Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[H-].[Na+].Cl[C:13]1[N:14]=[N:15][C:16]([N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)=[CH:17][CH:18]=1>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([CH3:8])[CH:7]=1)[O:9][C:13]1[N:14]=[N:15][C:16]([N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)=[CH:17][CH:18]=1
Reactant: Clc1ccc(-n2ccnc2)nn1
Reactant: Cc1cc(C)cc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(Oc2ccc(-n3ccnc3)nn2)c1
Reaction time: 0.25 h

Procedure:
A mixture of 3 parts of 3,5-dimethylphenol, 1.25 parts of sodium hydride dispersion 50% and 25 parts of N,N-dimethylformamide was stirred for 15 minutes. Then there was added a solution of 4.5 parts of 3-chloro-6-(1H-imidazol-1-yl)pyridazine in 25 parts of N,N-dimethylformamide and the whole was stirred over weekend at 50° C. The reaction mixture was poured onto water and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from 2-propanone, yielding 3.5 parts of 3-(3,5-dimethylphenoxy)-6-(1H-imidazol-1-yl)pyridazine; mp. 169.8° C. (compound 2).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[O:3].Cl.[CH2:8]([O:15][C:16](=[O:19])[CH2:17][NH2:18])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:8]([O:15][C:16](=[O:19])[CH2:17][NH:18][C:1](=[O:5])[C:2]([CH3:4])=[O:3])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)C(=O)Cl
Reactant: NCC(=O)OCc1ccccc1
Agent: Cl
Product: CC(=O)C(=O)NCC(=O)OCc1ccccc1

Procedure:
Since it was initially determined that pyruvamide is not a preferred pyruvate analog, other pyruvate precursors were investigated. It was then found that other hydrolyzable, non-salt, pyruvate precursors could be synthesized. For example, an improved synthesis of pyruvyl-glycine via a benzyl ester protection method, was discovered. The traditional method of synthesis of pyruvyl-glycine involves reacting phosphorous oxychloride or p-toluene sulfonyl chloride with pyravic acid to yield pyruvyl chloride. The pyruvyl chloride formed using the traditional synthesis is then reacted with glycine benzyl ester hydrochloride to form pyruvyl-glycine benzyl ester, or with glycine in pyridine to yield pyruvyl-glycine. The yield of pyruvyl-glycine benzyl ester was about 35%, and the yield of pyruvyl-glycine was about 12%.
Reaction SMILES: [O:1]=[C:2]1[C:12]2[C:7](=[N+:8]([O-])[CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2.S(Cl)(C1C=CC(C)=CC=1)(=O)=[O:19].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O>[O:1]=[C:2]1[C:12]2[CH:11]=[CH:10][C:9](=[O:19])[NH:8][C:7]=2[CH:6]=[CH:5][C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2
Reactant: O=c1c2ccccc2ccc2c1ccc[n+]2[O-]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=c1ccc2c(=O)c3ccccc3ccc2[nH]1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of 2.23 grams (0.01 mole) of 5-oxo-benzo[4,5]cyclohepta[1,2-b]pyridine N-oxide intermediate and 2.29 grams (0.012 mole) of tosyl chloride in 100 milliliters of chloroform was added a solution of 1.76 grams of potassium carbonate in 25 milliliters of water and the resulting mixture stirred vigorously for 4 days at room temperature. During this period the desired 5-oxo-benzo[4,5]cyclohepta[1,2-b]pyrid-2(1H)one product formed in the reaction mixture as a solid. The solid was recovered by filtration, was washed successively with 10 percent sodium hydroxide solution, water and hot methanol, and was dried. The dried product was a TLC homogeneous 5-oxo-benzo-[4,5]cyclohepta[1,2-b]pyrid-2(1H)one.0.25 methanol solvate, m.p. 320° C. The elemental analyses were as follows:
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:15][CH:14]=1)=[N+:2]=[N-:3].[I:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]#[CH:37])=[CH:30][CH:29]=1.O>C1COCC1.[O-]S([O-])(=O)=O.[Cu+2]>[I:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]2[N:3]=[N:2][N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][C:13]3[CH:14]=[CH:15][C:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[CH:17][CH:18]=3)[CH:37]=2)=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(OCCOCCOCCN=[N+]=[N-])cc1
Reactant: C#CCOc1ccc(I)cc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(OCCOCCOCCn2cc(COc3ccc(I)cc3)nn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.2 %

Procedure:
To a solution of tert-butyl 4-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)phenylcarbamate (1.78 g, 4.86 mmol) and 1-iodo-4-(prop-2-ynyloxy)benzene (1.25 g, 4.86 mmol) in THF (30 mL) was added H2O (8.0 mL), Cu powder (0.31 g, 4.86 mmol) and CuSO4 (0.12 g, 0.486 mmol). The reaction mixture was stirred at room temperature for at least 12 hours (overnight). The reaction mixture was filtered through celite and washed with EtOAc. The organic layer was separated, washed with EDTA solution, dried and concentrated in vacuo to give a crude product which was purified by flash chromatography with hexane/EtOAc (1:1) as eluent to give tert-butyl 4-(2-(2-(2-(4-((4-iodophenoxy)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)ethoxy)ethoxy)phenylcarbamate (2.069 g, 68%). 1H NMR (400 MHz, CDCl3) δ 7.74 (s, 1H), 7.46 (d, J=9.2 Hz, 2H), 7.15 (d, J=8.8 Hz, 2H), 6.74 (d, J=9.2 Hz, 2H), 6.66 (d, J=8.8 Hz, 2H), 6.25 (brs, 1H), 5.04 (s, 2H), 4.47 (t, J=5.0 Hz, 2H), 3.99 (t, J=4.8 Hz, 2H), 3.79 (t, J=5.0 Hz, 2H), 3.80 (t, J=5.0 Hz, 2H), 3.71 (t, J=5.0 Hz, 2H), 3.60-3.53 (m, 4H), 1.44 (s, 9H); MS (ESI), 625 (M+H)+.
Reaction SMILES: [CH:1]1([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][C:8]=2[N+:14]([O-:16])=[O:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(CC)CC.[C:24](OC(=O)C)(=[O:26])[CH3:25]>C(Cl)Cl>[CH:1]1([C:7]2[CH:13]=[CH:12][C:10]([NH:11][C:24](=[O:26])[CH3:25])=[CH:9][C:8]=2[N+:14]([O-:16])=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(C2CCCCC2)c([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc(C2CCCCC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
To a solution of 4-cyclohexyl-3-nitro-aniline (1.54 g, 6.99 mmol) in DCM (15 mL) was added Et3N (1.9 mL, 13.63 mmol), followed by the addition of acetic anhydride (3.3 mL, 34.98 mmol). The reaction mixture was stirred at room temperature for 2 h, quenched with water, the layers separated and the organic layer was washed with 0.1N HCl, followed by washing with H2O. The organic layer was dried over MgSO4, filtered and concentrated to obtain N-(4-cyclohexyl-3-nitrophenyl)acetamide (1.7 g, 93%). 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J=2.2 Hz, 1H), 7.69 (dd, J=8.6, 2.2 Hz, 1H), 7.52 (s, 1H), 7.40 (d, J=8.6 Hz, 1H), 3.01-2.87 (m, 1H), 2.22 (s, 3H), 1.95-1.78 (m, 5H), 1.42 (t, J=10.4 Hz, 4H), 1.32-1.21 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=O)=[CH:4][CH:3]=1.[O-]S([O-])(=O)=O.[Na+].[Na+].[CH3:17][NH2:18].[O-]S([O-])(=O)=O.[Mg+2]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[N:18][CH3:17])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)nc1
Reactant: CN
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN=Cc1ccc(Cl)nc1
Reaction time: 8 h
Yield: 68.1 %

Procedure:
In 30 ml of toluene, 0.8 g (5.7×10-3 moles) of 6-chloropyridine-3-aldehyde and 10 g of Na2SO4 were mixed and while the mixtures was stirred, a 40% aqueous solution of methylamine (1.4 g, 1.1×10-2 mole) was added dropwise over 30 minutes, followed by addition of 10 g of MgSO4. The mixture was allowed to stand at room temperature overnight, after which it was filtered. The filtrate was concentrated to give 0.6 g (yield 68%) of N-(6-chloro-3-pyridylmethylidene)methylamine as crystals.
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].CC([O-])(C)C.[K+].[Br:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][C:35]=1[F:42]>CS(C)=O>[Br:33][C:34]1[CH:41]=[CH:40][C:37](/[CH:38]=[CH:7]/[CH2:6][CH2:5][C:2]([OH:4])=[O:3])=[CH:36][C:35]=1[F:42]
Reactant: O=Cc1ccc(Br)c(F)c1
Reactant: O=C(O)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(O)CC/C=C/c1ccc(Br)c(F)c1
Reaction time: 0.67 h
Yield: 47.4 %

Procedure:
To a solution of 3-carboxypropyltriphenylphosphonium bromide (8.6 g, 20 mmol) in DMSO (20 mL) was added solid KOt-Bu (4.49 g, 40.0 mmol) at rt. After stirring for 40 min, a solution of 4-bromo-3-fluorobenzaldehyde (3.45 g, 17.00 mmol) in DMSO was added slowly. The mixture was stirred at rt for 16 h. The reaction was quenched with water (200 mL), washed with EtOAc/hexanes (1/1). The aqueous layer was neutralized with concentrated hydrochloric acid to pH=2, extracted with EtOAc. The organic layer was concentrated. The residue was purified by silica gel column chromatography (hexanes-100% EtOAc) to give (E)-5-(4-bromo-3-fluorophenyl)pent-4-enoic acid (2.2 g, 8.06 mmol, 40% yield). LCMS (M−H)−=273.1. 1H NMR (500 HMz, chloroform-d) δ 7.47 (dd, J=8.2, 7.2 Hz, 1H), 7.12 (dd, J=9.9, 2.0 Hz, 1H), 7.00 (dd, J=8.2, 2.0 Hz, 1H), 6.41-6.36 (m, 1H), 6.29-6.22 (m, 1H), 2.58-2.56 (m, 4H).
Reaction SMILES: Br[CH2:2][C:3]1[N:10]=[C:9]([Cl:11])[CH:8]=[C:7]([Cl:12])[C:4]=1[C:5]#[N:6].[C:13]([O-:16])(=[O:15])[CH3:14].[Na+]>CN(C=O)C>[C:13]([O:16][CH2:2][C:3]1[C:4]([C:5]#[N:6])=[C:7]([Cl:12])[CH:8]=[C:9]([Cl:11])[N:10]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)[O-]
Reactant: N#Cc1c(Cl)cc(Cl)nc1CBr
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCc1nc(Cl)cc(Cl)c1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2-(bromomethyl)-4,6-dichloronicotinonitrile (354.8 mg, 1.334 mmol) in DMF (7 ml) was charged with sodium acetate (198 mg, 2.414 mmol) and stirred at RT for 2 hr. The reaction was quenched with water, extracted twice with Et2O. The organics was washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give (4,6-dichloro-3-cyanopyridin-2-yl)methyl acetate. MS ESI calc'd. For C9H7O2N2O2 [M+I-1]+ 245. found 245.
Reaction SMILES: [C:1]([C:3]1([C:6]([OH:8])=O)[CH2:5][CH2:4]1)#[N:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH2:43]([O:45][C:46]1[CH:51]=[CH:50][C:49]([CH:52]2[CH2:57][CH2:56][N:55]([C:58]3[CH:63]=[CH:62][C:61]([C@@H:64]([NH2:66])[CH3:65])=[CH:60][CH:59]=3)[CH2:54][CH2:53]2)=[CH:48][CH:47]=1)[CH3:44]>CN(C=O)C>[CH2:43]([O:45][C:46]1[CH:47]=[CH:48][C:49]([CH:52]2[CH2:53][CH2:54][N:55]([C:58]3[CH:59]=[CH:60][C:61]([C@@H:64]([NH:66][C:6]([C:3]4([C:1]#[N:2])[CH2:5][CH2:4]4)=[O:8])[CH3:65])=[CH:62][CH:63]=3)[CH2:56][CH2:57]2)=[CH:50][CH:51]=1)[CH3:44]
Reactant: N#CC1(C(=O)O)CC1
Reactant: CCOc1ccc(C2CCN(c3ccc([C@H](C)N)cc3)CC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(C2CCN(c3ccc([C@H](C)NC(=O)C4(C#N)CC4)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 14 mg (0.13 mmol) 1-cyano-cyclopropanecarboxylic acid in 1 mL DMF are added 52 μL (0.30 mmol) DIPEA and 49 mg (0.13 mmol) HATU. The mixture is stirred for 10 min at rt. Subsequently a mixture of 36 mg (0.10 mmol) (S)-1-{4-[4-(4-ethoxy-phenyl)-piperidin-1-yl]-phenyl}-ethylamine hydrochloride (XII.1) in 1 mL DMF is added and stirring is continued for 6 h at rt. The crude mixture is directly purified by HPLC (Sunfire, narrow gradients, water (+0.1% TFA)/methanol) to yield the desired product.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[I:9]I.CO.S([O-])([O-])=O.[Na+].[Na+]>O>[F:1][C:2]1[N:7]=[C:6]([I:9])[C:5]([OH:8])=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)nc1
Reactant: II
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Oc1ccc(F)nc1I
Temperature: 25 °C
Reaction time: 120 h
Yield: 19 %

Procedure:
6-Fluoro-3-hydroxypyridine (870 mg) and iodine (9.76 g) were dissolved in a mixed solvent composed of methanol (20 ml) and water (10 ml) to prepare a solution which was then stirred at room temperature for 120 hr. Thereafter, sodium sulfite was added until the solution became transparent. Methanol in the reaction solution was removed under the reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give 6-fluoro-2-iodo-pyridin-3-ol (350 mg, yield 19%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[N:12]=[C:13]=[O:14].[NH2:15][C:16]1[CH:21]=[N:20][CH:19]=[CH:18][N:17]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[NH:12][C:13]([NH:15][C:16]1[CH:21]=[N:20][CH:19]=[CH:18][N:17]=1)=[O:14]
Reactant: Nc1cnccn1
Reactant: COc1cc([N+](=O)[O-])ccc1N=C=O
Solvent: C1CCOC1
Product: COc1cc([N+](=O)[O-])ccc1NC(=O)Nc1cnccn1

Procedure:
A mixture of 2-methoxy-4-nitrophenyl isocyanate (15.0 g, 77 mmol) and aminopyrazine (7.35 g, 77 mmol) in THF (600 mL) was stirred at reflux for 24 hours. The product precipitated from the cooled reaction mixture and was collected by filtration, washed with ethyl acetate, triturated with hot ethanol, and dried in vacuo (16.3 g, 73%). 1H NMR (300 Mhz, d6DMSO) δ: 10.50 (br s, 1H), 10.42 (s, 1H), 8.94 (s, 1H), 8.48 (d, 1H), 8.39 (s, 1H), 8.32 (d, 1H), 7.95 (dd, J=9.1, 2.4 Hz, 1H), 7.84 (d, J=2.4 Hz, 1H), 4.08 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([S:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:19])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:8][CH:7]=1)=[O:4].[H-].[K+].[CH3:23]I>C1COCC1.CCOCC>[CH3:20][N:2]([CH3:1])[C:3]([S:5][C:6]1[CH:7]=[CH:8][C:9]([C:12](=[O:19])[CH:13]([CH3:23])[CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:11]=1)=[O:4]
Reactant: CI
Reactant: COC(=O)CCC(=O)c1ccc(SC(=O)N(C)C)cc1
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)CC(C)C(=O)c1ccc(SC(=O)N(C)C)cc1
Temperature: -45 °C
Reaction time: 0.5 h

Procedure:
The compound from Step D, (10.0 g, 33.9 mmoles) was dissolved in THF (100 ml) and added dropwise to a stirred mixture of potassium hydride (1.6 g, 40.7 mmoles) in THF (10 ml) at -45° C. The reaction mixture was warmed to 0° to initiate the reaction, then cooled to -45° C. After 30 minutes, the reaction mixture was warmed to 0° C., and stirred for 10 minutes A solution of methyl iodide (3.17 ml, 50.9 mmoles) in THF (10 ml) was added slowly to the cold solution. The mixture was stirred at 0° for one hour. The reaction mixture was diluted with ether, washed with water, brine, dried and evaporated to yield an oil which was purified by HPLC to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([Br:14])=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4].[C:15](=O)([O-])[O-].[K+].[K+].CI>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([Br:14])=[CH:11][CH:12]=2)[N:7]([CH3:15])[CH:6]=1)=[O:4]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1c[nH]c2cc(Br)ccc12
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: COC(=O)c1cn(C)c2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 88.3 %

Procedure:
To a mixture of 25 g (98.39 mmol) of 6-bromo-1H-indole-3-carboxylic acid methyl ester and 27.20 g (196 mmol) of potassium carbonate in 300 mL of acetonitrile is added at room temperature Methyl Iodide (20.95 g, 147.6 mmol). The reaction mixture is stirred at room temperature for 3 days. The solvent is evaporated, 500 ml of water is added, and the organic layer is extracted with (3×300 ml) ethyl acetate. The organics are combined, dried over magnesium sulfate and evaporated. The crude is purified by silica gel chromatography eluting with hex/EtOAc 8:2. The title compound (23.3 g (88%)) is obtained as a brown solid. MS (m/e): 268 (M+1).
Reaction SMILES: [C:1]([CH2:3][CH:4]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[O:9][CH2:8][CH2:7][N:6]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:5]1)#[N:2].C(=O)([O-])[OH:27].[Na+].OO.S([O-])([O-])(=O)=S.[Na+].[Na+]>CO.O>[NH2:2][C:1](=[O:27])[CH2:3][CH:4]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[O:9][CH2:8][CH2:7][N:6]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:5]1
Reactant: O=C([O-])O
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(CC#N)C1
Agent: O=S([O-])([O-])=S
Agent: OO
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(CC(N)=O)C1
Reaction time: 72 h

Procedure:
To a solution of tert-butyl (6RS,7RS)-6-(cyanomethyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (900 mg) in methanol (7 mL)-water (2 mL) were added saturated aqueous sodium hydrogen carbonate (1 mL) and 35% aqueous hydrogen peroxide (3 mL), and the mixture was stirred for 3 days. To the reaction mixture was added saturated aqueous sodium thiosulfate solution, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (492 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]2[N:7]([CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[N:6]=[C:5]3[C:20]4[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:21]=4[S:22][C:3]=1[C:4]=23.Br.[Br:30][CH2:31][CH2:32][NH2:33]>CCO>[BrH:30].[CH2:16]([N:15]([CH2:18][CH3:19])[CH2:14][CH2:13][N:7]1[C:8]2[C:9]([O:11][CH3:12])=[CH:10][C:2]([NH:1][CH2:31][CH2:32][NH2:33])=[C:3]3[S:22][C:21]4[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:20]=4[C:5]([C:4]=23)=[N:6]1)[CH3:17]
Reactant: NCCBr
Reactant: CCN(CC)CCn1nc2c3c(c(N)cc(OC)c31)Sc1ccc(OC)cc1-2
Agent: Br
Solvent: CCO
Product: CCN(CC)CCn1nc2c3c(c(NCCN)cc(OC)c31)Sc1ccc(OC)cc1-2
Yield: 36.3 %

Procedure:
Reaction of a solution of 3.6 g (0.0095 mol) of 5-amino-N,N-diethyl-3,9-dimethoxy-2H[1]benzothiopyrano[4,3,2-cd]indazole-2-ethanamine and 5.8 g (0.0283 mol) of 2-bromoethylamine, hydrobromide, in 30 ml of EtOH as described in Example 38 gave 1.8 g of product.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:3]=1[CH:4]=[N:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13].[BH4-].[Na+].C(O)C>O>[CH3:1][C:2]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:3]=1[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13]
Reactant: Cc1ccc(C=Nc2ccc(Cl)cc2Cl)c(C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(CNc2ccc(Cl)cc2Cl)c(C)c1

Procedure:
A mixture of 13.9 g. of N-(2,4-dimethylbenzylidene)-2,4-dichloroaniline, 1.89 g. of sodium borohydride and 150 ml of ethanol is stirred under reflux for one hour, allowed to cool and poured into water. Recrystallization from ethanol yields N-(2,4-dimethylbenzyl)-2,4-dichloroaniline, m.p. 88°-90°.
Reaction SMILES: C([Li])CCC.[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22](Br)=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1.[CH3:32][N:33]1[C:37]([CH:38]=[O:39])=[CH:36][N:35]=[C:34]1[CH3:40].O>O1CCCC1>[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22]([CH:38]([C:37]3[N:33]([CH3:32])[C:34]([CH3:40])=[N:35][CH:36]=3)[OH:39])=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Reactant: Cc1ncc(C=O)n1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1nc2ccc(C(O)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Temperature: 23 °C
Reaction time: 0.05 h

Procedure:
A solution of n-butyllithium in hexanes (1.6 M, 1.5 mL, 2.3 mmol) was added dropwise to a stirring solution of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxyquinoline (1 g, 2.3 mmol, Intermediate 4: step d) in tetrahydrofuran (18 mL) at −78° C. After 3 minutes, a solution of 1,2-dimethyl-1H-imidazole-5-carbaldehyde (347 mg, 2.8 mmol) in tetrahydrofuran (5 mL) was added dropwise. After 5 minutes, the flask was placed into an ice-water bath. After 30 minutes, water (10 mL) was added and the biphasic mixture was allowed to warm to 23° C. The mixture was partitioned between half-saturated sodium chloride solution (50 mL) and ethyl acetate (100 mL). The layers were separated. The organic layer was dried with sodium sulfate and the dried solution was filtered. Silica gel (3 g) was added to the filtrate and the solvent was removed by rotary evaporation to afford a free-flowing powder. The powder was loaded onto a column of silica gel for purification. Elution with ethyl acetate initially, grading to 7% methanol-ethyl acetate provided the title compound as an off-white solid. 1H NMR (500 MHz, CDCl3) δ ppm 8.24-8.22 (m, 1H), 7.86-7.84 (m, 1H), 7.82 (d. J=8.6 Hz, 1H), 7.68 (d, J=1.7 Hz, 1H), 7.62-7.59 (m, 1H), 7.58-7.54 (m, 2H), 7.38-7.35 (m, 2H), 6.54 (s, 1H), 6.44-6.41 (m, 1H), 6.00 (s, 1H), 4.33 (s, 2H), 4.09 (s, 3H), 3.47 (s, 3H), 2.33 (s, 3H); MS (ESI): mass calcd. for C26H24ClN5O2, 473.2; m/z found, 474.0 [M+H]+.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]3[CH:15]=[CH:14][NH:13][C:10]3=[N:11][CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:16]([S:19]([N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([CH:31]=[O:32])[CH:29]=2)[CH:24]=[CH:23]1)(=[O:21])=[O:20])[CH2:17][CH3:18].[OH-].[K+].CO>O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]3[C:15]([CH:31]([C:28]4[CH:29]=[C:30]5[C:25]([CH:24]=[CH:23][N:22]5[S:19]([CH2:16][CH2:17][CH3:18])(=[O:21])=[O:20])=[CH:26][CH:27]=4)[OH:32])=[CH:14][NH:13][C:10]3=[N:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: c1cc2cc(OC3CCCC3)cnc2[nH]1
Reactant: CCCS(=O)(=O)n1ccc2ccc(C=O)cc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCS(=O)(=O)n1ccc2ccc(C(O)c3c[nH]c4ncc(OC5CCCC5)cc34)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 0 %

Procedure:
Into a round bottom flask, was added 5-cyclopentyloxy-1H-pyrrolo[2,3-b]pyridine (P-0001, 0.110 g, 0.544 mol, prepared as describes in Example 12), 1-(propane-1-sulfonyl)-1H-indole-6-carbaldehyde (60, 0.169 g, 0.674 mol), potassium hydroxide (91.6 mg, 1.63 mol) and methanol (2 mL, 0.05 mol). The reaction was allowed to stir at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with a gradient of ethyl acetate (with 4% acetic acid) in hexanes to provide 88 mg of the desired compound. MS (EST) [M+H+]+=454.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:19]2[CH2:18][CH2:17][N:16]([C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])[CH2:21][CH2:20]2)=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cn2)CC1
Temperature: 25 °C
Yield: 79.6 %

Procedure:
To a solution of 5-bromo-2-chloropyrimidine (50.0 g, 258 mmol) and 1-tert-butoxycarbonylpiperazine (72.2 g, 387 mmol) in 1,4-dioxane (500 mL) was added potassium carbonate (67.8 g, 491 mmol), and the mixture was stirred under reflux for 1.5 h. The reaction was cooled to RT, quenched by water (500 mL) and extracted with diethyl ether (1000 mL*2). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified with silica gel chromatography (petroleum ether:ethyl acetate=8:1-4:1) to give the title compound (70.5 g, 80%) as a white solid. MS (ES+) C13H19BrN4O2 requires: 342. found: 243 [M+H−100]+.