Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:30](=[O:38])[C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=3)=[C:8]([CH3:29])[N:9]2[CH2:12][C:13]2[CH:14]=[C:15]([CH:26]=[CH:27][CH:28]=2)[CH2:16][O:17][C:18]2([C:21]([O:23]CC)=[O:22])[CH2:20][CH2:19]2)=[CH:5][CH:4]=1.C1COCC1.[OH-].[Na+]>CO.O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:30](=[O:38])[C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=3)=[C:8]([CH3:29])[N:9]2[CH2:12][C:13]2[CH:14]=[C:15]([CH:26]=[CH:27][CH:28]=2)[CH2:16][O:17][C:18]2([C:21]([OH:23])=[O:22])[CH2:19][CH2:20]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)C1(OCc2cccc(Cn3c(C)c(C(=O)c4ccc(C)cc4)c4ccc(OC)cc43)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(C(=O)c3ccc(C)cc3)c(C)n(Cc3cccc(COC4(C(=O)O)CC4)c3)c2c1
Reaction time: 20 h

Procedure:
The compound of Example 66-1 (10 mg, 0.02 mmol) was dissolved in methanol (1 ml) and THF (1 ml) and thereto was added 1N aqueous sodium hydroxide solution (1 ml), followed by stirring for 20 hours. The reaction mixture was diluted with water and washed with diethyl ether. The aqueous layer was adjusted to around pH4 with 5% aqueous potassium hydrogen sulfate solution and the solution was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo to give the subject compound (quant.).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:14]1=[O:27])=[O:11].[C:35](#[N:38])[CH:36]=[CH2:37].CN(C)C=O.[OH-].[Na+]>N12CCCN=C1CCCCC2.O.CO>[C:35]([CH2:36][CH2:37][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:14]1=[O:27])=[O:11])#[N:38]
Reactant: CCCCCN1C(=O)C(CCC(=O)OCC)(NC(=O)c2cc3ccccc3[nH]2)c2ccccc21
Reactant: C=CC#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCCCCN1C(=O)C(CCC(=O)O)(NC(=O)c2cc3ccccc3n2CCC#N)c2ccccc21
Temperature: 80 °C
Reaction time: 22 h
Yield: 37.9 %

Procedure:
A mixture of 375 mg of ethyl 3-[2,3-dihydro-3-(1H-indol-2-ylcarbonyl)amino-2-oxo-1-pentyl-1H-indol-3-yl]propionate, 530 mg of acrylonitrile, 3 drops of 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU) and 4 ml of dimethylformamide was stirred at 80° C. for 22 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. After the extract was washed, dried and then treated with activated charcoal, the solvent was removed by evaporation under reduced pressure to afford a caramel. A mixture of the residue obtained, 1.4 ml of an aqueous 2N sodium hydroxide solution and 10 ml of methanol was stirred at room temperature for 20 hours. After removal of methanol from the reaction mixture by evaporation under reduced pressure, the residue was made acidic with 10% hydrochloric acid and extracted with chloroform. After the extract was dried, the solvent was removed by evaporation under reduced pressure. The residue was recrystallized from diisopropyl ether to afford 150 mg of 3-[3-[1-(2-cyanoethyl)-1H-indol-2-ylcarbonylamino]-2,3-dihydro-2-oxo-1-pentyl-1H-indol-3-yl]propionic acid. Melting point 125° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[C@H:10]([CH2:19][CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)[NH:11][C:12]([O:14]C(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:38]([O:42][C:43]([NH:45][C@H:46](C(O)=O)[C:47]([CH3:50])([CH3:49])[CH3:48])=[O:44])([CH3:41])([CH3:40])[CH3:39].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N1CCOCC1)C>C(#N)C.ClCCl>[CH2:1]([O:8][C:9](=[O:25])[C@H:10]([CH2:19][CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24]1)[NH:11][C:12](=[O:14])[C@H:46]([C:47]([CH3:50])([CH3:49])[CH3:48])[NH:45][C:43]([O:42][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:44])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCC1)C(=O)OCc1ccccc1
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](C(=O)N[C@@H](CC1CCCC1)C(=O)OCc1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.4 %

Procedure:
1.54 g (4.44 mmol) of N-(tert-butoxycarbonyl)-3-cyclopentyl-L-alanine benzyl ester and 2.53 g (13.32 mmol) of 4-toluenesulphonic acid hydrate were dissolved in 20 ml of acetonitrile and the solution was left to standat room temperature for 18 hours. The white precipitate formed was filteredoff and added to a mixture of 867 mg (3.75 mmol) of N-(tert-butoxycarbonyl)-3-methyl-L-valine, 557 mg (3.64 mmol) of 1-hydroxybenzotriazole, 793 mg (4.14 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 475 mg (4.13 mmol) of N-ethylmorpholine in 25 ml of dichloromethane and stirred at room temperature for 18 hours. The solution was extracted with 2M hydrochloric acid and saturated sodium bicarbonate solution and then driedover anhydrous magnesium sulphate. Evaporation and chromatography on silicagel using ethyl acetate/petrol (1:3) for the elution gave 1.06 g of N-[N-(tert-butoxycarbonyl)-3-methyl-L-valyl]-3-cyclopentyl-L-alanine benzyl ester as an off-white foam; MS: m/e 461 [M+H].
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2].[F:21][C:22]1[CH:23]=[C:24]2[C:28](=[C:29]([NH:31][CH:32]=[O:33])[CH:30]=1)[NH:27][C:26](=[O:34])[CH2:25]2>>[CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=[C:25]3[C:24]4[C:28](=[C:29]([NH:31][CH:32]=[O:33])[CH:30]=[C:22]([F:21])[CH:23]=4)[NH:27][C:26]3=[O:34])=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2]
Reactant: CCN(CC)CCN1CCc2[nH]c(C=O)c(C)c2C1=O
Reactant: O=CNc1cc(F)cc2c1NC(=O)C2
Product: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4c(NC=O)cc(F)cc43)c(C)c2C1=O
Yield: 40.5 %

Procedure:
The title compound was prepared under the same conditions as described in Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-7-yl)-formamide to give N-{3-[5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-ylmethylene]-5-fluoro-2-oxo-2,3-dihydro-1H-indol-7-yl}-formamide (36 mg, 40.5%) as a red solid.
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]([CH2:6][O:7][C:8]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][C:12]([NH:18][S:19]([C:22]([F:25])([F:24])[F:23])(=[O:21])=[O:20])=[CH:13]3)=[CH:4][CH:3]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>CS(C)=O>[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:2]2[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]3[CH:17]=[CH:16][CH:15]=[C:14]4[C:9]=3[CH:10]=[CH:11][C:12]([NH:18][S:19]([C:22]([F:23])([F:25])[F:24])(=[O:21])=[O:20])=[CH:13]4)=[CH:26][CH:27]=2)=[CH:31][CH:30]=1
Reactant: O=S(=O)(Nc1ccc2c(OCc3ccc(Br)cc3)cccc2c1)C(F)(F)F
Reactant: OB(O)c1ccc(F)cc1
Solvent: CS(C)=O
Product: O=S(=O)(Nc1ccc2c(OCc3ccc(-c4ccc(F)cc4)cc3)cccc2c1)C(F)(F)F

Procedure:
The title compound was prepared from the product of Example 1 and 4-florophenyl boronic acid according to the procedure of Example 2, m.p. 139-140° C. DMSO: δ 12.0 broad (s, 1H), 7.0-8.3(m, 14H, arom), 5.36 (s, 2H). CHN 60.63, 3.60, 2.94. Found 60.60, 3.50, 2.83.
Reaction SMILES: [CH2:1]1COCC1.C([Li])CCC.[C:11]([C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[C:17]([Cl:23])[N:16]=1)([CH3:14])([CH3:13])[CH3:12]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCCCCC>[C:11]([C:15]1[N:16]=[C:17]([Cl:23])[C:18]([CH:19]=[CH2:1])=[CH:21][CH:22]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1ccc(C=O)c(Cl)n1
Reactant: C1CCOC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Product: C=Cc1ccc(C(C)(C)C)nc1Cl
Reaction time: 0.5 h
Yield: 71 %

Procedure:
To a diethyl ether (17 ml) solution of 6-tert-butyl-2-chloronicotinonitrile (Tetrahedron 1965, 21, 2453-2467, 1.0 g, 5.4 mmol) was added 0.94 M diisobutylaluminum hydride in toluene solution (8.6 ml, 8.0 mmol) at −78° C. and the reaction was allowed to warm to room temperature over 2 hours with stirring. Then the reaction was quenched with 10% potassium sodium tartrate tetrahydrate aqueous solution and the whole was extracted with EtOAc, and washed with 2M sodium hydroxide aqueous solution and brine. The organic layer was evaporated and purified by silica gel column chromatography, eluting with hexane/EtOAc (5:1), to give 6-tert-butyl-2-chloronicotinaldehyde (1.0 g, 95%). To a THF (24 ml) suspension of methyltriphenylphosphonium bromide (5.3 g, 14.8 mmol) was added 1.60 M n-butyllithium (9.3 ml, 14.8 mmol) in hexane solution at 0° C. and the reaction was stirred for 30 minutes. Then to this mixture was added a THF (5 ml) solution of the 6-tert-butyl-2-chloronicotinaldehyde (1.0 g, 5.2 mmol) at 0° C., and the reaction was stirred for 2 hours at room temperature. The reaction was quenched with saturated ammonium chloride aqueous solution, and the whole was extracted with EtOAc, and dried over magnesium sulfate. The organic layer was evaporated and purified by silica gel column chromatography, eluting with hexane/EtOAc (10:1), to give the title compound (735 mg, 71%).
Reaction SMILES: [CH2:1]([Zn]CC)C.ICI.[CH3:9][C:10]1([CH3:22])[C:14]([CH3:15])=[CH:13][CH2:12][CH:11]1[CH2:16][CH:17]1[O:21][CH2:20][CH2:19][O:18]1.C(=O)([O-])[O-].[K+].[K+]>CCCCCC.ClCCCl>[CH3:15][C:14]12[CH2:1][CH:13]1[CH2:12][CH:11]([CH2:16][CH:17]1[O:18][CH2:19][CH2:20][O:21]1)[C:10]2([CH3:22])[CH3:9]
Reactant: CC[Zn]CC
Reactant: CC1=CCC(CC2OCCO2)C1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Solvent: ICI
Solvent: CCCCCC
Product: CC1(C)C(CC2OCCO2)CC2CC21C
Temperature: 17.5 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
150 ml (0.15 mol) of 1.0 M solution of diethylzinc in hexane was added to 500 ml of 1,2-dichloroethane under nitrogen. After having added 66.0 g (0.23 mol) of diiodomethane, while maintaining the temperature at 15-20° C. (ice bath), the solution was stirred at room temperature for 30 minutes, then 20.0 g (0.10 mol) of 2-(2,2,3-trimethylcyclopent-3-enylmethyl)-[1,3]dioxolane was added dropwise at 25° C. and the stirring continued for three hours. The reaction mixture was treated with 100 ml of 20% aqueous potassium carbonate, the organic layer separated and the aqueous layer extracted with diethyl ether. The combined organic phases were dried (MgSO4) and evaporated in vacuo. 22 g of the crude product was distilled at 95° C./0.1 Torr to give 14.9 g (71% yield) of 2-(1,2,2-trimethylbicyclo[3.1.0]hex-3-ylmethyl)-[1,3]dioxolane used in the next step without further purification
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][C:13]3([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:12]2=[O:21])=[CH:7][CH:6]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([S:30](Cl)(=[O:32])=[O:31])[CH:25]=1.Cl>>[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([S:30]([N:18]2[CH2:17][CH2:16][C:13]3([C:12](=[O:21])[N:11]([C:8]4[CH:9]=[CH:10][C:5]([O:4][CH2:3][C:2]([F:1])([F:22])[F:23])=[CH:6][CH:7]=4)[CH2:15][CH2:14]3)[CH2:20][CH2:19]2)(=[O:32])=[O:31])[CH:25]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: O=C1N(c2ccc(OCC(F)(F)F)cc2)CCC12CCNCC2
Agent: Cl
Product: O=C1N(c2ccc(OCC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1cccnc1)CC2

Procedure:
The title compound was prepared in analogy to example 180 step D from 2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one (prepared in analogy to example 180 step B-D using 1-benzyl-4-(2-methoxyethyl)-piperidine-4-carboxylic acid ethyl ester and 4-(2,2,2-trifluoro-ethoxy)aniline) and pyridine-3-sulfonyl chloride; hydrochloride. White solid. MS (ESI): 470.1 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.Cl.Cl[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]Cl>CC1C=CC=CC=1C>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([N:1]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:3]=1
Reactant: ClCCNCCCl
Reactant: Nc1cccnc1
Agent: Cl
Solvent: Cc1ccccc1C
Product: c1cncc(N2CCNCC2)c1
Temperature: 140 °C
Reaction time: 20 h
Yield: 15.9 %

Procedure:
A suspension of 3-aminopyridine (2.0 g) and bis(2-chloroethyl)amine hydrochloride (3.8 g) in o-xylene (40 ml) was stirred at 140° C. for 20 hr. The reaction mixture was extracted with water and the aqueous layer was made alkaline with a 2N aqueous sodium hydroxide solution and extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (developing solvent; chloroform:methanol:aqueous amnmonia=9:1:0.5) to give the title compound (0.55 g) as a black brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[S:14][C:13]([C:15](OCC)=[O:16])=[CH:12][CH:11]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Cl:9][C:10]1[S:14][C:13]([C:15](=[O:16])[CH2:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=2)=[CH:12][CH:11]=1
Reactant: CCOC(=O)c1ccc(Cl)s1
Reactant: Cc1ccnc(Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Cc1ccnc(Cl)c1)c1ccc(Cl)s1
Temperature: 5 °C
Reaction time: 2 h
Yield: 101.3 %

Procedure:
To a solution of 2-chloro-4-methylpyridine (15.6 mmol) and ethyl 5-chlorothiophene-2-carboxylate (17.2 mmol) in anhydrous THF (17 mL) at 0° C., under N2 was added dropwise a solution of lithium bis(trimethylsilyl)amide (1 molar solution in hexanes, 31.3 mmol). The mixture was stirred 2 h at 5° C. The solvent was then evaporated and the residue was dissolved in a mixture of water and dichloromethane. The organic layer was separated, and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried with MgSO4, and concentrated under reduced pressure to afford 4.3 g (96% yield) of 1-(5-chloro-2-thienyl)-2-(2-chloropyridin-4-yl)ethanone.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([O:18][CH2:19][CH:20]1[O:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.[NH4+].[Cl-]>ClCCl>[CH2:11]([O:18][CH2:19][CH:20]1[O:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: OC1CCC(COCc2ccccc2)OC1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C1CCC(COCc2ccccc2)OC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
DMSO (1.15 mL, 16.2 mmol) was added to a stirred solution of oxalyl chloride (1 mL, 10.8 mmol) in dichloromethane (60 mL) at −78° C. After 10 minutes, a dichlotomethane solution of 6-(benzyloxymethyl)tetrahydro-2H-pyran-3-ol (14) (1.20 g, 5.40 mmol) was added. Stirring was continued for one hour then triethylamine (3.8 mL, 27 mmol) was added and slowly warmed to 0° C. The reaction was poured into saturated NH4Cl solution and the organic phase was washed with brine and dried (NaSO4). The residue was purified over silica gel using EtOAc and hexanes to give 6-(benzyloxymethyl)dihydro-2H-pyran-3(4H)-one (15).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[CH:18][C:17]=1[O:24][CH2:25][C:26]([F:29])([F:28])[F:27]>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[CH:18][C:17]=1[O:24][CH2:25][C:26]([F:27])([F:29])[F:28]
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: OCc1ccc(Cl)c(OCC(F)(F)F)c1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(Cl)c(OCC(F)(F)F)c2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and [4-chloro-3-(2,2,2-trifluoroethoxy)phenyl]methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 4.41 (2H, d, J=7.6 Hz), 5.20 (2H, s), 5.73 (1H, d, J=2.0 Hz), 7.08 (1H, dd, J=2.0 Hz, 8.0 Hz), 7.14 (1H, d, J=2.0 Hz), 7.41-7.44 (2H, m), 7.57 (1H, d, J=1.6 Hz), 8.05 (1H, s), 8.67 (1H, d, J=4.8 Hz). [M+H] Calc'd for C18H12ClF3N4O2, 409; Found, 409.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([CH2:21][OH:22])[CH:18]([CH3:20])[CH3:19].[CH3:23][C:24](=[CH2:26])[CH3:25].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[C:24]([O:16][C:15](=[O:17])[CH2:14][O:13][C:7]1[CH:6]=[C:5]2[C:10](=[C:9]([Cl:11])[C:8]=1[Cl:12])[C:2](=[O:1])[C:3]([CH:18]([CH3:20])[CH3:19])([CH2:21][O:22][C:3]([CH3:18])([CH3:4])[CH3:2])[CH2:4]2)([CH3:25])([CH3:23])[CH3:26]
Reactant: CC(C)C1(CO)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Reactant: C=C(C)C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)C1(COC(C)(C)C)Cc2cc(OCC(=O)OC(C)(C)C)c(Cl)c(Cl)c2C1=O
Temperature: 25 °C

Procedure:
A solution of (1-oxo-2-hydroxymethyl-2-isopropyl-6,7-dichloro-5-indanyloxy)acetic acid (4.0 g., 0.012 mole), isobutylene (6 ml.), chloroform (20 ml.) and concentrated sulfuric acid (0.1 ml.) is sealed from the atmosphere and stirred at 25°C. for two weeks. After this time, the reaction mixture is poured into saturated aqueous sodium bicarbonate. The chloroform layer is separated, washed with water, dried and the chloroform distilled at reduced pressure affording tert.-butyl-(1-oxo-2-isopropyl-2-tert.-butoxymethyl-6,7-dichloro-5-indanyloxy)acetate which is hydrolyzed in a refluxing solution of methanolic potassium hydroxide. Acidification of the hydrolysis solution affords (1-oxo-2-isopropyl-2-tert.-butoxymethyl-6,7-dichloro-5-indanyloxy)acetic acid which melts at 148°-149° C. after recrystallization from acetic acid-water.
Reaction SMILES: [NH:1]([C:28]([CH3:30])=[O:29])[C@@H:2]([C:18]([N:20]1[CH2:27][CH2:26][CH2:25][C@@H:21]1[C:22]([OH:24])=O)=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].Cl.[NH2:32][C@@H:33]([C:37]([NH2:39])=[O:38])[CH:34]([CH3:36])[CH3:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>CN(C=O)C>[NH:1]([C:28]([CH3:30])=[O:29])[C@@H:2]([C:18]([N:20]1[CH2:27][CH2:26][CH2:25][C@@H:21]1[C:22]([NH:32][C@@H:33]([C:37]([NH2:39])=[O:38])[CH:34]([CH3:36])[CH3:35])=[O:24])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9]
Reactant: CC(=O)N[C@H](CCCCNC(=O)OCc1ccccc1)C(=O)N1CCC[C@@H]1C(=O)O
Reactant: CC(C)[C@@H](N)C(N)=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N[C@H](CCCCNC(=O)OCc1ccccc1)C(=O)N1CCC[C@@H]1C(=O)N[C@@H](C(N)=O)C(C)C
Temperature: 5 °C
Reaction time: 1.65 h

Procedure:
In an inert thermostable reactor provided with a mechanical stirrer, 94.25 g of Ac-D-Lys(Z)-D-Pro-OH (XI) (224.7 mmol) are introduced followed by 470 ml of DMF. 32.58 g of HCl. H-D-Val-NH2 (V) (213.5 mmol, 0.95 eq) and 85.22 g of HBTU (1 eq) are then added. The medium is cooled down to 5° C., and 96.6 ml of ethyldiisopropylamine (2.5 eq) are added dropwise within 15 minutes. This is allowed to reach 0° C. again and after 1.30 to 2 hours, a strong crystallization could be observed. The reaction completion is CCM controlled. The reaction medium is then poured onto 2350 ml of AcOEt, stirred for 15 minutes, filtered and washed successively with 470 ml of AcOEt and 470 ml of diisopropyl ether. The derivate (XII) is vacuum dried at 25° C. This way, 107.2 g (92%) pf Ac-D-Lys(Z)-D-Pro-D-Val-NH2 are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][C:7]2=[O:19].[BH4-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][N:9]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:8][CH:7]2[OH:19]
Reactant: CC(C)(C)OC(=O)N1CC(=O)c2cccc(Br)c2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1Cc2c(Br)cccc2C(O)C1
Temperature: 25 °C

Procedure:
To a flask containing tert-butyl 8-bromo-4-oxo-3,4-dihydroisoquinoline-2(1H)-carboxylate (24-3) (644 mg, 1.974 mmol) was added anhydrous THF (5 ml), followed by NaBH4 (399 mg, 10.55 mmol). The reaction mixture was then capped (not under N2) & stirred at room temperature. Followed by LC/MS. After 10 minutes the reaction mixture was quenched with saturated NaHCO3, then suspended in EtOAc, washed with saturated NaHCO3, then H2O, then brine; organics dried over Na2SO4, filtered & concentrated. Purification by silica gel chromatography (0-50% EtOAc/Hex; 40 g ISCO); desired fractions concentrated to yield tert-butyl 8-bromo-4-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (24-4). HRMS [M+H]: calculated; 328.0543, observed; 328.0537.
Reaction SMILES: C(O)(=O)C#CC.[O:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.C(Cl)(=O)C(Cl)=O.Cl.[NH2:19][C:20]1[N:21]=[C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:30]=[CH:31][C:32]([CH3:45])=[C:33]([NH:35][C:36]([C:38]4[N:42]([CH3:43])[N:41]=[C:40]([CH3:44])[CH:39]=4)=[O:37])[CH:34]=3)=[N:24][N:23]2[CH:46]=1>CN(C)C=O.CN(C)C(=O)C>[C:11]([NH:19][C:20]1[N:21]=[C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:30]=[CH:31][C:32]([CH3:45])=[C:33]([NH:35][C:36]([C:38]4[N:42]([CH3:43])[N:41]=[C:40]([CH3:44])[CH:39]=4)=[O:37])[CH:34]=3)=[N:24][N:23]2[CH:46]=1)(=[O:7])[C:10]#[C:9][CH3:8]
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)cn4n3)ccc2C)n(C)n1
Reactant: C1CCOC1
Agent: CC#CC(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: CC#CC(=O)Nc1cn2nc(Oc3ccc(C)c(NC(=O)c4cc(C)nn4C)c3)ccc2n1
Yield: 37 %

Procedure:
In the same manner as in Example 279 and using but-2-ynoic acid (46 mg, 0.54 mmol), tetrahydrofuran (1.5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (47 μL, 0.54 mmol), N-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide hydrochloride (150 mg, 0.36 mmol) and N,N-dimethylacetamide (5 mL) as starting materials, the title compound (60 mg, 37%) was obtained as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.[C:10]([Cu])#[N:11]>CN1C(=O)CCC1.CCOCC>[C:10]([C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1)#[N:11]
Reactant: N#C[Cu]
Reactant: Oc1ccc(Br)cc1F
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(O)c(F)c1
Temperature: 150 °C
Yield: 96.2 %

Procedure:
4-Bromo-2-fluorophenol (10 ml, 91 mmol) and 9.85 g (0.11 mol) of CuCN were combined in 75 ml of NMP with stirring under nitrogen, and the mixture was heated at 150° C. for 5 h. The mixture was diluted with 200 ml of ether, stirred, and decanted. The residue was diluted again with 200 ml of ether, heated, and decanted. The combined decantates were washed with water, 1N HCl solution, water, and brine, and dried over magnesium sulfate. The organic solution was concentrated in vacuo to provide 12 g of a white solid which was triturated in carbon tetrachloride and filtered to afford 7.29 g (72.1%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[BH4-].[Na+].B(F)(F)F.CCOCC>C1COCC1>[Cl:1][C:2]1[C:3]([CH2:4][OH:5])=[CH:7][CH:8]=[C:9]([Cl:11])[N:10]=1
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCc1ccc(Cl)nc1Cl
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a solution of 2,6-dichloronicotinic acid (1 g, 5.2 mmol) in THF (10 mL) was added NaBH4 (591 mg, 15.6 mmol) at 0° C. The mixture was stirred for 30 min and then BF3.OEt2 (2.2 g, 15.6 mmol) was added drop wise at 0° C. After addition was complete, the mixture was stirred at room temperature for 10 hr, until the reaction was completed. The reaction mixture was quenched by the addition of saturated NH4Cl solution (50 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and concentrated to give the desired product as a white solid which was used in next step without further purification. (820 mg, Yield 80%).