Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Al](C)C.CCCCCC.[C:32]([C:34]1[CH:35]=[C:36]([C:40]2[CH2:44][CH2:43][CH2:42][C:41]=2[C:45](OCC)=[O:46])[CH:37]=[CH:38][CH:39]=1)#[N:33]>ClCCl>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:45]([C:41]2[CH2:42][CH2:43][CH2:44][C:40]=2[C:36]2[CH:37]=[CH:38][CH:39]=[C:34]([C:32]#[N:33])[CH:35]=2)=[O:46])=[CH:17][CH:16]=1)(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C1=C(c2cccc(C#N)c2)CCC1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(N)cc1
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(NC(=O)C2=C(c3cccc(C#N)c3)CCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
To a solution of 2′-tert-butylaminosulfonyl-4-amino-[1,1′]-biphenyl (60 mg, 0.197 mmol) in 4 ml anhydrous dichloromethane was added a solution of 2M trimethylaluminum in hexane (0.3 ml, 0.59 mmol). Reaction was stirred at room temperature for 20 minutes to which a solution of ethyl 2-(3-cyanophenyl)-1-cyclopentene-1-carboxylate (48 mg, 0.197 mmol) in lml anhydrous dichloromethane. Reaction was stirred at room temperature overnight. Reaction was quenched with 15 ml 1N HCl after which an additional 10 ml dichloromethane was added. Organic was washed with 2×20 ml water, dried over magnesium sulfate and concentrated to give N-[4-(2-{[(tert-butyl)amino]sulfonyl}phenyl)phenyl][2-(3-cyanophenyl)cyclopent-1-enyl]carboxamide (80 mg, 80%) as a white powder which was sufficiently pure to be used without further purification.
Reaction SMILES: Br[C:2]1[C:3]([N:22]([CH2:24][CH2:25][OH:26])[CH3:23])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:27][C:28]1[CH:29]=[N:30][CH:31]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:33]=1>>[Cl:20][C:17]([F:19])([F:18])[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7]([C:6]2[CH:21]=[C:2]([C:32]3[CH:31]=[N:30][CH:29]=[C:28]([F:27])[CH:33]=3)[C:3]([N:22]([CH2:24][CH2:25][OH:26])[CH3:23])=[N:4][CH:5]=2)=[O:8])=[CH:11][CH:12]=1
Reactant: CC1(C)OB(c2cncc(F)c2)OC1(C)C
Reactant: CN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)Cl)cc2)cc1Br
Product: CN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)Cl)cc2)cc1-c1cncc(F)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 169 using 5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-((2-hydroxyethyl)(methyl)amino)nicotinamide (Stage 179.1) and 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine to afford an off-white foam. HPLC (Condition 4) tR=5.51 min, UPLC-MS (Condition 3) tR=1.07 min, m/z=467.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.69 (s, 3H) 3.39-3.61 (m, 4H) 4.65 (t, J=5.08 Hz, 1H) 7.33 (d, J=8.99 Hz, 2H) 7.77-7.94 (m, 3H) 8.11 (d, J=2.35 Hz, 1H) 8.50-8.63 (m, 2H) 8.74 (d, J=2.35 Hz, 1H) 10.21 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)[CH3:4].O.C(=O)(O)[O-].[Na+].[C:19](Cl)(=[O:21])[CH3:20]>C(OCC)(=O)C>[C:19]([NH:1][CH2:2][CH:3]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)[CH3:4])(=[O:21])[CH3:20]
Reactant: COc1ccc(C(C)CN)cc1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(C(C)CNC(C)=O)cc1
Yield: 99.8 %

Procedure:
A mixture of 19.8 g of 1-amino-2-(4-methoxyphenyl)propane, 200 ml of ethyl acetate, 200 ml of water and 84 g of sodium bicarbonate is cooled at 5° to 10° C. under stirring, and 18.8 g of acetyl chloride in 100 ml of ethyl acetate are added dropwise thereto at the same temperature. After the reaction, the ethyl acetate layer is separated therefrom, washed, dried and then condensed to dryness under reduced pressure. 24.8 g of 1-acetylamino-2-(4-methoxyphenyl)propane are obtained as oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH:13]([OH:15])[CH3:14])=[CH:11][N:12]=2)=[CH:4][CH:3]=1.Cl[C:17]1[CH:23]2[O:24][C:20]([CH3:25])([CH2:21][CH2:22]2)[C:19](=[O:26])[CH:18]=1.[H-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]([CH:13]([O:15][C:17]3[CH:23]4[O:24][C:20]([CH3:25])([CH2:21][CH2:22]4)[C:19](=[O:26])[CH:18]=3)[CH3:14])=[CH:11][N:12]=2)=[CH:6][CH:7]=1
Reactant: CC(O)c1cnc(-c2ccc(Cl)cc2)s1
Reactant: CC12CCC(O1)C(Cl)=CC2=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(OC1=CC(=O)C2(C)CCC1O2)c1cnc(-c2ccc(Cl)cc2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
To a solution of 1-[2-(4-Chlorophenyl)thiazol-5-yl]ethanol (129 mg, 0.54 mmol) and 4-chloro-1-methyl-8-oxabicyclo[3.2.1]oct-3-en-2-one (93 mg, 0.54 mmol) in dry THF (5 ml) is added in one portion the sodium hydride, 60% dispersion in mineral oil, (21 mg, 0.54 mmol). The reaction mixture is stirred at room temperature overnight. Silica gel is added to the crude reaction mixture, and the solvent is evaporated under reduced pressure. The residue is purified by flash chromatography on silica gel to give 4-{1-[2-(4-Chlorophenyl)thiazol-5-yl]-ethoxy}-1-methyl-8-oxabicyclo[3.2.1]oct-3-en-2-one (160 mg).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11][C:12]#N)[N:2]=1.[Cl:14][C:15]1[CH:16]=[C:17]([N+:23]([O-:25])=[O:24])[CH:18]=[C:19]([Cl:22])C=1Cl.[H-].[Na+]>>[Cl:14][C:15]1[CH:16]=[C:17]([N+:23]([O-:25])=[O:24])[CH:18]=[C:19]([Cl:22])[C:12]=1[CH2:11][C:3]1[N:2]=[CH:1][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: N#CCc1cc2ccccc2cn1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Product: O=[N+]([O-])c1cc(Cl)c(Cc2cc3ccccc3cn2)c(Cl)c1

Procedure:
3-(2,6-Dichloro-4-nitro-benzyl)-isoquinoline was synthesized (79%) from isoquinolin-3-yl-acetonitrile (234, 1.22 g, 7.26 mmol), 3,4,5-trichloronitrobenzene (Acros, 1.64 g, 7.26 mmol) and NaH (Aldrich, 640 mg, 60%, 16.0 mmol) in a similar manner in two steps as described in Example 222. 1H NMR (400 MHz, DMSO-d6) δ 9.21 (s, 1H), 8.38 (s, 2H), 8.07 (d, J=8.2 Hz, 1H), 7.89 (d, J=8.2 Hz, 1H), 7.75 (t, J=7.5 Hz, 1H), 7.64 (t, J=7.5 Hz, 1H), 7.57 (s, 1H), 4.68 (s, 2H). MS (EI): m/z 333 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]=[CH2:10])=[CH:4][C:3]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([SiH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=1>O1CCCC1.C(OCC)(=O)C>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([Si:26]([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([O:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:4]=2)([CH3:27])[CH3:28])=[CH:22][CH:21]=1
Reactant: C=CCc1ccc(F)c(Oc2ccccc2)c1
Reactant: COc1ccc([SiH](C)C)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc([Si](C)(C)CCCc2ccc(F)c(Oc3ccccc3)c2)cc1
Temperature: 150 °C

Procedure:
To a mixture of 1.14 g (0.005 mole) of 3-(4-fluoro-3-phenoxyphenyl)-1-propene and 0.004 g (0.00001 mole) of hydrogen hexachloroplatinate hydrate in 1 mL of tetrahydrofuran under nitrogen was added slowly 0.83 g (0.005 mole) of (4-methoxyphenyl)dimethylsilane. After completion of addition the reaction mixture was diluted with a mixture of petroleum ether and ethyl acetate. This solution was treated with activated carbon and then was filtered through a short column of silica gel. The solvent was evaporated under reduced pressure, leaving a residue. This residue was heated at 150° C. at 0.1 mm of Hg to remove impurities. The pot residue was a light brown liquid weighing 1.25 g. The ir and proton nmr spectra confirmed that this residue was (4-methoxyphenyl)[3-(4-fluoro-3-phenoxyphenyl)propyl]dimethylsilane, compound 37 of Table 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:17]([O-:19])=[O:18])=[C:6]([CH:16]=1)[O:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=[O:11].C([O:22]CC)C.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.OS(O)(=O)=O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:17]([O-:19])=[O:18])=[C:6]([CH:16]=1)[O:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[C:10]([OH:22])=[O:11]
Reactant: CCOCC
Reactant: O=Cc1ccccc1Oc1cc(Cl)ccc1[N+](=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)(O)O
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccccc1Oc1cc(Cl)ccc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
The 2-(5'-chloro-2-nitrophenoxy)benzoic acid was prepared as follows: Crude 2-(5-chloro-2-nitrophenoxy)benzaldehyde was heated under reflux with 200 ml of diethylether, 120 ml of water, 41.1 g of Na2Cr2O7 ·2H2O and 6.0 g of a 40% tetra-n-butylammonium hydroxide solution, and to it was added 63 ml of 9M H2SO4 over three hours. Heating was continued for an additional two hours, and the aqueous layer was extracted with ether and evaporated to dryness to provide the product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([CH3:25])=[CH2:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.ClCCl.ClC1C=CC=C(C(OO)=[O:38])C=1>C(OC)(C)(C)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]3([CH3:25])[CH2:24][O:38]3)([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[O:12][C:11]2=[O:26])[CH3:9])=[CH:6][CH:7]=1
Reactant: C=C(C)C[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC2(C)CO2)(c2ccccc2)OC1=O
Temperature: 22.5 °C

Procedure:
To a 1.0 L 2-neck RBF was charged (R)-3-[(S)-1-(4-bromo-phenyl)-ethyl]-6-(2-methyl-allyl)-6-phenyl-perhydro-1,3-oxazin-2-one (F, 135.8 g, 59 wt %, 3.1:1 dr, 193 mmol, 1.00 equiv), dichloromethane (700 mL), and then 3-chloroperbenzoic acid (MCPBA, 70%, 95.3 g, 386 mmol, 2.0 equiv). The resulting solution was agitated at RT (Tint=20-25° C.) for 1H, which HPLC analysis indicates >99 A % (220 nm) conversion. The resulting solution was diluted with 700 mL of methyl tert-butyl ether (MTBE) and washed with 1×500 mL of 30 wt % solution of sodium thiosulfate and 1×500 mL of saturated aqueous solution of sodium bicarbonate. The wash sequence were repeated until the peak on an HPLC trace of the organic solution that corresponds to a HPLC sample peak of MCPBA is <2.5 A % (220 nm), which in this example the wash sequence was repeated 3 times. The resulting organic layer was dried with anhydrous sodium sulfate, filtered and then concentrated to an oil via reduced pressure. The resulting material was diluted with 200 mL of anhydrous tetrahydrofuran and then concentrated to a thick oil via reduced pressure to provide (S)-3-[(S)-1-(4-bromo-phenyl)-ethyl]-6-(2-methyl-oxiranylmethyl)-6-phenyl-perhydro-1,3-oxazin-2-one (G) which was used directly in the following reduction.
Reaction SMILES: CN(OC)[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[CH2:13]([Mg]Cl)[CH2:14][CH3:15]>C1COCC1>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:3](=[O:10])[CH2:13][CH2:14][CH3:15])[CH:5]=1
Reactant: CCC[Mg]Cl
Reactant: CON(C)C(=O)c1cccnc1
Solvent: C1CCOC1
Product: CCCC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A flask is charged with N-methyl-N-methoxy-nicotinamide (1.0 g, 6.02 mmol) and THF (10 mL). Propyl magnesium chloride (2M in THF, 3.31 mL, 6.62 mmol) is added and the mixture is stirred at room temperature overnight. It is quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The combined organic layer is dried over sodium sulfate and concentrated in vacuo to afford 1-pyridin-3-yl-butan-1-one as a yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.03 (t, J=7.5 Hz, 3H), 1.74-1.87 (m, 2H), 2.97 (t, J=7.3 Hz, 2H), 7.42 (dd, J=8.0, 4.9 Hz, 1H), 8.24 (dt, J=8.0, 2.0, 1.9 Hz, 1H), 8.78 (dd, J=4.9, 2.0 Hz, 1H), 9.18 (d, J=2.0 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[NH3:10]>>[Br:8][C:6]1[CH:5]=[C:4]([CH3:9])[N:3]=[C:2]([NH2:10])[CH:7]=1
Reactant: Cc1cc(Br)cc(Br)n1
Reactant: N
Product: Cc1cc(Br)cc(N)n1
Temperature: 160 °C
Reaction time: 4 h

Procedure:
A mixture of 2,4-dibromo-6-methyl-pyridine (J. Bernstein et al., J. Amer. Chem. Soc., 1947, 69, 1147) (22.6 g, 90 mmol) and aqueous ammonia (25%, 260 ml) was stirred in an autoclave at 160° C. for 4 hr. The reaction mixture was cooled to rt and extracted with Et2O. The organic phase was dried (Na2SO4), concentrated and chromatographed (SiO2 with AcOEt/hexane/NEt3=10/30/1) to yield the title compound as a white crystalline material (4.0 g, 6%). NMR (250 MHz, DMSO): δ=3.33 (s, 3H, CH3), 6.13 (s, broad, 2H, NH2), 6.44 (s, 1H, arom-H), 6.54 (s, 1H, arom-H).
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[NH2:12][NH2:13]>C1COCC1>[NH:12]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1)[NH2:13]
Reactant: NN
Reactant: COC(=O)c1ccc(F)nc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NN)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
A solution of methyl 6-fluoronicotinate (13.9 g, 89.60 mmol) and hydrazine (5.625 ml, 179.2 mmol) in THF (200 mL) were heated at 56° C. for 2 hours. After cooling to ambient temperature, the solvent was removed under reduced pressure and water (200 mL) was added. The suspension was stirred at ambient temperature for 1 hour. The solid was collected by filtration, washed with water and dried to give methyl 6-hydrazinylnicotinate (13.4 g, 89.5%) as a solid.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[S:14][C:15]([Br:19])=[C:16]([Br:18])[CH:17]=2)[CH2:11][N:10]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:9]1)=[O:7])(C)(C)C.[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30]>C(Cl)Cl>[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[CH2:20]([N:10]1[CH2:11][CH:12]([C:13]2[S:14][C:15]([Br:19])=[C:16]([Br:18])[CH:17]=2)[CH:8]([C:6]([OH:7])=[O:5])[CH2:9]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccccc2)CC1c1cc(Br)c(Br)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1CN(Cc2ccccc2)CC1c1cc(Br)c(Br)s1

Procedure:
The product of step b) (2.6 g, 5.2 mmol) in CH2Cl2 (25 ml) and trifluoroacetic acid (TFA) (75 ml) was stirred at 22° C. for 16 hours. Next, the solvent was evaporated and toluene (50 ml) was added and subsequently evaporated in vacuo at 40° C. to remove residual TFA. The crude subtitle product was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:17][N:16]=[N:15][N:14]=2)=[CH:9][CH:8]=1.C(O)CC.[OH-].[K+].[Br-].[C:28](#[N:31])[CH2:29][CH3:30]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[N:15][N:16]([CH2:30][CH2:29][C:28]#[N:31])[N:17]=2)=[CH:11][CH:12]=1
Reactant: Clc1cccc(COc2ccc(-c3nnn[nH]3)cc2)c1
Reactant: CCC#N
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: CCCO
Product: N#CCCn1nnc(-c2ccc(OCc3cccc(Cl)c3)cc2)n1

Procedure:
To a solution made tepid of 10-2 mole of 5-[4-(3-chloro benzyloxy) phenyl] tetrazole in 60 ml of n-propanol containing 10-2 mole of KOH, 1.2×10-2 mole of propionitrile bromide (IIa) is added and the reaction mixture is heated to reflux for 25 hours. After concentration by evaporating the solvent, the residue is taken up in ether, the etherated solution is washed twice with 20 ml of 0.5N aqueous NaOH, then with water, dried and concentrated. After recrystallization in methanol, the expected compound is obtained.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[CH3:29][C:30]([OH:39])([CH3:38])[CH2:31][CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[CH3:38][C:30]([OH:39])([CH3:29])[CH2:31][CH:32]1[CH2:33][CH2:34][N:35]([CH2:2][C:3]2[N:4]([CH3:28])[C:5]3[C:10]([N:11]=2)=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:8]=[C:7]([N:18]2[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[N:20]=[C:19]2[CH3:27])[N:6]=3)[CH2:36][CH2:37]1
Reactant: CC(C)(O)CC1CCNCC1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(CC(C)(C)O)CC3)n(C)c2n1

Procedure:
Following General Procedure E of amine alkylation, 4-(8-(bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine and 2-methyl-1-(piperidin-4-yl)propan-2-ol were reacted to give 266. LCMS: M+H+=519.4
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:42]/[O:43][C:44]2([C:47]([OH:49])=[O:48])[CH2:46][CH2:45]2)/[C:8]([NH:10][C@@H:11]2[C:14](=[O:15])[N:13]([S:16]([OH:19])(=[O:18])=[O:17])[C@@H:12]2[CH2:20][N:21]2[N:25]=[C:24]([CH2:26][NH:27][C:28](=[NH:41])[NH:29][CH2:30][CH2:31][CH2:32][NH:33]C(=O)OC(C)(C)C)[CH:23]=[N:22]2)=[O:9])[N:6]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:33][CH2:32][CH2:31][CH2:30][NH:29][C:28](=[NH:41])[NH:27][CH2:26][C:24]1[CH:23]=[N:22][N:21]([CH2:20][C@@H:12]2[C@H:11]([NH:10][C:8](=[O:9])/[C:7](=[N:42]\[O:43][C:44]3([C:47]([OH:49])=[O:48])[CH2:45][CH2:46]3)/[C:5]3[N:6]=[C:2]([NH2:1])[S:3][CH:4]=3)[C:14](=[O:15])[N:13]2[S:16]([OH:19])(=[O:18])=[O:17])[N:25]=1
Reactant: CC(C)(C)OC(=O)NCCCNC(=N)NCc1cnn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)O)CC3)c3csc(N)n3)C(=O)N2S(=O)(=O)O)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N=C(NCCCN)NCc1cnn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)O)CC3)c3csc(N)n3)C(=O)N2S(=O)(=O)O)n1
Yield: 55.1 %

Procedure:
Followed the general procedure for the acid mediated deprotection using 1-(((Z)-(1-(2-aminothiazol-4-yl)-2-(((2R,3S)-2-((4-(3-imino-11,11-dimethyl-9-oxo-10-oxa-2,4,8-triazadodecyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxo-1-sulfoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)cyclopropanecarboxylic acid (37 mg, 15 μmol), DCM (0.8 mL), and TFA (0.2 mL, 2.60 mmol) for 1.5 h. The crude residue was purified by reverse phase prep HPLC (XSelect CSH, 19×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 24 mL/min) affording the title compound (5.2 mg, 20%). LCMS: Rt=0.39 min, m/z=629.2 (M+1), Method 2m_acidic; 1H NMR (400 MHz, D2O) δ 7.77 (s, 1H), 7.15 (s, 1H), 5.63 (d, J=5.7 Hz, 1H), 5.06-4.99 (m, 1H), 4.98-4.89 (m, 2H), 4.57 (s, 2H), 3.39-3.34 (m, 2H), 3.14-3.06 (m, 2H), 2.01 (p, J=7.2 Hz, 2H), 1.39-1.29 (m, 2H), 1.26-1.15 (m, 2H).
Reaction SMILES: [CH2:1]([N:8]1[C:15](=O)[CH:14]2[CH:10]([NH:11][CH2:12][CH2:13]2)[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([N:8]1[CH2:15][CH:14]2[CH:10]([NH:11][CH2:12][CH2:13]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C2CCNC2C(=O)N1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc(CN2CC3CCNC3C2)cc1

Procedure:
57.7 g (0.25 mol) of crude 5-benzyl-4,6-dioxo-octahydropyrrolo[3,4-b]pyrrole are reduced with 21.4 g (0.56 mol) of lithium aluminum hydride by boiling in 700 ml of absolute tetrahydrofuran for 10 hours in accordance with the working instructions of Example Ic. Working up by distillation gives 21.0 g (41.1% of theory) of an oil of boiling point 95° C./0.1 mbar.
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[N:6][C:7]=1[Cl:8].[NH3:10]>>[Cl:8][C:7]1[N:6]=[CH:5][N:4]=[C:3]([NH2:10])[C:2]=1[NH2:1]
Reactant: Nc1c(Cl)ncnc1Cl
Reactant: N
Product: Nc1ncnc(Cl)c1N
Temperature: 118 °C

Procedure:
A suspension of 5-Amino-4,6-dichloropyrimidine (3 g, 0.02 mol) in ammonia (25 mL, 7N/MeOH, 0.175 mole) was heated at 118° C. overnight (under pressure). The reaction was cooled to 23° C., filtered and washed with ethanol to obtain 1.92 g (70%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:16]=[CH:15][C:14]2[C:13](=[O:17])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:18])[C:5]=2[CH:4]=1.[CH2:19]([OH:22])[CH2:20][OH:21]>C(Cl)(Cl)Cl>[OH:21][CH2:20][CH2:19][O:22][CH2:2][C:3]1[CH:16]=[CH:15][C:14]2[C:13](=[O:17])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:18])[C:5]=2[CH:4]=1
Reactant: O=C1c2ccccc2C(=O)c2cc(CCl)ccc21
Reactant: OCCO
Solvent: ClC(Cl)Cl
Product: O=C1c2ccccc2C(=O)c2cc(COCCO)ccc21
Temperature: 160 °C
Reaction time: 14 h

Procedure:
A suspension of 10.14 g of 2-chloromethylanthraquinone in 50 ml of ethylene glycol is stirred for 14 hours at 160° C. It is taken up in chloroform and the resulting solution is washed with water and saturated sodium chloride solution. Crystallization of the residue of the organic phase (12 g) from toluene gives 9.0 g of 2-(2'-hydroxyethoxy)methylanthraquinone with an m.p. of 129°-130° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8](=[O:30])[NH:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1.Br[CH2:32][CH2:33][O:34][CH3:35].C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([O:30][CH2:32][CH2:33][O:34][CH3:35])=[N:9][N:10]([C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:4]=2[CH:3]=1
Reactant: O=c1[nH]n(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COCCOc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12
Yield: 84 %

Procedure:
In a manner similar to that described in Example 1 (Step 1), 6-chloro-1-trityl-1H-pyrazolo[4,3-c]pyridin-3(2H)-one (3B) was treated with 1-bromo-2-methoxyethane and potassium carbonate (DMF, room temperature, overnight) to provide 6-chloro-3-(2-methoxyethoxy)-1-trityl-1H-pyrazolo[4,3-c]pyridine (84% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl.[CH:17]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([CH3:19])[CH3:18].[NH4+].[Cl-]>C(O)CCC>[CH:17]([N:20]1[CH2:25][CH2:24][N:23]([C:2]2[N:7]=[N:6][C:5]([C:8]3[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=3)=[CH:4][CH:3]=2)[CH2:22][CH2:21]1)([CH3:19])[CH3:18]
Reactant: N#Cc1ccc(-c2ccc(Cl)nn2)cc1
Reactant: CC(C)N1CCNCC1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCO
Product: CC(C)N1CCN(c2ccc(-c3ccc(C#N)cc3)nn2)CC1
Yield: 70.1 %

Procedure:
To a solution of 4-(6-chloro-pyridazin-3-yl)-benzonitrile (20 g, 92.8 mmol) in 1-butanol (150 mL) was added 1-isopropyl-piperazine hydrochloride (29.8 g, 148.5 mmol) and NH4Cl (4.96 g, 92.8 mmol). The reaction mixture was heated at reflux for 48 h and then concentrated under reduced pressure. The residue was dissolved into a 10% solution of citric acid in water and filtered. Solid K2CO3 was added to the filtrate until pH 9. The precipitate was isolated and washed with water to give 4-[6-(4-isopropyl-piperazin-1-yl)-pyridazin-3-yl]-benzonitrile (20 g, 70%).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:7]([Cl:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([NH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:11].Br[C:20]1[S:21][CH:22]=[C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:24]=1>>[Cl:2][C:3]1[C:7]([Cl:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([NH:12][CH:13]1[CH2:18][CH2:17][N:16]([C:20]2[S:21][CH:22]=[C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:24]=2)[CH2:15][CH2:14]1)=[O:11]
Reactant: CCOC(=O)c1csc(Br)n1
Reactant: Cc1[nH]c(C(=O)NC2CCNCC2)c(Cl)c1Cl
Agent: Cl
Product: CCOC(=O)c1csc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)n1

Procedure:
The title compound was prepared in a manner analogous to Example 320 from 3,4-dichloro-5-methyl-N-piperidin-4-yl-1H-pyrrole-2-carboxamide hydrochloride (intermediate 1) and ethyl 2-bromo-1,3-thiazole-4-carboxylate (commercially available).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH3:19].[CH:20]1([C:26](Cl)=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH3:19])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:26]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:27])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CCCN
Reactant: O=C(Cl)C1CCCCC1
Product: Cc1nc2c(N)nc3ccccc3c2n1CCCNC(=O)C1CCCCC1
Yield: 46.8 %

Procedure:
Using the general method of Example 195 except that the acid chloride was added in a dropwise fashion, 1-(3-aminopropyl)-2-methy-1H-imidazo[4,5-c]quinolin-4-amine (2.00 g, 7.83 mmol) was reacted with cyclohexanecarbonyl chloride (1.14 g, 7.83 mmol) to provide 1.34 g of N-[3-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]cyclohexanecarboxamide as a white powder, m.p. 234.4-235.4° C. Analysis: Calculated for C21H27N5O: % C, 69.01; % H, 7.45; % N, 19.16. Found: % C, 68.70; % H, 7.39; % N, 19.24.