Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:5]([C:15]1[N:16]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[N:17]=[C:18]2[C:23]=1[CH:22]=[CH:21][CH:20]=[CH:19]2)[C:6](NC1CCCCC1)=O)CCC.C(N)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN1CCCC1=O>[CH2:6]([NH:5][C:15]1[N:16]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[N:17]=[C:18]2[C:23]=1[CH:22]=[CH:21][CH:20]=[CH:19]2)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCCCN(C(=O)NC1CCCCC1)c1c2ccccc2nn1-c1ccc(Cl)cc1
Reactant: NCc1ccccc1
Solvent: CN1CCCC1=O
Product: Clc1ccc(-n2nc3ccccc3c2NCc2ccccc2)cc1

Procedure:
In analogy to the procedure described in example 4.1, 3-chloro-2-(4-chloro-phenyl)-2H-indazole (Ardakani, Manouchehr; Smalley, Robert K.; Smith, Richard H., Synthesis (1979), (4), 308-9) was reacted with benzylamine in N-methyl 2-pyrrolidone for 48 h at 175° C. in a sealed tube to give the title compound as yellow oil. MS: m/e=334.4 [M+H+].
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].C(N(CC)CC)C.[C:13](Cl)(=[O:35])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].C(OC(C)C)(C)C.Cl>C1COCC1.CN(C)C1C=CN=CC=1>[C:13]([CH:1]([OH:5])[CH2:2][CH2:3][OH:4])(=[O:35])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: OCCCO
Reactant: CCCCCCCC/C=C\CCCCCCCCCCCC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCC/C=C\CCCCCCCCCCCC(=O)C(O)CCO
Temperature: 30 °C

Procedure:
1,3-Propanediol, 153 g (MW 76.1; 2 mol) is dissolved in 1 l of THF and, after addition of 60 g of triethylamine (MW 101.2, 0.6 mol) and 7.3 g of 4-dimethylaminopyridine (MW 122.2, 0.06 mol), equilibrated at 200° C. in a water bath. While stirring continuously, 178 g of erucoyl chloride (MW 357.0; 0.5 mol) in 500 ml of THF are slowly added dropwise so that the temperature in the reaction mixture does not exceed 30° C. The dropwise addition is followed by warming at 30° C. for 30 minutes and then addition of 1.5 1 of diisopropyl ether and 1.5 1 of 1N HCl. After vigorous shaking and phase separation, the upper ether phase is washed once again with 1% NaCl solution and evaporated in vacuo at 45° C. The residue is taken up in 2 l of hexane and cooled to −20° C. The white crystals are filtered off with suction and dried in vacuo. The yield of pure erucoyl-1,3-propanediol is 123 g (MW 396.7; 62%). The substance is pure by thin-layer chromatography (Rf value 0.3 in ether/pentane/acetic acid 200/200/2 parts by volume).
Reaction SMILES: C(N([P:8]([N:10]([CH:14]([CH3:16])[CH3:15])[CH:11]([CH3:13])[CH3:12])[Cl:9])C(C)C)(C)C.P(Cl)(Cl)[Cl:18]>C(#N)C>[CH:11]([N:10]([P:8]([Cl:18])[Cl:9])[CH:14]([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: ClP(Cl)Cl
Reactant: CC(C)N(C(C)C)P(Cl)N(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)N(C(C)C)P(Cl)Cl
Temperature: 25 °C
Yield: 81 %

Procedure:
Bis-(N,N-Diisopropylamino) chlorophosphine, 10 grams (37 mmols), was dissolved in 500 ml of anhydrous acetonitrile. Phosphorus trichloride, 5.16 grams (37 mmols), was added to the solution and the reaction was allowed to stir over-night at room temperature. The reaction was assayed for completion by 31P NMR of an aliquot of the reaction using an external lock. Complete conversion of the starting material at δ 134 ppm to the product at δ 165 ppm was observed. The solvent was evaporated from the reaction mixture on a rotary evaporator and the resulting oil distilled under vacuum yielding 5.7 grams of product (81% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][CH:7]=[N:8][CH:9]=1)=[O:4].Br[CH2:11][C:12]1[CH:16]=[C:15]([C:17]2[S:18][C:19]([Cl:22])=[CH:20][CH:21]=2)[O:14][N:13]=1.O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:11][C:12]2[CH:16]=[C:15]([C:17]3[S:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[O:14][N:13]=2)[CH:7]=[N:8][CH:9]=1)=[O:4]
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Reactant: COC(=O)c1cnc[nH]1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cncn1Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 250 mg 3H-Imidazole-4-carboxylic acid methyl ester in 2 ml DMF 273 mg potassium carbonate and 607 mg 3-Bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole [prepared by adopting a procedure described by Ewing, William R.; Becker, Michael R.; Choi-Sledeski, Yong Mi; Pauls, Heinz W.; He, Wei; Condon, Stephen M.; Davis, Roderick S.; Hanney, Barbara A.; Spada, Alfred P.; Burns, Christopher J.; Jiang, John Z.; Li, Aiwen; Myers, Michael R.; Lau, Wan F.; Poli, Gregory B; PCT Int. Appl. (2001), 460 pp. WO 0107436 A2] were added and the mixture was stirred for 2 h at RT. After addition of 5 ml water the mixture was filtered through a chem elut® cartridge by elution with ethyl acetate and then concentrated under reduced pressure. The residue was directly subjected to the subsequent saponification reaction without further purification. Yield: 288 mg
Reaction SMILES: [O:1]([CH:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:15]=[C:16]([NH:31][CH2:32][C:33](=O)[NH:34][C@@H:35]1[CH2:39]CNC1)[CH2:17][NH:18][C:19](=[O:30])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CC(O)=O.C(Cl)Cl.CCOC(C)=O>[O:15]=[C:16]([NH:31][C@@H:32]1[CH2:39][CH2:35][N:34]([CH:11]2[CH2:12][CH2:13][CH:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][CH2:10]2)[CH2:33]1)[CH2:17][NH:18][C:19](=[O:30])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1
Reactant: O=C1CCC(Oc2ccccc2)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NCC(=O)N[C@@H]1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(C2CCC(Oc3ccccc3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-phenoxycyclohexanone (0.091 g, 0.475 mmol) and N-[2-oxo-2-({2-oxo-2-[(3R)-pyrrolidin-3-ylamino]ethyl}amino)ethyl]-3-(trifluoromethyl)benzamide in 2% AcOH/CH2Cl2 (10 mL) was added NaB(OAc)3H (0.134 g, 0.634 mmol). After being stirred overnight at room temperature under N2, the reaction mixture was diluted with EtOAc and washed with saturated Na2CO3. The aqueous was extracted with EtOAc (3×). The combined organic layers were dried (MgSO4), concentrated and flash chromatographed (EtOAc to EtOAc:MeOH:Et3N=9:1:0.1) to give 0.12 g of the title compound. MS (EI) calcd: (M+H)+=490.2; found 490.0.
Reaction SMILES: [F:1][C:2]12[CH2:14][CH2:13][CH2:12][CH:11]1[C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:4][C:3]2=S.[NH3:16]>>[NH2:16][C:3]1[C:2]2([F:1])[CH2:14][CH2:13][CH2:12][CH:11]2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]=1
Reactant: N
Reactant: FC12CCCC1c1ccccc1NC2=S
Product: NC1=Nc2ccccc2C2CCCC12F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
142 mg (0.64 mmol) of 3a-fluoro-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinoline-4-thione is dissolved in 50 ml of 7 M methanolic ammonia solution. After 1 hour of stirring at room temperature, the batch is concentrated by evaporation in a vacuum, and the residue is purified by column chromatography on silica gel with dichloromethane-ethanol as an eluant: 108 mg of product, melting point 174-6° C.
Reaction SMILES: [OH:1][CH:2](CO)[CH2:3][NH:4][C:5](=[O:26])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8](/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:7]=1.NCCO>>[OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:26])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8](/[CH:14]=[CH:15]/[C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:20][CH:21]=2)[CH:7]=1
Reactant: COc1ccc(C(=O)NCC(O)CO)cc1/C=C/c1ccc(C(F)(F)F)cc1
Solvent: NCCO
Product: COc1ccc(C(=O)NCCO)cc1/C=C/c1ccc(C(F)(F)F)cc1

Procedure:
The captioned compound was synthesized from 4-methoxy-3-[(E)-2-(4-trifluoromethylphenyl)vinyl]benzoic acid obtained in step B of Example 2-2-38 and 2-aminoethanol in accordance with the same procedure as in the methods described in step C of Example 1-2-3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.[C:9]([N:16]1[CH2:21][CH2:20][CH:19](O)[CH2:18][CH2:17]1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOC(C)=O>[C:12]([O:11][C:9]([N:16]1[CH2:21][CH2:20][CH:19]([O:8][C:5]2[CH:4]=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:18][CH2:17]1)=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: Oc1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.2 %

Procedure:
A solution of 2-chloro-5-hydroxy pyridine (5.00 g, 38.60 mmol), 1-Boc-4-hydroxypiperidine (9.32 g, 46.31 mmol) and triphenyl phosphine (15.19 g, 57.90 mmol) in THF (200 mL) at 0° C. was treated dropwise with diisopropylazodicarboxylate (11.14 mL, 57.90 mmol). The mixture was stirred at room temperature for 18 hours, diluted with EtOAc, washed with water and brine, dried over Na2SO4 and concentrated under vacuum. Purification by silica gel column chromatography (25-40% EtOAc in petrol (40-60° C.)) gave 4-(6-chloro-pyridin-3-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (5.70 g, 47%) as a pale yellow residue. 1H NMR (300 MHz, CDCl3) δ 8.06 (d, J=2.8 Hz, 1H), 7.23-7.16 (m, 2H), 4.51-4.41 (m, 1H), 3.75-3.64 (m, 2H), 3.40-3.29 (m, 2H), 1.99-1.86 (m, 2H), 1.83-1.67 (m, 2H), 1.47 (s, 9H). LCMS (m/z, Method A) ES+ 311.1 [M+1]+.
Reaction SMILES: [CH2:1]([Zn]CC)C.ICI.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]([O:28][CH:29]=[CH2:30])[CH3:27])=[CH:20][CH:19]=2)[CH:11]=1>ClCCl>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]([O:28][CH:29]3[CH2:1][CH2:30]3)[CH3:27])=[CH:20][CH:19]=2)[CH:11]=1
Reactant: C=COC(C)COc1ccc(Cc2cc(Br)ccc2Cl)cc1
Reactant: CC[Zn]CC
Solvent: ICI
Solvent: ClCCl
Product: CC(COc1ccc(Cc2cc(Br)ccc2Cl)cc1)OC1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
To a solution of diethyl zinc (1.9 mL, 1.0 M in hexane) in dichloromethane (10 mL) at 0° C. under argon was added slowly diiodomethane (0.15 mL) in dichloromethane (2 mL). After stirring for 30 min, 4-bromo-1-chloro-2-(4-(2-(vinyloxy)propoxy)benzyl)benzene (290 mg, 0.76 mmol) in dichloromethane (3 mL) was added dropwise. The reaction mixture was warmed to room temperature and stirred overnight, and then quenched with saturated aqueous ammonium chloride. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with saturated aqueous sodium bicarbonate and then with brine, and then dried over sodium sulfate. The residue was concentrated and purified by preparative TLC to obtain intermediate DB as an oil (200 mg, yield 66%). 1H NMR (CDCl3, 400 MHz): δ 7.24-7.31 (m, 3H), 7.10-7.12 (m, 2H), 6.87-6.89 (m, 2H), 3.90-4.01 (m, 5H), 3.47-3.48 (m, 1H), 1.31-1.33 (m, 3H), 0.64 (m, 2H), 0.50-0.53 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5](I)=[CH:4][N:3]=1.[CH3:12][C:13]1([CH3:27])[C:17](=[O:18])[C:16]2[C:19]([Sn](C)(C)C)=[CH:20][CH:21]=[CH:22][C:15]=2[O:14]1>C1(C)C=CC=CC=1.C(OCC)(=O)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>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([C:19]2[C:16]3[C:17](=[O:18])[C:13]([CH3:12])([CH3:27])[O:14][C:15]=3[CH:22]=[CH:21][CH:20]=2)=[CH:4][N:3]=1
Reactant: Cc1c(I)cnc(N)c1C#N
Reactant: CC1(C)Oc2cccc([Sn](C)(C)C)c2C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1c(-c2cccc3c2C(=O)C(C)(C)O3)cnc(N)c1C#N
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, a stirred solution of 1.8 grams (0.007 mole) of 2-amino-3-cyano-5-iodo-4-methylpyridine, 2.3 grams (0.007 mole) of (2,3-dihydro-2,2-dimethyl-3-benzofuranon-4-yl)trimethyltin (prepared in Step D of this Example), and 0.5 gram (catalyst) of tetrakis(triphenylphosphine)palladium(0) in 25 mL of toluene is heated at reflux for about 22 hours. After this time the reaction mixture is cooled to ambient temperature and diluted with 50 mL of ethyl acetate. The mixture is filtered through diatomaceous earth, and the filtrate is concentrated under reduced pressure to a residue. The residue is purified using column chromatography, yielding 2-amino-3-cyano-4-methyl-5-(2,3-dihydro-2,2-dimethyl-3-benzofuranon-4-yl)pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[O:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11]([NH2:13])=[O:12])[CH2:7]1.[CH3:18][N:19]([CH3:23])[CH2:20][CH2:21]N.Cl>O1CCCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[O:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11]([NH:13][CH2:21][CH2:20][N:19]([CH3:23])[CH3:18])=[O:12])[CH2:7]1
Reactant: CN(C)CCN
Reactant: NC(=O)N1CCC(Oc2ccc(Cl)c(Cl)c2)C1
Agent: Cl
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)N1CCC(Oc2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Yield: 40.1 %

Procedure:
A stirred solution of 17.7 g (0.06 mole) of 3-(3,4-dichlorophenoxy)-1-pyrrolidinecarboxamide in 170 ml of tetrahydrofuran was treated by the rapid addition of 10.6 g (0.12 mole) of N,N-dimethylethylenediamine. The reaction was slightly exothermic and the mixture was stirred at ambient temperature over the weekend. Filtration removed some precipitated diamine hydrochloride, and the filtrate was concentrated in vacuo to give an oil, 23 g. The oil was treated with ethereal hydrogen chloride to give a granular solid which was recrystallized twice from acetone to give 4.6 g of pale green product, m.p. 143°-145° C.
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[NH:10][CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:22][C:23]1[CH:31]=[C:30]([C:32]2[N:36]=[C:35]([CH3:37])[N:34]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)[N:33]=2)[CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>CN(C)C=O.O>[Cl:22][C:23]1[CH:31]=[C:30]([C:32]2[N:36]=[C:35]([CH3:37])[N:34]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)[N:33]=2)[CH:29]=[CH:28][C:24]=1[C:25]([N:10]1[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[NH:7][C:6]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:11]1)=[O:26]
Reactant: c1cnc2c(c1)CNc1ccccc1N2
Reactant: COc1ccc(Cn2nc(-c3ccc(C(=O)Cl)c(Cl)c3)nc2C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(-c3ccc(C(=O)N4Cc5cccnc5Nc5ccccc54)c(Cl)c3)nc2C)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 37.9 %

Procedure:
To a solution of 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine of Example 1, Step B (0.55 g, 2.8 mmol) in dimethylformamide (10 mL) under nitrogen was added solid potassium carbonate (0.39 g, 2.8 mmol). The mixture was treated dropwise with a solution of the crude acid chloride (2.8 mmol) of Step F in dimethylformamide (10 mL). After stirring at room temperature for 90 minutes, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic extracts were combined and washed with 1N aqueous sodium hydroxide, dried over sodium sulfate and evaporated to dryness. The residue was dissolved in dichloromethane and absorbed on a column of flash silica Merck-60. Less polar impurities were eluted with 1:1 ethyl acetate-hexane. Further elution with 2% methanol in dichloromethane provided the title compound as a white solid (0.57 g), m.p. 218-221° C.
Reaction SMILES: [NH:1]([C:38]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C@H:2]([C:24]([NH:26][C@H:27]([C:35](O)=[O:36])[CH2:28][S:29][CH2:30][NH:31][C:32]([CH3:34])=[O:33])=[O:25])[CH2:3][S:4][C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH2:57][C@H:58]([C:66]([NH:68][C@H:69]([C:76]([O:78][CH3:79])=[O:77])[CH2:70][O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:67])[C@@H:59]([CH3:65])[O:60][C:61]([CH3:64])([CH3:63])[CH3:62].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1>C(OCC)(=O)C>[NH:1]([C:38]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)([C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C@H:2]([C:24]([NH:26][C@H:27]([C:35]([NH:57][C@H:58]([C:66]([NH:68][C@H:69]([C:76]([O:78][CH3:79])=[O:77])[CH2:70][O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:67])[C@@H:59]([CH3:65])[O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:36])[CH2:28][S:29][CH2:30][NH:31][C:32]([CH3:34])=[O:33])=[O:25])[CH2:3][S:4][C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)NCSC[C@H](NC(=O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Reactant: COC(=O)[C@H](COC(C)(C)C)NC(=O)[C@@H](N)[C@@H](C)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](COC(C)(C)C)NC(=O)[C@@H](NC(=O)[C@H](CSCNC(C)=O)NC(=O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@@H](C)OC(C)(C)C
Reaction time: 4 h

Procedure:
5.43 g of Trt-Cys(Trt)-Cys(Acm)-OH and 2.33 g of H-Thr(But)-Ser(But)-OMe are dissolved in 70 ml of ethyl acetate and 1.55 g of dicyclohexylcarbodiimide and 1.02 g of N-hydroxybenzotriazole are added at 0°C. After 4 hours at 0°C and 17 hours at 4°C, the mixture is filtered and the solution is diluted with 200 ml of ethyl acetate and washed with 1 N citric acid, 1 N sodium bicarbonate and water. After drying over sodium sulphate, the solution is evaporated and the residue is reprecipitated from ether acetatepetroleum ether.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[CH:16]=[C:17]([C:21]([OH:23])=O)[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[OH:25][CH2:26][CH:27]([NH2:29])[CH3:28]>>[OH:25][CH2:26][CH:27]([NH:29][C:21]([C:17]1[N:18]([CH3:20])[N:19]=[C:15](/[CH:14]=[CH:13]/[C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][O:10][C:11]=2[CH3:24])[CH:16]=1)=[O:23])[CH3:28]
Reactant: CC(N)CO
Reactant: Cc1onc(-c2ccc(F)cc2)c1/C=C/c1cc(C(=O)O)n(C)n1
Product: Cc1onc(-c2ccc(F)cc2)c1/C=C/c1cc(C(=O)NC(C)CO)n(C)n1
Yield: 17 %

Procedure:
As described for example 122, 5-{(E)-2-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-vinyl}-2-methyl-2H-pyrazole-3-carboxylic acid was converted, using 2-hydroxy-1-methylethylamine instead of isopropylamine, to the title compound (6.7 mg, 17%) which was obtained as an off white solid. MS: m/e=385.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[N:15][NH:16][C:17]3=[O:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.Cl[CH2:24][C:25]1[O:29][N:28]=[C:27]([CH3:30])[N:26]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>CCOC(C)=O.O>[CH3:30][C:27]1[N:26]=[C:25]([CH2:24][N:16]2[N:15]=[CH:14][C:13]3[C:18](=[CH:19][C:10]([C:7]4[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=4)=[CH:11][CH:12]=3)[C:17]2=[O:20])[O:29][N:28]=1
Reactant: O=c1[nH]ncc2ccc(-c3ccc(OC(F)(F)F)cc3)cc12
Reactant: Cc1noc(CCl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1noc(Cn2ncc3ccc(-c4ccc(OC(F)(F)F)cc4)cc3c2=O)n1
Temperature: 80 °C

Procedure:
To a mixture of 7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one (50 mg, 0.163 mmol), 5-(chloromethyl)-3-methyl-1,2,4-oxadiazole (47.5 mg, 0.359 mmol), and potassium carbonate (68 mg, 9.68 mmol) was added DMF (1 mL) and the reaction was heated to 80° C. overnight. The reaction was diluted with EtOAc and water, the layers were separated, and the organic layer was concentrated to an oil. The residue was purified by flash chromatography (Rf=0.32, 1:1 hexanes/ethyl acetate) to afford 2-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one as a white solid. C19H13F3N4O3. 403.1 (M+1). 1H NMR (DMSO) δ 8.58 (s, 1H), 8.48 (d, J=2.0 Hz, 1H), 8.34 (dd, J=2.0, 8.4 Hz, 1H), 8.12 (d, J=8.4 Hz, 1H), 7.98-8.02 (m, 2H), 7.54 (d, J=8.0 Hz, 1H), 5.67 (s, 2H), 2.31 (s, 1H).
Reaction SMILES: [NH:1]1[CH:6]=[C:5]([C:7]([OH:9])=O)[C:4](=[O:10])[C:3]2[CH2:11][CH2:12][CH2:13][C:2]1=2.CN(C=O)C.ClC(OCC)=O.[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1>C1COCC1.O>[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH:32][C:7]([C:5]2[C:4](=[O:10])[C:3]3[CH2:11][CH2:12][CH2:13][C:2]=3[NH:1][CH:6]=2)=[O:9])=[CH:29][CH:28]=1
Reactant: O=C(O)c1c[nH]c2c(c1=O)CCC2
Reactant: COc1ccc(CN)cc1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CNC(=O)c2c[nH]c3c(c2=O)CCC3)cc1
Temperature: 90 °C
Yield: 48.9 %

Procedure:
A quantity of 100 mg (0.61 mmole, 1.0 eq) of 4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-4-one-3-carboxylic acid is dissolved in 5 mL THF and 1 mL DMF and treated at 0° C. with 0.18 mL (1.2 mmole, 2.2 eq) TEA followed by 0.12 mL (1.2 mmole, 2.2 eq) of ethyl chloroformate. The resulting solution is stirred for 30 min. at which time 0.17 mL (1.2 mmole, 2.2 eq) of 4-methoxybenzylamine is added. The solution is allowed to warm to room temperature for 1 hr before the addition of 20 mL of H2O, the THF is removed under reduced pressure, and the resulting solid is filtered and washed with H2O and then Et2O. The resulting solid is slurried in 1 mL EtOH and 5 mL 10% NaOH, warmed to 90° C. for 10 min., cooled to 0° C., and pH adjusted to 9.0 with 3N HCl. The resulting solid is filtered, washed with H2O, Et2O, and purified by chromatography (silica gel, 10% CH3OH/CH2Cl2), to yield 89 mg of N-(4-Methoxybenzyl)-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-4-one-3-carboxamide (compound 1), mp 240-241° C.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C([Mg]Cl)(C)C.[CH3:12][C:13]([CH3:15])=[O:14]>C1COCC1>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[C:13]([OH:14])([CH3:15])[CH3:12]
Reactant: Brc1nccs1
Reactant: CC(C)=O
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)(O)c1nccs1
Temperature: -20 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
2-Bromothiazole (12.00 g, 73.2 mmol) was taken up in THF (150 mL) and cooled to −20° C. Isopropylmagnesium chloride (2.0 M in THF, 38.4 mL, 77 mmol) was added dropwise. After stirring for 1 h (−10° C. to 0° C.), the reaction was cooled to back −20° C., and acetone (5.10 g, 88 mmol) was added dropwise. The reaction was stirred for 30 min at −20° C. then warmed to room temperature. After 2 h at room temperature, the reaction was quenched with saturated NH4Cl and extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried (MgSO4), and evaporated. The residue was purified by flash chromatography (0-50% ethyl acetate in hexanes) to afford 8.97 g (86%) of 2-(1,3-thiazol-2-yl)propan-2-ol as a pale yellow low-melting solid. MS ESI: [M+H]+ m/z 144.0.