Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].N>CCO.[Ni]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[C:6]([CH:9]=1)[CH2:7][NH2:8]
Reactant: N#Cc1cc(Cl)ccc1-n1cncn1
Agent: [Ni]
Agent: N
Solvent: CCO
Product: NCc1cc(Cl)ccc1-n1cncn1
Reaction time: 26 h

Procedure:
To a suspension of 5-Chloro-2-[1,2,4]triazol-1-yl-benzonitrile (11.87 g, 58 mmol) in EtOH saturated with NH3 (500 ml) was added Raney Nickel (ca. 5 pipettes of suspension in water, washed/decanted with EtOH several times). The mixture was hydrogenated at 1 atm for 26 h. The reaction mixture was filtered on celite under a flow of argon and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, 5% MeOH containing 10% NH4OH in CH2Cl2 to 10%) to give 5-Chloro-2-[1,2,4]triazol-1-yl-benzylamine as a white solid. 1H NMR (CDCl3, 400 MHz) δ8.47 (s, 1H); 8.14 (s, 1H); 7.58 (d, J=2.3 Hz, 1H); 7.38 (dd, J=2.3, 7.9 Hz, 1H); 7.30 (d, J=7.9 Hz, 1H); 3.70 (s, 2H). 8.72 (d, J=4.8 Hz, 1H); 8.42 (s, 1H); 8.18 (s, 1H); 7.70 (d, J=7.6 Hz, 1H); 7.40 (dd, J=4.8, 7.6 Hz, 1H); 5.85 (bs, 1H); 4.43 (d, J=5.4 Hz, 2H); 1.45 (s, 9H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][O:9][C@@H:10]1[C@@H:14]2[O:15]C(C)(C)[O:17][C@H:18]([CH:19]=[CH2:20])[C@@H:13]2[O:12][C:11]1=[O:23].O>C1COCC1>[OH:15][C@@H:14]1[C@H:13]([C@H:18]([OH:17])[CH:19]=[CH2:20])[O:12][C:11](=[O:23])[C@@H:10]1[O:9][CH3:8]
Reactant: C=C[C@H]1OC(C)(C)O[C@@H]2[C@H]1OC(=O)[C@@H]2OC
Solvent: C1CCOC1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: C=C[C@@H](O)[C@@H]1OC(=O)[C@H](OC)[C@@H]1O
Reaction time: 8 h
Yield: 94.4 %

Procedure:
10 ml of TFA are added dropwise, at 0° C., to a 100 ml round-bottomed flask containing 1.0 g of 17 (4.38 mmol), 10 ml of water and 14 ml of THF. The medium is left to return to AT and stirred overnight. The medium is then concentrated at reduced pressure, at AT, and 50 ml of water are added, and the mixture is frozen and lyophilized. The lyophilizate is made into a paste in heptane, in the presence of a minimum amount of methanol, after the solvents have been evaporated off. 778 mg of expected product 18 (white solid) are obtained.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[C:12]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:11]=[CH:10][CH:9]=2)=[O:4].[NH2:25][CH2:26][C:27]([OH:29])=[O:28]>>[C:23]([C:7]1[C:8]2[C:13](=[C:12]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:10][CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:4])[N:6]=1)#[N:24]
Reactant: NCC(=O)O
Reactant: COC(=O)c1nc(C#N)c2cccc(Oc3ccccc3)c2c1O
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2c(Oc3ccccc3)cccc12

Procedure:
The title compound was synthesized from 1-Cyano-4-hydroxy-5-phenoxy-isoquinoline-3-carboxylic acid methyl ester and glycine in analogy to example 1b; MS-(+)-ion: M+1=363.9.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]([C@H:12]([C@@H:21]([CH2:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[OH:22])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[CH3:37][C:38]([Si:41](Cl)([CH3:43])[CH3:42])([CH3:40])[CH3:39]>CN(C=O)C>[CH2:1]([O:8][C@@H:9]([C@H:12]([C@@H:21]([CH2:23][O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[OH:22])[O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:10][O:11][Si:41]([C:38]([CH3:40])([CH3:39])[CH3:37])([CH3:43])[CH3:42])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC[C@@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@H](O)COCc1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@H](O)COCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
A mixture of 239 (5.24 g, 12.4 mmol), imidazole (3.72 g, 54.6 mmol), and TBDMSCl (2.07 g, 13.6 mmol) in dry DMF (50 mL) was stirred at 0° C. under N2 for 30 min. The reaction was quenched with ice (20 mL), and the reaction mixture was partitioned between Et2O (200 mL) and H2O (100 mL). The separated organic phase was washed with H2O (100 mL) and brine (100 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash chromatography (hexanes:EtOAc, 3:1) to give a colorless oil 240 (6.164 g, 93%): [α]D −140.4° (c 0.87, CHCl3); 1H NMR (CDCl3) δ 7.35-7.25 (15H, m, Ar), 4.74 and 4.60 (2H, 2d, Ja,b=11.7 Hz, CH2Ph), 4.69 and 4.51 (2H, 2d, Ja,b=11.9 Hz, CH2Ph), 4.51 and 4.45 (2H, 2d, Ja,b=11.6 Hz, CH2Ph), 4.05 (1H, dddd, J3,4=2.3 Hz, J4,5a=J4,5b=5.9 H,J4,OH=5.9 Hz, H-4), 3.88 (1H, dd, J1a,1b=11.0 Hz, J1a,2=4.2 Hz, H-1a), 3.78 (1H, dd, J1b,2=4.9 Hz, H-1b), 3.77 (1H, dd, J2,3=4.1 Hz, H-3), 3.73 (1H, ddd, H-2), 3.54(1H, dd, H-5a), 3.49 (1H, dd, H-5b), 3.02 (1H, d, OH), 0.891 (9H, s, (CH3)3CSi), 0.05 (6H, s, (CH3)2Si); 13C NMR (CDCl3) δ 149.11, 145.62, 140.95 (3Cipso), 128.35-127.60 (15C, Ar), 80.25 (C-2), 77.25 (C-3), 73.65, 73.26, 72.84 (3CH2Ph), 71.16 (C-5), 69.75 (C-4), 62.04 (C-1), 25.88 (3C, (CH3)3CSi) 18.23 (1C, CSi), −5.40, −5.44 (2C, (CH3)2Si); MALDI-TOF MS: m/e 537.89 (M++H), 559.33 (M++Na). Anal. Calcd for C32H44O5Si: C, 71.60; H, 8.26. Found: C, 71.44; H, 8.34.
Reaction SMILES: C(N[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=C.[CH2:11]([N:13](CC)CC)[CH3:12].[Cl:18][CH2:19][CH2:20][S:21]([CH:24]([CH3:28])[C:25](Cl)=[O:26])(=[O:23])=[O:22].Cl>O1CCCC1.C1(C=CC(O)=CC=1)O>[CH:11]([NH:13][C:25](=[O:26])[C:24]([CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)([S:21]([CH2:20][CH2:19][Cl:18])(=[O:23])=[O:22])[CH3:28])=[CH2:12]
Reactant: CCN(CC)CC
Reactant: CC(C(=O)Cl)S(=O)(=O)CCCl
Reactant: C=CNCc1ccccc1
Agent: Cl
Agent: Oc1ccc(O)cc1
Solvent: C1CCOC1
Product: C=CNC(=O)C(C)(Cc1ccccc1)S(=O)(=O)CCCl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56.2 %

Procedure:
A mixture of 100 ml of tetrahyrofuran, 20.1 g of vinylbenzylamine, 16.7 g of triethylamine, and 0.1 g of hydroquinone was placed in a reactor, and while cooling with ice water, a solution containing 36.1 g of β-chloroethylsulfonylpropionic acid chloride dissolved in 200 ml of tetrahydrofuran was added dropwise thereto over a period of 30 minutes. The resulting mixture was allowed to stand overnight at room temperature. The reaction mixture was then poured into a solution prepared by diluting 16.5 g of concentrated hydrochloric acid with 1.5 liters of ice water, and the thus formed precipitate was collected by filtration. The precipitate was recrystallized from a solvent mixture of 200 ml of ethanol and 200 ml of water to provide 26.8 g of N-vinylbenzyl-β-chloroethylsulfonyl propionic acid amide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([C:14]2[CH:31]=[CH:30][C:17](/[CH:18]=[CH:19]/[C:20]3[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=3)[C:23]([O:25]C)=[O:24])=[CH:16][C:15]=2[CH3:32])=[CH:12][C:11]([C:33]([OH:36])([CH3:35])[CH3:34])=[N:10]1.O.O.[OH-].[Li+].CO>C1COCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[N:9]1[C:13]([C:14]2[CH:31]=[CH:30][C:17](/[CH:18]=[CH:19]/[C:20]3[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=3)[C:23]([OH:25])=[O:24])=[CH:16][C:15]=2[CH3:32])=[CH:12][C:11]([C:33]([OH:36])([CH3:34])[CH3:35])=[N:10]1
Reactant: COC(=O)c1cccc(/C=C/c2ccc(-c3cc(C(C)(C)O)nn3-c3c(Cl)cccc3Cl)c(C)c2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(/C=C/c2cccc(C(=O)O)c2)ccc1-c1cc(C(C)(C)O)nn1-c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.6 %

Procedure:
To a solution of (E)-methyl 3-(4-(1-(2,6-dichlorophenyl)-3-(2-hydroxypropan-2-yl)-1H-pyrazol-5-yl)-3-methylstyryl)benzoate (180 mg of impure material from previous step, 0.35 mmol) in THF (2.0 mL) was added H2O (0.4 mL) followed by lithium hydroxide monohydrate (25.3 mg, 0.6 mmol). After stirring for 1 hour at ambient temperature a biphasic mixture had formed, and LC/MS analysis of the reaction showed no reaction. a small amount of MeOH was added to homogenize the mixture, and the reaction was then heated to 50° C. in an oil bath. After 2 hours stirring at 50° C., LC/MS analysis showed the reaction to be complete. Heating was discontinued, and after stirring at ambient temperature overnight, the reaction was quenched by the addition of 5% aqueous citric acid, and EtOAc. The layers were separated and the aqueous was extracted with EtOAc (3×). Combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to afford a clear film. This material was purified by reverse phase preparative HPLC eluting with a gradient of MeCN/H2O with 0.05% TFA. The major peak from the HPLC was concentrated under reduced pressure to remove most of the solvents, and the resulting acidic aqueous was extracted with CH2Cl2 (3×). The combined organic extracts were washed with H2O until the washings were no longer acidic (2×), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford (E)-3-(4-(1-(2,6-dichlorophenyl)-3-(2-hydroxypropan-2-yl)-1H-pyrazol-5-yl)-3-methylstyryl)benzoic acid (45.4 mg, 26% yield) as a white powder. 1H NMR (400 MHz CDCl3): δ 821 (1H, s), 7.98 (1H, d, 7.69 (1H, d), 7.45 (1H, t), 7.39 (1H, d), 7.37-7.31 (2H, m), 7.23 (1H, m), 7.15 (1H, m), 7.12-7.07 (2H, m), 7.06 (1H, m), 6.46 (1H, s), 2.45 (3H, s), 1.71 (6H, s). MS(ES): 529 [M+H]+.
Reaction SMILES: N[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11](O)=[C:12]([O:14][CH:15]([C:17]3[C:22]([Cl:23])=[CH:21][CH:20]=[C:19]([F:24])[C:18]=3[Cl:25])[CH3:16])[CH:13]=2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:46]1([CH2:52][CH2:53][OH:54])[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1.CCOC(/[N:60]=N/C(OCC)=O)=O>>[Cl:25][C:18]1[C:19]([F:24])=[CH:20][CH:21]=[C:22]([Cl:23])[C:17]=1[CH:15]([O:14][C:12]1[CH:13]=[C:8]([C:5]2[CH:6]=[N:7][C:2]([O:54][CH2:53][CH2:52][N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[CH:3][CH:4]=2)[CH:9]=[N:10][C:11]=1[NH2:60])[CH3:16]
Reactant: CC(Oc1cc(-c2ccc(N)nc2)cnc1O)c1c(Cl)ccc(F)c1Cl
Reactant: CCOC(=O)/N=N/C(=O)OCC
Reactant: OCCN1CCOCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(Oc1cc(-c2ccc(OCCN3CCOCC3)nc2)cnc1N)c1c(Cl)ccc(F)c1Cl
Reaction time: 8 h
Yield: 52.2 %

Procedure:
To a mixture of 6′-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-[3,3′]bipyridinyl-6-ol (78 mg, 0.20 mmol), triphenylphosphine (63 mg, 0.24 mmol) and 2-morpholin-4-yl-ethanol (0.026 mL, 0.22 mmol) was added DEAD (0.034 mL, 0.22 mmol). After stirring overnight more PPh3 (63 mg, 0.24 mmol) and more DEAD (0.034 mL, 0.22 mmol) were added. After several hours, more alcohol (0.026 mL, 0.22 mmol) was added. After several more hours, more PPh3 (63 mg, 0.24 mmol) and more DEAD (0.034 mL, 0.22 mmol) were added. After stirring overnight, the mixture was partitioned between dichloromethane and half-saturated brine. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over Na2SO4 and concentrated by rotary evaporation. The residue was purified by silica gel chromatography using gradient elution of dichloromethane, methanol to afford 5-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-6′-(2-morpholin-4-yl-ethoxy)-[3,3′]bipyridinyl-6-ylamine (53 mg, 53%).
Reaction SMILES: [CH2:1]1[O:19][C:4]([CH2:17][CH3:18])([CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[C:7]=2[NH2:16])[O:3][CH2:2]1.[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[CH:33]=[CH:32][C:31]([CH2:34]Br)=[CH:30][CH:29]=1)#[N:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH2:2]1[O:3][C:4]([CH2:17][CH3:18])([CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[C:7]=2[NH:16][CH2:34][C:31]2[CH:30]=[CH:29][C:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[C:20]#[N:21])=[CH:33][CH:32]=2)[O:19][CH2:1]1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CCC1(Cc2cccc(C(=O)OC)c2N)OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC1(Cc2cccc(C(=O)OC)c2NCc2ccc(-c3ccccc3C#N)cc2)OCCO1
Yield: 43.2 %

Procedure:
A mixture of 1-(2-amino-3-methoxycarbonylphenyl)butan-2-one ethylene ketal (T) (0.7 g) (prepared, e.g., as described in Preparation 14), 2'-(cyano)biphenyl-4-yl-methylbromide (0.826 g) and potassium carbonate (0.41 g) in dimethylformamide (20 ml) was heated at 80°-90° C. for 16 hours under an inert atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue obtained was diluted with ethyl acetate (100 ml), washed twice with cold water, and then brine. The solvent was removed under reduced pressure and the residue was chromatographed on silica gel, eluting with 20% ethyl acetate/hexane, to give 1-[2-(2"-cyanobiphenyl-4'-ylmethylamino)-3-methoxycarbonylphenyl]butan-2-one ethylene ketal (0.52 g), a compound of Formula (U), as an oil.
Reaction SMILES: [C:1]1(C=CC=C(O)C=1)[OH:2].[C:9]1([CH:16]=[CH:15][C:13](O)=[CH:12][CH:11]=1)[OH:10].OC1C=CC(C(C2C=CC(O)=CC=2)(C)C)=CC=1.BrC1C=C(C(C2C=C(Br)C(O)=C(Br)C=2)(C)C)C=C(Br)C=1O.C1C(O)=CC=C(S(C2C=CC(O)=CC=2)(=O)=O)C=1>>[CH2:1]=[O:2].[C:9]1([OH:10])[CH:16]=[CH:15][CH:13]=[CH:12][CH:11]=1
Reactant: Oc1cccc(O)c1
Reactant: Oc1ccc(O)cc1
Agent: CC(C)(c1cc(Br)c(O)c(Br)c1)c1cc(Br)c(O)c(Br)c1
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: O=S(=O)(c1ccc(O)cc1)c1ccc(O)cc1
Product: C=O
Product: Oc1ccccc1

Procedure:
The epoxy compounds may also be derived from mononuclear phenols, such as resorcinol or hydroquinone; or else they are based on polynuclear phenols, such as on bis(4-hydroxyphenyl)methane, 2,2-bis(4-hydroxyphenyl)propane, 2,2-bis(3,5-dibromo-4-hydroxyphenyl)propane or 4,4′-dihydroxydiphenyl sulfone, or on condensates of phenols with formaldehyde that are obtained under acidic conditions, such as phenol novolaks.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[C:16]([F:17])=[C:15]([F:18])[CH:14]=[CH:13][C:5]=1[NH:6][C@@H:7]([CH3:12])[C:8](OC)=[O:9].CO.O>C1CCCCC1>[F:3][C:4]1[C:16]([F:17])=[C:15]([F:18])[CH:14]=[CH:13][C:5]=1[NH:6][C@@H:7]([CH3:12])[CH2:8][OH:9]
Reactant: COC(=O)[C@H](C)Nc1ccc(F)c(F)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCCCC1
Solvent: CO
Product: C[C@@H](CO)Nc1ccc(F)c(F)c1F
Reaction time: 6 h

Procedure:
At room temperature, sodium borohydride (35.7 mg) was suspended in cyclohexane (0.2 ml). Then a solution (0.8 ml) of methyl (2S)-2-(2,3,4-trifluoroanilino)propionate (200 mg, 99.8% ee) in cyclohexane was added to the solution. After adding methanol (137.4 mg), the liquid reaction mixture was stirred for 6 hours. Then water was added to the liquid reaction mixture followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of ammonium chloride and dried over anhydrous magnesium sulfate. After evaporating the solvent, the obtained residue was subjected to silica gel column chromatography to thereby give 176 mg (99.8% ee) of the title compound as an oily substance. The 1H-NMR and IR spectral data of this product was identical with those of the compound obtained in Example 51.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[C:18]2[C:5]([C@@:6]3([CH3:25])[C@H:15]([CH2:16][S:17]2(=[O:21])=[O:20])[C@:14]2([CH3:22])[C@H:9]([C:10]([CH3:24])([CH3:23])[CH2:11][CH2:12][CH2:13]2)[CH2:8][CH2:7]3)=[C:4]([C:26]([OH:28])=O)[CH:3]=1.[CH3:29][N:30](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.CN>CN(C=O)C.C1COCC1>[OH:1][C:2]1[CH:19]=[C:18]2[C:5]([C@@:6]3([CH3:25])[C@H:15]([CH2:16][S:17]2(=[O:21])=[O:20])[C@:14]2([CH3:22])[C@H:9]([C:10]([CH3:24])([CH3:23])[CH2:11][CH2:12][CH2:13]2)[CH2:8][CH2:7]3)=[C:4]([C:26]([NH:30][CH3:29])=[O:28])[CH:3]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC1(C)CCC[C@]2(C)[C@H]3CS(=O)(=O)c4cc(O)cc(C(=O)O)c4[C@]3(C)CC[C@@H]12
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(O)cc2c1[C@]1(C)CC[C@H]3C(C)(C)CCC[C@]3(C)[C@H]1CS2(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.7 %

Procedure:
A mixture of (1R,10R,11S,16S)-5-hydroxy-1,11,15,15-tetramethyl-8,8-dioxo-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-3-carboxylic acid (65) (0.49 g, 1.2 mmol), HATU (0.70 g, 1.8 mmol), N-methyl morpholine (0.40 mL, 3.6 mmol), methylamine (2 M in THF, 3.0 mL, 6.0 mmol), THF (10 mL) and DMF (2.0 mL) were placed in a sealed tube. The mixture was stirred at room temperature for 18 h. The THF was evaporated and the residue was quenched with water. The resulting solid was collected by filtration. The crude product was purified by flash chromatography on silica gel (Hexanes/EtOAc, 1:1) to yield (1R,10R,11S,16S)-5-hydroxy-N,1,11,15,15-pentamethyl-8,8-dioxo-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-3-carboxamide (66) (0.25 g, 44%) as a white solid. 1H NMR (CDCl3): δ 7.62 (s, 1H), 7.09 (s, 1H), 6.70 (s, 1H), 6.36 (m, 1H), 3.39 (m, 2H), 2.97 (d, 3H), 2.54 (m, 1H), 2.13 (m, 1H), 1.75-0.96 (m, 13H), 0.94 (s, 3H), 0.88 (s, 3H), 0.82 (s, 3H). MS m/z 420 (C23H33NO4S+H+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14](Br)[N:13]=2)=[O:9])[CH:5]=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.[NH4+:24].[OH-].C(O)CO.O>Cl.[Cu-]=O>[NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH2:24])[N:13]=2)=[O:9])[CH:5]=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1
Reactant: [NH4+]
Reactant: Nc1nc(C(=O)NCc2cccc(Br)n2)cc(-c2ccco2)n1
Agent: O=[Cu-]
Agent: Cl
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: Nc1cccc(CNC(=O)c2cc(-c3ccco3)nc(N)n2)n1
Temperature: 90 °C
Yield: 22 %

Procedure:
A mixture of 2-amino-N-(6-bromo-2-pyridylmethyl)-6-(2-furyl)pyrimidine-4-carboxamide (350 mg, 0.93 mmol) and copper(I)oxide (6.7 mg, 0.046 mmol) in 4-M NH4OH in ethylene glycol (20.23 ml, 80.92 mmol) was heated in a sealed tube at 90° C. for 20 h, cooled, poured into water (100 mL) and extracted with EtOAc (2×25 mL). The combined organic phase was washed with brine (10 mL), dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2; Hexane:EtOAc (1:4)-(0:1)] to give the title compound (65 mg, 22%) as a cream solid.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C:27]4[CH:32]=[CH:31][C:30]([CH2:33]Br)=[CH:29][CH:28]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C:27]4[CH:32]=[CH:31][C:30]([CH2:33][N:35]5[CH2:40][CH2:39][O:38][CH2:37][CH2:36]5)=[CH:29][CH:28]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ncnn2c(-c3ccc(CBr)cc3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: C1COCCN1
Product: Nc1ncnn2c(-c3ccc(CN4CCOCC4)cc3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Yield: 28 %

Procedure:
Using a procedure similar to that of Example 282, step 2, with 5-(2-benzyl-2H-indazol-6-yl)-7-(4-bromomethyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine and morpholine as starting material, 55 mg (28%) of the desired product was isolated. 1H NMR (300 MHz, DMSO-d6) δ 8.80 (s, 1 H), 8.05 (d, 2 H), 8.0 (s, 1 H), 7.90 (d, 1 H), 7.70 (s, 1 H), 7.60-7.40 (m, 7 H), 7.25 (d, 1 H), 7.20 (s, 1 H), 5.70 (s, 2 H), 3.60 (t, 4 H), 3.50 (s 2 H), 2.405 (t, 4 H); ES-MS m/z 516.25 [M+H]+, HPLC RT (min) 2.61.
Reaction SMILES: [C:1]1([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)=O)[CH:6]=CC=CC=1.[Cl:28][C:29]1[N:34]=[C:33]([CH:35]=O)[C:32]([NH:37]C(=O)OC(C)(C)C)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(OCC)(=O)C.O>[Cl:28][C:29]1[N:34]=[C:33]2[C:32](=[CH:31][CH:30]=1)[N:37]=[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]3([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:24])[CH3:25])[CH2:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=1)[C:7]([C:1]1[CH:8]=[CH:7][CH:1]=[CH:6][CH:6]=1)=[CH:35]2
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)nc1C=O
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)Cc3ccccc3)cc2)CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccc(Cl)nc4cc3-c3ccccc3)cc2)CCC1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
To a round bottom flask was added tert-butyl {1-[4-(phenylacetyl)phenyl]cyclobutyl}carbamate (1-3) (2.7 g, 6.1 mmol), tert-butyl (6-chloro-2-formylpyridin-3-yl)carbamate (1-4) (1.6 g, 6.1 mmol), potassium carbonate (5.0 g, 6.0 mmol), and DMF (20 mL). The reaction mixture was heated to 80° C. while stirring in a hot oil bath under an atmosphere of nitrogen for 15 hours. Then the reaction mixture was warmed to 120° C. for 1 hour. The reaction mixture was permitted to cool to room temperature, added water, suspended in ethyl acetate, washed with a saturated solution of sodium bicarbonate, followed by water, brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (5-50% EtOAc/5% DCM/Hexane) to give tert-butyl {1-[4-(6-chloro-3-phenyl-1,5-naphthyridin-2-yl)phenyl]cyclobutyl}carbamate (1-5) as an off-white solid. HRMS (M+H)+: observed=486.1954, calculated=486.1943.
Reaction SMILES: [O:1]=[O+][O-].C([C:6](=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:7]([C@@H:9]([NH:14][C:15](=[O:29])[O:16][C:17]1([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1)[CH2:10][CH2:11][CH2:12][CH3:13])=[O:8])#N.[CH3:49][C@H:50]([NH2:57])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>ClCCl>[O:1]=[C:6]([NH:57][C@@H:50]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[CH3:49])[C:7]([C@@H:9]([NH:14][C:15](=[O:29])[O:16][C:17]1([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1)[CH2:10][CH2:11][CH2:12][CH3:13])=[O:8]
Reactant: CCCC[C@H](NC(=O)OC1(Cc2ccccc2)CCCC1)C(=O)C(C#N)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=[O+][O-]
Reactant: C[C@H](N)c1ccccc1
Solvent: ClCCl
Product: CCCC[C@H](NC(=O)OC1(Cc2ccccc2)CCCC1)C(=O)C(=O)N[C@H](C)c1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 15 %

Procedure:
Ozone was bubbled through a solution of 304.6 mg (493.9 μmol) of 1-benzylcyclopentyl(1S)-1-[cyano(triphenylphosphoranylidene)acetyl]pentylcarbamate in 10 mL of dichloromethane at −78° C. for 15 min. The solution was purged with nitrogen for 5 min, then 63.7 μL (493.9 μmol) of (S)-α-methylbenzylamine was added and the solution was stirred at −78° C. for 15 min. The solution was concentrated and 5 mL of a 1 M solution of silver nitrate in tetrahydrofuran:water (4:1) was added and the mixture was stirred for 16 h at room temperature. The solution was extracted with ethyl acetate. The organic layer was washed with 10% citric acid, followed by saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with an ethyl acetate:hexanes solution (1:4) to give 33.4 mg (15%) of 1-benzylcyclopentyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate. Rf=0.23 (1:4 ethyl acetate:hexanes); 1H NMR (300 MHz, DMSO-d6) δ 9.19 (d, J=8 Hz, 1H), 8.31-7.11 (m, 11H), 4.98 (p, J=8 Hz, 1H), 4.82-4.74 (m, 1H), 3.18 (s, 2H), 1.94-1.80 (m, 2H), 1.78-1.54 (m, 6H), 1.42 (d, J=7 Hz, 3H), 1.40-1.16 (m, 6H), 0.81 (t, J=7 Hz, 3H); HRMS C28H36N2O4+Na m/z 487.2573 (M+Na)Cal; 487.2568 (M+Na)Obs.