Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH3:9])=[N:5][O:6][C:7]=1[CH3:8].[CH3:10][N:11]1[C:16](=[O:17])[C:15]2=[C:18]([C:32]3[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=3)[C:35]([OH:37])=[O:36])[N:19]([CH2:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][CH:23]=3)[N:20]=[C:14]2[NH:13][C:12]1=[O:41].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:9][C:4]1[C:3]([CH2:2][N:13]2[C:14]3=[N:20][N:19]([CH2:21][C:22]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH:25]=[CH:24][CH:23]=4)[C:18]([C:32]4[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=4)[C:35]([OH:37])=[O:36])=[C:15]3[C:16](=[O:17])[N:11]([CH3:10])[C:12]2=[O:41])=[C:7]([CH3:8])[O:6][N:5]=1
Reactant: Cn1c(=O)[nH]c2nn(Cc3cccc4ccccc34)c(-c3cccc(C(=O)O)c3)c2c1=O
Reactant: Cc1noc(C)c1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1noc(C)c1Cn1c(=O)n(C)c(=O)c2c(-c3cccc(C(=O)O)c3)n(Cc3cccc4ccccc34)nc21
Temperature: 85 °C
Reaction time: 20 h

Procedure:
4-(chloromethyl)-3,5-dimethylisoxazole (0.145 g) was added to a suspension of Resin bound 3-[5-methyl-2-(1-naphthylmethyl)-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl]benzoic acid (0.120 g) and potassium carbonate (0.397 g) in dimethylformamide (1 ml). Reaction mixture was shaken at 85° C. for 20 hours. The resin was filtered and washed (3 times) DMF, H2O, DMF, CH2Cl2, MeOH, CH2Cl2, and dried in vacuum to give the subtitle compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:16])[CH:5]=[C:6]([Cl:15])[C:7]=1[CH2:8][N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.N1C=CC=CC=1.[F:23][C:24]([F:30])([F:29])[S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([O:16][S:25]([C:24]([F:30])([F:29])[F:23])(=[O:27])=[O:26])[CH:5]=[C:6]([Cl:15])[C:7]=1[CH2:8][N:9]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: Oc1cc(Cl)c(CN2CCCCC2)c(Cl)c1
Reactant: O=S(=O)(Cl)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Oc1cc(Cl)c(CN2CCCCC2)c(Cl)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77.4 %

Procedure:
To a stirred solution of 3,5-dichloro-4-piperidin-1-ylmethylphenol (290 mg, 1.1 mmol) and pyridine (0.36 mL, 4.5 mmol) in DCM (10 mL) at −20° C. was added trifluoromethanesulfonyl chloride (0.38 mL, 2.2 mmol). After the addition was complete the reaction was allowed to warm to ambient temperature and stirred for 10 minutes. The mixture was diluted with DCM (20 mL), washed with water (10 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 12 g column, ISCO, 0-100% ethyl acetate in cyclohexane) to afford the title compound as a colourless oil (334 mg, 76%). 1H NMR (CDCl3, 300 MHz): 7.26 (s, 2H), 3.66 (s, 2H), 2.53-2.44 (m, 4H), 1.58-1.48 (m, 4H), 1.50-1.34 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:8]=1)=[O:6].[CH2:25]([C:29]1[CH:34]=[CH:33][C:32]([CH:35](Cl)[C:36]2[CH:41]=[CH:40][C:39]([CH2:42][CH:43]([CH3:45])[CH3:44])=[CH:38][CH:37]=2)=[CH:31][CH:30]=1)[CH:26]([CH3:28])[CH3:27].C(N(C(C)C)CC)(C)C.Cl>ClCCl>[CH2:42]([C:39]1[CH:40]=[CH:41][C:36]([CH:35]([NH:1][C:2]2[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=2)[C:5]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:8]=2)=[O:6])[C:32]2[CH:33]=[CH:34][C:29]([CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:30][CH:31]=2)=[CH:37][CH:38]=1)[CH:43]([CH3:45])[CH3:44]
Reactant: Nc1cccc(C(=O)c2cn(CCCC(=O)O)c3ccccc23)c1
Reactant: CC(C)Cc1ccc(C(Cl)c2ccc(CC(C)C)cc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Cc1ccc(C(Nc2cccc(C(=O)c3cn(CCCC(=O)O)c4ccccc34)c2)c2ccc(CC(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
A mixture of 4-[3-(3-aminobenzoyl)indol-1-yl]butyric acid (880 mg), bis(4-isobutylphenyl)methyl chloride (1.03 g) and diisopropylethylamine (0.945 g) in dichloromethane (20 ml) was stirred at 25° C. overnight, and bis(4-isobutylphenyl)methyl chloride (170 mg) and diisopropylethylamine (86 mg) were added thereto. After stirring at 25° C. for 3 hours, the reaction mixture was poured into cold 1N hydrochloric acid. The organic layer was separated, washed with water, and dried over magnesium sulfate. After evaporation of the solvent, the residue was chromatographed on silica gel (100 g) with a mixture of chloroform and methanol (50:1) as eluent and freeze-dried from benzene to give 4-[3-[3-[bis(4-isobutylphenyl)methylamino]benzoyl]indol-1-yl]butyric acid (820 mg) as pale yellow powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]([CH2:20][C:21](=[O:28])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[O:10][C:9]1([CH3:30])[CH3:29])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].C(O)(=O)C>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]([CH2:20][CH:21]([OH:28])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[O:10][C:9]1([CH3:29])[CH3:30])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CC(=O)CC1OC(C)(C)N(C(=O)OC(C)(C)C)C1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)CC(O)CC1OC(C)(C)N(C(=O)OC(C)(C)C)C1Cc1ccccc1
Reaction time: 0.5 h
Yield: 100.6 %

Procedure:
A solution of 4-benzyl-5-(3-ethoxycarbonyl-2-oxo-propyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (10 g) in ethanol (100 ml) was stirred at 15° C. under an atmosphere of nitrogen during the portion-wise addition of sodium borohydride (450 mg). The solution was stirred for a further 30 minutes, treated with glacial acetic acid (2 ml) and evaporated. The residue was partitioned between diethyl ether (200 ml) and 2M aqueous hydrochloric acid (100 ml). The organic solution was washed sequentially with water, 5% aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried (anhydrous magnesium sulfate) and evaporated to give 4-benzyl-5-(3-ethoxycarbonyl-2-hydroxy-propyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (10.11 g, 100%). Mass spectrum 422 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[CH:12][N+:13]([O-])=O)[CH:9]([CH3:16])[N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[C:6]=2[CH:24]=1>O1CCCC1CO.[Ni]>[NH2:13][CH2:12][CH:10]1[CH:9]([CH3:16])[N:8]=[C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[C:6]2[CH:24]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[NH:11]1
Reactant: CC1N=C(c2ccccc2F)c2cc(Cl)ccc2NC1=C[N+](=O)[O-]
Agent: [Ni]
Solvent: OCC1CCCO1
Product: CC1N=C(c2ccccc2F)c2cc(Cl)ccc2NC1CN

Procedure:
A solution of 5.2 g (0.015 m) of 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-3-methyl-2-nitromethylene-2H-1,4-benzodiazepine in 450 ml of 2:1 tetrahydrofuran-methanol was hydrogenated for 3 hrs. using a Parr apparatus, Raney nickel catalyst (3 teaspoonsful) and an initial pressure of 18 psi. The mixture was filtered and evaporated at reduced pressure to give crude 2-aminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-3-methyl-1H-1,4-benzodiazepine as a yellow oil.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[Se:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][C:19](=[O:28])[C:20]1[C:21](=[CH:24][CH:25]=[CH:26][CH:27]=1)[O:22][SH:23]>>[CH3:17][O:18][C:19](=[O:28])[C:20]1[C:21](=[CH:24][CH:25]=[CH:26][CH:27]=1)[O:22][S:23][Se:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[C:11](=[O:12])[NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1c2ccccc2[se]n1-c1ccccc1
Reactant: COC(=O)c1ccccc1OS
Product: COC(=O)c1ccccc1OS[Se]c1ccccc1C(=O)Nc1ccccc1

Procedure:
Prepared similar to example 1 from 5 g (18,2 mmol) of 2-phenyl-1,2-benzisoselenazole-3(2H)-one and 3,1 g (18,4 mmol) of mercaptosalicylic acid methyl ester.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.Cl[C:25]([O:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[O:26]>>[CH2:28]([O:27][C:25](=[O:26])[NH:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1)[CH:29]([CH3:31])[CH3:30]
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: CC(C)COC(=O)Cl
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)OCC(C)C)nc3cc21

Procedure:
[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-carbamic acid isobutyl ester was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and isobutyl chloroformate (115 μl, 0.89 mmol). The title compound was obtained as brown solid (85 mg, 25%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:17][C@H:16]3[N:12]([CH2:13][CH2:14][CH2:15]3)[C:11]([CH3:19])([CH3:18])[CH2:10]2)[C:5]([F:20])=[CH:4][N:3]=1.[O:21]1[CH2:24][CH:23]([N:25]2[CH2:30][CH2:29][CH:28]([O:31][C:32]3[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][C:33]=3[C:39]([F:42])([F:41])[F:40])[CH2:27][CH2:26]2)[CH2:22]1.CC1C=CC(S(O)(=O)=O)=CC=1>CC(O)C.CCOC(C)=O>[CH3:18][C:11]1([CH3:19])[CH2:10][C@H:9]([NH:8][C:6]2[C:5]([F:20])=[CH:4][N:3]=[C:2]([NH:36][C:35]3[CH:37]=[CH:38][C:32]([O:31][CH:28]4[CH2:27][CH2:26][N:25]([CH:23]5[CH2:24][O:21][CH2:22]5)[CH2:30][CH2:29]4)=[C:33]([C:39]([F:42])([F:41])[F:40])[CH:34]=3)[N:7]=2)[CH2:17][C@H:16]2[N:12]1[CH2:13][CH2:14][CH2:15]2
Reactant: CC1(C)C[C@H](Nc2nc(Cl)ncc2F)C[C@@H]2CCCN21
Reactant: Nc1ccc(OC2CCN(C3COC3)CC2)c(C(F)(F)F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CC1(C)C[C@H](Nc2nc(Nc3ccc(OC4CCN(C5COC5)CC4)c(C(F)(F)F)c3)ncc2F)C[C@@H]2CCCN21
Temperature: 100 °C
Yield: 70 %

Procedure:
A mixture of (7R,8aS)-N-(2-chloro-5-fluoropyrimidin-4-yl)-5,5-dimethyloctahydroindolizin-7-amine (0.25 g, 1.0 eq, 0.8 mmol), 4-((1-(oxetan-3-yl)piperidin-4-yl)oxy)-3-(trifluoromethyl)aniline (0.3 g, 1.2 eq, 1.0 mmol), PTSA (0.14 g, 0.9 eq, 0.8 mmol) was taken in iPrOH (20 mL) and heated at 100° C. overnight. The volatiles were removed under vacuum to leave a crude solid. The crude mixture was dissolved in EtOAc (50 mL) and partitioned with 1N aqueous NaOH solution (25 mL). Organic layers were separated and the aqueous layer was washed with EtOAc (2×20 mL). The combined organic layers were dried over Na2SO4 and concentrated under vacuum to leave a crude solid. The solid was purified by column chromatography on silica gel (ISCO System) using 2M NH3 in MeOH/CH2Cl2 (gradient system from 0:1 to 2:8) as eluent to give the product in 70% yield.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH:5]1[CH2:8][C:7]([C:13]([O:15][CH3:16])=[O:14])([C:9]([O:11][CH3:12])=[O:10])[CH2:6]1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[CH2:17]([O:3][CH2:4][CH:5]1[CH2:6][C:7]([C:9]([O:11][CH3:12])=[O:10])([C:13]([O:15][CH3:16])=[O:14])[CH2:8]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)C1(C(=O)OC)CC(CO)C1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1(C(=O)OC)CC(COCc2ccccc2)C1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
Sodium hydride (60% oil dispersion, 2.1 g, 53 mmol) is added in portions to a solution of dimethyl 3-(hydroxymethyl)cyclobutane-1,1-dicarboxylate (51), benzyl bromide, and n-tetrabutylammonium iodide in dry DMF at 25° C. (Step 47). The mixture is stirred for 1 hr at 65° C., poured onto ice and then extracted with ether (2×50 mL). The combined ether extract is washed with water (3×50 mL) and dried over MgSO4. Chromatography on silica gel.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[N:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10](O)=[O:11])[CH:2]=1.C(Cl)(=O)C([Cl:20])=O>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[N:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([Cl:20])=[O:11])[CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cccnc1Oc1cccnc1
Solvent: C1CCOC1
Product: O=C(Cl)c1cccnc1Oc1cccnc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 2-(pyridin-3-yloxy)-nicotinic acid (0.432 g, 2.0 mmol) in THF (15 mL) at 0° C. was added oxalylchloride (2 mL, 2M in CH2Cl2, 4.0 mmol) dropwise. The solution was stirred at room temperature for 3 h. The solvent was evaporated in vacuo to yield 2-(pyridin-3-yloxy)-nicotinoyl chloride as a solid. To a solution of 2-(pyridin-3-yloxy)-nicotinoyl chloride in 15 mL THF was added 3-trifluoromethyl-benzylidene-hydrazine (0.376 g, 2.0 mmol) in 5 mL THF and 1 mL Et3N at 0° C. The reaction mixture was refluxed for 6 h and the solvent was evaporated. The residue was purified by chromatography with EtOAc:hexanes, 1:2, yielding (0.425 g, 55%) of the title compound. 1H NMR (DMSO-d6): 12.20 (s, 1H), 8.70 (s, 1H), 8.37 (s, 1H), 8.24 (s, 1H), 8.21 (d, J=7.8 Hz, 1H), 8.01 (d, J=7.5 Hz, 1H), 7.90 (m, 2H), 7.78 (t, J=7.8 Hz, 1H), 7.41 (m, 2H), 6.43 (m, 2H).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:10]([C:11]([O:13]CC)=[O:12])=[CH:9][N:8]=[C:7]2[CH:16]=[N:17][NH:18][C:6]=12)[CH:2]=[CH2:3].[OH-].[Na+]>O>[CH2:1]([NH:4][C:5]1[C:10]([C:11]([OH:13])=[O:12])=[CH:9][N:8]=[C:7]2[CH:16]=[N:17][NH:18][C:6]=12)[CH:2]=[CH2:3]
Reactant: C=CCNc1c(C(=O)OCC)cnc2cn[nH]c12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CCNc1c(C(=O)O)cnc2cn[nH]c12
Yield: 97.4 %

Procedure:
Ethyl 7-allylamino-1H-pyrazolo[4,3-b]pyridine-6-carboxylate (5.0 g, 20 mmol) was added to a solution of sodium hydroxide (2.4 g, 60 mmol) in water (100 ml) and heated under reflux for 60 min. The solution was filtered, diluted with water (200 ml) and made neutral with 5N hydrochloric acid. The solid was filtered off, washed with water and dried to give the title compound (4.25 g, 96%), m.p. 240°-242° C.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:28])=[C:8]2[C:16]([Cl:17])=[C:15]([Cl:18])[N:14]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([F:27])[CH:21]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])C.[NH2:29][CH2:30][C:31]([OH:33])=[O:32].C[O-].[Na+].CO>>[Cl:18][C:15]1[N:14]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[C:22]([F:27])[CH:21]=2)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=[C:6]([C:4]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:5])[C:7]([OH:28])=[C:8]2[C:16]=1[Cl:17]
Reactant: CCOC(=O)c1nc(C#N)c2c(c1O)c(Cl)c(Cl)n2Cc1ccc(F)c(F)c1
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2c(Cl)c(Cl)n(Cc3ccc(F)c(F)c3)c12

Procedure:
Prepared in analogy to that of Example 1(e) from 2,3-dichloro-7-cyano-1-(3,4-difluoro-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 455 (M+H)+.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][C@H:18]([C:34]([NH:36][C@H:37]([C:42]([NH:44][C@H:45]([C:50]([O:52][CH3:53])=[O:51])[CH2:46][CH:47]([CH3:49])[CH3:48])=[O:43])[CH2:38][CH:39]([CH3:41])[CH3:40])=[O:35])[CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[ClH:61]>CO>[NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][C@H:18]([C:34]([NH:36][C@H:37]([C:42]([NH:44][C@H:45]([C:50]([O:52][CH3:53])=[O:51])[CH2:46][CH:47]([CH3:49])[CH3:48])=[O:43])[CH2:38][CH:39]([CH3:40])[CH3:41])=[O:35])[CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[ClH:61]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC(C)C
Temperature: 5 °C
Reaction time: 4.5 h

Procedure:
Boc-Leu-Leu-Lys(Z)-Leu-Leu-OMe (SEQ. ID No. 2) (18.2 g, 21.5 mmol) was added to a solution of HCl gas (31.0 g, 850 mmol) in MeOH (360 g) and cooled to 5° C. The reaction mixture was stirred, allowed to warm up to room temperature and stirring was continued for 4.5 h. The reaction mixture was cooled to 0° C., poured into ice/H2O (630 g) and stirred for 1 h. The white solid was collected by filtration, washed with distilled water (500 mL) and air dried. Yield of product: 14.8 g, 87.6%; HPLC area % purity: 99.2%.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8](F)=[CH:7][CH:6]=1)=[O:4].C(N(CC)CC)C.[CH2:21]([NH2:24])[C:22]#[CH:23]>C(#N)C>[F:1][C:2]([F:13])([F:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:24][CH2:21][C:22]#[CH:23])=[CH:7][CH:6]=1)=[O:4]
Reactant: C#CCN
Reactant: O=C(c1ccc(F)cc1)C(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C#CCNc1ccc(C(=O)C(F)(F)F)cc1
Yield: 100.1 %

Procedure:
To a solution of 8.64 g (45 mmol) of 2,2,2-trifluoro-1-(4-fluorophenyl)ethanone (Journal of Organic Chemistry, Vol. 32, pp. 1311-1318 (1967)) and 7.53 ml (54 mmol) of triethylamine in 150 ml of acetonitrile, cooled in an ice-bath, is added 31.13 ml (0.45 mol) of 2-propynylamine. The ice-bath is removed and the solution is heated under reflux for eighteen hours. The reaction solution is cooled and concentrated to give a solid, which is partitioned between ethyl acetate and water. The ethyl acetate layer is separated, dried (magnesium sulfate), and concentrated to give 10.23 g of a red-brown oil. This is applied to a column of 250 g of flash silica gel packed in n-heptane-dichloromethane (2:1). Elution with the same solvent gives 4.05 g (39.6%) of the product as a fluffy white solid; mp 96°-98° C.
Reaction SMILES: [CH2:1]([O:4][CH3:5])[C:2]#[CH:3].I[C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1/[C:9](=[CH:17]/[C:18]1[NH:19][CH:20]=[CH:21][C:22]=1[O:23][CH3:24])/[C:10](=[O:16])[NH:11]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C.CCN(CC)CC>[CH3:5][O:4][CH2:1][C:2]#[C:3][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1/[C:9](=[CH:17]/[C:18]1[NH:19][CH:20]=[CH:21][C:22]=1[O:23][CH3:24])/[C:10](=[O:16])[NH:11]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Reactant: C#CCOC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCC#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method C above, methyl propargyl ether (34 mg, 0.49 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (150 mg, 0.41 mmol) (Starting Material 2 supra) using (Ph3P)2PdCl2 (20 mg) and Cul (10 mg) as catalyst in DMF (2 mL) and Et3N (2 mL) as solvent at 70° C. for 18 h to yield (Z)-1,3-dihydro-4-(3-methoxy-1-propynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 69 mg, 55%).
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH2:8]([O:10][C:11](=[O:16])[CH2:12][N+:13]([O-])=[O:14])[CH3:9].C1N2CCN(CC2)C1>CCO>[O:14]1[C:2]2([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[CH2:1][C:12]([C:11]([O:10][CH2:8][CH3:9])=[O:16])=[N:13]1
Reactant: C=C1CCCCC1
Reactant: CCOC(=O)C[N+](=O)[O-]
Agent: C1CN2CCN1CC2
Solvent: CCO
Product: CCOC(=O)C1=NOC2(CCCCC2)C1
Temperature: 80 °C
Yield: 63.4 %

Procedure:
To a 300 mL pressure vessel equipped with a magnetic stir bar was added methylenecyclohexane (5.83 g, 60.6 mmol) and EtOH (150 mL). Nitro-acetic acid ethyl ester (16.8 mL, 152 mmol) and DABCO (680 mg, 6.06 mmol) were then added. Additional EtOH (30 mL) was added to rinse the sides of the vessel, which was tightly capped. The mixture was heated to 80° C. for 42 h and then cooled to RT. The solvent was removed under reduced pressure, and the residue was divided into three equal portions. Each portion was purified by column chromatography using an 80-g SiO2 pre-packed column eluting with EtOAc/hexanes, 0:1 to 1:4, v/v over 30 min, yielding 8.12 g (64%) of the desired ester. 1H-NMR (400 MHz, CDCl3) δ: 4.34 (q, J=7.2 Hz, 2H), 2.91 (s, 2H), 1.71-1.88 (m, 4H), 1.60-1.71 (m, 2H), 1.39-1.53 (m, 4H), 1.37 (t, J=7.1 Hz, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][N:8]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:9]=1[CH2:10][O:11][CH3:12])=[O:4].[OH-].[Li+]>O.CO.C1COCC1>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([N:8]2[C:9]([CH2:10][O:11][CH3:12])=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[N:7]2)=[CH:18][CH:17]=1
Reactant: COCc1c(C(=O)OC)cnn1-c1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COCc1c(C(=O)O)cnn1-c1ccc(Cl)cc1
Reaction time: 18 h
Yield: 67.9 %

Procedure:
To a solution of 1-(4-chloro-phenyl)-5-methoxymethyl-1H-pyrazole-4-carboxylic acid methyl ester (6.0 g, 21 mmol) in H2O-MeOH-THF (1:1:2) is added lithium hydroxide (620 mg, 26 mmol). After stiffing at room temperature for 18 h, the reaction mixture is concentrated in vacuo and purified by flash chromatography on silica gel (eluted with 15 to 100% EtOAc/hexanes) to afford 1-(4-chloro-phenyl)-5-methoxymethyl-1H-pyrazole-4-carboxylic acid as a white solid (3.8 g, 66%).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].I[C:8]1[N:9]=[CH:10][NH:11][CH:12]=1.C(OC([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]1B(O)O)=O)(C)(C)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[NH:11]1[CH:12]=[C:8]([C:21]2[NH:20][C:28]3[C:23]([CH:22]=2)=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:9]=[CH:10]1
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccccc21
Reactant: Ic1c[nH]cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc2[nH]c(-c3c[nH]cn3)cc2c1
Temperature: 85 °C
Yield: 37 %

Procedure:
A mixture of DMF (3 mL) and 2M Na2CO3 (0.75 mL) was purged with nitrogen for 10 minutes. 4-iodo-1H-imidazole (145.5 mg, 0.75 mmol), (1-(tert-butoxycarbonyl)-1H-indol-2-yl)boronic acid (235.0 mg, 0.9 mmol) and Pd(PPh3)4 (86.7 mg, 75.0 μmol) were added followed by purging with nitrogen for an additional 2 minutes. The solution was heated at 85° C. over night. The solution was poured into water (20 mL) and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with water (2×10 mL), brine and dried. The solvent was removed under reduced pressure and the crude residue was purified by column chromatography on silica gel using 10% MeOH/DCM as the eluent. The BOC protecting group was lost during the reaction sequence. Yield=37%. 1H NMR: 6.66 (s, 1H), 7.07-7.15 (m, 2H), 7.32 (s, 1H), 7.33 (d, 1H, J=7.8 Hz), 7.57 (d, 1H, J=7.5 Hz), 7.63 (s, 1H), 9.47 (s, 1H).
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][OH:14])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1>[CH2:15]([O:14][CH2:13][CH2:12][CH2:11][CH:10]=[CH:9][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: OCCCC=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C(=Cc1ccccc1)CCCOCc1ccccc1
Reaction time: 0.08 h

Procedure:
To a suspension of sodium hydride (50%; 0.6 g) (deprived of mineral oil) in tetrahydrofuran (10 ml), there was added dropwise a solution of 5-phenyl-4-pentenol [1.66 g; known compound; cf. e.g. Journal of the Chemical Society, page 1863 (1961)] in tetrahydruforan (10 ml) in argon atmosphere at room temperature. The mixture was stirred at the same temperature for 5 minutes. A solution of benzyl bromide (1.93 g) in tetrahydrofuran (10 ml) was added dropwise and the mixture was stirred at the same temperature for 20 hours. The tetrahydrofuran was distilled off under reduced pressure and water was added to the residue, followed by extraction with ether. After washing with water and drying over magnesium sulfate, the solvent was distilled off, and the residue was subjected to silica gel chromatography, elution being carried out with chlorofrom to give 5-benzyloxy-1-phenyl-1-pentene (2.5 g) as a colorless oil.