Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[NH2:11][C:12]1[S:13][C:14]([C:17]2[CH2:24][S:23][CH:22]3[N:19]([C:20](=[O:33])[CH:21]3[NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:18]=2[C:34]([O:36][CH:37]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])=[CH:15][N:16]=1.C(N(CC)CC)C.C(OCC)(=O)C>O1CCCC1>[CH:37]([O:36][C:34]([C:18]1[N:19]2[CH:22]([S:23][CH2:24][C:17]=1[C:14]1[S:13][C:12]([NH:11][C:2](=[O:9])[C:3]3[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=3)=[N:16][CH:15]=1)[CH:21]([NH:25][C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[C:20]2=[O:33])=[O:35])([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(N)s3)CSC12
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(NC(=O)c4cccnc4)s3)CSC12
Temperature: 3 °C
Reaction time: 1 h
Yield: 55.2 %

Procedure:
Nicotinoyl chloride hydrochloride (7.12 g) is added to a solution of 3-(2-aminothiazol-5-yl)-2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (11.3 g) in tetrahydrofuran (300 cc), cooled to 3° C., and triethylamine (11.12 cc) is then added in the course of 10 minutes. The mixture is stirred for 1 hour at 3° C. and then for 2 hours while allowing the temperature to ri$e to 20° C. The reaction mixture is poured into ethyl acetate (400 cc) and washed with distilled water (3×120 cc) and a saturated solution of sodium chloride (100 cc). The organic phase is dried and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue is crystallised from ethyl acetate (20 cc) to give 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-(2-nicotinoylaminothiazol-5-yl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (7.4 g) in the form of a yellow solid.
Reaction SMILES: [CH2:1]([C:7]1[C:8](/[CH:21]=[CH:22]/[C:23]2[S:27][C:26]([C:28]([O:30]C)=[O:29])=[CH:25][CH:24]=2)=[CH:9][C:10]2[C:11]([CH3:20])([CH3:19])[CH2:12][CH2:13][C:14]([CH3:18])([CH3:17])[C:15]=2[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH-].[K+].C1COCC1.Cl>C(O)C.O>[CH2:1]([C:7]1[C:8](/[CH:21]=[CH:22]/[C:23]2[S:27][C:26]([C:28]([OH:30])=[O:29])=[CH:25][CH:24]=2)=[CH:9][C:10]2[C:11]([CH3:19])([CH3:20])[CH2:12][CH2:13][C:14]([CH3:18])([CH3:17])[C:15]=2[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1cc2c(cc1/C=C/c1ccc(C(=O)OC)s1)C(C)(C)CCC2(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CCCCCCc1cc2c(cc1/C=C/c1ccc(C(=O)O)s1)C(C)(C)CCC2(C)C
Temperature: 45 °C
Reaction time: 2.5 h
Yield: 90.7 %

Procedure:
A solution of 1.084 g of methyl (E)-5-[2-(3-hexyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-vinyl]-thiophene-2-carboxylate (from Example 8.1) in 15 ml ethanol was treated with a solution of 2.77 g KOH in 8 ml H20, followed by the addition of 7 ml THF. The mixture was stirred at 45° C. for 2.5 hours. The reaction mixture was diluted with 40 ml water and acidified to pH 2 with HCl 25%. The mixture was extracted with 4 portions of 50 ml of ethyl acetate. The combined extracts were washed with 50 ml water and 50 ml of aqueous saturated sodium chloride solution. Drying (MgSO4), filtration and concentration in vacuo gave a pale yellow solid. Trituration in pentane and filtration afforded 952 mg of the title product as a pale yellow solid. M.p. 164-165° C.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[CH:14]=[O:15].Br[CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21].[Mg]>C(OCC)C.COCCOCCOC.C(Cl)Cl>[CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[CH:14]([OH:15])[CH2:21][CH2:20][CH2:19][CH:18]=[CH2:17]
Reactant: C=CCCCBr
Reactant: O=Cc1ccc2c(c1)Cc1ccccc1-2
Agent: [Mg]
Solvent: COCCOCCOC
Solvent: CCOCC
Solvent: ClCCl
Product: C=CCCCC(O)c1ccc2c(c1)Cc1ccccc1-2
Reaction time: 0.5 h

Procedure:
2-Fluorenecarboxaldehyde (3 g) was dissolved in a mixture of anhydrous diethyl ether (30 ml) and anhydrous diglyme (5 ml) and was reacted with a grignard prepared from 5-bromopentene and magnesium, as described for example 23. The mixture was stirred for 30 min and a precipitate filtered off and washed with diethyl ether to give a white powder. The powder was dissolved in DCM and washed with saturated NH4Cl and water. Evaporation gave an oil which rapidly solidified. Column chromatography gave the title compound as a white solid. δC (CDCl3, 62.9 MHz): 25.2, 33.7, 36.9, 38.7, 74.8, 114.8, 119.8, 119.9, 122.6, 124.7, 125.1, 126.7, 126.8, 138.7, 141.2, 141.5, 143.4, 143.6 and 143.6.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:20])[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:21][O:22][CH2:23][CH2:24][N:25]1[CH:29]=[CH:28][C:27]([NH2:30])=[N:26]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:20])[C:8]([NH:30][C:27]2[CH:28]=[CH:29][N:25]([CH2:24][CH2:23][O:22][CH3:21])[N:26]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COCCn1ccc(N)n1
Reactant: O=C(O)[C@H](CC1CCCC1)N1Cc2ccccc2C1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCn1ccc(NC(=O)[C@H](CC2CCCC2)N2Cc3ccccc3C2=O)n1
Temperature: 25 °C
Yield: 64.1 %

Procedure:
To a solution of (S)-3-cyclopentyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (100 mg, 0.37 mmol) and 1-(2-methoxy-ethyl)-1H-pyrazol-3-ylamine (prepared as in US 20080021032, Example 72, 0.054 g, 0.38 mmol) and benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (Chemimpex, 0.19 g, 0.44 mmol) in methylene chloride (5 mL) was added N,N-diisopropylethylamine (0.19 mL, 1.1 mmol) dropwise and the resulting solution stirred at room temperature over night. The solution was diluted with methylene chloride, washed with a 1 N hydrochloric acid solution (15 mL), a saturated sodium chloride solution (20 mL) dried over magnesium sulfate. The mixture was filtered and evaporated and the resulting material purified via automated flash chromatography (Analogix, SF4-40 g column, 50-70% ethyl acetate/hexanes) to give (S)-3-cyclopentyl-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide (94 mg, 65%) as an off white solid: [α]29D=−62.6°, (C=0.31, chloroform); HR-ES(+) m/e calcd for C22H28N4O3 [M+Na]+ 419.2053, observed 419.2055; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.01-2.09 (m, 7H), 3.18 (s, 4H), 3.61 (t, J=5.28 Hz, 2H), 4.12 (t, J=5.13 Hz, 2H), 4.38-5.23 (m, 4H), 6.37 (d, J=2.11 Hz, 1H), 7.32-7.84 (m, 7H), 10.84 (s, 1H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].Cl[S:27]([C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33]([OH:35])=[O:34])(=[O:29])=[O:28]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([S:27]([C:30]4[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=4)[C:33]([OH:35])=[O:34])(=[O:29])=[O:28])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4cccc(C(=O)O)c4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 3-(chlorosulfonyl)benzoic acid as starting compounds. Instead of using the work-up procedure described for GP1, the following procedure is used. After the reaction has been quenched with 1 M aqueous sodium carbonate solution, the phases are separated and the aqueous phase is slightly acidified with aqueous hydrochloric acid.
Reaction SMILES: [N:1]1([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][CH2:5][CH:4]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1.F[C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:16]([O:15][C:13]([N:1]1[CH2:6][CH2:5][CH:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=3)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: N#Cc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCNCC2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C2CCN(c3ccc(C#N)cc3)CC2)CC1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
A solution of tert-butyl 4,4′-bipiperidine-1-carboxylate (181 mg; 0.674 mmol) in DMF (3 mL) was treated with 4-fluorobenzonitrile (98 mg; 0.809 mmol) and cesium carbonate (264 mg; 0.809 mmol). The mixture was stirred at 70° C. for 18 hr. The mixture was partitioned between isopropyl acetate (25 mL) and pH7 phosphate buffer (10 mL). The organic was washed twice more with pH7 phosphate buffer (2×10 mL). The organic was dried over magnesium sulfate, filtered and evaporated to a solid. The crude product was chromatographed over silica gel (PTLC; 2:1 hex/MTBE). The major band was recovered affording the title compound. LRMS calc: 369.2 obs: 370.1 (M+H), 270.1 (M-BOC+H).
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([BH3-])#N.[Na+].[BH4-].[Na+]>CC#N.C1COCC1.C(O)(=O)C>[CH2:17]([NH:10][CH2:9][CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccccc1
Reactant: NCCC(c1ccccc1)c1ccccc1
Agent: [BH3-]C#N
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: c1ccc(CNCCC(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3,3-diphenylpropylamine (1.01 g, 4.79 mmol), acetic acid (28 ml, 049 mmol), and benzaldehyde (490 μl, 4.80 mmol) in CH3CN (2 ml) was added sodium cyanoborohydride (4.80 ml of a 1 M solution in THF, 4.8 mmol) at 0° C. The reaction was allowed to warm to room temperature and stirred for 18 hrs. The solvent was evaporated in vacuo, quenched with sat. aq. NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4) and the solvent evaporated in vacuo. The residue was dissolved in MeOH (100 ml) and sodium borohydride (182 mg, 5.55 mmol) added and the reaction was stirred for 30 min. The solvent was evaporated and the residue treated with sat. aq. NaHCO3 and extracted with EtOAc. The organic layer was separated, washed with saturated brine, dried (Na2SO4) and the solvent evaporated in vacuo to afford the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]([NH2:29])=[N:13][CH2:14][CH2:15][CH2:16][C@H:17]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:18](O)=[O:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:30]CN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.[N:46]1([O:55][P+](N(C)C)(N(C)C)N(C)C)[C:50]2C=CC=CC=2N=N1>CN(C=O)C>[NH:21]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[C@H:17]([C:18]([N:46]([O:55][CH3:30])[CH3:50])=[O:19])[CH2:16][CH2:15][CH2:14][NH:13][C:12](=[NH:29])[NH:11][S:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)(=[O:10])=[O:9]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1ccc(S(=O)(=O)NC(N)=NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CON(C)C(=O)[C@H](CCCNC(=N)NS(=O)(=O)c1ccc(C)cc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 10 h
Yield: 70 %

Procedure:
To a suspension of Boc-Arg(Tos)--OH (2 g, 4.7 mmol) in DMF (20 mL) at 0° C. is added MeNHOMeHCl (1 g, 10.3 mmol), DIEA (6 mL) and BOP (2.5 g, 5.6 mmol). The solution is stirred at 0° C. for 10 hours. DMF is evaporated by vacuum. The oily residue is dissolved in EtOAc (200 mL) and water (20 mL). The organic layer is washed with sat. NaHCO3, water (20 mL), 1 M HCl (10 mL) and sat. NaCl (2×20 mL). The organic layer is dried over MgSO4, filtered and evaporated to give a suspension. The suspension is filtered, washed with cold EtOAc (10 mL) and dried to give Boc-Arg(Tos)-N(Me)OMe, shown above, (1.5 g, 70 % yield). FAB-MS (M+H)+=472
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][C:19]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)=[O:20])=[N:2]1.C([Li])CCC.C[CH:32]([OH:34])C.[Cl-].[NH4+].C1C[O:40]CC1>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][C:19]([C:21]2[S:22][CH:23]=[CH:24][C:25]=2[C:32]([OH:34])=[O:40])=[O:20])=[N:2]1
Reactant: CC(C)O
Reactant: O=C(Nc1ccccc1/C=C/c1n[nH]c2ccccc12)c1cccs1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Product: O=C(O)c1ccsc1C(=O)Nc1ccccc1/C=C/c1n[nH]c2ccccc12
Reaction time: 1 h
Yield: 44 %

Procedure:
To a solution of (E)-N-{2-[2-(1H-indazol-3-yl)vinyl]phenyl}thiophene-2-carboxamide (0.28 g, 0.81 mmol) obtained in Example 14 in THF (5.6 mL), n-butyllithium (2.7 mol/L n-hexane solution, 3.0 mL, 8.1 mmol) was added dropwise at −78° C. under nitrogen atomosphere, followed by stirring for 1.0 hour. Then, under carbon dioxide gas atmosphere, the mixture was stirred at −78° C. for 30 minutes and at 0° C. for 2.0 hours. The reaction mixture was added with 2-propanol and saturated aqueous ammonium chloride solution, extracted with ethyl acetate and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 80/20) to obtain (E)-2-{2-[2-(1H-indazol-3-yl)vinyl]phenylcarbamoyl}thiophene-3-carboxylic acid (0.14 g, 44%).
Reaction SMILES: Cl[CH:2]([NH:7][C:8](=[O:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][C:16](=[O:18])[CH3:17])[C:3]([Cl:6])([Cl:5])[Cl:4].[CH:20]1[C:25]([OH:26])=[CH:24][CH:23]=[C:22]([CH3:27])[CH:21]=1.C(N(CC)CC)C.O>CC(C)=O>[CH3:27][C:22]1[CH:21]=[CH:20][C:25]([O:26][CH:2]([NH:7][C:8](=[O:19])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:16](=[O:18])[CH3:17])[C:3]([Cl:6])([Cl:5])[Cl:4])=[CH:24][CH:23]=1
Reactant: Cc1ccc(O)cc1
Reactant: CC(=O)Oc1ccccc1C(=O)NC(Cl)C(Cl)(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(=O)Oc1ccccc1C(=O)NC(Oc1ccc(C)cc1)C(Cl)(Cl)Cl
Yield: 83.9 %

Procedure:
15.0 g of N-(1',2',2',2'-tetrachloroethyl)-2-acetoxybenzamide and 5.65 g of p-cresol were dissolved in 250 ml of acetone. 5.3 g of triethylamine were added dropwise thereto at a temperature below 12° C. After effecting the reaction at room temperature for 30 minutes, the reaction mixture was poured into water. 15.2 g of white N-(1'-p-methylphenoxy-2',2',2'-trichloroethyl)-2-acetoxybenzamide were obtained. The compound was suspended in 300 ml of ethanol, then 3.6 ml of concentrated hydrochloric acid were added thereto and the reaction was carried out at --60°-70° C. for three hours. After cooling, the reaction mixture was poured into water to obtain 14.3 g of N-(1'-p-methylphenoxy-2',2',2'-trichloroethyl)-2-hydroxbenzamide as white crystals. M.p. 126°-127° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:21]([O-])=O)=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]2[O:17][CH2:18][O:19][C:13]=2[CH:12]=1)=[O:8].C(O)(=O)C.O>[Fe].C(O)C>[NH2:21][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:20][C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]2[O:17][CH2:18][O:19][C:13]=2[CH:12]=1)=[O:8]
Reactant: O=C(NCc1ccc2c(c1)OCO2)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: Nc1ccc(Cl)cc1C(=O)NCc1ccc2c(c1)OCO2
Yield: 92.1 %

Procedure:
5-Chloro-N-(3,4-methylenedioxybenzyl)-2-nitrobenzamide (620 mg), acetic acid (1 ml), water (1 ml) and ethanol (20 ml) were mildly heated together under reflux, followed by the addition of 1.0 g of powdered iron in portions under stirring. The obtained mixture was refluxed for one hour and filtered under heating to remove brown insolubles. The filtrate was concentrated, followed by the addition of ethanol. The resulting mixture was dissolved by heating. Concentrated hydrochloric acid was added to the obtained solution in portions, by which the brown solution turned yellow and transparent. This yellow transparent solution was seeded to give crystals. The resulting mixture was cooled and filtered to recover the crystals. The crystals were washed with ethanol and ether and dried to give 520 mg of 2-amino-5-chloro-N-(3,4-methylenedioxybenzyl)benzamide.
Reaction SMILES: [CH2:1]([C:4]1([CH3:38])[C:10](=[O:11])[N:9]([CH2:12][C:13]([N:15]([CH:24]([CH3:26])[CH3:25])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[O:14])[C:8]2[CH:27]=[CH:28][CH:29]=[CH:30][C:7]=2[N:6]([C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)[C:5]1=[O:37])[CH:2]=C.I([O-])(=O)(=O)=[O:40].[Na+]>O1CCOCC1.[Os](=O)(=O)(=O)=O.O.CCOC(C)=O>[CH:24]([N:15]([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)[C:13](=[O:14])[CH2:12][N:9]1[C:10](=[O:11])[C:4]([CH3:38])([CH2:1][CH:2]=[O:40])[C:5](=[O:37])[N:6]([C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)[C:7]2[CH:30]=[CH:29][CH:28]=[CH:27][C:8]1=2)([CH3:26])[CH3:25]
Reactant: C=CCC1(C)C(=O)N(CC(=O)N(c2ccc(OC)cc2)C(C)C)c2ccccc2N(c2cccnc2)C1=O
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(N(C(=O)CN2C(=O)C(C)(CC=O)C(=O)N(c3cccnc3)c3ccccc32)C(C)C)cc1
Reaction time: 4 h
Yield: 103.5 %

Procedure:
To a stirring solution of 1.5 g (2.93 mmol) of 2-(3-Allyl-3-methyl-2,4-dioxo-5-pyridin-3-yl-2,3,4,5-tetrahydro benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-[4-methoxyphenyl]acetamide, prepared as in Part C, in 10 mL of dioxane and 10 mL of H2O at 0° C. is added 3.13 g (14.63 mmol, 2 equiv.) of sodium periodate followed by the addition of 2 drops of osmium tetroxide solution (4% in H2O). The resulting suspension is stirred for 4 h and then diluted with 200 mL H2O and 200 mL of EtOAc. The organic phase is washed with H2O (2×250 mL) and a solution of Na2S2O3 (10%) and then dried (MgSO4), and the solvents removed in vacuo. Purification by silica gel flash column chromatography using hexane/EtOAc 5/1 as eluent afforded 1.56 g of N-Isopropyl-N-[4-methoxyphenyl]-2-[3-methyl-2,4-dioxo-3-(2-oxo-ethyl)-5-pyridin-3-yl-2,3,4,5-tetrahydro benzo[b][1,4]diazepin-1-yl]acetamide as an oil: 1H NMR (CDCl3, 300 MHz) δ8.51 (m, 2H), 7.68 (d, 1H, J=9), 7.39-6.93 (m, 8H), 6.71 (d, 1H, J=8), 5.78-5.64 (m, 1H), 5.08-5.00 (m, 2H), 4.72 (d, 1H, J=16), 4.39 (d, 1H, J=17), 4.08 (m, 1H), 3.85 (s, 3H), 3.81-3.79 (m, 1H), 2.11 (d, 1H, J=8), 1.77 (s, 1H), 1.60 (s, 2H), 1.21-1.07 (m, 6H); low resolution MS (FAB)m/e 513 (MH+).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]([NH2:12])[C:6]3[N:13]=[CH:14][N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:5]=3[C:4]=2[CH:3]=1.[S:20]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21]1>>[CH2:16]([N:15]1[C:5]2[C:4]3[CH:3]=[C:2]([C:22]4[CH:23]=[CH:24][S:20][CH:21]=4)[CH:11]=[CH:10][C:9]=3[N:8]=[C:7]([NH2:12])[C:6]=2[N:13]=[CH:14]1)[CH:17]([CH3:19])[CH3:18]
Reactant: OB(O)c1ccsc1
Reactant: CC(C)Cn1cnc2c(N)nc3ccc(Br)cc3c21
Product: CC(C)Cn1cnc2c(N)nc3ccc(-c4ccsc4)cc3c21

Procedure:
8-Bromo-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and thiophene-3-boronic acid were coupled according to the general procedure described in Part J of Example 1. Recrystallization from isopropanol followed by chromatography on silica gel (7% methanol in CH2Cl2) afforded 1-isobutyl-8-(thiophen-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, m.p. 235-236° C.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.[NH2:15][C@@H:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][C:17]1([CH3:30])[CH3:29].CCN(C(C)C)C(C)C>CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]2[C:9]([NH:15][C@@H:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][C:17]3([CH3:30])[CH3:29])=[C:8]([C:11](=[O:12])[NH2:13])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C(C)(C)C1
Reactant: NC(=O)c1cnn2cc(Br)nc2c1Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC[C@@H](Nc2c(C(N)=O)cnn3cc(Br)nc23)C(C)(C)C1
Temperature: 90 °C
Yield: 88.5 %

Procedure:
To a solution of 2-bromo-8-chloroimidazo[1,2-b]pyridazine-7-carboxamide (170 mg, 0.617 mmol) and (R)-tert-butyl 4-amino-3,3-dimethylpiperidine-1-carboxylate (144 mg, 0.633 mmol) in DMF (1543 μl) was added DIEA (237 μl, 1.358 mmol). The reaction was heated at 90° C. for 2 hours. After cooling to room temperature, the reaction mixture was partitioned between water and ethyl acetate (100 ml). The ethyl acetate layer was washed with water (3×100 ml), dried with sodium sulfate, filtered, and concentrated under reduced pressure. The crude solid was purified via flash chromatography (ISCO silica gel column, 0-10% MeOH-DCM) to afford (R)-tert-butyl 4-((2-bromo-7-carbamoylimidazo[1,2-b]pyridazin-8-yl)amino)-3,3-dimethylpiperidine-1-carboxylate (255 mg, 0.546 mmol, 88% yield) as a faint yellow solid. ESI-MS (analytical LCMS Method A): m/z 467.0 ([M+H]+). HPLC (analytical HPLC Method A) Rt: 3.413 min.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH3:7][N:8]([CH3:42])[CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][N:20]([CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-])=O)=[CH:35][CH:34]=1)[C:21](=[O:30])[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[H][H]>C(O)C.[Pd]>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[NH2:39][C:36]1[CH:37]=[CH:38][C:33]([CH2:32][CH2:31][N:20]([CH2:19][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[O:12][CH2:11][CH2:10][CH2:9][N:8]([CH3:42])[CH3:7])[C:21](=[O:30])[CH:22]=[CH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:34][CH:35]=1
Reactant: [H][H]
Reactant: CN(C)CCCOc1ccccc1CN(CCc1ccc([N+](=O)[O-])cc1)C(=O)C=Cc1ccccc1
Agent: [Pd]
Agent: O=C(O)C(=O)O
Solvent: CCO
Product: CN(C)CCCOc1ccccc1CN(CCc1ccc(N)cc1)C(=O)C=Cc1ccccc1

Procedure:
A suspension of 10 parts of N-[[2-[3-(dimethylamino)-propoxy]phenyl]methyl]-N-[2-(4-nitrophenyl)ethyl]-3-phenyl-2-propenamide, oxalate salt (1:1) in 100 ml of ethanol is treated with 1 part of 5% palladium on carbon and placed under 3 atmospheres of gaseous hydrogen. The mixture is shaken until one equivalent of hydrogen is consumed, filtered and the solvent evaporated under reduced pressure to give the title compound.