,6R)-5-(tert-butoxycarbonylamino)-6-methoxy-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate.
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]1[C:13](Cl)=[O:14].Cl.[NH2:18][CH2:19][CH2:20][CH2:21][C:22]#[N:23].N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:19]([CH2:20][CH2:21][CH2:22][NH:23][C:13]([C:6]1[N:5]([CH2:4][CH2:3][CH:2]([CH3:16])[CH3:1])[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=1)=[O:14])#[N:18]
Reactant: N#CCCCN
Reactant: CC(C)CCn1cc([N+](=O)[O-])cc1C(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)CCn1cc([N+](=O)[O-])cc1C(=O)NCCCC#N
Temperature: 50 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To a mixture of the acid chloride 45 (0.6 g, 2.45 mmol) and 3-aminopropylcyanide hydrochloride (0.31 g, 2.57 mmol) in anhydrous toluene was added 1.5 ml of anhydrous pyridine. The reaction mixture was stirred at 50° C. overnight and then evaporated to dryness. The product was purified by chromatography using toluene-ethyl acetate (2:1) to yield white crystals (0.623 g, 87%). 1H NMR (DMSO-d6) δ 8.46 (t, 1H), 8.17 (d, 1H), 7.39 (d, 1H), 4.37 (t, 2H), 3.27 (quintet, 2H), 2.53 (d, 2H), 1.77 (quintet, 2H), 1.60–1.42 (q and quintet, 3H), 0.87 (d, 6H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:25])[C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH2:18][C@@H:19]([NH2:24])[CH2:20][CH:21]([CH3:23])[CH3:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31](Cl)=[O:32]>>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:25])[C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH2:18][C@@H:19]([NH:24][C:31]([C:27]2[S:26][CH:30]=[CH:29][CH:28]=2)=[O:32])[CH2:20][CH:21]([CH3:22])[CH3:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1cccs1
Reactant: CC(C)C[C@H](N)CN1CCC[C@H]1C(=O)NCCCCc1ccccc1
Product: CC(C)C[C@@H](CN1CCC[C@H]1C(=O)NCCCCc1ccccc1)NC(=O)c1cccs1
Yield: 55 %

Procedure:
Using the procedure described in Example 7, treatment of 1-[2-(S)-amino-4-methylpentyl]-L-proline 4-phenylbutylamide (113 mg) with 2-thiophenecarbonyl chloride (50 uL) provided 74 mg (55%) of the title compound. The 1H NMR and Mass spectrum analysis of this compound was consistent with the structure. Rf=0.46 (EtOAc). LSIMS=456; (mass calculated for C26H37N3O2S=455.60).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][C@@:6]12[CH2:17][CH2:16][CH2:15][C:13]3[C:14]1=[C:9]([CH:10]=[CH:11][CH:12]=3)[NH:8][C:7]2=[O:18].C(Br)(Br)(Br)[Br:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[Br:20][CH2:2][CH2:3][CH2:4][CH2:5][C@@:6]12[CH2:17][CH2:16][CH2:15][C:13]3[C:14]1=[C:9]([CH:10]=[CH:11][CH:12]=3)[NH:8][C:7]2=[O:18]
Reactant: BrC(Br)(Br)Br
Reactant: O=C1Nc2cccc3c2[C@@]1(CCCCO)CCC3
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: O=C1Nc2cccc3c2[C@@]1(CCCCBr)CCC3
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.3 %

Procedure:
(S)-2a-(4-hydroxybutyl)-2a,3,4,5-tetrahydro-1H-benz[cd]indol-2-one (1.96 g, 8.0 mmol) was dissolved in acetonitrile (50 ml). Then, carbon tetrabromide (3.31 g, 10.0 mmol) and triphenylphosphine (2.72 g, 9.6 mmol) were added to the resulting solution and stirred at room temperature for four hours. The solvent was evaporated from the reaction mixture, and ethyl acetate, water and hydrochloric acid (1N) were added to the resulting residue. The reaction product was extracted with ethyl acetate, and the extracted product was washed with saturated saline solution, successively dried over anhydrous sodium sulfate, followed by evaporating the solvent. The resulting product was separated and purified by means of silica gel column chromatography, whereby 2.40 g (yield 97%) of the above-described object compound could be obtained.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][C:20]=1[F:21])[NH:17][C:16]([C:22]1[CH:23]=[CH:24][C:25]([O:29][CH3:30])=[C:26]([NH2:28])[CH:27]=1)=[CH:15]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)(=O)C>[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][C:20]=1[F:21])[NH:17][C:16]([C:22]1[CH:23]=[CH:24][C:25]([O:29][CH3:30])=[C:26]([NH:28][CH2:7][C:6]3[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[CH:27]=1)=[CH:15]2
Reactant: N#Cc1ccc(C=O)cc1
Reactant: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1NCc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.5 %

Procedure:
4-Cyanobenzaldehyde (0.262 g, 2.0 mmol) was added to a stirred mixture of 5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine (0.548 g, 2.0 mmol) in methylene chloride (125 mL), followed by acetic acid (0.2 g). The resulting mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.46 g, 2.2 mmol) was added in one portion, and the resulting homogeneous solution stirred at room temperature for 4 days. Saturated aqueous sodium bicarbonate solution (100 mL) was added and the mixture stirred for 2 hours. The mixture was shaken, the organic layer separated and dried over Na2SO4. The solvent was evaporated to give a colorless gum. Recrystallization from methanol gave the product (300 mg), mp 158-159° C.
Reaction SMILES: [C:1]1([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:12]1[O:15][CH:13]1[CH3:14]>>[C:1]1([C:7]2[O:8][C:9]([CH2:12][CH:13]([OH:15])[CH3:14])=[CH:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2ccco2)cc1
Reactant: CC1CO1
Product: CC(O)Cc1ccc(-c2ccccc2)o1

Procedure:
2-Phenylfuran(14.4g,0.1 mole) was reacted in a similar manner to Example 40 but using propylene oxide (9ml,0.13 mole). The title compound was obtained as a straw coloured oil (16.0g) b.p. 145° C./0.05 mm with decomposition.
Reaction SMILES: [CH3:1][C:2]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[C:21](=[O:25])[N:20](CC1C=CC(OC)=CC=1)[CH2:19][CH2:18]2)([CH3:14])[CH2:3][O:4][CH2:5][CH2:6][O:7]C1CCCCO1>FC(F)(F)C(O)=O>[OH:7][CH2:6][CH2:5][O:4][CH2:3][C:2]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[C:21](=[O:25])[NH:20][CH2:19][CH2:18]2)([CH3:14])[CH3:1]
Reactant: COc1ccc(CN2CCc3cc(C(C)(C)COCCOC4CCCCO4)ccc3C2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(COCCO)c1ccc2c(c1)CCNC2=O
Yield: 94.9 %

Procedure:
140 mg 6-{1,1-Dimethyl-2-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-ethyl}-2-(4-methoxy-benzyl)-3,4-dihydro-2H-isoquinolin-1-one (0.3 mmol, 1 eq) was dissolved in 5 ml trifluoroacetic acid, and the mixture heated to 80 C for 16 hours. The reaction was concentrated to dryness, partitioned between ethyl acetate and saturated sodium bicarbonate, separated layers and washed ethyl acetate with brine, dried MgSO4 and concentrated to give 75 mg 6-[2-(2-Hydroxy-ethoxy)-1,1-dimethyl-ethyl]-3,4-dihydro-2H-isoquinolin-1-one, M+H=264 which was used without purification in the next step.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][N:8]=[C:9]=[O:10])=[C:2]=[O:3].[NH2:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][NH:23][S:24]([C:27]1[CH:32]=[CH:31][C:30]([CH:33]2[C:42]3[C:37](=[C:38]([Cl:44])[CH:39]=[C:40]([Cl:43])[CH:41]=3)[CH2:36][N:35]([CH3:45])[CH2:34]2)=[CH:29][CH:28]=1)(=[O:26])=[O:25]>>[O:3]=[C:2]([NH:1][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:10])[NH:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][NH:23][S:24]([C:27]1[CH:28]=[CH:29][C:30]([CH:33]2[C:42]3[C:37](=[C:38]([Cl:44])[CH:39]=[C:40]([Cl:43])[CH:41]=3)[CH2:36][N:35]([CH3:45])[CH2:34]2)=[CH:31][CH:32]=1)(=[O:26])=[O:25])[NH:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][NH:23][S:24]([C:27]1[CH:28]=[CH:29][C:30]([CH:33]2[C:42]3[C:37](=[C:38]([Cl:44])[CH:39]=[C:40]([Cl:43])[CH:41]=3)[CH2:36][N:35]([CH3:45])[CH2:34]2)=[CH:31][CH:32]=1)(=[O:26])=[O:25]
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(S(=O)(=O)NCCOCCOCCOCCN)cc2)C1
Reactant: O=C=NCCCCN=C=O
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(S(=O)(=O)NCCOCCOCCOCCNC(=O)NCCCCNC(=O)NCCOCCOCCOCCNS(=O)(=O)c3ccc(C4CN(C)Cc5c(Cl)cc(Cl)cc54)cc3)cc2)C1
Yield: 64.9 %

Procedure:
Compound 248 was prepared following the procedure outlined in Example 208 using 1,4-diisocyanatobutane (7.64 mg, 0.545 mmol) and N-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)-4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide (Compound 82, 84.4 mg, 0.109 mmol). Purification by preparative HPLC gave the title compound (43.6 mg) as a TFA salt. 1H-NMR (400 MHz, CD3OD): δ 7.89 (d, 4H), 7.54 (s, 2H), 7.45 (d, 4H), 6.84 (s, 2H), 4.79-4.71 (m, 4H), 3.89-3.85 (dd, 2H), 3.59-3.56 (m, 17H), 3.49-3.43 (m, 14H), 3.28-3.23 (m, 5H), 3.14 (s, 7H), 3.09-3.04 (m, 9H), 1.42 (s, 4H). MS (m/z): 1233.03 [M+H]+.