Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].[C:2]1(I)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1([S:15]([NH:18][CH2:19][C:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:24][CH:23]=2)=[O:21])(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl-].[NH4+]>O1CCCC1.BrCCBr>[C:9]1([S:15]([NH:18][CH2:19][C:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:24][CH:23]=2)([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[OH:21])(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(CNS(=O)(=O)c1ccccc1)c1ccc(OCc2ccccc2)cc1
Reactant: Ic1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: O=S(=O)(NCC(O)(c1ccccc1)c1ccc(OCc2ccccc2)cc1)c1ccccc1
Temperature: 25 °C
Yield: 58.3 %

Procedure:
5.83 g of magnesium are suspended in 100 ml of dry tetrahydrofuran, and 5 drops of 1,2-dibromoethane are added thereto. After the mixture is stirred at room temperature, a solution of 28.3 g of phenyl iodide in 70 ml of tetrahydrofuran is added dropwise thereto. A solution of 7.65 g of 2-benzenesulfonylamino-1-(4-benzyloxyphenyl)ethanone in 100 ml of tetrahydrofuran is added dropwise to the reaction mixture under ice-cooling and stirring. The mixture is stirred at room temperature, and an aqueous ammonium chloride solution is added thereto. The mixture is extracted with ethyl acetate, and the extract is washed, dried and evaporated to remove the solvent. The residue is purified by silica gel flash column chromatography (solvent; chloroform), and recrystallized from a mixture of ethyl acetate and n-hexane. 5.37 g of 2-benzenesulfonylamino-1-(4-benzyloxyphenyl)-1-phenylethanol are obtained as colorless crystals. m.p. 147.5°-149° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([OH:12])=O.S(Cl)(Cl)=O.[OH:17][CH2:18][CH2:19][NH2:20]>C(Cl)(Cl)Cl>[OH:17][CH2:18][CH2:19][NH:20][C:10]([C:2]1[NH:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)=[O:12]
Reactant: NCCO
Reactant: O=C(O)c1nc2ccccc2[nH]1
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: O=C(NCCO)c1nc2ccccc2[nH]1
Temperature: 25 °C
Yield: 74.9 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was purged with nitrogen and charged with 1H-benzo[d]imidazole-2-carboxylic acid (1.50 g, 9.26 mmol) and thionyl chloride (10 mL). After heating at reflux for 16 h, the suspension was cooled to room temperature and filtered. The filter cake was washed with toluene (10 mL) and dried under vacuum at room temperature for 5 h. The resulting solid was charged into a 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser, followed by chloroform (10 mL) and 2-hydroxyethylamine (559 mg, 9.17 mmol). After stirring at reflux for 16 h, the reaction mixture was concentrated under reduced pressure, and the resulting residue was triturated with water (20 mL) and dried in a vacuum oven at 45° C. to afford a 73% yield (1.41 g) of 152a as a white solid: mp 194-195° C.; 1H NMR (500 MHz, DMSO-d6) d 13.13 (s, 1H), 8.74 (s, 1H), 7.71-7.29 (m, 4H), 4.80 (s, 1H), 3.55 (dd, 2H, J=10.5, 5.5 Hz), 3.38 (dd, 2H, J=10.5, 5.5 Hz); MS (APCI+) m/z 206.6 (M+H).
Reaction SMILES: [F:1][C:2]1[S:6][C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=2)=[N:4][C:3]=1[C:15]1[CH:16]=[N:17][NH:18][CH:19]=1.[O-:20][C:21]#[N:22].[K+].CC(O)=O>O>[F:1][C:2]1[S:6][C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=2)=[N:4][C:3]=1[C:15]1[CH:16]=[N:17][N:18]([C:21]([NH2:22])=[O:20])[CH:19]=1
Reactant: N#C[O-]
Reactant: Cc1cccc(Nc2nc(-c3cn[nH]c3)c(F)s2)n1
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cccc(Nc2nc(-c3cnn(C(N)=O)c3)c(F)s2)n1
Yield: 2.5 %

Procedure:
According to Scheme 19: A solution of N-(5-fluoro-4-(1H-pyrazol-4-yl)thiazol-2-yl)-6-methylpyridin-2-amine (1.22 mmol, 337 mg), potassium cyanate (1.47 mmol, 119 mg), AcOH (5 mL) and water (5 mL) was stirred for 2.5 hours at room temperature. The reaction mixture was quenched with water (100 mL) and the precipitate was filtered. The resulting crude product was purified by flash chromatography over silica gel using DCM/EDA (80:20; EDA: DCM/EtOH/NH3 90:9:1) as eluent to yield 4-(5-fluoro-2-(6-methylpyridin-2-ylamino)thiazol-4-yl)-1H-pyrazole-1-carboxamide (31 μmol, 10 mg, 3%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26][C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[C:35]([C:39]1[CH:44]=[CH:43]C(O)=[CH:41][CH:40]=1)([CH3:38])([CH3:37])[CH3:36].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:26][C:24]2[CH:43]=[CH:44][C:39]([C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:40][CH:41]=2)=[CH:18][CH:17]=1
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Oc4ccc(C(C)(C)C)cc4)cc3)c2cc1OC
Yield: 94.1 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (100 mg) was added to toluene (10 ml) and triethylamine (1 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (151 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 4-(tert-butyl)phenol (77 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (150 mg, yield 87%).
Reaction SMILES: [S:1]([O:11][CH:12](OS(C1C=CC(C)=CC=1)(=O)=O)/[CH:13]=[CH:14]/[CH3:15])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].CC1C=CC([C@@H]2C(C(O[11CH3])=O)C3N(C/C=C/C[F:50])[C@H](CC3)C2)=CC=1.NCCC1C=CC(O)=C(O)C=1>>[C:7]1([CH3:8])[CH:9]=[CH:10][C:4]([S:1]([O:11][CH2:12]/[CH:13]=[CH:14]/[CH2:15][F:50])(=[O:3])=[O:2])=[CH:5][CH:6]=1
Reactant: C/C=C/C(OS(=O)(=O)c1ccc(C)cc1)OS(=O)(=O)c1ccc(C)cc1
Reactant: Cc1ccc([C@H]2C[C@H]3CCC(C2C(=O)O[11CH3])N3C/C=C/CF)cc1
Agent: NCCc1ccc(O)c(O)c1
Product: Cc1ccc(S(=O)(=O)OC/C=C/CF)cc1
Yield: 28 %

Procedure:
This compound was prepared, starting from (E)-but-2-enediol ditosylate (0.50 g, 1.26 mmol), according to the procedure described by Dollé, F.; Emond, P.; Mavel, S.; Demphel, S.; Hinnen, F.; Mincheva, Z.; Saba, W.; Valette, H.; Chalon, S.; Halldin, C.; Helfenbein, J.; Legaillard, J.; Madelmont, J. C.; Deloye, J. B.; Bottlaender, M.; Guilloteau, D. Synthesis, radiosynthesis and in vivo preliminary evaluation of [11C]LBT-999, a selective radioligand for the visualisation of the dopamine transporter with PET Bioorg. Med. Chem. 2006, 14, 1115-1125. Reaction time under reflux: 1 h; the purification was performed using column chromatography (SiO2, CH2Cl2/pentane, 8/2, v/v) to give compound 55 (87 mg, 0.36 mmol) as a colourless oil. Yield 28%; Rf (SiO2, CH2Cl2/pentane, 8/2, v/v) 0.42; IR (CCl4) ν 1179, 1190, 1375, 1599 cm−1; 1H NMR (200 MHz, CDCl3) δ 2.45 (s, 3H), 4.57 (m, 2H), 4.82 (dd, 2H, 2JH-F=46.7 Hz, J=4.7 Hz), 5.85 (m, 2H), 7.36 (d, 2H, J=8.2 Hz), 7.79 (d, 2H, J=8.2 Hz).
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]1[C:7](=[O:8])[O:6][CH2:5][C@@H:4]1[CH2:9][C:10]1[N:14]([CH3:15])[CH:13]=[N:12][CH:11]=1.Cl.[OH-:17].[Na+:18].Cl>O>[CH3:1][CH2:2][C@@H:3]([C:7]([O-:6])=[O:8])[C@H:4]([CH2:5][OH:17])[CH2:9][C:10]1[N:14]([CH3:15])[CH:13]=[N:12][CH:11]=1.[Na+:18]
Reactant: [OH-]
Reactant: CC[C@@H]1C(=O)OC[C@@H]1Cc1cncn1C
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC[C@@H](C(=O)[O-])[C@H](CO)Cc1cncn1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Pilocarpine hydrochloride (3.92 g; 16.00 moles) was dissolved in distilled water (4 ml) and the solution was cooled to about 0° C. To the solution 18 ml of ice cold 2M NaOH were added in four portions. The solution was left standing at about 0° C. for one hour. After neutralizing excess NaOH with 5 ml of 1M HCl, the solution was evaporated under reduced pressure. The residue was dissolved in 60 ml of absolute ethanol and mixed for 10 minutes at 60° C. After cooling to 4° C. undissolved NaCl was removed by filtration. The filtrate was evaporated under reduced pressure, whereby 3.93 g of sodium pilocarpate were obtained as a white, extremely hygroscopic substance.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH2:25]([NH2:29])[CH2:26][CH2:27][CH3:28].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.O.CN(C)C=O>[CH2:25]([NH:29][C:14]([CH:11]1[CH2:10][CH2:9][N:8]([C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:18][CH:17]=2)[CH2:13][CH2:12]1)=[O:16])[CH2:26][CH2:27][CH3:28]
Reactant: CCCCN
Reactant: O=C(O)C1CCN(C(=O)c2ccc(F)cc2)CC1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CCCCNC(=O)C1CCN(C(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(4-Fluorobenzoyl)piperidine-4-carboxylic acid (8.79 g, 35.0 mmol) is dissolved in methylene chloride (75 mL) at 0° C., and dimethylformamide (0.20 mL) and oxalyl chloride (4.9 g, 39 mmol) are added. The mixture is stirred at room temperature for 2 hr. In a second flask, butylamine (2.6 g, 35 mmol) and potassium carbonate (9.67 g, 75.4 mmol) are dissolved in water (100 mL) and methylene chloride (200 mL) at 0° C. The first mixture is added to the second dropwise over 45 min, and the mixture is stirred at 0° C. for 2 hr. The organic phase is separated, washed twice with saturated sodium bicarbonate, twice with 1N HCl, dried over magnesium sulfate, and evaporated. Recrystallization from ethyl acetate-hexane affords the title compound.
Reaction SMILES: [ClH:1].Cl.C1(NC(C2C3C=C(C4C([Cl:24])=CN=C(NCCC5CCNCC5)N=4)SC=3C=CC=2)=O)CC1.[CH:34]1([NH:37][C:38]([C:40]2[C:48]3[CH:47]=[C:46]([C:49]4[C:54]([Br:55])=[CH:53][N:52]=[C:51]([Cl:56])[N:50]=4)[S:45][C:44]=3[CH:43]=[CH:42][CH:41]=2)=[O:39])[CH2:36][CH2:35]1.C(OC([N:64]1[CH2:69][CH2:68][N:67]([CH2:70][CH2:71][NH2:72])[CH2:66][CH2:65]1)=O)(C)(C)C>>[ClH:24].[ClH:56].[ClH:1].[CH:34]1([NH:37][C:38]([C:40]2[C:48]3[CH:47]=[C:46]([C:49]4[C:54]([Br:55])=[CH:53][N:52]=[C:51]([NH:72][CH2:71][CH2:70][N:67]5[CH2:68][CH2:69][NH:64][CH2:65][CH2:66]5)[N:50]=4)[S:45][C:44]=3[CH:43]=[CH:42][CH:41]=2)=[O:39])[CH2:36][CH2:35]1
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(Cl)ncc3Br)cc12
Reactant: CC(C)(C)OC(=O)N1CCN(CCN)CC1
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(NCCC4CCNCC4)ncc3Cl)cc12
Agent: Cl
Product: O=C(NC1CC1)c1cccc2sc(-c3nc(NCCN4CCNCC4)ncc3Br)cc12

Procedure:
Using the synthetic method of 2-[5-chloro-2-(2-piperidin-4-ylethylamino)-pyrimidin-4-yl]-benzo[b]thiophene-4-carboxylic acid cyclopropylamide di-hydrochloride, the title compound is synthesized from 2-(5-bromo-2-chloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid cyclopropylamide and 4-(2-aminoethyl)-piperazine-1-carboxylic acid tert-butyl ester and isolated as a yellow solid (67% yield). ES+(m/z) 501 (79Br) and 503 (81Br) [M(free base)+H].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[CH:4][CH:3]=1.N1C=CC=CC=1.[Br:33]Br.C(OCC)(=O)C>CN(C=O)C>[Br:33][C:14]1[C:15](=[O:19])[N:16]([CH3:18])[CH:17]=[C:12]([C:10](=[O:11])[CH2:9][C@H:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH:13]=1
Reactant: BrBr
Reactant: Cc1ccccc1[C@H](CC(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1ccccc1[C@H](CC(=O)c1cc(Br)c(=O)n(C)c1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2.25 h
Yield: 78 %

Procedure:
To a solution of (R)-5-(3-(4-bromophenyl)-3-o-tolylpropanoyl)-1-methylpyridin-2(1H)-one (0.1 g, example 223) in DMF (1 mL) were added pyridine (217 μL) and then bromine (12.6 μL) dropwise. The resulting solution was stirred at rt for 2.25 h. The reaction mixture was poured on water and ethyl acetate and the layers were separated. The aqueous layer was extracted with 2× ethyl acetate. The organic layers were washed with water and once with brine, dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by chromatography (SiO2, n-heptane/ethyl acetate 100:0 to 50:50) to give the title compound as a light brown solid (0.093 g; 78%), MS (ESI+): m/z=489.0 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[CH:17]=[CH:18][CH:19]=[C:20]4[C:25]=3[N:24]=[C:23]([NH2:26])[CH:22]=[CH:21]4)[CH:10]=2)=[CH:5][CH:4]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>>[F:28][C:2]([F:1])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[CH:17]=[CH:18][CH:19]=[C:20]4[C:25]=3[N:24]=[C:23]([NH:26][C:29](=[O:31])[CH3:30])[CH:22]=[CH:21]4)[CH:10]=2)=[CH:5][CH:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2cccc(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)c2n1
Product: CC(=O)Nc1ccc2cccc(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)c2n1

Procedure:
This material was prepared according to the method described in Example 66 using 8-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-quinolin-2-ylamine, (Example 2(d), Method B), (0.79 g, 2.1 mmol) and acetic anhydride (2.5 mL, 2.6 mmol). Purification by silica gel chromatography (2:1 hexanes: EtOAc) provided the title compound as a white solid. MS (ESI, pos. ion) m/z: 425 (M+1). Mp: 203.8-206.0° C. Anal. Calcd for C22H15F3N4O2: C, 62.26; H, 3.56; N, 13.20. Found: C, 62.28; H, 3.51; N, 13.15.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][CH2:10][CH3:11])[CH:4]=1.[CH3:12][O:13][C:14]1[CH:23]=[CH:22][C:17]([C:18](=[O:21])[CH2:19][Br:20])=[CH:16][CH:15]=1>CC(C)=O>[Br-:20].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N+:6]([CH2:19][C:18]([C:17]2[CH:22]=[CH:23][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)=[O:21])=[C:5]([CH2:9][CH2:10][CH3:11])[CH:4]=1
Reactant: CCCc1cc(OC)ccn1
Reactant: COc1ccc(C(=O)CBr)cc1
Solvent: CC(C)=O
Product: CCCc1cc(OC)cc[n+]1CC(=O)c1ccc(OC)cc1
Product: [Br-]
Yield: 91 %

Procedure:
A solution of 4-methoxy-2-n-propylpyridine (45.7 g, 0.3 mol) and 4-methoxyphenacylbromide (69.2 g, 0.3 mol) in 400 ml of dry acetone was heated to reflux for eight hours. The mixture was cooled and the precipitate was isolated and dried to afford 103.8 g (90%) of 4-methoxy-1-(4-methoxyphenacyl)-2-n-propylpyridinium bromide. The quaternary salt (103.8 g) was suspended in 480 ml of water and sodium hydrogen carbonate (102.0 g) was added. The mixture was refluxed for two hours. The resulting precipitate was filtered off, washed with water and dried to yield overall 73.2 g (86%) of 1-ethyl-7-methoxy-2-(4-methoxyphenyl)indolizine. M.p. 101-3° C. 1H-NMR (DMSO-d6, 200 MHz) δ: 1.10 (t, 3H), 2.77 (q, 2H), 3.77 (s, 3H), 3.80 (s, 3H), 6.23 (dd, 1H), 6.65 (d, 1H), 7.00 (d, 2H), 7.35 (s, 1H), 7.38 (d, 2H), 8.06 (d, 1H).
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[OH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]1[CH:26]([CH:27]=[CH:28][C:29](=[O:37])[CH:30]([CH2:35][CH3:36])[CH2:31][CH2:32][CH2:33][CH3:34])[CH2:25][CH2:24][CH:23]1[OH:38]>CC(C)=O.O.[Cr]>[O:38]=[C:23]1[CH2:24][CH2:25][CH:26]([CH:27]=[CH:28][C:29](=[O:37])[CH:30]([CH2:35][CH3:36])[CH2:31][CH2:32][CH2:33][CH3:34])[CH:22]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][C:15]([OH:3])=[O:14]
Reactant: CC(C)=O
Reactant: CCCCC(CC)C(=O)C=CC1CCC(O)C1CCCCCCCO
Agent: O=[Cr](=O)=O
Agent: [Cr]
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCCC(CC)C(=O)C=CC1CCC(=O)C1CCCCCCC(=O)O
Reaction time: 1 h

Procedure:
8N Jones' reagent (0.4 ml.) was added to a stirred solution of 2-(7-hydroxyheptyl)-3-(4-ethyl-3-oxo-1-octenyl)cyclopentanol (0.42 g.) in acetone (4 ml.) at below 20°C. at such a rate that the deep red coloration caused by the addition of one drop of reagent had changed to green before addition of the next drop. The reaction mixture was diluted with sufficient water to dissolve the precipitated chromium salts and then extracted three times with diethyl ether. The combined ether extracts were washed with 2N aqueous sulphuric acid and then added to 10% aqueous sodium carbonate (50 ml.) and stirred for 1 hour. The aqueous layer was separated and covered with a layer of diethyl ether and concentrated hydrochloric acid added dropwise until the pH was 1. The ether layer was separated and the aqueous layer again extracted with diethyl ether. The combined extracts were dried over magnesium sulphate and the ether was removed in vacuo to give 7-[2-oxo-5-(4-ethyl-3-oxo- 1-octenyl)cyclopentyl]-heptanoic acid (0.12 g.), νmax 1620 cm-1, 1680 cm-1, 1700 cm-1 and 1730 cm-1 (liquid film).
Reaction SMILES: [OH:1][N:2]=[CH:3][C@H:4]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)[CH:19]=2)=[CH:12][CH:11]=1)[CH2:5][C:6]([O:8][CH3:9])=[O:7].N1C=C[CH:37]=[CH:36][CH:35]=1.C1C(=O)N(Cl)C(=O)C1.CC#C>C(Cl)Cl>[F:33][C:30]([F:32])([F:31])[C:27]1[CH:26]=[CH:25][C:24]([C:20]2[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=2)[CH2:17][O:16][C:13]2[CH:12]=[CH:11][C:10]([C@@H:4]([C:3]3[CH:35]=[C:36]([CH3:37])[O:1][N:2]=3)[CH2:5][C:6]([O:8][CH3:9])=[O:7])=[CH:15][CH:14]=2)=[CH:29][CH:28]=1
Reactant: c1ccncc1
Reactant: COC(=O)C[C@H](C=NO)c1ccc(OCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1
Agent: C#CC
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: COC(=O)C[C@@H](c1ccc(OCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1)c1cc(C)on1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Compound 39.2 (100 mg, 0.22 mmol) was dissolved in DCM, and pyridine (0.05 mL) and NCS (30 mg, 0.22 mmol) were added. The resulting mixture was stirred at room temperature for 3 hours. Additional NCS (60 mg) was added, and the mixture was left at room temperature overnight. Then TEA (0.4 mL) was added to the mixture, and a stream of methylacetylene was passed through the reaction mixture for 20 minutes. LCMS detected the desired product. The solvent was removed, and the residue was purified by CombiFlash to give 39.3.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].I[C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18]>>[CH3:8][C:7]1[O:6][N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[C:1]#[C:2][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18]
Reactant: C#Cc1c(-c2ccccc2)noc1C
Reactant: Nc1ccccc1I
Product: Cc1onc(-c2ccccc2)c1C#Cc1ccccc1N
Yield: 85 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (110 mg, 0.60 mmol) was converted (using 2-iodo-aniline instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=100:0 to 50:50, 139 mg, 85%) which was obtained as a light brown oil. MS: m/e=375.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([C:24]([NH:26][CH2:27][C:28]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:29]=2[CH:30]=[N:31][N:32]3C2CCCCO2)=[O:25])[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][C@H:7]([C:17]([OH:19])=[O:18])[CH2:8][NH:9][C:10]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=[O:11])=[O:5].[CH3:43]O>Cl>[Cl:1][C:2]1[CH:23]=[C:22]([C:24]([NH:26][CH2:27][C:28]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:29]=2[CH:30]=[N:31][NH:32]3)=[O:25])[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][C@H:7]([C:17]([OH:19])=[O:18])[CH2:8][NH:9][C:10]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=[O:11])=[O:5].[Cl:1][C:2]1[CH:23]=[C:22]([C:24]([NH:26][CH2:27][C:28]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:29]=2[CH:30]=[N:31][NH:32]3)=[O:25])[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][C@H:7]([C:17]([O:19][CH3:43])=[O:18])[CH2:8][NH:9][C:10]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=[O:11])=[O:5]
Reactant: CO
Reactant: O=C(NCc1cccc2c1cnn2C1CCCCO1)c1ccc(C(=O)N[C@@H](CNC(=O)c2cccs2)C(=O)O)c(Cl)c1
Agent: Cl
Product: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1ccc(C(=O)NCc2cccc3[nH]ncc23)cc1Cl
Product: O=C(NCc1cccc2[nH]ncc12)c1ccc(C(=O)N[C@@H](CNC(=O)c2cccs2)C(=O)O)c(Cl)c1
Yield: 26 %
Yield: 42 %

Procedure:
A solution of N-[2-chloro-4-[[[[1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl]methyl]amino]carbonyl]benzoyl]-3-(thiophene-2-carbonyl)amino-L-alanine (35 mg, 0.057 mmol) in 2 M HCl (2 mL) and methanol (2 mL) was heated at reflux for 3 h. The solution was concentrated, diluted with aqueous acetic acid and purified by HPLC to give N-[2-chloro-4-[[[(1H-indazol-4-yl)methyl]amino]carbonyl]benzoyl]-3-(thiophene-2-carbonyl)amino-L-alanine (8 mg, 26%) along with N-[2-chloro-4-[[[(1H-indazol-4-yl)methyl]amino]carbonyl]benzoyl]-3-(thiophene-2-carbonyl)amino-L-alanine, methyl ester (13 mg, 42%).
Reaction SMILES: C(O)C.[NH2:4][C:5]1[CH:9]=[CH:8][S:7][C:6]=1[C:10]([O:12]C)=O.[CH2:14]([N:17]=[C:18]=[S:19])[CH2:15][CH3:16]>C(N(CC)CC)C>[CH2:14]([N:17]1[C:10](=[O:12])[C:6]2[S:7][CH:8]=[CH:9][C:5]=2[NH:4][C:18]1=[S:19])[CH2:15][CH3:16]
Reactant: COC(=O)c1sccc1N
Reactant: CCCN=C=S
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCn1c(=S)[nH]c2ccsc2c1=O
Temperature: 25 °C

Procedure:
To a suspension of 150 mL of ethanol containing 9.5 g of methyl 3-amino-2-thiophenecarboxylate was added dropwise 9.3 mL of n-propyl isothiocyanate with stirring. To this reaction mixture was added 12.64 mL of triethylamine. The reaction mixture was heated at reflux for 3 h, allowed to cool to room temperature and then stirred for approximately 24 h. The mixture was then heated at reflux for an additional 32 h, cooled to approximately 5° C. and filtered to obtain 5.5 g of the title compound of Step A as an off-white solid melting at 246-249° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[CH2:26]([NH2:33])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][NH2:32]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][NH2:33])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: NCCCCCCN
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCCCCCN)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and hexane-1,6-diamine. MS obsd. (ESI+) [(M+H)+] 453, 1H NMR (400 MHz, CD3OD) δ ppm 8.07 (dd, J=1.2, 0.8 Hz, 1 H), 7.97 (s, 1 H), 7.92 (d, J=7.6 Hz, 1 H), 7.80 (d, J=8.8 Hz, 1 H), 7.70 (d, J=1.2 Hz, 1 H), 7.57 (dd, J=7.20, 1.6 Hz, 2 H), 5.91 (s, 1 H), 5.32 (s, 2 H), 4.52 (brs, 2 H), 3.75 (d, J=4.80 Hz, 2 H), 3.31 (d, J=1.60 Hz, 2 H), 2.94 (m, 2 H), 2.45 (s, 3 H), 1.72 (m, 4 H), 1.50 (m, 4 H).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[C:14](=[O:23])[NH:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7].Cl[CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[C:14](=[O:23])[N:13]([CH2:36][CH2:37][N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[CH2:12]2)[CH2:10][CH2:9]1)=[O:7]
Reactant: ClCCN1CCOCC1
Reactant: Cc1ccccc1N1C(=O)NCC12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2
Product: Cc1ccccc1N1C(=O)N(CCN2CCOCC2)CC12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2

Procedure:
The title compound, MS: m/e=599.1 (M+H+), was prepared in accordance with the general method of example 99 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-o-tolyl-1,3,8-triaza-spiro[4.5]decan-2-one and 4-(chloroethyl)morpholine.