Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([O-])(=O)=O.C[S:7]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([C:16]1[CH:17]=[NH+:18][CH:19]=[CH:20][CH:21]=1)=O)(=O)=[O:8].C(N(CC)C(C)C)(C)C.C(O)(=S)C.O>O1CCCC1>[N:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:14]2[S@:7](=[O:8])[CH2:10][CH2:11][CH2:12][CH:13]=2)[CH:17]=1
Reactant: CS(=O)(=O)CCCCC(=O)c1ccc[nH+]c1
Agent: CC(O)=S
Agent: CS(=O)(=O)[O-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=[S@@]1CCCC=C1c1cccnc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.7 %

Procedure:
A solution of 3-(5-methanesulphonyl-pentanoyl)pyridinium methanesulphonate (35.3 g) in tetrahydrofuran (200 ml) is treated with N,N-diisopropylethylamine (39 ml) and the resulting solution is stirred for 10 minutes. It is then treated with thioacetic acid (8.25 ml), dropwise, and the mixture is stirred at ambient temperature for 17 hours. It is then treated with water (200 ml), the mixture is stirred for 5 minutes, and the product is then extracted into toluene (150 ml;75 ml). The combined organic solution is washed with aqueous sodium chloride solution (250 ml), dried over magnesium sulphate and filtered. The filtrate is extracted with hydrochloric acid (1N;2×125 ml). The acid solution is then stirred at reflux for 2 hours, cooled to room temperature and washed with toluene (50 ml). The aqueous layer is stirred with charcoal (0.5 g) and filtered. This filtrate is stirred with dichloromethane (75 ml) and it is then treated with aqueous sodium hydroxide solution until the pH is between 10 and 11. The organic layer is separated and the aqueous fraction is extracted with dichloromethane (75 ml). The combined organic solution is dried over magnesium sulphate and filtered. The filtrate is added to a solution of diethyl L-tartrate (45.34 g) in dichloromethane (176ml), followed by a solution of titanium isopropoxide (16.36 ml) in dichloromethane (24 ml), and the solution is cooled to between -19° C. and -21°C. under an atmosphere of nitrogen. It is then treated with a solution of cumene hydroperoxide (24.42 ml) in dichloromethane (22 ml) is added during 20 minutes keeping the mixture between -19° C. and -21° C., then the mixture is stirred at this temperature for 7 hours. It is then treated with dilute hydrochloric acid (1N;250 ml) and the mixture is warmed to room temperature with stirring. The aqueous fraction is separated and washed with dichloromethane (125 ml), then treated with tartaric acid (7.5 g) and toluene (156 ml). The pH is adjusted to 10 by treatment with aqueous sodium hydroxide solution and the toluene fraction is removed. The aqueous fraction is extracted with dichloromethane (5×156 ml), adjusting the pH to 10 for each extraction. The combined dichloromethane and toluene solutions are washed with an aqueous solution of sodium disulphite saturated with sodium chloride, then dried over magnesium sulphate, filtered and concentrated under reduced pressure, to give crude (R)-6-(3-pyridyl)-3,4-dihydro-2H-thiopyran 1-oxide (12.48 g) in the form of a yellow oil.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=[C:9]([C:15]#[N:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:2]2.[H][H]>C(O)C.[Pd]>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([CH:9]([C:15]#[N:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:2]2
Reactant: [H][H]
Reactant: CCOC(=O)C(C#N)=C1CN2CCC1CC2
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(C#N)C1CN2CCC1CC2

Procedure:
A solution of ethyl (1-azabicyclo[2.2.2]octan-3-ylidene)cyanoacetate (73 g, 0.33 mol) in absolute ethanol (1 l) was treated with 10% palladium on charcoal (10 g) and hydrogen in a parr shaker at 20 psi for 5 h. Filtration and evaporation gave the wanted product in 68 g yield.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:3]=1.[OH:18][C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[CH:24][CH:25]=[N:26]2)=[CH:21][CH:20]=1.CC(C)([O-])C.[K+]>CN1CCCC1=O>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([C:4]2[CH:3]=[C:2]([O:18][C:19]3[CH:28]=[C:27]4[C:22]([CH:23]=[CH:24][CH:25]=[N:26]4)=[CH:21][CH:20]=3)[CH:7]=[CH:6][N:5]=2)=[CH:9][CH:10]=1
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)ccn2)cc1
Reactant: Oc1ccc2cccnc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: FC(F)(F)c1ccc(-c2cc(Oc3ccc4cccnc4c3)ccn2)cc1

Procedure:
This material was prepared following the methods described in Example 8 (b) using 4-chloro-2-(4-trifluoromethyl-phenyl)-pyridine (Example 8 (a), 43 mg, 0.16 mmol), 7-hydroxyquinoline (46 mg, 0.32 mmol) and potassium t-butoxide (38 mg, 0.34 mmol) in N-methylpyrrolidone (0.6 mL). The compound was purified by flash chromatography using 1:4 of EtOAc/hexanes, to provide the title compound as a white solid. MS (ESI, pos. ion) m/z: 367 (M+1).
Reaction SMILES: CS(C1C=CC(C2N3C(C=NC(NC4C=CC(N5CCOCC5)=CC=4)=N3)=C(C)C=2)=CC=1)(=O)=O.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([N:41]2[CH2:46][CH2:45][CH2:44][CH:43]([C:47]([N:49]3[CH2:54][CH2:53][N:52]([CH3:55])[CH2:51][CH2:50]3)=[O:48])[CH2:42]2)=[CH:37][CH:36]=1.[F:56][C:57]([F:62])([F:61])[C:58]([OH:60])=[O:59].[CH3:63][O:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][C:66]=1[C:71]1[N:79]2[C:74]([CH:75]=[N:76][C:77](NC3C=NC(N4CCOCC4)=CC=3)=[N:78]2)=[CH:73][CH:72]=1.COCC(O)C>CN1CCCC1=O>[F:56][C:57]([F:62])([F:61])[C:58]([OH:60])=[O:59].[CH3:63][O:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][C:66]=1[C:71]1[N:79]2[C:74]([CH:75]=[N:76][C:77]([NH:34][C:35]3[CH:40]=[CH:39][C:38]([N:41]4[CH2:46][CH2:45][CH2:44][CH:43]([C:47]([N:49]5[CH2:54][CH2:53][N:52]([CH3:55])[CH2:51][CH2:50]5)=[O:48])[CH2:42]4)=[CH:37][CH:36]=3)=[N:78]2)=[CH:73][CH:72]=1
Reactant: CN1CCN(C(=O)C2CCCN(c3ccc(N)cc3)C2)CC1
Reactant: COc1ccccc1-c1ccc2cnc(Nc3ccc(N4CCOCC4)nc3)nn12
Agent: Cc1cc(-c2ccc(S(C)(=O)=O)cc2)n2nc(Nc3ccc(N4CCOCC4)cc3)ncc12
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCCC1=O
Solvent: COCC(C)O
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc(N4CCCC(C(=O)N5CCN(C)CC5)C4)cc3)nn12

Procedure:
The titled compound (1-{4-[7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-3-yl)-(4-methyl-piperazin-1-yl)-methanone; compound with trifluoro-acetic acid was prepared in an analogous fashion to [7-(4-Methanesulfonyl-phenyl)-5-methyl-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-(4-morpholin-4-yl-phenyl)-amine of Example 107 after: replacing 4-(4-morpholino)aniline with [1-(4-Amino-phenyl)-piperidin-3-yl]-(4-methyl-piperazin-1-yl)-methanone, replacing 2-Methanesulfinyl-7-(4-methanesulfonyl-phenyl)-5-methyl-pyrrolo[2,1-f][1,2,4]triazine with 2-Methanesulfinyl-7-(2-methoxy-phenyl)-5-methyl-pyrrolo[2,1-f][1,2,4]triazine (of Example 47), and replacing the solvent N-Methylpyrrolidinone with 1-Methoxy-2-propanol, to give after purification via reverse phase HPLC (1-{4-[7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-3-yl)-(4-methyl-piperazin-1-yl)-methanone; compound with trifluoro-acetic acid as a brown lyophylate (29 mg, 22%). LC/MS (E/I+) 526.22 (M+H). NMR 1H (DMSO-d6)-10.01 (bs, 1H), 9.45 (bs, 1H), 8.96 (s, 1H), 7.81-7.79 (m, 1H), 7.72-7.69 (d, 2H, J=8.58 Hz), 7.50-7.46 (m, 1H), 7.23-7.11 (m, 4H), 6.96-6.93 (m, 2H), 4.46-4.19 (bm, TFA salt and water provided poor resolution), 3.81 (s, 3H), 3.58-2.93 (bm; smeared as TFA salt), 2.83 (s, 3H), 1.86 (bs, 3H), 1.75 (bs, 1H).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3][C:2]1=[O:11].C(N(C(C)C)CC)(C)C.[C:21](OC(=O)C)(=[O:23])[CH3:22]>ClCCl>[C:21]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH:1][C:2](=[O:11])[CH2:3]1)(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1CNc2ccccc2N1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CC(=O)Nc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cold (0° C.) solution of 3,4-dihydroquinoxalin-2(1H)-one (1.0 g, 6.7 mmol; J. Med. Chem. 758, 1994) and N,N-diisopropyl-N-ethylamine (1.7 mL, 10.1 mmol) in dichloromethane (30 mL) under an atmosphere of nitrogen, acetic anhydride (0.76 mL, 8.1 mmol) was added and stirred at room temperature overnight. The resultant solution was concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a 1% methanol in chloroform. Collection and concentration of appropriate fractions provided the acetylation product.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([S:14][CH3:15])=[C:11]([CH:13]=1)N.N([O-])=O.[Na+].[I-:20].[K+]>O.C(#N)C>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([S:14][CH3:15])=[C:11]([I:20])[CH:13]=1
Reactant: CSc1ccc(Cl)cc1N
Reactant: [I-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CSc1ccc(Cl)cc1I
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
To a 0° C. solution of concentrated sulfuric acid (0.3 mL, 5.0 mmol) in 5.0 mL water and 5.0 mL acetonitrile was added 5-chloro-2-(methylthio)aniline (472 mg, 2.72 mmol), followed by slow addition of sodium nitrite (210 mg, 3.0 mmol) as a solution in 1 mL water. The reaction mixture was stirred at 0° C. for 30 minutes. This mixture was then slowly added to a 0° C. solution of potassium iodide (691.7 mg, 4.167 mmol) in 5 mL water. The reaction was stirred for 1 hour, allowing the ice bath to warm to room temperature. The reaction mixture was then partitioned between water and ethyl acetate. The organic layer was dried with brine and magnesium sulfate and concentrated. The crude product was purified by flash chromatography on silica gel (0 to 30% ethyl acetate in dichloromethane) to yield 598.4 mg (77%) of (4-chloro-2-iodophenyl)(methyl)sulfane. LCMS (ESI) no m/z signal; 1H NMR (400 MHz, DMSO-d6) δ: 7.87 (d, 1H), 7.47 (dd, 1H), 7.20 (d, 1H), 2.47 (s, 3H).
Reaction SMILES: [Al].ClC(Cl)=[CH:4][C@@H:5]1[C@H:7]([C:8]([OH:10])=[O:9])[C:6]1([CH3:12])[CH3:11].O.[Br:15][CH2:16][Br:17]>>[Br:15][C:16]([Br:17])=[CH:4][C@@H:5]1[C@H:7]([C:8]([OH:10])=[O:9])[C:6]1([CH3:12])[CH3:11]
Reactant: BrCBr
Reactant: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)O
Agent: [Al]
Solvent: O
Product: CC1(C)[C@H](C=C(Br)Br)[C@@H]1C(=O)O
Temperature: 55 °C
Reaction time: 1 h

Procedure:
Under a dry nitrogen atmosphere, approximately 3 g of aluminum shot was added to 225 ml of dibromomethane. The temperature was raised to 35°-40° C., and hydrogen bromide gas was bubbled into the mixture. After 1 hour a reaction began to occur, and, with the temperature being maintained at 35°-40° C., a second and third portion of aluminum shot (total of 9.67 g, 0.358 mole) was added to the mixture. After complete addition, the reaction mixture was heated at 55° C. for 1 hour. The hydrogen bromide gas flow was stopped, and the reaction mixture was cooled to approximately 6° C. Cis-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylic acid (50.0 g, 0.239 mole) in 150 ml of dibromomethane was added to the cooled reaction mixture during 1 hour. After complete addition, the reaction mixture was stirred for 30 minutes. A nitrogen inlet was placed in the reaction mixture, and nitrogen was pulled through the mixture for 90 minutes by applying a slight vacuum to the reaction pot. Distilled water was added dropwise, and the resulting mixture was allowed to stand at room temperature for approximately 18 hours. The organic phase was separated, and the aqueous phase was extracted with 600 ml and 200 ml portions of diethyl ether. The ether washes were combined with the organic phase, and the whole was washed once with a 1 N hydrochloric acid solution and one with a saturated aqueous solution of sodium chloride. The organic phase was dried with magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a solid. The solid was dried under a vacuum for 18 hours, then was crystallized twice from n-heptane and sublimed to give (+)-cis-3-(2,2-dibromoethenyl)-2,2-dimethylcyclopropanecarboxylic acid, m.p. 109°-111° C.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([CH:38]=O)=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)#[N:25].O>COC(C)(C)C.O1CCCC1.C(OCC)(=O)C>[CH3:2][O:3][CH:4]=[CH:38][C:35]1[CH:34]=[CH:33][C:32]([C:29]2[CH:28]=[CH:27][C:26]([C:24]#[N:25])=[CH:31][CH:30]=2)=[CH:37][CH:36]=1
Reactant: N#Cc1ccc(-c2ccc(C=O)cc2)cc1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: COC(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: COC=Cc1ccc(-c2ccc(C#N)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
A suspension of 12.4 g of methoxymethyl-triphenylphosphonium chloride in 120 ml of t-butyl methyl ether was treated within 3 minutes with 4.1 g of potassium t-butylate while gassing with argon at 0° C. and the mixture was stirred for a further 1 hour at 0° C. Thereafter, the mixture was treated within 10 minutes with a solution of 5.0 g of 4'-cyano-4-biphenylcarboxaldehyde in 40 ml of tetrahydrofuran and the resulting mixture was stirred for a further 1.5 hours at room temperature. The reaction mixture was subsequently poured into 200 ml of water and extracted three times with 150 ml of diethyl ether each time. The organic phases were washed twice with 150 ml of water each time, dried over magnesium sulphate and concentrated. The residue obtained was dissolved in 25 ml of ethyl acetate and the solution was treated with 350 ml of petroleum ether. After leaving to stand for 10 minutes at -20° C. the precipitated triphenylphosphine oxide was filtered off and the filtrate was concentrated to dryness. Low-pressure chromatography (0.5 bar) of the dark brown oil (9.5 g) on silica gel with ethyl acetate/petroleum ether (vol. 10:90) gave 5.2 g (91%) of 4'-(2-methoxyvinyl)-4-biphenylcarbonitrile as yellowish crystals; Rf-value (ethyl acetate/petroleum ether vol. 10:90) 0.17.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@H:9]1[C@@H:14]([NH:15]C(=O)OC(C)(C)C)[CH2:13][C@@H:12]([N:23]2[CH2:28][CH2:27][N:26]3[N:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[N:31]=[C:25]3[CH2:24]2)[C:11](=O)[N:10]1[CH3:37].CO>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@H:9]1[C@@H:14]([NH2:15])[CH2:13][C@@H:12]([N:23]2[CH2:28][CH2:27][N:26]3[N:29]=[C:30]([C:32]([F:34])([F:33])[F:35])[N:31]=[C:25]3[CH2:24]2)[CH2:11][N:10]1[CH3:37]
Reactant: CN1C(=O)[C@H](N2CCn3nc(C(F)(F)F)nc3C2)C[C@H](NC(=O)OC(C)(C)C)[C@H]1c1cc(F)ccc1F
Solvent: CO
Solvent: C1CCOC1
Product: CN1C[C@H](N2CCn3nc(C(F)(F)F)nc3C2)C[C@H](N)[C@H]1c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product from Step A (320 mg, 0.603 mmol) was partially dissolved in THF (20 mL) at room temperature. Borane-methyl sulfide complex (3.62 mL, 3.62 mmol) was added. The mixture was stirred at room temperature for 1 h, and then refluxed overnight. Borane-methyl sulfide complex (1.206 mL, 1.206 mmol) was added to the solution and the mixture was stirred at room temperature for 0.5 h, and then heated to (65-67° C.) for 6 h. Methanol (4 mL) was added with caution and the mixture was concentrated under reduced pressure. The residue was dissolved in n-PrOH (45 mL) and the solution was refluxed for overnight. The residue was purified by column chromatography on silica gel Biotage 25M™, eluting with EtOAc/CH2Cl2 (gradient from 0% to 60%) to give the desired product which was treated with 1:1 TFA/CH2Cl2 for 1 h. The residue was purified by preparative TLC on silica gel, eluting with CH2Cl2/MeOH/aqueous NH3 (90/9/1) to give the title compound. LC-MS: 416.91 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:44])[C@H:15]([NH:24][C:25]([C@@H:27]2[CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29][N:28]2[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:26])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:10][CH2:9]1.[CH2:45]1[CH:47]([CH:48](O)C#N)[CH2:46]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][C@@H:15]([NH:24][C:25]([C@@H:27]2[CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29][N:28]2[C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])=[O:26])[C:14]([N:11]2[CH2:12][CH2:13][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[NH:1][CH2:48][CH:47]3[CH2:45][CH2:46]3)[CH2:9][CH2:10]2)=[O:44])=[CH:22][CH:21]=1
Reactant: N#CC(O)C1CC1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2N)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2NCC2CC2)CC1
Yield: 85.6 %

Procedure:
To a 50 round-bottomed flask equipped with stirring was added tert-butyl 3-(N-{(1R)-2-[4-(2-aminophenyl)piperidyl]-1-[(4-chlorophenyl)methyl]-2-oxoethyl)carbamoyl)(3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (Example 20) (462 mg, 0.75 mmol) followed by 1,2-dichloroethane (20 mL) and cyclopropyl-carboxaldehyde (Aldrich) (58 mg, 0.83 mmol). The reaction mixture was stirred for 6 h, then treated with sodium triacetoxyborohydride (Aldrich) (176 mg, 0.83 mmol) at 0° C. After stirring for 12 h at RT, the reaction mixture was quenched with satd NaHCO3 (20 mL). The organic layer was separated and the aqueous layer extracted with CH2Cl2 (2×20 mL). The organic fractions were combined, washed with satd NaCl (50 mL), dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (1:10 MeOH:EtOAc) provided the title compound as a white foam (431 mg). MS (ESI, pos. ion) m/z: 671 (M+1); MS (ESI, neg. ion) m/z: 669 (M−1). Calcd for C39H47ClN4O4: 670.33.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:16]4[C:17]([CH3:25])=[CH:18][C:19]([N:22]([CH3:24])[CH3:23])=[N:20][CH:21]=4)[CH2:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:39])C=1>ClCCl>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:16]4[CH:21]=[N+:20]([O-:39])[C:19]([N:22]([CH3:24])[CH3:23])=[CH:18][C:17]=4[CH3:25])[CH2:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[CH:4][CH:3]=1
Reactant: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1cnc(N(C)C)cc1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1c[n+]([O-])c(N(C)C)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.8 %

Procedure:
To a solution of 5-[10-chloro-7-(1-ethylpropyl)-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]benzimidazol-1-yl]-N,N,4-trimethylpyridin-2-amine (43 mg, 0.10 mmol) in dichloromethane (2 mL) was added m-chloroperbenzoic acid (27 mg, 0.11 mmol) at 0° C. The mixture was warmed to room temperature and stirred for 2 hr. The reaction mixture was purified by flash chromatography on NH-silica gel eluting with a 0-20% methanol/ethyl acetate gradient mixture. The filtrate was concentrated in vacuo to give a solid, which was recrystallized from ethyl acetate/n-hexane to give the title compound (30 mg, 0.0678 mmol, 68%) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:8](O)=[O:9])([CH3:4])[CH3:3].C(Cl)(=O)C([Cl:32])=O>C(Cl)Cl.CN(C)C=O>[CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:8]([Cl:32])=[O:9])([CH3:4])[CH3:3]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)cc1C(C)(C)C
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)Cl)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 9.9 %

Procedure:
To a solution of 30.0 g of product from Example 32 in 300 ml of methylene chloride and 10 drops of dimethylformamide is added, dropwise, 14.62 g of oxalyl chloride. The reaction is stirred at room temperature for 18 hours and concentrated in vacuo. The residue is dissolved in diethyl ether, filtered through diatomaceous earth and concentrated to give 3.12 g of the desired product as yellow crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][CH:9]=[C:10]([C:12]3[C:13](=[O:24])[NH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][CH:18]=[C:17]([CH:22]=[O:23])[CH:16]=4)[N:11]=2)=[CH:3][CH:2]=1.C(OC)(OC)OC.CC1CCCNC1.[OH-].[NH4+].C(Cl)[Cl:42]>CN(C=O)C.CCN(CC)CC.CC(O)=O>[ClH:42].[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][CH:9]=[C:10]([C:12]3[C:13](=[O:24])[NH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][CH:18]=[C:17]([CH:22]=[O:23])[CH:16]=4)[N:11]=2)=[CH:3][CH:2]=1
Reactant: ClCCl
Agent: CC1CCCNC1
Agent: O=Cc1ccc2cc(-c3csc(-c4ccncc4)n3)c(=O)[nH]c2c1
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: COC(OC)OC
Solvent: CN(C)C=O
Product: Cl
Reaction time: 2 h

Procedure:
A solution of 3-(2-pyridin-4-yl-thiazol-4-yl)-1H-quinolin-2-one-7-carbaldehyde (step (a), 60 mg, 0.18 mmol), 1 mL of CH2Cl2, 0.5 mL of trimethyl orthoformate, 3-methylpiperidine (0.2 mL), and 10 mL of 5% HOAc in DMF was allowed to stir for 2 h. At this time, 0.9 g of polymer bounded MP-NEt3:BH3(CN) (Argonaut, 1 mmol/g) was added and the mixture was stirred at RT overnight. The resins were carefully removed by filtration and the filtrate was concentrated. The resulting residue was dissolved in DMSO and purified by preparative HPLC. The solid obtained after lyophilization was neutralized with aqueous ammonium hydroxide and subsequently lyophilized. Treatment with excess 1 N HCl solution afforded the title compound as a yellow solid after lyophilization (HCl salt). MS m/z: 417.0 (M+1).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([O:11][C:12]([NH:14][C@@H:15]([CH2:22][CH2:23][S:24]([CH3:27])(=[O:26])=[O:25])[C:16](N(OC)C)=[O:17])=[O:13])([CH3:10])([CH3:9])[CH3:8].S([O-])(O)(=O)=O.[K+]>CCOCC.C1COCC1.O>[C:7]([O:11][C:12]([NH:14][C@@H:15]([CH2:22][CH2:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:16]=[O:17])=[O:13])([CH3:9])([CH3:10])[CH3:8]
Reactant: CON(C)C(=O)[C@H](CCS(C)(=O)=O)NC(=O)OC(C)(C)C
Agent: O=S(=O)([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N[C@H](C=O)CCS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of lithium aluminum hydride (5.15 g, 0.136 mol) in ether (290 mL) was stirred at room temperature for one hour. The solution was cooled to -75° C. under nitrogen, and a solution of the product from Step B (23.9 g, 73.6 mol) in THF (60 mL) was added over ca. 30 min, maintaining the temperature below -40° C. When the addition was complete, the reaction was warmed to -15° C., then recooled to -35° C. A solution of potassium hydrogen sulfate (19.4 g) in 77 mL water was slowly added. The mixture was warmed to room temperature, and stirred for one hour. The solution was filtered through a pad of celite, washed with 10% HCl solution, sat. NaHCO3 solution and brine, dried (Na2 SO4), filtered, and concentrated in vacuo to provide the titled aldehyde.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[C:15](Br)[CH:16]=[C:11]2[C:10]([C:18](=[O:27])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1B(O)O.C(=O)([O-])[O-].[K+].[K+].O1CCCC1>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.O>[C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([C:29]3[S:28][CH:32]=[CH:31][CH:30]=3)[CH:16]=[C:11]2[C:10]([C:18](=[O:27])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cccs1
Reactant: COc1ccc(C(=O)c2cn(C(=O)OC(C)(C)C)c3ncc(Br)cc23)cc1
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: O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2cn(C(=O)OC(C)(C)C)c3ncc(-c4cccs4)cc23)cc1
Yield: 100.1 %

Procedure:
5-Bromo-3-(4-methoxy-benzoyl)-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (117, 100.0 mg, 0.23 mmol), thiophene-2-boronic acid (59 mg, 0.46 mmol), tetrakis(triphenylphosphine)palladium(0) (20.0 mg, 0.017 mmol), potassium carbonate (80 mg, 0.58 mmol), tetrahydrofuran (15.0 mL) and water (5.0 mL) were combined under an atmosphere of nitrogen. The reaction mixture was refluxed overnight, then poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified with silica gel chromatography to give compound 118 (100 mg).