Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2.[Cl:17][CH2:18][C:19](N(OC)C)=[O:20].Cl.C([O-])(O)=O.[Na+]>CCOCC.C1COCC1>[Cl:17][CH2:18][C:19]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2)=[O:20]
Reactant: CON(C)C(=O)CCl
Reactant: Brc1cccc2cccnc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(CCl)c1cccc2cccnc12
Reaction time: 0.37 h
Yield: 51.1 %

Procedure:
To a solution of n-BuLi (28 mL, 44.0 mmol, 1.6M in hexanes) at −78° C. was added a solution of 8-bromoquinoline (8.5 g, 40.0 mmol) in Et2O (60 mL) over 20 minutes. After stirring for 22 minutes, a solution of 2-chloro-N-methoxy-N-methylacetamide (5.7 g, 41 mmol) in THF (35 mL) was added over 12 minutes (see Tillyer, R. et al; Synlett 225-226, 1996; and Dolling, U. H. et al; U.S. Pat. No. 5,786,515). After 3 hours the reaction was poured into 11 mL, 4N HCl. The aqueous phase was neutralized to pH 7 using solid NaHCO3 and partitioned with Et2O (2×100 mL). The combined organic phase was washed with brine (50 mL), dried over Na2SO4 and concentrated in vacuo. Purification via SiO2 chromatography (20% EtOAc/hexanes) afforded the product as a yellow solid (4.2 g). 1H NMR (300 Hz, CDCl3) δ 9.0-8.96 (m, 1H), 8.26-8.19 (m, 2H), 8.04-8.01 (m, 1H), 7.68-7.63 (m, 1H), 7.52-7.48 (m, 1H), 5.37 (s, 2H).
Reaction SMILES: [F:1][C:2]([F:34])([O:6][C:7]1[CH:33]=[CH:32][C:10]([CH:11]=[N:12][NH:13][C:14]([NH:16][N:17]=[CH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]([F:31])([F:30])[CH:27]([F:29])[F:28])=[CH:21][CH:20]=2)=[NH:15])=[CH:9][CH:8]=1)[CH:3]([F:5])[F:4].C(N(C(C)C)CC)(C)C.[CH3:44][N:45]([CH3:49])[C:46](Cl)=[O:47]>C(#N)C>[F:1][C:2]([F:34])([O:6][C:7]1[CH:33]=[CH:32][C:10]([CH:11]=[N:12][NH:13][C:14](=[NH:15])[N:16]([N:17]=[CH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]([F:31])([F:30])[CH:27]([F:29])[F:28])=[CH:21][CH:20]=2)[C:46]([N:45]([CH3:49])[CH3:44])=[O:47])=[CH:9][CH:8]=1)[CH:3]([F:4])[F:5]
Reactant: CN(C)C(=O)Cl
Reactant: N=C(NN=Cc1ccc(OC(F)(F)C(F)F)cc1)NN=Cc1ccc(OC(F)(F)C(F)F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CN(C)C(=O)N(N=Cc1ccc(OC(F)(F)C(F)F)cc1)C(=N)NN=Cc1ccc(OC(F)(F)C(F)F)cc1
Yield: 92.9 %

Procedure:
A solution of 1,3-bis{[p-(1,1,2,2-tetrafluoroethoxy)benzylidene]amino}guanidine (29.84 g, 0.06 mol), diisopropylethylamine, (15.51 g, 0.12 mol) and dimethylcarbamoyl chloride (129.2 g, 0.12 mol) in acetonitrile (200 mL) is stirred at reflux for 22 hours. The reaction mixture is cooled, and the acetonitrile is evaporated under reduced pressure. The residue is dissolved in ethyl acetate (250 mL), and the organic solution is washed with water, saturated NaCl and dried over Na2SO4. The solvent is evaporated under reduced pressure, and the residue is crystallized from benzene-hexanes to give the desired product as a yellow solid, mp 141.5°-143.5° C. in 92.9% yield.
Reaction SMILES: [O:1]1[C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=[N:2]1.O=[C:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1.C([O-])(=O)C.[NH4+]>C1(C)C=CC=CC=1>[C:7]([C:6]([C:5]1[O:1][N:2]=[CH:3][CH:4]=1)=[C:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1)#[N:8]
Reactant: N#CCc1ccno1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(=C(C#N)c2ccno2)CC1
Yield: 54.5 %

Procedure:
A mixture of isoxazol-5-ylacetonitrile from Example 48A (3.00 g, 27.8 mmol), tert-butyl 4-oxopiperidine-1-carboxylate (5.53 g, 27.8 mmol) and ammonium acetate (4.28 g, 55.5 mmol) in toluene (50 mL) was heated for 8 h to reflux. Subsequently, the mixture was extracted with water, dried over sodium sulfate, and the solvent was removed in vacuo. The crude product was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 2:1) to yield an oil, which precipitated upon treatment with petroleum ether/tert-butyl methyl ether to yield 4.38 g (54.6%) of the title compound as yellowish crystals.
Reaction SMILES: [NH:1]([CH:3]=[O:4])[NH2:2].C(N(CC)CC)C.[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1>C1COCC1>[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:2][NH:1][CH:3]=[O:4])=[O:18])=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: NNC=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=CNNC(=O)c1ccc(Br)cc1
Temperature: 60 °C

Procedure:
To hydrazinecarboxaldehyde (1.20 g, 20 mmol) in 100 ml THF, triethylamine (Et3N) (2.63 g, 26 mmol) was added. The mixture was heated at 60° C. to a clear solution and cooled to room temperature. 4-Bromobenzoyl chloride (4.39 g, 20 mmol) was added to the reaction mixture over 20 min. The mixture was refluxed for 1 hr., cooled to room temperature and filtered. The filtrate was concentrated to give a light yellow solid (2-[(4-bromophenyl)carbonyl]-hydrazinecarboxaldehyde).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH:9]1[CH2:15][CH2:14][C:12](=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])[CH3:3].[C:16]([NH2:20])([CH3:19])([CH3:18])[CH3:17].[BH4-].[Na+].[OH-].[Na+]>[Ti+4].C(Cl)Cl.CO>[C:2]([O:5][C:6](=[O:7])[NH:8][CH:9]1[CH2:15][CH2:14][CH:12]([NH:20][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:1]
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Reactant: CC(C)(C)N
Agent: [Ti+4]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)NC1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.7 %

Procedure:
N-4-BOC-aminocyclohexanone (5.00 g, 23 mmol, 1 eq.), tert-butylamine (2.46 mL, 23 mmol, 1 eq.), and titanium (IV) isoproproxide (6.87 mL, 23 mmol, 1 eq.), were mixed and stirred at RT under nitrogen overnight. MeOH (50 mL) was added followed by NaBH4 pellets (0.89 g, 23 mmol, 1 eq.). After 30 minutes added 50 mL of 1 N NaOH. Methylene chloride was added, the insoluble matter filtered, and the layers separated. The aqueous layer was extracted twice more with methylene chloride. The organic layers were combined, dried and stripped to yield (4-tert-Butylamino-cyclohexyl)-carbamic acid tert-butyl ester (6.26 g) as an amber oil, which solidified upon standing. MS found: (M+H)+=271.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:50]([C:52]([OH:85])([CH2:83][CH3:84])[CH2:53][CH2:54][C:55]1[CH:60]=[CH:59][C:58]([C:61]([CH2:80][CH3:81])([C:64]2[CH:69]=[CH:68][C:67](B3OC(C)(C)C(C)(C)O3)=[C:66]([CH3:79])[CH:65]=2)[CH2:62][CH3:63])=[CH:57][C:56]=1[CH3:82])[CH3:51].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:67]2[CH:68]=[CH:69][C:64]([C:61]([CH2:62][CH3:63])([C:58]3[CH:59]=[CH:60][C:55]([CH2:54][CH2:53][C:52]([CH2:83][CH3:84])([OH:85])[CH2:50][CH3:51])=[C:56]([CH3:82])[CH:57]=3)[CH2:80][CH3:81])=[CH:65][C:66]=2[CH3:79])=[CH:7][CH:6]=1
Reactant: CCC(O)(CC)CCc1ccc(C(CC)(CC)c2ccc(B3OC(C)(C)C(C)(C)O3)c(C)c2)cc1C
Reactant: COC(=O)Cc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(O)(CC)CCc1ccc(C(CC)(CC)c2ccc(-c3ccc(CC(=O)OC)cc3)c(C)c2)cc1C
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 52.2 %

Procedure:
(4-Bromo-phenyl)acetic acid methyl ester (Tetrahedron Letters 44 (2003) 331-334; 38.5 mg, 0.168 mmol), palladium acetate (2.5 mg, 0.011 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (9.0 mg, 0.022 mmol), potassium phosphate (71 mg, 0.336 mmol) and water (0.2 mL) were added to a solution of 3-ethyl-1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-pentan-3-ol (Example 29; 55 mg, 0.112 mmol) in toluene (2 mL). After replacement with nitrogen, the mixture was stirred at 100° C. for 3.5 hours. The reaction mixture was then poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=4:1) to give the target compound as a colorless oil (30.1 mg, 52%).
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[I:9][C:10]1[C:18]2[C:13](=[CH:14][C:15](/[CH:19]=[C:20]3/[C:21](=[O:29])[NH:22][C:23]4[C:28]/3=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:16][CH:17]=2)[N:12]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[N:11]=1>CN(C=O)C>[I:9][C:10]1[C:18]2[C:13](=[CH:14][C:15]([C@H:19]3[C@@:20]4([C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[NH:22][C:21]4=[O:29])[CH2:2]3)=[CH:16][CH:17]=2)[N:12]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:36])([CH3:35])[CH3:37])[N:11]=1
Reactant: C[S+](C)(C)=O
Reactant: C[Si](C)(C)CCOCn1nc(I)c2ccc(/C=C3/C(=O)Nc4ccccc43)cc21
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1nc(I)c2ccc([C@@H]3C[C@@]34C(=O)Nc3ccccc34)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of trimethylsulfoxonium iodide (1.89 g, 8.6 mmol) in anhydrous DMF (40 mL) was added sodium hydride (60% dispersion in oil) (1.03 g, 25.8 mmol) at 0° C. The mixture was stirred for 15 min after which time (E)-3-((3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)methylene)indolin-2-one (2.2 g, 4.3 mmol) was added. The solution was stirred overnight at rt. The reaction was quenched with sat. NH4Cl solution (50 mL), extracted with EtOAc (4×100 mL), dried over MgSO4 and concentrated to dryness. The title compound was isolated by silica gel chromatography (CH2Cl2/MeOH 98:2) as a yellow solid (1.5 g, 66%). 1H NMR (400 MHz, CDCl3) δ 7.46 (s, 1H), 7.39 (d, 1H J=8.3 Hz), 7.09 (t, 1H, J=7.5 Hz), 7.04 (d, 1H, J=8.0 Hz), 6.92 (d, 1H, J=7.8 Hz), 6.61 (t, 1H, J=8.0 Hz), 5.90 (d, 1H, 8.0 Hz), 5.70 (s, 2H), 3.57-3.53 (m, 2H), 3.49-3.44 (m, 1H), 2.31-2.28 (m, 1H), 2.12-2.09 (m, 1H), 0.89-0.84 (m, 2H), −0.05 (s, 9H); MS ESI 532.1 [M+H]+, calcd for [C23H26IN3O2Si+H]+ 532.4.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[C:5]([O:11][CH3:12])[CH:4]=1)=C.N1C(C)=CC=CC=1C.I([O-])(=O)(=O)=[O:22].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[C:9]([C:6]1[CH:7]=[CH:8][C:3]([CH:1]=[O:22])=[CH:4][C:5]=1[O:11][CH3:12])#[N:10]
Reactant: C=Cc1ccc(C#N)c(OC)c1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: Cc1cccc(C)n1
Product: COc1cc(C=O)ccc1C#N
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
To a solution of 1-vinyl-4-cyano-3-methoxybenzene (0.343 g, 2.16 mmol, 1.0 eq) in dioxane (7 mL) was added 2,6-lutidine (0.461 g, 0.50 mL, 4.31 mmol, 2.0 eq) followed by osmium tetroxide (1.37 g, 1.32 mL of a 4% solution in water, 0.22 mmol, 0.1 eq). A brown/black solution resulted after 1→2 minutes. Sodium periodate (1.847 g, 8.63 mmol as a solution in 7 mL of water, 4.0 eq) was added forming a white precipitate. The mixture was stirred at room temperature for 35 minutes before partitioning between EtOAc (100 mL) and HCl (1M, 100 mL). The organics were washed with brine (100 mL), dried (Na2SO4) and concentrated under reduced pressure. MPLC (10→50% EtOAc-hexane) yielded the title compound as a white solid; 1H nmr (CDCl3) d 9.89 (1H, s, CHO), 8.09 (2H, m, ArH-2, H-6), 7.12 (1H, d, J 9.5 Hz, ArH-3), 4.04 (3H, s, OCH3); m/z 162 [M+H]+.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[NH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([NH:18][C:19]([NH:21][C:22]2[N:23]=[C:24]3[CH:30]=[CH:29][N:28]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:25]3=[N:26][CH:27]=2)=[O:20])[CH2:13]1.[F:39][C:40]([F:46])([F:45])[CH2:41][C:42](O)=[O:43].CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O>C(Cl)Cl>[F:39][C:40]([F:46])([F:45])[CH2:41][C:42]([N:12]1[CH2:17][CH2:16][CH2:15][CH:14]([NH:18][C:19]([NH:21][C:22]2[N:23]=[C:24]3[CH:30]=[CH:29][N:28]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:25]3=[N:26][CH:27]=2)=[O:20])[CH2:13]1)=[O:43]
Reactant: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NC3CCCNC3)cnc21
Reactant: O=C(O)CC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NC3CCCN(C(=O)CC(F)(F)F)C3)cnc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 56.3 %

Procedure:
DIPEA (0.082 mL, 0.47 mmol) was added at RT to a mixture of 1-piperidin-3-yl-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea dihydrochloride (0.066 g, 0.142 mmol), 3,3,3-trifluoropropionic acid (0.015 mL, 0.171 mmol), EDCI (0.033 g, 0.171 mmol), HOBt monohydrate (0.026 g, 0.171 mmol) in 1 mL of DCM. The resulting mixture was stirred at RT for 24 hours before being partitioned between H2O and DCM. The aqueous layer was back extracted twice with DCM. The combined organic layers were dried (Na2SO4), filtered, and evaporated. The residue was purified by SiO2 flash chromatography (DCM/(DCM:MeOH:NH4OH 60:10:1] 80% DCM) to give 0.04 g of 1-[1-(3,3,3-trifluoro-propionyl)-piperidin-3-yl]-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea (56% yield).
Reaction SMILES: Cl.NO.[NH2:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[C:7]([Cl:13])[C:6]=1[F:14].C([N:17](CC)CC)C.C1CCC(N=C=NC2CCCCC2)CC1>O.C(Cl)Cl.[Cu].C(O)=O.N1C=CC=CC=1>[NH2:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:17])=[C:7]([Cl:13])[C:6]=1[F:14]
Reactant: CCN(CC)CC
Reactant: Nc1ccc(C=O)c(Cl)c1F
Agent: [Cu]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: O
Solvent: O=CO
Solvent: ClCCl
Product: N#Cc1ccc(N)c(F)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
To a solution of hydroxylamine hydrochloride (336 mg, 4.84 mmol) in water (1.2 mL) was added 4-amino-2-chloro-3-fluoro-benzaldehyde (9A) (0.800 g, 4.61 mmol) and pyridine (2.5 mL). After stirring at rt for 1 h, copper (H) sulfate pentahydrate (230 mg, 0.922 mmol) was added followed by a solution of triethylamine (1.40 mL, 9.68 mmol) in CH2Cl2 (2.5 mL). To the resulting dark green reaction mixture was then added a solution of DCC (1.14 g, 5.53 mmol) in CH2Cl2 (10 mL) and the reaction was stirred for 2 h. Formic acid (1 mL) was added and the reaction was stirred for 20 min, filtered through celite, and concentrated. The resulting residue was purified via silica gel chromatography eluting with 20-30% EtOAc/hexane to provide the title compound (0.780 g) as a light brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:9])[NH:6][C:7]=1[CH3:8].IC.[C:12]([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:9])[N:6]([CH3:12])[C:7]=1[CH3:8]
Reactant: O=C([O-])[O-]
Reactant: Cc1[nH]c(=O)ccc1Br
Agent: [K+]
Solvent: CS(C)=O
Solvent: CI
Product: Cc1c(Br)ccc(=O)n1C
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 5-bromo-6-methylpyridin-2(1H)-one (164 mg, 0.872 mmol) and iodomethane (0.065 mL, 1.047 mmol) in DMSO (3 mL) was added K2CO3 (145 mg, 1.047 mmol). The mixture was stirred at 60° C. overnight, filtered, and purified via preparative HPLC, eluting with a gradient of 20-70% ACN (containing 0.035% TFA) in H2O (containing 0.05% TFA) to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][N:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[Cl:26][C:27]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30]>O1CCOCC1>[N:21]1[CH:20]=[CH:19][N:11]2[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:8]([C:6]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:29](=[O:30])[C:28]4[CH:32]=[CH:33][C:34]([Cl:36])=[CH:35][C:27]=4[Cl:26])=[CH:23][CH:22]=3)=[O:7])[CH2:9][C:10]=12
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: Nc1ccc(C(=O)N2Cc3nccn3Cc3ccccc32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(Nc1ccc(C(=O)N2Cc3nccn3Cc3ccccc32)cc1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A slurry of 0.330 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-imidazo[2,1-c][1,4]benzodiazepine in 15 ml of dioxane is stirred and warmed slightly to obtain a nearly complete solution. The reaction mixture is cooled to room temperature and 43 mg of sodium hydride in oil added. The mixture is warmed slightly. Gas evolution stops in a few minutes. The reaction mixture is cooled to room temperature and 153 μl of 2,4-dichlorobenzoyl chloride in 2.5 ml of dioxane added. An additional 3.5 ml of dioxane is added and the reaction mixture stirred at room temperature for 2 days. The volatiles are evaporated in vacuo to a residue which is partitioned between water and chloroform. The organic layer is separated and the aqueous phase extracted with chloroform two more times. The combined organic layers are trated with activated carbon and filtered through MgSO4. The filtrate is evaporated in vacuo to a tan foam which is purified by flash chro- matography on silica gel by elution with CHCl3 and 3-7% CH3OH in chloroform to give 310 mg of tan foam.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.C(OCC)C.Cl[C:19]([O:21][C:22]([CH2:25][CH3:26])([CH3:24])[CH3:23])=[O:20].O>N1C=CC=CC=1.C(Cl)Cl>[C:22]([O:21][C:19]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)=[O:20])([CH2:25][CH3:26])([CH3:24])[CH3:23]
Reactant: CCC(C)(C)OC(=O)Cl
Reactant: CCOC(=O)Cc1csc(N)n1
Agent: CCOC(=O)Cc1csc(=N)[nH]1
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)Cc1csc(NC(=O)OC(C)(C)CC)n1

Procedure:
To a solution of ethyl 2-(2-amino-1,3-thiazol-4-yl)acetate, which can be represented as ethyl 2-(2-imino-2,3-dihydro-1,3-thiazol-4-yl)acetate, (14 g.) in a mixture of pyridine (40 g.) and methylene chloride (300 ml.) was gradually added diethyl ether solution of tert-pentyl chloroformate (70 ml.) containing 0.35 mole of tert-pentyl chloroformate over 10 minutes at -20° C. with stirring, and the mixture was stirred for 2 hours at the same temperature and further stirred for 0.5 hour at 0° C. After the reaction, the reaction mixture was poured into water (200 ml.), and then the organic layer was separated. The organic layer was washed with 2 N hydrochloric acid, water, 5% sodium bicarbonate aqueous solution and water in turn and then dried over magnesium sulfate. The solvent was distilled off from the organic layer to give dark brown oil of ethyl 2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)acetate, which can be represented as ethyl 2-(2-tert-pentyloxycarbonylimino-2,3-dihydro-1,3-thiazol-4-yl)acetate, (12 g.).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[S:10][CH:11]=1.[CH3:17]B1OB(C)OB(C)O1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:16][N:5]1[C:6]([C:7]2[CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[S:10][CH:11]=2)=[C:2]([CH3:17])[CH:3]=[N:4]1
Reactant: COC(=O)c1cc(-c2c(Br)cnn2C)cs1
Reactant: CB1OB(C)OB(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2c(C)cnn2C)cs1
Temperature: 110 °C
Yield: 76.4 %

Procedure:
To a 350 mL sealed flask reactor was added methyl 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (3.45 g, 11.46 mmol) [prepared according to the procedure of Example 156], trimethylboroxine (2.7 ml, 19.40 mmol), K2CO3 (4.75 g, 34.4 mmol) and Pd(dppf)Cl2 (599 mg, 1.17 mmol) in N,N-Dimethylformamide (DMF) (57 mL). The reaction was heated at 110° C. for 1 hour, cooled to room temperature and partitioned between CHCl3/H2O. The organic layer was separated, dried with Na2SO4, adsorbed onto silica and purified via column chromatography (0-30% EtOAc/Hexane) affording the title compound (2.07 g, 8.76 mmol, 76%): LC-MS (ES) m/z=251 (M+H)+.
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[CH2:9][NH2:10])[CH:2]=[CH2:3].C(Cl)(Cl)Cl.[CH3:15][NH:16][S:17]([C:20]1[CH:21]=[C:22]([C:30](Cl)=[O:31])[C:23]2[O:28][CH2:27][CH2:26][O:25][C:24]=2[CH:29]=1)(=[O:19])=[O:18]>O>[CH2:1]([N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[CH2:9][NH:10][C:30]([C:22]1[C:23]2[O:28][CH2:27][CH2:26][O:25][C:24]=2[CH:29]=[C:20]([S:17](=[O:19])(=[O:18])[NH:16][CH3:15])[CH:21]=1)=[O:31])[CH:2]=[CH2:3]
Reactant: CNS(=O)(=O)c1cc2c(c(C(=O)Cl)c1)OCCO2
Reactant: C=CCN1CCCC1CN
Solvent: O
Solvent: ClC(Cl)Cl
Product: C=CCN1CCCC1CNC(=O)c1cc(S(=O)(=O)NC)cc2c1OCCO2
Yield: 49 %

Procedure:
85 g of levorotatory 1-allyl-2-aminomethyl-pyrrolidine, 610 cm3 of chloroform, and gradually, 178 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride at a temperature of from 5°-10° C. were introduced into a balloon flask provided with an agitator and a thermometer. After agitation of the mixture 1.2 liters of water were added and then chloroform was distilled. The remaining solution was filtered and then the base was precipitated with 70 cm3 of 20% ammonia. The crystals formed were dried off and washed with water. After recrystallization from ethyl acetate, 117 g of levorotatory-N-(1-allyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide was produced (M.P.: 101°-102° C.; yield: 49%).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH:19]=[N:20][NH:21][C:22]1[CH:27]=[C:26]([O:28][CH2:29][CH2:30][O:31][CH3:32])[CH:25]=[CH:24][N:23]=1)[CH:15]=[CH:14]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(O)(=O)C.C(O)(=O)C.I(C1C=CC=CC=1)=O>C(Cl)Cl>[Si:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([C:19]1[N:23]3[CH:24]=[CH:25][C:26]([O:28][CH2:29][CH2:30][O:31][CH3:32])=[CH:27][C:22]3=[N:21][N:20]=1)[CH:15]=[CH:14]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COCCOc1ccnc(NN=Cc2ccc3cccc(O[Si](C)(C)C(C)(C)C)c3n2)c1
Agent: O=Ic1ccccc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: COCCOc1ccn2c(-c3ccc4cccc(O[Si](C)(C)C(C)(C)C)c4n3)nnc2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 69.7 %

Procedure:
To a solution of 8-(tert-butyldimethylsilyloxy)-2-((2-(4-(2-methoxyethoxy)pyridin-2-yl)hydrazono)methyl) quinoline (0.101 g, 0.223 mmol) in DCM (1.0 mL) was added iodosobenzene diacetate (0.0719 g, 0.223 mmol). After stirring at ambient temperature for 5 hours the reaction mixture was partitioned between DCM and aqueous saturated Na2S2O3. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (40:1 DCM/MeOH) to provide 70 mg (70%) of desired product.