Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:16]([O:18][CH3:19])=[O:17])[C:8](=[O:24])[CH:7]=1.[Br:30]N1C(=O)CCC1=O>C(Cl)Cl>[Br:30][C:7]1[C:8](=[O:24])[N:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:16]([O:18][CH3:19])=[O:17])[C:10]([CH3:12])=[CH:11][C:6]=1[O:5][CH2:4][C:3]1[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)c(-n2c(C)cc(OCc3ccc(F)cc3F)cc2=O)c1
Solvent: ClCCl
Product: COC(=O)c1ccc(C)c(-n2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl 3-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoate (as prepared above) (1.8 g, 4.51 mmol) was taken up in CH2Cl2 (10 ml). N-bromosuccinimide (0.80 g, 4.51 mmol) was added and the mixture stirred at room temperature for two hours. The CH2Cl2 is removed in vacuo and the residue is taken up in CH3CN. The resulting precipitate is collected on a filter pad and washed with CH3CN to yield a white solid (0.30 g, 14%, first crop)
Reaction SMILES: S(O[CH2:12][C@H:13]1[O:17][C:16](=[O:18])[NH:15][CH2:14]1)(C1C=CC(C)=CC=1)(=O)=O.[C-:19]#[N:20].[Na+]>CO.O>[C:19]([CH2:12][CH:13]1[O:17][C:16](=[O:18])[NH:15][CH2:14]1)#[N:20]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CNC(=O)O2)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#CCC1CNC(=O)O1
Yield: 70 %

Procedure:
To a stirring solution of (S)-5-tosyloxymethyl-1,3-oxazolidine-2-one (0.54 g, 1.99 mmol) in MeOH-water (15-3 mL) was added NaCN (0.39 g, 8.00 mmol) at room temperature and then heated to reflux for 4 h. After completion of the reaction, solvent in the reaction mixture was completely evaporated and the residue was purified by column chromatography employing EtOAc-hexane (70:30) as eluent to afford pure 5-cyanomethyl-1,3-oxazolidine-2-one in 70% yield. [α]26D=+4.5 (c 1.0, MeOH); IR (Neat) 3349, 2918, 2839, 2243, 1710, 1255, 1051 cm1; 1HNMR (200 MHz, CD3OD) δ 2.57 (d, 2H, J=6.6 Hz), 3.20-3.55 (m, 2H), 4.00-4.18 (m, 1H).
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH2:17][C:18]4[C:26]5[N:25]=[CH:24][N:23](C6CCCCO6)[C:22]=5[CH:21]=[CH:20][CH:19]=4)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CO.O>[NH:23]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:17][NH:16][C:12]3[N:11]=[C:10]([NH:9][C:6]4[CH:5]=[C:4]([CH:1]5[CH2:2][CH2:3]5)[NH:8][N:7]=4)[CH:15]=[CH:14][N:13]=3)[C:26]=2[N:25]=[CH:24]1
Reactant: c1cc(CNc2nccc(Nc3cc(C4CC4)[nH]n3)n2)c2ncn(C3CCCCO3)c2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: c1cc(CNc2nccc(Nc3cc(C4CC4)[nH]n3)n2)c2nc[nH]c2c1
Temperature: 80 °C

Procedure:
A mixture of 60 (110 mg, 0.26 mmol) and p-TsOH.H2O (44 mg, 0.26 mmol) in MeOH (5 mL) and water (1 mL) was heated at 80° C. for 14 h. The solvent was removed in vacuo. The crude product was purified by preparative HPLC to afford 45 mg (51%) I-39 as white solid.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([C:9]#[N:10])=[CH:7][N:6]=[CH:5][CH:4]=1)[CH3:2].[CH3:11]I>>[CH:1]([C:3]1[C:8]([C:9]#[N:10])=[CH:7][N:6]=[CH:5][CH:4]=1)([CH3:11])[CH3:2]
Reactant: CI
Reactant: CCc1ccncc1C#N
Product: CC(C)c1ccncc1C#N

Procedure:
By the reaction in the same manner as in Example 64-i) using 4-ethylnicotinonitrile (2.95 g) and methyl iodide (7 ml), the title compound (1.90 g) was obtained as a yellow oil.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[CH3:13][CH2:14][O:15][C:16](/[CH:18]=[CH:19]/[CH2:20]P(OCC)(OCC)=O)=[O:17].[H-].[Na+].Cl>CN(C)C=O>[CH:1]([O:4][C:5]1[CH:12]=[CH:11][C:8](/[CH:9]=[CH:20]/[CH:19]=[CH:18]/[C:16]([O:15][CH2:14][CH3:13])=[O:17])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(C=O)cc1
Reactant: CCOC(=O)/C=C/CP(=O)(OCC)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/C=C/c1ccc(OC(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.6 %

Procedure:
To a mixture of 4-isopropoxybenzaldehyde (15.0 g), triethyl 4-phosphonocrotonate (27.3 g) and N,N-dimethylformamide (DMF) (100 ml) was added oily sodium hydride (60%, 4.38 g), and the mixture was stirred for 16 hours at room temperature. The reaction mixture was poured into ice-water, and neutralized with 2N-HCl. The mixture was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried over magnesium sulfate (MgSO4). The solvent was distilled off and the residue was subjected to column chromatography. From the fractions eluted with ether-hexane, ethyl (E,E)-5-(4-isopropoxyphenyl)-2,4-pentadienoate (13.7 g, 58%) was obtained. Recrystallization from ether-hexane gave colorless prisms. Melting point 64-65° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].O1[C:15]2([CH2:20][CH2:19][CH:18]([CH2:21][C:22]([N:24]3[CH2:29][CH:28]=[C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:26][CH2:25]3)=O)[CH2:17][CH2:16]2)[O:14]CC1>O1CCCC1.C(OCC)C>[C:30]1([C:27]2[CH2:28][CH2:29][N:24]([CH2:22][CH2:21][CH:18]3[CH2:19][CH2:20][C:15](=[O:14])[CH2:16][CH2:17]3)[CH2:25][CH:26]=2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(CC1CCC2(CC1)OCCO2)N1CC=C(c2ccccc2)CC1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C1CCC(CCN2CC=C(c3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirring suspension of lithium aluminum hydride (9.24 g) in 250 ml of dry tetrahydrofuran under nitrogen is added dropwise a solution of aluminum chloride (10.82 g) in 250 ml of diethyl ether. The mixture is stirred at room temperature for 20 minutes and a solution of 1-(1,4-dioxaspiro-[4,5]-dec-8-ylacetyl)-1,2,3,6-tetrahydro-4-phenylpyridine (27.70 ) (Example Ia) in 500 ml of tetrahydrofuran is added dropwise. The resulting mixture is stirred at room temperature for 12 hours. The reaction is quenched by careful addition of 10 ml of water. After 30 minutes, 44 g of a 25% solution of sodium hydroxide is added dropwise and the mixture stirred for one additional hour. The inorganic salts are filtered through Celite and the filtrate evaporated in vacuo, taken up into 250 ml of a 10% solution of hydrochloric acid and 250 ml of acetone and refluxed for eight hours. The solution is cooled, concentrated in vacuo to remove the acetone, made basic with ammonium hydroxide, and extracted with chloroform (2×250 ml). The organic extracts are pooled, dried over magnesium sulfate, and evaporated to give a semisolid residue which is triturated with 100 ml of diethyl ether and filtered. The title compound is obtained (16.82 g) as a light yellow solid; mp 94°-96° C.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]([F:14])([F:13])[F:12])[CH:5]=[O:6].[CH3:15][N:16](C=O)C>C1(C)C=CC=CC=1.[C-]#N.[Zn+2].[C-]#N.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>[C:15]([C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]([F:14])([F:13])[F:12])[CH:5]=[O:6])#[N:16]
Reactant: CN(C)C=O
Reactant: O=Cc1ccc(OC(F)(F)F)c(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: N#Cc1cc(C=O)ccc1OC(F)(F)F
Temperature: 100 °C

Procedure:
To a stirred suspension of Compound 19 (6.85 g, 21.7 mmol) and zinc cyanide (4.07 g, 34.7 mmol) in dry DMF (35 ml) was added tetrakis(triphenylphosphine)palladium(0) (3.00 g, 2.60 mmol) portionwise at room temperature. The reaction mixture was heated at 100° C. for 9 h. The reaction mixture was diluted with toluene (100 ml)-2M NH3 aq. (100 ml). The organic layer was separated. The aqueous layer was diluted with toluene (100 ml), filtered through a pad of celite and the filter cake was washed with toluene. The organic layer was separated and the aqueous layer was extracted with toluene. The combined solution was washed with 2M NH3 aq. (50 ml) and brine, dried (MgSO4), and concentrated in vacuo to give crude product as a dark tan oil.
Reaction SMILES: C([C@H:3]([S:7]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[N:9][C:10]([C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=2)[CH:17]=1)=[O:11])=[O:8])[C:4]([O-:6])=O)C.[CH3:33][NH2:34]>>[OH:26][C:22]1[CH:21]=[C:20]([C:19]#[C:18][C:16]2[CH:15]=[N:14][CH:13]=[C:12]([CH:17]=2)[C:10]([N:9]=[S:7]([CH2:3][C:4]([NH:34][CH3:33])=[O:6])(=[O:8])[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:11])[CH:25]=[CH:24][CH:23]=1
Reactant: CC[C@@H](C(=O)[O-])S(=O)(=NC(=O)c1cncc(C#Cc2cccc(O)c2)c1)c1ccccc1
Reactant: CN
Product: CNC(=O)CS(=O)(=NC(=O)c1cncc(C#Cc2cccc(O)c2)c1)c1ccccc1
Yield: 90.2 %

Procedure:
In a manner similar to that described for Example 471, (S)-Ethyl[N-({5-[(3-hydroxyphenyl)ethynyl]pyridin-3-yl}carbonyl)-S-phenylsulfonimidoyl]acetate (50 mg, 0.11 mmol) and methylamine (2.0 M solution in MeOH, 0.5 mL, 1.0 mmol) were reacted to give the title compound as colorless oil (43 mg, 90%).
Reaction SMILES: [C:1]([O-:4])([OH:3])=O.[Na+].[CH2:6]([O:9][C:10]([C@H:12]1[CH2:17][CH2:16][C@H:15]([CH:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])CO)[CH2:14][CH2:13]1)=[O:11])[CH2:7][CH3:8].[K+].[Br-].CC1(C)N([O])C(C)(C)CCC1>CC(C)=O>[CH2:6]([O:9][C:10]([CH:12]1[CH2:17][CH2:16][CH:15]([CH:18]([NH:21][C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[C:1]([OH:4])=[O:3])[CH2:14][CH2:13]1)=[O:11])[CH2:7][CH3:8]
Reactant: CCCOC(=O)[C@H]1CC[C@H](C(CO)NC(=O)OC(C)(C)C)CC1
Reactant: O=C([O-])O
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: [Br-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOC(=O)C1CCC(C(NC(=O)OC(C)(C)C)C(=O)O)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
5% NaHCO3 (16 mL) was added to a 250 mL RB flask. A solution of cis-/trans-4-(1-tert-Butoxycarbonylamino-2-hydroxy-ethyl)cyclohexanecarboxylic acid propyl ester (1-5, prepared according to Example 1) (1.65 g, 1 eq) in acetone (37 mL) was added. The mixture was cooled to 0° C. with an ice-H2O bath. KBr (119.00, 60 mg, 0.1 eq) was added, followed by the addition of TEMPO (825 mg, 1.05 eq). Bleach (12.5 mL) was added dropwise. The reaction mixture was stirred at 0° C. for 1 hour. Another portion of bleach (4.7 mL) was added. The reaction mixture stir at 0° C. for 1 hour, followed by the addition of 5% NaHCO3 (19 mL). TLC and LC/MS indicated the absence of starting material. Acetone was removed under vacuum. The aqueous mixture was extracted with Et2O (2×30 mL). The aqueous layer was acidified to pH=3 with 10% HCl while cooling with ice-H2O bath, and then extracted with EtOAc (3×50 mL). The combined EtOAc was washed with brine. After drying over Na2SO4 and filtration, the filtrate was concentrated under vacuum to give 4-(tert-Butoxycarbonylamino-carboxy-methyl)-cyclohexanecarboxylic acid propyl ester (2-1) 1.71 g in 99.4% yield. The 1H NMR (DMSO-d6) data is depicted in FIG. 17.
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[C:15]([CH3:35])=[N:16][O:17][C:18]=2[C@@H:19]([NH:28][S@@](C(C)(C)C)=O)[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=O)=[CH:4][CH:3]=1.CCO.C(Cl)(=O)C>C([O-])(O)=O.[Na+].CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:14]3[C:15]([CH3:35])=[N:16][O:17][C:18]=3[C@H:19]([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])[N:28]=2)=[CH:36][CH:37]=1
Reactant: Cc1noc([C@H](CC(=O)OC(C)(C)C)N[S@](=O)C(C)(C)C)c1-c1ccccc1C(=O)c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1noc2c1-c1ccccc1C(c1ccc(Cl)cc1)=N[C@H]2CC(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 77.2 %

Procedure:
To a resealable vial was added (3S)-tert-butyl 3-(4-(2-(4-chlorobenzo yl)phenyl)-3-methylisoxazol-5-yl)-3-((R)-1,1-dimethylethylsulfinamido)propanoate (0.043 g, 0.079 mmol), EtOH (3 mL), and acetyl chloride (0.017 mL, 0.237 mmol). The vial was sealed and heated to 60° C. for 1.75 h before being cooled to room temperature and diluting with saturated NaHCO3 and EtOAc. The layers were separated and the aqueous was extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude residue was purified via Biotage (EtOAc/hex) to afford tert-butyl 2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetate (0.026 g, 0.061 mmol). 1H NMR (400 MHz, Acetone-d6) δ 7.87-7.83 (m, 1H), 7.76-7.70 (m, 1H), 7.51-7.41 (m, 2H), 7.40 (s, 4H), 4.40 (br. s, 1H), 3.32 (d, J=7.19 Hz, 2H), 2.54 (s, 3H), 1.48 (s, 9H); LC/MS m/z 423 [M+H]+.
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH:3]=[CH:2]1.[CH:7]1[CH2:11][CH:10]=[CH:9][CH:8]=1.Cl(O)(=O)(=O)=O.C([C@@H]1N[C@H](C2OC(C)=CC=2)N(C)C1=O)C1C=CC=CC=1>O>[C@@H:9]12[CH2:10][C@H:11]([CH:7]=[CH:8]1)[C@@H:3]1[C@@H:2]2[C:1](=[O:6])[CH2:5][CH2:4]1
Reactant: O=C1C=CCC1
Reactant: C1=CCC=C1
Agent: Cc1ccc([C@H]2N[C@@H](Cc3ccccc3)C(=O)N2C)o1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Product: O=C1CC[C@H]2[C@H]1[C@H]1C=C[C@H]2C1
Yield: 81 %

Procedure:
Prepared according to general procedure A from 2-cyclopenten-1-one (50 μL, 0.60 mmol), cyclopentadiene (74 μL, 0.90 mmol), 70% aqueous perchloric acid (10.3 μL, 0.12 mmol) and (2S, 5S)-5-benzyl-3-methyl-2-(5-methyl-furan-2-yl)-imidazolidin-4-one (32.4 mg, 0.12 mmol) in water (150 μL) for 12 hours at 0° C. Purification by silica gel chromatography (5:1 pentane:ether) provided the title compound as a volatile white powder in 81% yield (72 mg, 0.49 mmol); 15:1 endo:exo, endo 48% ee. IR (film) 3058, 2964, 2941, 2868, 1730, 1475, 1402, 1341, 1318, 1225, 1172, 1129, 1090, 1040, 936.0, 902.3, 840.8, 804.2, 732.8 cm−1; 1H NMR (300 MHz, CDCl3) δ 6.22 (dd, J=5.7, 2.7 Hz, 1H, CH═CH), 6.11 (dd, J=5.7, 3.0 Hz, 1H, CH═CH), 3.19 (m, 1H, CHCH═CH), 3.00 (m, 1H, CHCH═CH), 2.97 (m, 1H, CHCO), 2.85 (m, 1H, C(H)HCO), 2.02 (m, 4H, CHCH2CH2, C(H)HCO, and CHCH2CH), 1.48 (m, 2H, CH2CH2CO); 13C NMR (75 MHz, CDCl 3) δ 222.6, 136.3, 135.0, 54.7, 52.6, 47.8, 47.4, 41.6, 40.9, 23.1; HRMS (CI) exact mass calc'd for (C10H12O) requires m/z 148.0888, found m/z 148.0887. [α]D+122.3 (c=1.0, CHCl3). Product ratios were determined by GLC analysis (140° C., 23 psi); (1R, 2R, 6R, 7R) endo isomer tr=7.1 min, and (1S, 2S, 6S, 7S) endo isomer tr=6.7 min, exo isomers tr=6.1 min.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][C@@H:9]([N:11]([CH3:22])[S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:8][N:7]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:6]1)=[O:4].C(O)C.[Li+].[OH-]>O>[C:26]([O:25][C:23]([N:7]1[CH2:8][C@H:9]([N:11]([CH3:22])[S:12]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)(=[O:14])=[O:13])[CH2:10][C@H:5]([C:3]([OH:4])=[O:2])[CH2:6]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: COC(=O)[C@H]1C[C@@H](N(C)S(=O)(=O)c2ccc(C)cc2)CN(C(=O)OC(C)(C)C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)N(C)[C@@H]2C[C@H](C(=O)O)CN(C(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of this ester (160 mg, 0.375 mmol), ethanol (4 ml) and 1N LiOH solution (1.88 ml, 1.88 mmol) is stirred for 14 h at RT. The mixture is diluted with H2O and extracted with methyl tert.-butyl ether. The organic layer is discarded, the aqueous phase acidified to pH 2 with a 10% NaHSO4 solution and extracted three times with methyl tert-butyl ether. The combined organic extracts are dried (Na2SO4) and evaporated to afford the title compound. MS (LC-MS): 413.4 [M+H]+; tR (HPLC, Symmetry C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 7 min, flow 1.5 ml/min): 4.31 min.
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH3:16])[CH:13]([CH3:15])[CH3:14])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]#[N:18])[CH:8]=2)[N:3]=1.[CH3:19][C:20]1[NH:21][C:22]2[C:27]([CH:28]=1)=[CH:26][C:25](B1OC(C)(C)C(C)(C)O1)=[CH:24][CH:23]=2.C(=O)([O-])[O-].[K+].[K+].O>COCCOC.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>[CH3:16][N:12]([CH:13]([CH3:15])[CH3:14])[C:11]1[C:2]([C:25]2[CH:26]=[C:27]3[C:22](=[CH:23][CH:24]=2)[NH:21][C:20]([CH3:19])=[CH:28]3)=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([C:17]#[N:18])=[CH:6][CH:5]=2
Reactant: CC(C)N(C)c1nc2cc(C#N)ccc2nc1Cl
Reactant: Cc1cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc2cc(-c3nc4ccc(C#N)cc4nc3N(C)C(C)C)ccc2[nH]1
Temperature: 90 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
To a solution of 2-chloro-3-[methyl(propan-2-yl)amino]quinoxaline-6-carbonitrile (250 mg, 0.96 mmol) in DME (8 ml) was added 2-methyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (494 mg, 1.92 mmol), potassium carbonate (265 mg, 1.92 mmol), Pd(PPh3)4 (58 mg, 0.05 mmol) and water (2 ml). The resulting solution was stirred for 1 h at 90° C. under an inert atmosphere of nitrogen. Then the mixture was quenched with water (100 ml) and extracted with ethyl acetate (3×50 ml), and the organic layers combined and dried over anhydrous magnesium sulfate. The filtrate was concentrated in vacuo to give a residue, which was purified via silica gel column chromatography (10%-20% ethyl acetate in petroleum ether) to afford 3-[methyl(propan-2-yl)amino]-2-(2-methyl-1H-indol-5-yl)quinoxaline-6-carbonitrile as a yellow solid (200 mg, 58%).
Reaction SMILES: [CH3:1]/[C:2](=[CH:6]\[CH3:7])/[C:3](=[O:5])[CH3:4].CCN(CC)CC.[Si:15](OS(C(F)(F)F)(=O)=O)([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][CH3:17].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:16]([Si:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[O:5][C:3](/[C:2](/[CH3:1])=[CH:6]/[CH3:7])=[CH2:4])[CH3:17]
Reactant: CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F
Reactant: C/C=C(\C)C(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(O[Si](CC)(CC)CC)/C(C)=C/C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (E)-3-methylpent-3-en-2-one (2.69 mL, 24.1 mmol) in DCM (200 mL) cooled to 0° C. was added Et3N (10.5 mL, 79.5 mmol) followed by TESOTf (6.0 mL, 26.5 mmol). The mixture was warmed to room temperature and stirred for 18 hr. Saturated aqueous NaHCO3 solution (100 mL) and DCM (200 mL) were added. The aqueous layer was extracted with DCM (3×200 mL) and the combined organic layers were washed with brine (100 mL), separated, dried over MgSO4 and concentrated under reduced pressure to give (E)-triethyl((3-methylpenta-1,3-dien-2-yl)oxy)silane. To a solution of 2-methyl-4-nitro-pyrazole-3-carbaldehyde (1.0 g, 8 mmol, intermediate 3) in CDCl3 (28 mL) was added (E)-triethyl((3-methylpenta-1,3-dien-2-yl)oxy)silane (1.6 g, 7.55 mmol) followed by EuFOD (220 mg, 0.50 mmol). The reaction mixture was heated at 65° C. behind a blast shield for 18 hr in a pressure tube. The mixture was cooled to room temperature and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave 5-(5,6-dimethyl-4-((triethylsilyl)oxy)-3,6-dihydro-2H-pyran-2-yl)-1-methyl-4-nitro-1H-pyrazole as a colourless oil (2.92 g, quantitative). 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 5.64 (dd, J=10.9, 3.6 Hz, 1H), 4.33-4.28 (m, 1H), 4.25-3.94 (m, 3H), 2.50-2.41 (m, 1H), 2.31 (m, 1H), 1.61 (s, 3H), 1.31 (d, J=6.4 Hz, 3H), 1.05-0.97 (m, 6H), 0.73-0.61 (m, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[NH:16][C:15]4[N:23]=[CH:24][CH:25]=[CH:26][C:14]=4[N:13]3[C:27]=2[C:28]2[CH:33]=[CH:32][C:31]([C:34]3([NH:38]C(=O)OC(C)(C)C)[CH2:37][CH2:36][CH2:35]3)=[CH:30][CH:29]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[ClH:46].O1CCOCC1>C(Cl)Cl>[ClH:46].[ClH:46].[ClH:46].[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[NH:16][C:15]4[N:23]=[CH:24][CH:25]=[CH:26][C:14]=4[N:13]3[C:27]=2[C:28]2[CH:29]=[CH:30][C:31]([C:34]3([NH2:38])[CH2:37][CH2:36][CH2:35]3)=[CH:32][CH:33]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc([N+](=O)[O-])cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC1(c2ccc(-c3c(-c4ccc([N+](=O)[O-])cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
tert-Butyl (1-{4-[2-(4-nitrophenyl)-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl]phenyl}cyclobutyl)carbamate (7.70 mg, 0.0128 mmol) was dissolved in DCM (0.5 mL). 4M HCl/dioxane (0.5 mL) was added to the mixture and stirred at room temperature for 4 hours. The mixture was concentrated and solidified with ether. The precipitated solids were collected by filtration and washed with ether to afford desired product (8.04 mg, quant.) as an orange solid. 1HNMR (DMSO-d6) 400 MHz δ: 8.72 (br s, 2H), 8.65 (s, 1H), 8.19-8.14 (m, 2H), 8.13-8.10 (m, 1H), 8.00-7.96 (m, 1H), 7.73-7.68 (m, 2H), 7.62-7.56 (m, 2H), 7.42-7.36 (m, 3H), 7.33-7.29 (m, 1H), 7.18-7.12 (m, 1H), 6.96-6.92 (m, 1H), 6.75 (dd, J=8.0, 4.8 Hz, 1H), 2.69-2.44 (m, 4H), 2.28-2.15 (m, 1H), 1.93-1.78 (m, 1H); LCMS: 501 [M+H].
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2.[CH:13]1([CH:16]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])O)[CH2:15][CH2:14]1.ClC1C=CC(C(C2CC2)C2C3C(=C(CSC)C=CC=3)NC=2)=CC=1>>[CH:13]1([CH:16]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])[C:9]2[C:8]3[C:12](=[C:4]([CH2:3][S:2][CH3:1])[CH:5]=[CH:6][CH:7]=3)[NH:11][CH:10]=2)[CH2:14][CH2:15]1
Reactant: CSCc1cccc2cc[nH]c12
Reactant: OC(c1ccc(F)cc1F)C1CC1
Agent: CSCc1cccc2c(C(c3ccc(Cl)cc3)C3CC3)c[nH]c12
Product: CSCc1cccc2c(C(c3ccc(F)cc3F)C3CC3)c[nH]c12

Procedure:
The title compound was prepared starting from 300 mg (1.69 mmol) of the compound from Example 8A and 312 mg (1.69 mmol) of the compound from Example 154A in analogy to the synthesis of the compound from Example 227. 170 mg (29% of theory) of the target compound were obtained.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]=[C:11]([C:14]#[N:15])[C:12]#[N:13])=[CH:5][CH:4]=1.FC(F)(F)C1C=CC(N)=CC=1.C(#N)CC#N.O.[NH2:35][NH2:36]>>[NH2:15][C:14]1[C:11](=[N:10][NH:9][C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:16])[F:17])=[CH:4][CH:5]=2)[C:12]([NH2:13])=[N:36][N:35]=1
Reactant: N#CC(C#N)=NNc1ccc(C(F)(F)F)cc1
Reactant: NN
Agent: Nc1ccc(C(F)(F)F)cc1
Solvent: N#CCC#N
Solvent: O
Product: NC1=NN=C(N)C1=NNc1ccc(C(F)(F)F)cc1
Temperature: 75 °C
Yield: 50 %

Procedure:
This compound was prepared using 119 mg (0.5 mmol) of 2-[(4-trifluoromethylphenyl)-hydrazono]malononitrile, which was derived from 4-(trifluoromethyl)aniline (126 μL, 1.0 mmol) and malononitrile (1.5 mmol) as described in Example 8, and hydrazine hydrate. No precipitate had formed after heating at 75° C. for 1 hr, however, analysis of the reaction solution by TLC indicated that no starting material remained. The solution was allowed to cool to room temperature and the solvent was evaporated. The residue was dissolved in ethyl acetate and then precipitated by the addition of hexanes. The resulting solid was isolated by filtration and dried to yield 67 mg (50%) of the title compound as a greenish brown solid. 1H NMR (ppm, DMSO-d6): 6.03 (br s, 2H), 6.48 (br s, 2H), 7.63 (d, 2H), 7.80 (d, 2H), 10.80 (br s, 1H).
Reaction SMILES: [CH:1]([O-:3])=[O:2].C([NH+](CC)CC)C.[CH3:11][O:12][C:13](=[O:24])/[C:14](/[CH2:22]Br)=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(#N)C>[CH3:11][O:12][C:13](=[O:24])/[C:14](/[CH2:22][O:3][CH:1]=[O:2])=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C[O-]
Reactant: COC(=O)/C(=C/c1ccccc1)CBr
Agent: CC[NH+](CC)CC
Solvent: CC#N
Product: COC(=O)/C(=C/c1ccccc1)COC=O

Procedure:
To a stirred solution of triethylammonium formate (1.87 g) in acetonitrile (4 ml) was added (Z)-2-bromomethyl-3-phenylacrylic acid methyl ester (1.30 g) and the mixture heated at reflux for 2 hours. The reaction was cooled and extracted into diethyl ether (3×10 ml). The combined organics were dried (MgSO4) and concentrated under reduced pressure to afford the title compound as a crude oil.