Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:12](=[O:17])[NH:13][CH2:14][CH2:15][SH:16])[CH:9]([CH3:11])[CH3:10])(C)(C)C.C(Cl)Cl.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>>[NH2:7][C@@H:8]([CH:9]([CH3:11])[CH3:10])[C:12]([NH:13][CH2:14][CH2:15][SH:16])=[O:17]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)NCCS
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@H](N)C(=O)NCCS
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To 26g (222.0 mg, 0.80 mmol) in a 100 mL round-bottom flask purged with argon were added CH2Cl2 (2.00 mL, 31.2 mmol), triethylsilane (1.28 mL, 8.0 mmol), and trifluoroacetic acid (616 μL, 8.0 mmol). The reaction was stirred for 2.5 hours at room temperature, then concentrated in vacuo. The crude product was purified by silica gel chromatography using 10% methanolic CH2Cl2 as eluant. Clean fractions were combined, and concentrated in vacuo to afford 27g as a colorless oil.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.CC(C)([O-])C.[K+].[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2([CH:34]=O)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>C1COCC1>[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2(/[CH:34]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=CC1(c2ccc(F)cc2)CCCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/C1(c2ccc(F)cc2)CCCCC1
Reaction time: 0.25 h
Yield: 91.9 %

Procedure:
To a solution of ethyl 2-(diethoxyphosphoryl)acetate (0.714 mL, 3.57 mmol) in 10 mL of THF at 0° C. was added 1 M potassium tert-butoxide in THF (3.57 mL, 3.57 mmol) dropwise, and the mixture was stirred for 15 mins at the same temperature. Then a solution of 1-(4-fluorophenyl)cyclohexanecarbaldehyde (Intermediate I-7A, 368 mg, 1.784 mmol) in 3 mL of THF was added dropwise, and the mixture was stirred at room temperature for 18 hrs. The reaction mixture was partitioned between ethyl acetate and water. The ethyl acetate extract was washed with brine, dried over sodium sulfate and evaporated to give an oily residue which was purified by Combiflash (80 g silica gel) eluting with hexane followed by 5:95 EtOAc-hexane to give the desired (E)-ethyl 3-(1-(4-fluorophenyl)cyclohexyl)acrylate (453 mg, 92% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.28 (2H, dd, J=9.02, 5.28 Hz), 7.01 (2H, t, J=8.80 Hz), 6.95 (1H, d, J=16.07 Hz), 5.60 (1H, d, J=16.07 Hz), 4.16 (2H, q, J=7.26 Hz), 1.99-2.08 (2H, m), 1.85-1.94 (2H, m), 1.39-1.62 (6H, m), 1.27 (3H, t, J=7.15 Hz).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=2)[C:10]([O:12]C)=[O:11])=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=2)[C:10]([OH:12])=[O:11])=[CH:3][CH:2]=1
Reactant: COC(=O)c1cccc(-c2ccncc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cccc(-c2ccncc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a solution of methyl 3-(pyridin-4-yl)benzoate (450 mg, 2.1 mmol) in MeOH (5 mL) was added an aqueous solution of NaOH (1.5 mL, 0.4M). The mixture was stirred at room temperature for 2 h. The reaction solution was then concentrated, the residue was next dissolved in water and adjusted pH to 5˜6 with the 2N HCl. After extraction with EtOAc, the organic layers were dried and concentrated to give the product desired (600 mg, Yield 90%). LCMS (m/z): 200.1 (M+1).
Reaction SMILES: C(NC(C1C=CC=CC=1)C)(=O)C.C([NH:16][CH:17]([CH2:26][CH:27]=[CH2:28])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)(=O)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CO>[NH2:16][C@@H:17]([CH2:26][CH:27]=[CH2:28])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1
Reactant: C=CCC(Cc1ccc(Cl)cc1)NC(C)=O
Agent: CC(=O)NC(C)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C=CC[C@H](N)Cc1ccc(Cl)cc1
Temperature: 28 °C
Reaction time: 21 h

Procedure:
Strain K1/1 is grown according to example 3 in a 30 l fermenter filled with 20 l of basic medium containing 1 g/l of racemic N-acetyl-1-phenylethylamine. The cells are harvested by continuous centrifugation and resuspended in the reaction mixture, which is prepared by adding a solution of 80 g racemic 2-acetylamino-1(4-chlorophenyl)-4-pentene in 500 ml methanol to 20 l of potassium phosphate buffer, 69 mM, pH 7. After stirring for 21 h at 28° C. and 500 rpm the amine formed and the unreacted amide are separated and analyzed for their optical purity analogously to the procedure given in example 30.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[C:7]([CH3:13])[CH:8]=[CH:9][C:10]=2[CH3:12])[NH:5][C:4]=1[C:14]([O:16][CH3:17])=[O:15])=O.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[SH:25].O>C(OCC)(=O)C>[S:25]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[C:1]1[C:3]1[C:11]2[C:6](=[C:7]([CH3:13])[CH:8]=[CH:9][C:10]=2[CH3:12])[NH:5][C:4]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)c1[nH]c2c(C)ccc(C)c2c1C=O
Reactant: Nc1ccccc1S
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1[nH]c2c(C)ccc(C)c2c1-c1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.6 %

Procedure:
In 10 ml of ethyl acetate were dissolved 0.50 g (2.16 mmol) of methyl 3-formyl-4,7-dimethylindole-2-carboxylate and 0.27 g (2.16 mmol) of o-aminothiophenol. The reaction mixture was stirred at room temperature overnight. After addition of 0.30 g of o-aminothiophenol, the reaction mixture was stirred for 1 day and then poured into water. The reaction mixture was extracted with diethyl ether, washed with water and concentrated. The crude crystals were purified by silica gel column chromatography (toluene) and recrystallized from methanol-water to provide 0.15 g of beige powder. Yield: 20%
Reaction SMILES: [N:1]1([CH2:6][C:7]2([CH2:10][NH:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]4[N:26]=[C:25]([O:27][CH2:28][C:29]([F:32])([F:31])[F:30])[N:24]=[C:23]([NH:33][C:34]5([C:37]6[CH:49]=[CH:48][C:40]([O:41][CH2:42][C:43]([O:45]CC)=[O:44])=[CH:39][CH:38]=6)[CH2:36][CH2:35]5)[N:22]=4)=[CH:16][CH:15]=3)=[O:13])[CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[OH-].O>C1COCC1>[N:1]1([CH2:6][C:7]2([CH2:10][NH:11][C:12]([C:14]3[CH:15]=[CH:16][C:17]([NH:20][C:21]4[N:26]=[C:25]([O:27][CH2:28][C:29]([F:32])([F:30])[F:31])[N:24]=[C:23]([NH:33][C:34]5([C:37]6[CH:49]=[CH:48][C:40]([O:41][CH2:42][C:43]([OH:45])=[O:44])=[CH:39][CH:38]=6)[CH2:36][CH2:35]5)[N:22]=4)=[CH:18][CH:19]=3)=[O:13])[CH2:9][CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)COc1ccc(C2(Nc3nc(Nc4ccc(C(=O)NCC5(CN6CCCC6)CC5)cc4)nc(OCC(F)(F)F)n3)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)COc1ccc(C2(Nc3nc(Nc4ccc(C(=O)NCC5(CN6CCCC6)CC5)cc4)nc(OCC(F)(F)F)n3)CC2)cc1
Temperature: 65 °C
Yield: 50.6 %

Procedure:
ethyl 2-(4-(1-(4-(4-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methylcarbamoyl)phenylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)cyclopropyl)phenoxy)acetate (268 mg, 0.392 mmol) was dissolved in THF (Ratio: 1.000, Volume: 2 mL) then LiOH (46.9 mg, 1.960 mmol) and Water (Ratio: 1.000, Volume: 2 mL) were added and the reaction was heated to 65° C. for 2 h. The solvent was removed under vacuum and water was added back to the flask and the pH adjusted to ˜7 with 1N HCl. A solid precipitated out of solution and this was collected, washed with water, and dried to give 2-(4-(1-(4-(4-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methylcarbamoyl)phenylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)cyclopropyl)phenoxy)acetic acid (130 mg). 1H NMR (400 MHz, MeOD) δ ppm 0.62-0.70 (m, 2H), 0.94-1.02 (m, 2H), 1.15-1.34 (m, 4H), 2.10 (br. s., 4H), 3.08 (br. s., 2H), 3.30-3.33 (m, 4H), 3.49 (s, 2H), 4.51 (s, 2H), 4.86-4.93 (m, 2H), 6.85-6.94 (m, 2H), 7.08-7.16 (m, 2H), 7.16-7.25 (m, 2H), 7.42-7.54 (m, 2H); LC-MS (Condition A), MS m/z (M++H) 656.1.
Reaction SMILES: [BrH:1].N[C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.CC1(C)N([O])C(C)(C)CCC1.N([O-])=O.[Na+].[OH-].[Na+]>O>[Br:1][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: Br
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc(Br)cc1
Temperature: 10 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
Water (45 ml) and 48% hydrobromic acid (27 ml) were added to 4-aminobenzonitrile (2d) (2.36 g, 20 mmol) at room temperature. To the mixed solution, 2,2,6,6-tetramethylpiperidine 1-oxyl (0.31 g, 2 mmol) was added at room temperature, and the mixture was cooled to 10° C. or lower. Then, sodium nitrite (2.07 g) dissolved in water (15 ml) was added thereto. The mixture was heated to 55° C., then stirred for approximately 2 hours, and cooled to room temperature. Then, a 10 mol/L aqueous sodium hydroxide solution (40 ml) was added thereto, followed by extraction twice with toluene (300 ml). The toluene layers were combined and washed with water (50 ml). The solvent was distilled off by the concentration of the toluene layer under reduced pressure to obtain 4-bromobenzonitrile (1d) (3.35 g, 83.0%). The instrumental spectrum data and HPLC retention time (Rt) of the obtained compound (1d) were completely consistent with those of the commercially available compound (1d).
Reaction SMILES: N[C@@H](C)CNC1SC([C:11](OCC)=[O:12])=C(C)N=1.[NH2:17][CH2:18][C@@H:19]([NH:21][C:22]1[S:23][C:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:25]([CH3:27])[N:26]=1)[CH3:20]>>[CH3:27][C:25]1[N:26]=[C:22]([N:21]2[C@@H:19]([CH3:20])[CH2:18][NH:17][C:11]2=[O:12])[S:23][C:24]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CCOC(=O)c1sc(N[C@@H](C)CN)nc1C
Reactant: CCOC(=O)c1sc(NC[C@H](C)N)nc1C
Product: CCOC(=O)c1sc(N2C(=O)NC[C@@H]2C)nc1C

Procedure:
Following the procedure as described in Preparation 4, making variations as required to replace (S)-ethyl 2-(2-aminopropylamino)-4-methylthiazole-5-carboxylate with (S)-ethyl 2-(1-aminopropan-2-ylamino)-4-methylthiazole-5-carboxylate, the title compound was obtained as a colorless solid (52%): MS (ES+) m/z 269.7 (M+1).
Reaction SMILES: C(P(CCCC)CCCC)CCC.[CH3:14][C:15]1[C:20]([CH2:21][OH:22])=[CH:19][CH:18]=[C:17]([CH3:23])[N:16]=1.[CH3:24][O:25][C:26](=[O:40])[CH2:27][C:28]1[C:32]2[C:33]([CH3:39])=[CH:34][C:35](O)=[C:36]([CH3:37])[C:31]=2[O:30][CH:29]=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[CH3:24][O:25][C:26](=[O:40])[CH2:27][C:28]1[C:32]2[C:33]([CH3:39])=[CH:34][C:35]([O:22][CH2:21][C:20]3[C:15]([CH3:14])=[N:16][C:17]([CH3:23])=[CH:18][CH:19]=3)=[C:36]([CH3:37])[C:31]=2[O:30][CH:29]=1
Reactant: Cc1ccc(CO)c(C)n1
Reactant: COC(=O)Cc1coc2c(C)c(O)cc(C)c12
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)Cc1coc2c(C)c(OCc3ccc(C)nc3C)cc(C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
To a mixture of tri-n-butylphosphine (0.240 mL), (2,6-dimethylpyridin-3-yl)methanol (92 mg), methyl(6-hydroxy-4,7-dimethyl-1-benzofuran-3-yl)acetate (150 mg) and THF (6.0 mL) was added ADDP (242 mg) at room temperature. The mixture was stirred at room temperature overnight under nitrogen atmosphere. The mixture was concentrated. To the residue was added. IPE and the precipitate was filtered off and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (163.9 mg).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[CH2:12]([C:14]([CH2:19][CH3:20])([CH2:17]O)[CH2:15][OH:16])[CH3:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:12]([C:14]1([CH2:19][CH3:20])[CH2:15][O:16][CH:10]([C:7]2[CH:8]=[CH:9][C:2]([F:1])=[C:3]([C:4]#[N:5])[CH:6]=2)[O:11][CH2:17]1)[CH3:13]
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: CCC(CC)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCC1(CC)COC(c2ccc(F)c(C#N)c2)OC1
Yield: 90.7 %

Procedure:
2-Fluoro-5-formylbenzonitrile (250 mg, 1.68 mmol), 2,2-diethyl-1,3-propanediol (776 mg, 5.87 mmol) and a catalytic amount of p-toluenesulfonic acid monohydrate were refluxed in toluene (25 mL) overnight in a Dean-Stark apparatus. The reaction mixture was then concentrated and the residue dissolved in chloroform (50 mL) and washed with saturated sodium bicarbonate solution (2×25 mL) then brine (1×25 mL). The organic phase was dried (Na2SO4) and evaporated to give an oil. The oil was then chromatographed on silica gel (4:1 hexane/ethyl acetate) to give 5-(5,5-diethyl-1,3-dioxan-2-yl)-2-fluorobenzenecarbonitrile (43) as a light yellow oil (401 mg, 91%). 1H NMR (MeOD, 300 MHz): δ 0.90, t (7.7 Hz), CH2CH3; 0.97, t (7.5 Hz), CH2CH3; 1.25, q (7.6 Hz), CH2CH3; 1.86, q (7.6 Hz), CH2CH3; 3.72, d (11.5 Hz), CH2O; 4.02, d (11.4 Hz), CH2O; 5.52, s, H2; 7.42, t (9.3 Hz), H3; 7.86, m, H4,6. ESI (+ve) MS: m/z 264 (M+H, 11%).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]#[N:9].[Br:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=[O:15]>[NH4+].[Cl-]>[Br:10][C:11]1[CH:12]=[C:13]([CH:14]([OH:15])[CH2:7][C:8]#[N:9])[CH:16]=[CH:17][CH:18]=1
Reactant: CC#N
Reactant: O=Cc1cccc(Br)c1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Product: N#CCC(O)c1cccc(Br)c1
Temperature: -50 °C
Reaction time: 0.5 h

Procedure:
To a cold (−50° C.) stirred solution of potassium tert-butoxide (1M/THF, 703 mL, 703 mmol) under argon was added CH3CN (27.73 g, 675.6 mmol) via syringe over 5 min and the reaction mixture was stirred at −50° C. for 30 min. Then a solution of 3-bromobenzaldehyde (22) (100 g, 540.5 mmol) was added over 5 min. The reaction mixture was stirred for 30 min at −50° C. and allowed to warm to room temperature. Aqueous NH4Cl (25%, 250 mL) was added, the mixture was stirred and layers were separated. Organic layer was washed with saturated brine (200 mL), dried over anhydrous Na2SO4, filtered, the filtrate was concentrated under reduced pressure and the residue was dried in vacuum overnight to give hydroxynitrile 23 as a pale yellow oil. Yield (117.6 g, 96%); 1H NMR (400 MHz, DMSO-d6) δ 7.60 (t, J=1.6 Hz, 1H), 7.46 (ddd, J=7.6, 2.0, 1.2 Hz, 1H), 7.40 (dd, J=7.6, 2.0 Hz, 1H), 7.31 (t, J=7.6 Hz, 1H), 6.05 (d, J=4.8 Hz, 1H), 2.94-2.80 (m, 2H).
Reaction SMILES: [F:1][C:2]1[C:22]([OH:23])=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([OH:13])=O)[C:7](=[O:18])[CH:6]=1.[CH3:24][N:25]1[CH:29]=[CH:28][C:27]([NH2:30])=[N:26]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:24][N:25]1[CH:29]=[CH:28][C:27]([NH:30][C:11](=[O:13])[C@@H:10]([N:8]2[CH2:9][C:5]([O:4][C:3]3[CH:19]=[CH:20][CH:21]=[C:22]([OH:23])[C:2]=3[F:1])=[CH:6][C:7]2=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16])=[N:26]1
Reactant: CC(C)C[C@@H](C(=O)O)N1CC(Oc2cccc(O)c2F)=CC1=O
Reactant: Cn1ccc(N)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@@H](C(=O)Nc1ccn(C)n1)N1CC(Oc2cccc(O)c2F)=CC1=O
Temperature: 0 °C
Yield: 40.8 %

Procedure:
To a solution of (S)-2-[4-(2-fluoro-3-hydroxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (prepared as in Example 126, 0.226 g, 0.70 mmol) in N,N-dimethylformamide (4 mL) was added 1-methyl-1H-pyrazol-3-ylamine (0.340 g, 3.50 mmol) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.340 g, 0.77 mmol). The mixture was stirred at 0° C. and N,N-diisopropylethylamine (0.108 g, 0.84 mmol) was added. The mixture was stirred at room temperature overnight and the solvents were evaporated. The residue was extracted with ethyl acetate and washed with a citric acid solution. The organic layer was washed with brine and dried over sodium sulfate. The solvents were evaporated and the residue was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g, 10% to 100% (9:1 dichloromethane:methanol)/hexanes) which afforded (S)-2-[4-(2-fluoro-3-hydroxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (1-methyl-1H-pyrazol-3-yl)-amide (0.115 g, 41%) as a white solid: HR-ES-MS m/z calculated for C20H23FN4O4 [M+Na]+ 425.1595, observed 425.1597, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.00 0.90 (d, J=6.4 Hz, 3H), 0.93 (d, J=6.4 Hz, 3H), 1.45 (m, 1H), 1.53-1.63 (m, 1H), 1.67-1.79 (m, 1H), 3.73 (s, 3H), 4.20 (d, J=18.5 Hz, 1H), 4.57 (d, J=18.5 Hz, 1H), 4.84-4.92 (m, 2H), 6.40 (d, J=1.7 Hz, 1H), 6.85 (t, J=7.8 Hz, 1H), 6.91 (t, J=7.8 Hz, 1H), 7.05 (t, J=7.8 Hz, 1H), H), 7.54 (d, J=1.7 Hz, 1H), 10.35 (br. s., 1H), 10.72 (s, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][CH:9]=[N:8][C:7]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[CH:13]=1)=[O:5])C.[Li+].[OH-].C1COCC1>Cl>[C:18]([C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[O:11][C:7]1[N:8]=[CH:9][S:10][C:6]=1[C:4]([OH:5])=[O:3])#[N:19]
Reactant: CCOC(=O)c1scnc1Oc1cccc(C#N)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N#Cc1cccc(Oc2ncsc2C(=O)O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.9 %

Procedure:
A mixture of 375 mg (1.4 mmol) 4-(3-cyano-phenoxy)-thiazole-5-carboxylic acid ethyl ester, 1.4 ml 1M LiOH, and 10 mL of THF was stirred for 18 hours at room temperature. The mixture was concentrated via rotary evaporation to yield yellow oil. The oil was diluted with 1 N HCl (30 mL) precipitating a white solid. The solid was filtered then dried in a drying pistol giving 265 mg of white powder.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=2[C:9]=1[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18]C)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].B(Br)(Br)Br.C(Cl)Cl>C(Cl)Cl>[CH2:1]([C:5]1[O:6][C:7]2[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=2[C:9]=1[CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1oc2ccccc2c1CCc1ccc(OC)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCCc1oc2ccccc2c1CCc1ccc(O)cc1

Procedure:
The title compound was prepared according to the procedure in Example 5, step 3 using 2-butyl-3-[2-(4-methoxy-phenyl)-ethyl]-benzofuran (0.300 g, 0.973 mmol) and 1M boron tribromide/CH2Cl2 (3.11 mL) in CH2Cl2. Purification on silica gel eluting with 50% EtOAc/pet. ether gave the title compound as a dark oil. 1H NMR (DMSO-d6) δ 0.84 (t, 3 H), 1.22 (sextet, 2 H), 1.41 (quintet, 2 H), 2.52 (t, 2 H), 2.74 (t, 2 H), 2.82 (t, 2 H), 6.61 (d, 2 H), 6.91 (d, 2 H), 7.15-7.21 (m, 2 H), 7.40-7.43 (m, 1 H), 7.52-7.54 (m, 1 H), 9.10 (s, 1 H). IR (KBr) 3400, 2950, 1610, 1510 and 1450 cm-1. mass spectrum (FAB) m/z 295 (M+H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:16])[CH3:15])=[CH:9][CH:8]=2)[N:6]=1.[Cl:17][C:18]1[C:19]([CH3:28])=[C:20]([S:24](Cl)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1>>[Cl:17][C:18]1[C:19]([CH3:28])=[C:20]([S:24]([NH:1][C:2]2[S:3][CH:4]=[C:5]([C:7]3[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:16])[CH3:15])=[CH:11][CH:12]=3)[N:6]=2)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1
Reactant: CC(=O)Nc1ccc(-c2csc(N)n2)cc1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Product: CC(=O)Nc1ccc(-c2csc(NS(=O)(=O)c3cccc(Cl)c3C)n2)cc1

Procedure:
The title compound was prepared N-[4-(2-amino-1,3-thiazol-4-yl)penyl]acetamide and 3-chloro-2-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (16.1 mg) with purity >90%: MS (pos) m/z 422.1, (neg) m/z 420.3. HRMS m/z 421.0327 (calc. of monoisotopic mass for C18H16ClN3O3S2 gives 421.0322).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[S:6][C:7]3[CH:28]=[CH:27][CH:26]=[CH:25][C:8]=3[CH:9]=[C:10]([S:11][CH2:12][CH2:13][N:14](C)[C:15](OC3C=CC=CC=3)=O)[C:4]=2[CH:3]=1.[OH-].[K+].Cl>C(O)CO>[ClH:1].[Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[S:6][C:7]3[CH:28]=[CH:27][CH:26]=[CH:25][C:8]=3[CH:9]=[C:10]([S:11][CH2:12][CH2:13][NH:14][CH3:15])[C:4]=2[CH:3]=1
Reactant: CN(CCSC1=Cc2ccccc2Sc2ccc(Cl)cc21)C(=O)Oc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Product: CNCCSC1=Cc2ccccc2Sc2ccc(Cl)cc21
Temperature: 0 °C

Procedure:
A solution of 5.6 g of 2-chloro-11-[β-(N-methyl-N-phenoxycarbonylamino)ethylthio]dibenzo[b,f]thiepin, Example 6, 127 ml of ethylene glycol and 10.8 g of potassium hydroxide is stirred at 150°-155° C. for 30 minutes. Thereafter the reaction mixture is poured onto 300 ml of ice-water and the aqueous mixture is extracted with an ether-toluene (1:1) mixture. The combined extracts, successively, are washed well with water, dried and filtered and the filtrate evaporated leaving an orange oil. The oil is converted to its hydrogen chloride acid salt which is recrystallized from a methanol-acetone-ether mixture to give the product, mp 194°-196° C. of 2-chloro-11-[β-(methylamino)ethylthio]dibenzo[b,f]thiepin hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[I:37][C:38]1[CH:43]=[CH:42][C:41]([N:44]2[CH:48]=[CH:47][C:46]([CH2:49][NH2:50])=[CH:45]2)=[CH:40][CH:39]=1.O>CN(C=O)C>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:50][CH2:49][C:46]2[CH:47]=[CH:48][N:44]([C:41]3[CH:42]=[CH:43][C:38]([I:37])=[CH:39][CH:40]=3)[CH:45]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: NCc1ccn(-c2ccc(I)cc2)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1ccn(-c2ccc(I)cc2)c1)c1ccc(Cl)s1
Reaction time: 0.17 h
Yield: 86 %

Procedure:
To a solution of 5-chloro-thiophene-2-carboxylic acid (60 mg, 0.37 mmol) and TEA (0.102 mL, 0.73 mmol) in DMF (4 mL) was added BOP (196 mg, 0.44 mmol). After 10 min of stirring, the solution was added to a sample of (1-(4-iodophenyl)-1H-pyrrol-3-yl)methanamine (91 mg, 0.31 mmol) in a flask. The mixture was stirred at room temperature overnight. H2O was added to induce precipitation. The resulting precipitate was collected and dried on vacuum to give 5-chloro-N-((1-(4-iodophenyl)-1H-pyrrol-3-yl)methyl)thiophene-2-carboxamide (118 mg).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(Cl)Cl>[CH3:15][S:16]([O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (4.50 g, 22.4 mmol, 1.0 eq) and TEA (11.3 g, 5.0 eq) in DCM (30.0 mL) at 0° C. was added MsCl (5.10 g, 44.5 mmol, 2.0 eq) in DCM (10.0 mL) dropwise. The resulting mixture was stirred at 0° C. for 30 min and then warmed to room temperature with stirring for 3 hr. After being quenched with water and extracted with ethyl acetate, the organic layers were combined, washed with brine, dried over MgSO4, filtered, and evaporated to afford the crude product, which was purified via silica gel chromatography eluting with EtOAc/petroleum ether (1:5) to afford tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (4.8 g, 77% yield) as pale yellow solid. LCMS (ESI) m/z: 224.1 [M-56+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]O)=[CH:4][CH:3]=1.[BrH:16].S(=O)(=O)(O)O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][Br:16])=[CH:4][CH:3]=1
Reactant: Br
Reactant: OCCCCCCCc1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Product: Clc1ccc(CCCCCCCBr)cc1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
30 g of 7-(4-chlorophenyl)heptan-1-ol, 0.13 g of red phosphorus and 37 ml of 62% strength hydrogen bromide are boiled for 6 hours, 8 ml of concentrated sulfuric acid are then added dropwise and the mixture is boiled again for 6 hours. The reaction mixture is poured into 100 ml of ice-water and is extracted twice with diethyl ether; the ether extracts are concentrated and the residue is distilled. 33.5 g of 7-(4-chlorophenyl)heptyl bromide of b.p. 125° to 127° under 0.1 mm Hg are obtained.