Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:12][C:13]#[C:14][C@@H:15]([O:21][C:22](=[O:24])[CH3:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>CN(C)C=O.O>[CH2:1]([O:8][CH2:12][C:13]#[C:14][C@@H:15]([O:21][C:22](=[O:24])[CH3:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: CCCCC[C@@H](C#CCBr)OC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC[C@@H](C#CCOCc1ccccc1)OC(C)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Benzyl alcohol (1 molar equivalent) is added dropwise to a stirred suspension of sodium hydride (1 molar equivalent) in dry dimethylformamide maintained at 0° to 5° C. throughout the addition. The reaction mixture is allowed to warm to and then is maintained at room temperature for 1/2 hour. After cooling to 0° to 5° C., the reaction mixture is treated with 1-bromo-4(S)-acetyloxy-2-nonyne (1 molar equivalent) added dropwise over 1/2 hour. The resulting reaction mixture is stirred at ambient temperature for 2 hours and then diluted with water providing a turbid mixture which is extracted with ether. The organic extract is washed with water and saturated aqueous brine, dried over sodium sulfate and filtered. Evaporation (in vacuo at 40° to 50° C.) of the filtrate leaves an oily residue which is distilled to provide the pure title compound.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C([C:13]1[C:21]2[C:16](=[C:17]([CH2:23][S:24][CH3:25])[CH:18]=[C:19](F)[CH:20]=2)[NH:15][CH:14]=1)CCO.[CH:26]1([C:29]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[F:39])(O)[CH3:30])[CH2:28][CH2:27]1.C1(C(C2C3C(=C(CSC)C=CC=3)NC=2)(C2C=CC(F)=CC=2)C)CC1>>[CH:26]1([C:29]([C:13]2[C:21]3[C:16](=[C:17]([CH2:23][S:24][CH3:25])[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[F:39])[CH3:30])[CH2:28][CH2:27]1
Reactant: CSCc1cc(F)cc2c(C(CCO)c3ccc(Cl)cc3Cl)c[nH]c12
Reactant: CC(O)(c1ccc(F)cc1F)C1CC1
Agent: CSCc1cccc2c(C(C)(c3ccc(F)cc3)C3CC3)c[nH]c12
Product: CSCc1cccc2c(C(C)(c3ccc(F)cc3F)C3CC3)c[nH]c12

Procedure:
The title compound was prepared starting from 500 mg (2.82 mmol) of the compound from Example 8 and 615 mg (3.10 mmol) of the compound from Example 78A in analogy to the synthesis of the compound from Example 95. 227 mg (94% purity, 21% of theory) of the target compound were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](Cl)=[N:17][OH:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[C:25]([C:27]1[C:28]([NH2:33])=[N:29][CH:30]=[CH:31][CH:32]=1)#[CH:26].C(N(CC)CC)C>O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[CH:26]=[C:25]([C:27]3[C:28]([NH2:33])=[N:29][CH:30]=[CH:31][CH:32]=3)[O:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ON=C(Cl)Cc1ccc(OCc2ccccc2)cc1
Reactant: C#Cc1cccnc1N
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ncccc1-c1cc(Cc2ccc(OCc3ccccc3)cc2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.5 %

Procedure:
To a mixture of 4-benzyloxy-phenyl-acetohydroximoyl chloride (1.2 g, 4.4 mmol) described in Manufacturing Example 1-1-3 and tetrahydrofuran (34 mL) were added 3-Ethynyl-pyridin-2-ylamine (260 mg, 2.2 mmol) described in Manufacturing Example 1-2-3 and triethylamine (3.0 mL, 22 mmol) at 0° C., which was stirred for 1 hour at room temperature. To the reaction mixture was added water at room temperature, which was then extracted with ethyl acetate-tetrahydrofuran (2:1). The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:3) to obtain the title compound (240 mg, 15%).
Reaction SMILES: Cl[C:2]1[C:8]2[CH:9]=[C:10]([O:15][CH3:16])[C:11]([O:13][CH3:14])=[CH:12][C:7]=2[N:6]([CH3:17])[C:5](=[O:18])[CH2:4][N:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:38]1([C:44]#[CH:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CC#N.Cl[Pd]Cl.[Cu]I>[CH3:16][O:15][C:10]1[C:11]([O:13][CH3:14])=[CH:12][C:7]2[N:6]([CH3:17])[C:5](=[O:18])[CH2:4][N:3]=[C:2]([C:45]#[C:44][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:8]=2[CH:9]=1
Reactant: C#Cc1ccccc1
Reactant: COc1cc2c(cc1OC)N(C)C(=O)CN=C2Cl
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: COc1cc2c(cc1OC)N(C)C(=O)CN=C2C#Cc1ccccc1
Temperature: 55 °C
Reaction time: 0.08 h
Yield: 45 %

Procedure:
To a solution of 240 mg (0.89 mmol) of 5-chloro-7,8-dimethoxy-1-methyl-1,3-dihydro-1,4-benzodiazepin-2-one XVIIIaa in 7 ml of CH3CN, add under an inert atmosphere 17 mg (0.1 mmol) of PdCl2, 30 mg (0.16 mmol) of CuI. Stir for 5 minutes, then add 68 mg (0.23 mmol) of PPh3, 185 μl of Net3 and 150 μl of phenylacetylene. Heat the mixture at 55° C. for 3 hours. Evaporate to dryness and purify by silica chromatography (AcOEt 1/hexane 1, then AcOEt). Recrystallize in EtOH. Yield: 45%. 1H-NMR (DMSO, 200 MHz): d 3.33 (s, 3H, NCH3), 3.70–3.91 (m, 7H, 1HCH2+20CH3), 4.50–5.60 (m, 1HCH2), 7.06 (s, 1H Ar), 7.32 (s, 1H Ar), 7.48–7.68 (m, 5H Ar). Mass: (M+H)+=335.16.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:15]1[CH:28]=[CH:27][C:18]2[O:19][C:20]3[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][C:21]=3[C:17]=2[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>[Cu].ClC1C=CC=CC=1Cl>[Br:26][C:23]1[CH:24]=[CH:25][C:20]2[O:19][C:18]3[CH:27]=[CH:28][C:15]([N:12]4[C:11]5[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=5[C:5]5[C:13]4=[CH:1][CH:2]=[CH:3][CH:4]=5)=[CH:16][C:17]=3[C:21]=2[CH:22]=1
Reactant: Brc1ccc2oc3ccc(Br)cc3c2c1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [Cu]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Solvent: Clc1ccccc1Cl
Product: Brc1ccc2oc3ccc(-n4c5ccccc5c5ccccc54)cc3c2c1
Temperature: 200 °C
Reaction time: 45 h
Yield: 30.4 %

Procedure:
A mixture of carbazole (1.15 g, 6.87 mmol), 2,8-dibromodibenzo[b,d]furan (4.48 g, 13.74 mmol), copper powder (0.30 g, 4.58 mmol), potassium carbonate (3.80 g, 27.50 mmol), 18-crown-6 (0.61 g, 2.29 mmol), and 1,2-dichlorobenzene (50 mL) was degassed with bubbling argon for 45 min at 50° C. The reaction mixture was then heated to 200° C. and was stirred overnight (45 hours), maintaining an argon atmosphere. Production of decoupled material was shown by LCMS and the reaction was cooled to room temperature. The mixture was filtered, and the filtrate was dried. The copper was removed by a short silica gel plug with dichloromethane as the eluent, and the product was purified by silica gel column chromatography with toluene in hexanes as the eluent. The product fractions were then dried and the product was collected to yield Compound 12 (0.861 g, 30%). Confirmed by LCMS (APCI): calculated for C24H14BrNO (M+H): 412. Found: 412.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[CH:8][C:9]([O:29]C)=[C:10]([CH:28]=1)[C:11]([NH:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([C:24]([F:27])([F:26])[F:25])[CH:15]=1)=[O:12])(=[O:5])[CH:2]([CH3:4])[CH3:3].N1C(C)=CC(C)=CC=1C.[I-].[Li+].Cl>>[F:21][C:20]([F:22])([F:23])[C:18]1[CH:19]=[C:14]([NH:13][C:11](=[O:12])[C:10]2[CH:28]=[C:6]([C:1](=[O:5])[CH:2]([CH3:3])[CH3:4])[CH:7]=[CH:8][C:9]=2[OH:29])[CH:15]=[C:16]([C:24]([F:26])([F:27])[F:25])[CH:17]=1
Reactant: COc1ccc(C(=O)C(C)C)cc1C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Agent: [I-]
Agent: [Li+]
Solvent: Cc1cc(C)nc(C)c1
Product: CC(C)C(=O)c1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Yield: 65.3 %

Procedure:
A mixture of 5-isobutyryl-N-[3,5-bis(trifluoromethyl)phenyl]-2-methoxybenzamide (143.4 mg, 0.33 mmol), 2,4,6-collidine (3 ml) and lithium iodide (53.1 mg, 0.40 mmol) was refluxed for 1 hour. After cooling, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=3:1) and crystallized (ethyl acetate/isopropyl ether) to give the title compound (90.3 mg, 65.3%) as a white crystal.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH2:3]1.[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].N1C=CN=C1>CN(C=O)C>[Si:12]([O:1][C@@H:2]1[CH2:3][CH2:4][C@H:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:6][CH2:7]1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@H]1CC[C@@H](O)CC1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
99.0 g (0.63 mol) of the compound from Example 51A are dissolved in 2 liters of dry DMF, and 132.0 g (0.88 mol) of tert-butyldimethylsilyl chloride and 80.9 g (1.19 mol) of imidazole are added at RT. The mixture is stirred at RT for 16 h. The solvent is then removed almost to dryness on a rotary evaporator and the residue is taken up in 2 liters of a 1:1 mixture of tert-butyl methyl ether and saturated aqueous sodium bicarbonate solution. The phases are separated, the organic phase is dried over magnesium sulfate and the solvent is removed on a rotary evaporator. The product is used in the next reaction without further purification.
Reaction SMILES: [NH2:1][C@H:2]([P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C.FC(F)(F)S(O[C@H:32]([CH2:43][CH:44]([CH3:46])[CH3:45])[C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])(=O)=O>ClCCl>[CH2:36]([O:35][C:33](=[O:34])[C@H:32]([CH2:43][CH:44]([CH3:45])[CH3:46])[NH:1][C@H:2]([P:11]([O:12][CH2:13][CH3:14])([O:15][CH2:16][CH3:17])=[O:18])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CCOP(=O)(OCC)[C@@H](N)CCc1ccccc1
Reactant: CC(C)C[C@@H](OS(=O)(=O)C(F)(F)F)C(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOP(=O)(OCC)[C@H](CCc1ccccc1)N[C@@H](CC(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.9 %

Procedure:
To a solution of 400 mg of diethyl 1-(R)-amino-3-phenylpropylphosphonate in 5 ml of anhydrous dichloromethane was added a solution of 0.25 ml of triethylamine and 627 mg of benzyl 2-(R)-trifluoromethanesulfonyloxy-4-methylpentanoate in 2.5 ml of anhydrous dichloromethane, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with 30 ml of dichloromethane, and the diluted solution was washed with 20 ml of water and dried over anhydrous magnesium sulfate. Then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate=1:1) to yield the title compound as a colorless oil (238 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][N:7]=1.[Cl:10][C:11]1[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](N)=[NH:18])=[CH:13][CH:12]=1.CN(C)C=O>C(O)C>[NH2:9][C:8]1[C:3]2[C:2](=[N:7][CH:6]=[CH:5][N:4]=2)[N:1]=[C:17]([CH2:16][O:15][C:14]2[CH:20]=[CH:21][C:11]([Cl:10])=[CH:12][CH:13]=2)[N:18]=1
Reactant: N#Cc1nccnc1N
Reactant: N=C(N)COc1ccc(Cl)cc1
Solvent: CCO
Solvent: CN(C)C=O
Product: Nc1nc(COc2ccc(Cl)cc2)nc2nccnc12

Procedure:
Obtained using the procedure described in section c of Example 2, starting with 10.7 g (0.089 mole) of 3-amino-2-pyrazinecarbonitrile and 24.5 g (0.133 mole) of 2-(4-chlorophenoxy)acetamidine [prepared according to C. Djerassi and C. R. Scholz, U.S. Pat. No. 2,517,468; C.A. 1951, 45, 661f] in 320 ml of absolute ethanol. Refluxing time: 7 hours. Yld: 21.5 g (84%), m.p. 246°-248° C. (N,N-dimethylformamide).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:15]2[CH2:16][C@H:11]([CH2:12][CH2:13][C@@H:14]2[N:17]2[CH:25]=[N:24][C:23]3[C:18]2=[N:19][CH:20]=[N:21][C:22]=3[NH:26][C:27](=[O:36])[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[CH2:10][C:9]1=[O:37])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C[O:41]CC1.[Li+].[OH-].CO>O>[C:1]([O:5][C:6]([NH:8][C@H:15]1[CH2:16][C@@H:11]([CH2:10][C:9]([OH:41])=[O:37])[CH2:12][CH2:13][C@@H:14]1[N:17]1[CH:25]=[N:24][C:23]2[C:18]1=[N:19][CH:20]=[N:21][C:22]=2[NH:26][C:27](=[O:36])[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: C1CCOC1
Reactant: COc1ccc(C(=O)Nc2ncnc3c2ncn3[C@H]2CC[C@@H]3CC(=O)N(C(=O)OC(C)(C)C)[C@H]2C3)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(C(=O)Nc2ncnc3c2ncn3[C@H]2CC[C@H](CC(=O)O)C[C@@H]2NC(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
A 500 ml two-necked round-bottomed flask was loaded with 5.25 g of PMBzBoc-A lactam 15f (10.36 mmol) and 200 ml of THF. After cooling to 0° C., a solution of 2.17 g of LiOH×H2O (51.8 mmol) in 50 ml of H2O was added dropwise over a period of 20 min. 30 ml of MeOH were then added, the ice bath was removed and the reaction mixture was stirred at room temperature for 1 h. An ion-exchange resin (Amberlite IR-120, H+ form) was then added until a pH of 7 was reached. The resin was removed by filtration and the solution was concentrated under reduced pressure to a volume of 100 ml. 200 ml of H2O were then added and a pH of 2 was adjusted by addition of 1 M aqueous HCl. The solution was extracted with EtOAc (3×200 ml) and the combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was dissolved in 25 ml of hot MeOH. The product was then precipitated by addition of 10 ml of H2O. The precipitate was filtered, washed with H2O and dried over P4O10 to afford 1.95 g of 16. It was possible to obtain a further 0.57 g from the mother solution and the wash solutions to afford a total yield of 46%.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([N:12]1[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]1=[O:22])[CH2:6]2.B(Br)(Br)Br.C(Cl)Cl>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([N:12]1[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]1=[O:22])[CH2:6]2
Reactant: COc1ccc2c(c1)CC(N1C(=O)c3ccccc3C1=O)C2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1C1Cc2ccc(O)cc2C1
Temperature: -60 °C
Reaction time: 5 h
Yield: 79.1 %

Procedure:
To 2-(5-methoxyindan-2-yl)isoindole-1,3-dione (19.7 g; 67 mmol) dissolved in anhydrous CH2Cl2 (350 mL) and cooled to −60° C., is added a 1.0 M solution of boron tribromide-CH2Cl2 (340 mL), dropwise at a rate to maintain the internal temperature between −50 and −60° C. The reaction mixture is allowed to warm to RT and stirred for an additional 5 h. The reaction is cooled to 0° C., quenched with saturated NaHCO3 (500 mL) and stirred for an additional 0.5 h at RT. The precipitate is filtered, washed with H2O, suspended in ether, filtered and dried under vacuo to afford 14.8 g (79%) of 2-(5-hydroxyindan-2-yl)isoindole-1,3-dione as a beige solid.
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([C@H:5]1[NH:37][C:35](=[O:36])[C@@H:34]([NH:38][C:39]([C@H:41]([N:46](C([C@H]2N(C(C(O)C)=O)CCC2)=O)[CH3:47])[CH2:42][CH:43]([CH3:45])[CH3:44])=[O:40])[C@@H:33]([CH3:60])[O:32][C:30](=[O:31])[C@H:29]([CH2:61][C:62]2[CH:63]=[CH:64][C:65]([O:68][CH3:69])=[CH:66][CH:67]=2)[N:28]([CH3:70])[C:26](=[O:27])[C@H:25]2[N:21]([CH2:22][CH2:23][CH2:24]2)[C:19](=[O:20])[C@H:18]([CH2:71][CH:72]([CH3:74])[CH3:73])[NH:17][C:15](=[O:16])[C@@H:14]([CH3:75])[C:12](=[O:13])[C@H:11]([CH:76]([CH3:78])[CH3:77])[O:10][C:8](=[O:9])[CH2:7][C@@H:6]1[OH:79])[CH3:4]>Cl>[CH3:1][CH2:2][C@@H:3]([C@H:5]1[NH:37][C:35](=[O:36])[C@@H:34]([NH:38][C:39]([C@H:41]([NH:46][CH3:47])[CH2:42][CH:43]([CH3:44])[CH3:45])=[O:40])[C@@H:33]([CH3:60])[O:32][C:30](=[O:31])[C@H:29]([CH2:61][C:62]2[CH:67]=[CH:66][C:65]([O:68][CH3:69])=[CH:64][CH:63]=2)[N:28]([CH3:70])[C:26](=[O:27])[C@H:25]2[N:21]([CH2:22][CH2:23][CH2:24]2)[C:19](=[O:20])[C@H:18]([CH2:71][CH:72]([CH3:74])[CH3:73])[NH:17][C:15](=[O:16])[C@@H:14]([CH3:75])[C:12](=[O:13])[C@H:11]([CH:76]([CH3:78])[CH3:77])[O:10][C:8](=[O:9])[CH2:7][C@@H:6]1[OH:79])[CH3:4]
Reactant: CC[C@H](C)[C@H]1NC(=O)[C@@H](NC(=O)[C@@H](CC(C)C)N(C)C(=O)[C@@H]2CCCN2C(=O)C(C)O)[C@@H](C)OC(=O)[C@H](Cc2ccc(OC)cc2)N(C)C(=O)[C@@H]2CCCN2C(=O)[C@H](CC(C)C)NC(=O)[C@@H](C)C(=O)[C@H](C(C)C)OC(=O)C[C@@H]1O
Agent: Cl
Product: CC[C@H](C)[C@H]1NC(=O)[C@@H](NC(=O)[C@@H](CC(C)C)NC)[C@@H](C)OC(=O)[C@H](Cc2ccc(OC)cc2)N(C)C(=O)[C@@H]2CCCN2C(=O)[C@H](CC(C)C)NC(=O)[C@@H](C)C(=O)[C@H](C(C)C)OC(=O)C[C@@H]1O

Procedure:
The didemnin samples were hydrolyzed in 6N HCl at 110° C. for 24 hours. The resulting amino acids were identified by field desorption mass spectrometry (FDMS) of the mixture, as well as by gas chromatography (GC)/MS of the amino acids' trifluoroacetyl n-butyl ester derivatives. They were also quantitated by GC, and their identities confirmed by coinjection with derivatives of authentic samples.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:10]([C:11](=O)[C:12]#[C:13]C)=[C:4]2[CH:3]=1.[N+]([O-])(O)=O.[C:27]1([NH:33][C:34]([NH2:36])=[NH:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[C:10]([C:11]3[CH:12]=[CH:13][N:36]=[C:34]([NH:33][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:35]=3)=[C:4]2[CH:3]=1
Reactant: N=C(N)Nc1ccccc1
Reactant: CC#CC(=O)c1c(-c2ccc(F)cc2)nn2ccc(Cl)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=[N+]([O-])O
Solvent: CN1CCCC1=O
Product: Fc1ccc(-c2nn3ccc(Cl)cc3c2-c2ccnc(Nc3ccccc3)n2)cc1
Temperature: 150 °C
Yield: 35.8 %

Procedure:
To a solution of 1-[5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-butyn-1-one (1.0 g, 3.36 mmol) in 1-methyl-2-pyrrolidinone (4 mL) was added N-phenylguanidine nitrate (1.0 g, 5.0 mmol) and anhydrous potassium carbonate (0.7 g, 5.0 mmol). The resulting mixture was heated at 150° C. for 12 hours and concentrated in vacuo to a syrup. Ethyl acetate and water were added and the phases separated. The organic phase was dried (magnesium sulfate), filtered and concentrated to a solid. This solid was crystallized from acetonitrile to give 500 mg (36%) of 4-[5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-phenyl-2-pyrimidinamine as a yellow solid. 1H-NMR (CDCl3): δ 8.48 (d, 1H), 8.45 (d, 1H), 8.23 (d, 1H), 7.64 (m, 4H), 7.42 (t, 2H), 7.1-7.25 (m, 4H), 6.93 (dd, 1H), 6.52 (d, 1H); 19F-NMR (CDCl3): δ −112.29; MS m/z 416 (M+1).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:32][O:33][CH2:34][CH:35]=[CH2:36])[C:8]([NH:10][CH:11]2[C:30](=[O:31])[N:13]3[C:14]([C:27]([OH:29])=[O:28])=[C:15]([S:18]/[CH:19]=[CH:20]\[C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:43]([O:46][CH:47](Br)[CH3:48])(=[O:45])[CH3:44].C(OCC)(=O)C>CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:32][O:33][CH2:34][CH:35]=[CH2:36])[C:8]([NH:10][CH:11]2[C:30](=[O:31])[N:13]3[C:14]([C:27]([O:29][CH:47]([O:46][C:43](=[O:45])[CH3:44])[CH3:48])=[O:28])=[C:15]([S:18]/[CH:19]=[CH:20]\[C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(S/C=C\c3cccnc3)CS[C@H]12)c1csc(N)n1
Reactant: CC(=O)OC(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)OC(C)OC(C)=O)=C(S/C=C\c3cccnc3)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 23.3 %

Procedure:
To a solution of 7-[2-(2-aminothiazol-4-yl)-2-allyloxyiminoacetamido]-3-[(Z)-2-(3-pyridyl)vinylthio]-3-cephem-4-carboxylic acid (syn isomer) (1.0 g) in N,N-dimethylformamide (20 ml) was added cesium carbonate (0.31 g). The mixture was stirred for 20 minutes at room temperature, and 1-bromoethyl acetate (0.96 g) was added dropwise thereto at 0°-3° C. After the mixture was stirred for 40 minutes, 1-bromoethyl acetate (0.3 g) was added thereto. After stirring for 1 hour, reaction mixture was poured into ethyl acetate (120 ml) and the insoluble material was filtered off. The filtrate was washed with water (120 ml×2), an aqueous solution of sodium bicarbonate (50 ml × 1) and a saturated aqueous solution of sodium chloride successively and dried over magnesium sulfate. The ethyl acetate was distilled off under reduced pressure, and the residue was pulverized with diisopropyl ether to give 1-acetoxyethyl 7-[2-(2-aminothiazol- 4-yl)-2-allyloxyiminoacetamido]-3-[(Z)-2-(3-pyridyl) vinylthio]-3-cephem-4-carboxylate (syn isomer) (0.27 g).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)=[C:12]([CH3:26])[CH:11]=1)[CH3:9])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:26][C:12]1[CH:11]=[C:10]([C@@H:8]([NH2:7])[CH3:9])[N:15]=[CH:14][C:13]=1[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]([F:24])([F:25])[F:23])[CH:17]=1
Reactant: Cc1cc([C@H](C)NC(=O)OC(C)(C)C)ncc1-c1ccnc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc([C@H](C)N)ncc1-c1ccnc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a solution of (S)-tert-butyl(1-(4-methyl-2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethyl)carbamate (200 mg, 0.524 mmol) in DCM (2 ml) at −78° C. was added trifluoroacetic acid (2 mL, 12.98 mmol). The solution was stirred at r.t. for 1 hr. The mixture was concentrated, diluted with 10 mL DCM and stirred with solid MP-carbonate to remove TFA. Filtered and concentrated to give 147 mg (S)-1-(4-methyl-2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethanamine as a light brown sticky oil. MS m/z 282.1 (M+H). Rt=0.85 min. (Column: XBridge C18 3.5 um 2.1×50 mm. Solvent A: 2% Acetonitrile, 3.75 mM Ammonium Acetate, Water. Solvent B: Acetonitrile. Gradient: 5-95% B over 1.70 min. Flow rate: 2 mL/min.) The crude product was used to next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[N:9]=[C:10](I)[C:3]=12.[F:25][C:26]1[C:47]([F:48])=[CH:46][CH:45]=[CH:44][C:27]=1[O:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[N:9]=[C:10]([C:32]3[CH:31]=[CH:30][C:29]([O:28][C:27]4[CH:44]=[CH:45][CH:46]=[C:47]([F:48])[C:26]=4[F:25])=[CH:34][CH:33]=3)[C:3]=12
Reactant: CC1(C)OB(c2ccc(Oc3cccc(F)c3F)cc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1Cn1nc(I)c2c(N)ncnc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3cccc(F)c3F)cc2)c2c(N)ncnc21
Temperature: 100 °C
Reaction time: 12 h
Yield: 70.4 %

Procedure:
Into a 100 mL, 3-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed tert-butyl (2R)-2-([4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidine-1-carboxylate (300 mg, 0.68 mmol, 1.00 equiv), a solution of 2-[4-(2,3-difluorophenoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (290 mg, 0.87 mmol, 1.10 equiv) in dioxane (9 mL), tetrakis(triphenylphosphane)-palladium (40 mg, 0.03 mmol, 0.05 equiv), and a solution of sodium carbonate (179 mg, 1.67 mmol, 2.50 equiv) in water (3 mL). The resulting solution was stirred for 12 h at 100° C. in an oil bath. The resulting mixture was concentrated under vacuum, and the solution was diluted with ethyl acetate. The resulting mixture was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (20/1) to give 250 mg (71%) of tert-butyl (2R)-2-([4-amino-3-[4-(2,3-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidine-1-carboxylate as a white solid.