Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[C:16]2[C:17]3=[C:18]4[C:13](=[CH:14][CH:15]=2)C=CC=[C:9]4[CH:8]=[CH:7][C:6]3=[CH:5][CH:4]=1)=[CH2:2].C([Li])CCC.CC[O:26][CH2:27][CH3:28]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[C:28]1([CH:27]=[O:26])[C:15]2[C:16]3=[C:17]4[C:18](=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=[C:6]4[CH:5]=[CH:4][C:3]3=[CH:1][CH:2]=1
Reactant: CCOCC
Reactant: C=Cc1ccc2ccc3cccc4ccc1c2c34
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccc2ccc3cccc4ccc1c2c34

Procedure:
The procedure used to prepare 1-vinylpyrene was similar to that of K. Tanikawa, T. Ishizuka, K. Suzuki, S. Kusabayashi, and H. Mikawa, Bull. Chem. Soc. Japan, 41, 2719-2722, (1968) Under an argon atmosphere, methyltriphenylphosphonium bromide (0.16 mole) was mixed with butyllithium (0.16 mole of 2.0 M butyllithium in pentane) in dry ether (660 ml.). After the ylid color was obtained (4-8 hr.), pyrene-1-carboxaldehyde (0.14 mole) in dry tetrahydrofuran (500 ml.) was added dropwise. The mixture was stirred overnight under an argon atmosphere. Ether was removed by evaporation under reduced pressure, and the remaining tetrahydrofuran solution was boiled under reflux for 1 hour. After evaporation to dryness under reduced pressure, the residue was dissolved in toluene and the resulting solution was washed with 30% aqueous sodium sulfite solution and water. Toluene was evaporated under reduced pressure to precipitate the crude product, which, after dissolving in hot ethanol and treatment with charcoal, allowed 1-vinylpyrene to crystallize as a yellow powder (53% yield), m. p. 88°-89° C. (lit 88°-89° C.). The structure was confirmed by proton NMR.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[O:24][CH3:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1>>[F:23][C:22]1[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[O:5])[N:7]=[CH:8]3)[CH:12]=2)=[C:18]([O:24][CH3:25])[CH:19]=[CH:20][CH:21]=1
Reactant: Brc1ccccn1
Reactant: COc1cccc(F)c1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Product: COc1cccc(F)c1-c1cccc(-n2cnc(C(=O)c3ccccn3)c2)c1

Procedure:
This compound is prepared by method C using compound 12g and 2-bromopyridine
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].N[C@H](C(O)=O)[CH2:12][CH2:13][C:14](O)=[O:15]>>[C:14]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])(=[O:15])[CH:13]=[CH2:12]
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Reactant: NCCCCCC(=O)O
Product: C=CC(=O)NCCCCCC(=O)O
Yield: 85 %

Procedure:
Using the same procedure as previously described except substituting 6-aminocaproic acid for the glutamic acid, the crude product was obtained in greater than 85% yield. After crystallization from water or ethyl acetate, the white, crystalline N-acryloyl-6-aminocaproic acid had a melting point of 88°-90° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=[C:10]([C:20]([OH:22])=O)[N:9]=2)=[CH:4][CH:3]=1.[F:23][C:24]([F:33])([F:32])[C:25]1[CH:29]=[C:28]([CH2:30][NH2:31])[O:27][N:26]=1>>[F:33][C:24]([F:23])([F:32])[C:25]1[CH:29]=[C:28]([CH2:30][NH:31][C:20]([C:10]2[N:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:13]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])=[CH:12][N:11]=2)=[O:22])[O:27][N:26]=1
Reactant: NCc1cc(C(F)(F)F)no1
Reactant: O=C(O)c1ncc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)n1
Product: O=C(NCc1cc(C(F)(F)F)no1)c1ncc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyrimidine-2-carboxylic acid (example AA) and 3-trifluoromethyl-isoxazol-5-methanamine (example BA) as starting materials; MS: 481.0 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[Br:15][C:16]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:19]2[N:20]([CH3:26])[C:21]([CH2:23][CH2:24]Cl)=[N:22][C:18]=2[CH:17]=1.[OH-].[Na+].O>CO>[Br:15][C:16]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:19]2[N:20]([CH3:26])[C:21]([CH2:23][CH2:24][N:11]3[CH2:12][CH2:13][N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:9][CH2:10]3)=[N:22][C:18]=2[CH:17]=1
Reactant: Cn1c(CCCl)nc2cc(Br)c3ccccc3c21
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1c(CCN2CCN(Cc3ccccc3)CC2)nc2cc(Br)c3ccccc3c21

Procedure:
4 cc (0.022 mole) of 1-benzylpiperazine is added to a solution of 7.2 g (0.02 mole) of 5-bromo-2-(2-chloroethyl)-1-methyl-1H-naphth[1,2-d]imidazole hydrochloride and 40 cc (0.04 mole) of 1 N NaOH in 100 cc of hot methanol, and the obtained reaction mixture is heated under an argon atmosphere at reflux temperature for several hours. When the reaction, which is followed by thin layer chromatography, is completed, the solvent is boiled off and the obtained residue is taken up with a small amount of water, filtered and dried. Yield 8.87 g. M.p. 155°-157° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:16][CH:15]3[CH:11]([CH2:12][NH:13][CH2:14]3)[CH2:10]2)[N:3]=1.[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[C:21]([CH3:28])[CH:20]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:16][CH:15]3[CH2:14][N:13]([C:23]([C:22]4[CH:26]=[CH:27][C:19]([O:18][CH3:17])=[CH:20][C:21]=4[CH3:28])=[O:24])[CH2:12][CH:11]3[CH2:10]2)[N:3]=1
Reactant: COc1ccc(C(=O)O)c(C)c1
Reactant: Cc1cc(C)nc(N2CC3CNCC3C2)n1
Product: COc1ccc(C(=O)N2CC3CN(c4nc(C)cc(C)n4)CC3C2)c(C)c1

Procedure:
The title compound was prepared in a manner analogous to Example 15, utilizing Intermediate 23 and 4-methoxy-2-methylbenzoic acid. MS (ESI): mass calculated for C21H26N4O2, 366.21; m/z found 367.3 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.11 (d, J=7.9, 1H), 6.77-6.67 (m, 2H), 6.29 (s, 1H), 4.01-3.83 (m, 2H), 3.83-3.72 (m, 4H), 3.72-3.55 (m, 2H), 3.46 (dt, J=11.9, 6.0, 2H), 3.21-2.89 (m, 3H), 2.37-2.25 (m, 9H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH2:21][CH2:22][CH3:23].[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>N1C=CC=CC=1>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH2:21][CH2:22][CH3:23])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Solvent: c1ccncc1
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)c1ccccc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
1-(4-Aminobutyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (0.5 g, 1.6 mmol) was combined with pyridine (50 mL) and heated to 50° C. Benzoyl chloride (0.22 g, 1.6 mmol) was added via a pipette. After 1 hour analysis by HPLC indicated that all of the starting material was gone and that several products had formed. The reaction mixture was concentrated under vacuum. The residue was combined with dichloromethane and aqueous sodium bicarbonate. The organic layer was separated and then concentrated under vacuum. The residue was dissolved in dichloromethane and placed on a silica gel column. The column was eluted with 5% methanol in dichloromethane and then with 10% methanol in dichloromethane. The 10% methanol in dichloromethane fractions were combined and concentrated under vacuum to provide N1-[4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]benzamide as a solid, m.p. 174-175° C. 1H NMR (500 MHz, DMSO-d6) δ 8.48 (t, J=6.0 Hz, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.78 (d, J=8.0 Hz, 2H), 7.60 (d, J=8.0 Hz, 1H), 7.50 (t, J=8.0 Hz, 1H), 7.43 (t, J=8.0 Hz, 2H), 7.39 (t, J=8.0 Hz, 1H), 7.18 (t, J=8.0 Hz, 1H), 6.50 (broad s, 2H), 4.54 (t, J=7.0 Hz, 2H), 3.32 (m, 2H), 2.91 (t, J=7.0 Hz, 2H), 1.86 (quintet, J=7.0 Hz, 2H), 1.77 (quintet, J=7.0 Hz, 2H), 1.70 (quintet, J=7.0 Hz, 2H), 1.41 (sextet, J=7.0 Hz, 2H), 0.91 (t, J=7.0 Hz, 3H); MS (CI) m/e 416 (M+H).
Reaction SMILES: [CH3:1][Li].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:19]3[C:14](=[CH:15][C:16]([O:20][CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])=[CH:17][CH:18]=3)[C:13](=O)[C:12]([CH3:28])([CH3:27])[CH2:11]2)=[CH:6][CH:5]=1.O>CCOCC>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:19]3[C:14](=[CH:15][C:16]([O:20][CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])=[CH:17][CH:18]=3)[C:13](=[CH2:1])[C:12]([CH3:28])([CH3:27])[CH2:11]2)=[CH:6][CH:5]=1
Reactant: CN(C)CCOc1ccc2c(c1)C(=O)C(C)(C)CC2c1ccc(Cl)cc1
Reactant: [Li]C
Solvent: O
Solvent: CCOCC
Product: C=C1c2cc(OCCN(C)C)ccc2C(c2ccc(Cl)cc2)CC1(C)C

Procedure:
An ethereal solution of methyllithium (50 ml, 1.9 M) was added over 45 min. to a stirred solution of 4-(4-chlorophenyl)-2,2-dimethyl-7-(2-dimethylaminoethoxy)-1-tetralone (18.5 g) in dry ether (150 ml) and the mixture heated under reflux for 30 min. After cooling, excess methyllithium was decomposed with water, the ether layer was separated, dried (MgSO4) and treated with a solution of hydrogen chloride in ether. The hydrochloride salt of 4-(4-chlorophenyl)-2,2-dimethyl-7-(2-dimethylaminoethoxy)-1-methylidene tetralin precipitated as a white solid (15.6 g, 77%). A portion was recrystallized from ethanol-ether, m.p. 233°-235°.
Reaction SMILES: [OH-:1].[Na+].Cl.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](=O)[CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH:15]2[C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[CH:7][CH:6]=1.[BH4-].[Na+]>C(O)C.O>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:1])[CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH:15]2[C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[CH:7][CH:6]=1
Reactant: O=C(Cc1ccc(Cl)cc1)CN1CCC(O)CC1c1ccc(Cl)cc1
Reactant: [OH-]
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OC1CCN(CCC(O)c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)C1
Temperature: 50 °C
Yield: 100.4 %

Procedure:
To a solution containing 1.2 g (0.03 mol) of sodium hydroxide in 50 ml of an 50% by volume ethanol/water mixture, 12.41 g (0.03 mol) of 1-(4-chlorophenyl)-3-[4-hydroxy-(4-chlorophenyl)-1-piperidyl]propanone hydrochloride and then, over 1 hour 1.17 g of sodium borohydride are added. The suspension is heated at a temperature of 50° C. for 2 hours. After cooling down, the reaction mixture is filtered and washed with water to give 11.45 g of product, m.p.: 129°-132° C. After recrystallization of the latter product from 215 ml of acetonitrile, 9.1 g of title compound are obtained.
Reaction SMILES: [OH-:1].[Na+].[Cl-].[CH3:4][C:5]1([CH3:24])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14](=[O:22])C[N+]3C=CC=CC=3)[CH:12]=2)[NH:7][C:6]1=[O:23].Cl>O>[CH3:24][C:5]1([CH3:4])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([OH:22])=[O:1])[CH:12]=2)[NH:7][C:6]1=[O:23]
Reactant: CC1(C)C(=O)Nc2ccc(C(=O)C[n+]3ccccc3)cc21
Reactant: [OH-]
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CC1(C)C(=O)Nc2ccc(C(=O)O)cc21
Reaction time: 1.5 h
Yield: 73.2 %

Procedure:
To a solution of sodium hydroxide (14 g) in water (480 ml) was added 1-[2-(2,3-dihydro-3,3-dimethyl-2-oxoindol-5-yl)-2-oxoethyl]pyridinium chloride (44.3 g) and the mixture was stirred for 1.5 hours at 80° to 85° C. After cooling, the reaction mixture was acidified with conc. hydrochloric acid. The residual crystal was collected by filtration, washed with water and dried to give 2,3-dihydro-3,3-dimethyl-2-oxoindole-5-carboxylic acid (21 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:15]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:5]=[C:6]([Cl:14])[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.[F-].[Cs+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:14][C:6]1[CH:5]=[C:4]([CH:15]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:3]=[C:2]([C:30]2[CH:31]=[CH:32][C:27]([C:26]([F:37])([F:36])[F:25])=[CH:28][CH:29]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11]
Reactant: CCOC(=O)C(CC(C)C)c1cc(Cl)c(OCC(F)(F)F)c(Br)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: CCOC(=O)C(CC(C)C)c1cc(Cl)c(OCC(F)(F)F)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
A mixture of ethyl 2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate (1 g, 1 eq), 4-Trifluoromethyl phenylboronic acid (2.6 g, 1.4 eq), Pd(PPh3)4 (1.3 g, 0.1 eq) and Cesium Fluoride (13.1 g, 2 eq) in DME (30 ml) was stirred for overnight at 100° C. Upon completion, the precipitate was removed by filtration. The filtrate was diluted with water and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with water followed by brine, dried over Na2SO4 and concentrated under vacuo. The residue was purified by Flash Column Chromatography to give ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate in 74% yield (1.08 g). 1H NMR (CDCl3, 400 MHz): 7.68 (m, 5H), 7.43 (s, 1H); 7.24 (s, 1H); 4.4 (q, 2H), 4.13 (q, 2H); 3.55 (t, 1H); 1.93 (m, 1H), 1.58 (m, 1H); 1.45 (m, 1H); 1.24 (t, 3H), 0.92 (d, 6H);
Reaction SMILES: [C:1]([NH:7][C@@H:8]1[C:13](=[O:14])[O:12][C:10](=[O:11])[CH2:9]1)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C[O:16][C:17](=[O:27])[C@H:18]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH2:19]>>[C:1]([NH:7][C@H:8]([C:13]([NH:19][C@H:18]([C:17]([OH:27])=[O:16])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:14])[CH2:9][C:10](=[O:11])[OH:12])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: CC(=O)CC(=O)N[C@H]1CC(=O)OC1=O
Product: CC(=O)CC(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
reacting the resulting N-acetoacetyl-L-aspartic acid anhydride with L-phenylalanine methyl ester to form N-acetoacetyl-α-L-aspartyl-L-phenylalanine and
Reaction SMILES: [OH:1][NH:2][C:3](=[O:9])[CH2:4][CH2:5][C:6](N)=[O:7].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.[CH3:29][C:30]1([CH2:35][CH2:36][C:37](O)=[O:38])[O:34][CH2:33][CH2:32][O:31]1>ClCCl>[CH3:29][C:30]1([CH2:35][CH2:36][C:37]([O:1][N:2]2[C:6](=[O:7])[CH2:5][CH2:4][C:3]2=[O:9])=[O:38])[O:34][CH2:33][CH2:32][O:31]1
Reactant: NC(=O)CCC(=O)NO
Reactant: CC1(CCC(=O)O)OCCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC1(CCC(=O)ON2C(=O)CCC2=O)OCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.5 %

Procedure:
N-Hydroxysuccinamide (0.80 g, 6.9 mmol) followed by 4-methylmorpholine (0.70 g, 6.9 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (1.32 g, 6.9 mmol) were added to a 0° C. solution of 3-(2-methyl-1,3-dioxolan-2-yl)propanoic acid (1.00 g, 6.24 mmol) in dichloromethane (12 mL). The solution was allowed to warm to room temperature and was stirred overnight. The reaction mixture was diluted with dichloromethane (10 mL), transferred to a separatory funnel, and washed with water (2×10 mL), saturated aqueous sodium bicarbonate (2×10 mL), and brine (10 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 1.1 g of 1-{[3-(2-methyl-1,3-dioxolan-2-yl)propanoyl]oxy}pyrrolidine-2,5-dione as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]2[S:6][C:7]([C:10]3[N:14]4[N:15]=[C:16]([CH3:26])[CH:17]=[C:18]([C:19]([CH2:23][CH2:24][CH3:25])=[CH:20][CH2:21][CH3:22])[C:13]4=[N:12][C:11]=3[CH3:27])=[C:8]([CH3:9])[C:4]=2[CH:3]=1>[Pd].CO>[F:1][C:2]1[CH:29]=[CH:28][C:5]2[S:6][C:7]([C:10]3[N:14]4[N:15]=[C:16]([CH3:26])[CH:17]=[C:18]([CH:19]([CH2:20][CH2:21][CH3:22])[CH2:23][CH2:24][CH3:25])[C:13]4=[N:12][C:11]=3[CH3:27])=[C:8]([CH3:9])[C:4]=2[CH:3]=1
Reactant: CCC=C(CCC)c1cc(C)nn2c(-c3sc4ccc(F)cc4c3C)c(C)nc12
Agent: [Pd]
Solvent: CO
Product: CCCC(CCC)c1cc(C)nn2c(-c3sc4ccc(F)cc4c3C)c(C)nc12
Yield: 83.4 %

Procedure:
A solution of 3-(5-fluoro-3-methyl-benzo[b]thiophen-2-yl)-2,6-dimethyl-8-(1-propyl-but-1-enyl)-imidazo[1,2-b]pyridazine (23 mg, 0.06 mmol), MeOH (19 mL), and 10% Pd—C (69 mg) is hydrogenated at 30 psi at room temperature for 2 hours. The mixture is filtered through celite, washed with EtOAC and concentrated to dryness to give the title compound (20.5 mg, 89%) %). 1H NMR (CDCl3): δ 7.8 (dd, J=4.8, 8.5 Hz, 1H), 7.5 (dd, J=2.5, 9.7 Hz, 1H), 7.2 (m, 1H), 6.9 (s, 1H), 3.69 (s, 1H), 2.62 (s, 3H), 2.58 (s, 3H), 2.4 (m, 2H), 2.3 (s, 3H), 1.8 (m, 4H), 1.29 (m, 4H), 0.93 (t, J=7.1, 6H) ppm. Mass spectrum (m/e): 410 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([C:10](O)([CH3:12])[CH3:11])=[C:4]([O:14][CH3:15])[CH:3]=1>C(Cl)(Cl)Cl>[C:10]([C:5]1[C:6]([O:8][CH3:9])=[CH:7][C:2]([NH2:1])=[CH:3][C:4]=1[O:14][CH3:15])([CH3:12])=[CH2:11]
Reactant: COc1cc(N)cc(OC)c1C(C)(C)O
Solvent: ClC(Cl)Cl
Product: C=C(C)c1c(OC)cc(N)cc1OC

Procedure:
A solution of 2-(4-Amino-2,6-dimethoxy-phenyl)-propan-2-ol (2.2 g, 10.4 mmol) in chloroform (100 mL) was refluxed overnight. The cooled reaction mixture was concentrated under reduced pressure to yield 4-Isopropenyl-3,5-dimethoxy-phenylamine, which was used directly in the following step.
Reaction SMILES: ClC1N=C(N2CCOCC2)C2SC(C3C=C(C=CC=3)[C:14](O)=[O:15])=CC=2N=1.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([CH:14]=[O:15])[CH2:29][CH2:28]1
Reactant: O=C(O)c1cccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1
Reactant: CN1CCNCC1
Product: CN1CCN(C=O)CC1

Procedure:
3-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzoic acid (60 mg) was reacted with 1-methylpiperizine via General Procedure B to yield 3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)(4-methylpiperazin-1-yl)methanone. Crude 3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)(4-methylpiperazin-1-yl)methanone (71 mg) was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A to yield 22.4 mg of 339. MS (Q1) 540.1 (M)+
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[N:16]=[N:17][C:18](Cl)=[CH:19][CH:20]=1.CCN(C(C)C)C(C)C>C(O)(C)(C)C>[Cl:14][C:15]1[N:16]=[N:17][C:18]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)=[CH:19][CH:20]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Cl)nn2)CC1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 63.3 %

Procedure:
In a microwave vial were mixed: 1,1-dimethylethyl 1-piperazinecarboxylate (135 mg, 0.725 mmol, available from Fluke), 3,6-dichloropyridazine (90 mg, 0.604 mmol, available from Alfa Aesar) and DIPEA (0.137 mL, 0.785 mmol) in Tert-Butanol (2 mL). The reaction was stirred and heated in an Emrys Optimizer microwave at 100° C. for 20 mins then for 30 mins at 150° C. The reaction mixture was partitioned between EtOAc (20 mL) and water (20 mL) and the organic layer washed with brine (20 mL) before being dried through an hydrophobic frit and concentrated. The residue was dissolved in DCM and purified by SP4 on a 12+M silica cartridge using a gradient of 10-50% EtOAc in cyclohexane. The appropriate fractions were collected and concentrated to yield the desired product as a white solid, 1,1-dimethylethyl 4-(6-chloro-3-pyridazinyl)-1-piperazinecarboxylate (114.2 mg). LCMS (Method C): Rt=0.85, MH+=299
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[NH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[C:17](=[O:19])[N:16]([CH3:20])[CH2:15]2.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:9][C:10]1[CH:11]=[CH:12][C:13]([Br:8])=[C:14]2[C:18]=1[C:17](=[O:19])[N:16]([CH3:20])[CH2:15]2
Reactant: O=C1CCC(=O)N1Br
Reactant: CN1Cc2cccc(N)c2C1=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CN1Cc2c(Br)ccc(N)c2C1=O
Reaction time: 1 h
Yield: 73.6 %

Procedure:
NBS (2.3 g, 12.96) was added to a cold (−8° C. to −10° C.) solution of 7-amino-2-methyl-2,3-dihydro-1H-isoindol-1-one (2 g, 12.4 mmol) in DCM (40 mL) and the mixture stirred at −8° C. to −10° C. for 1 h. A solution of 10% aq. sodium thiosulfate (30 mL) was then added to the reaction mixture and stirring was continued for another 20 minutes. The layers were separated and the aqueous layer was extracted with DCM (2×20 mL). The combined organic extracts were washed with water (3×40 mL) and brine (30 mL), and the organic layer was dried (Na2SO4) and concentrated in vacuo to yield 3.2 g of crude product. This material was triturated with ethyl acetate (10 mL) to give 2.2 g of pure 7-amino-4-bromo-2-methyl-2,3-dihydro-1H-isoindol-1-one (XXXIX, yield: 74%).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:19]([O-:21])=[O:20])=[C:6]([NH:8][CH:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]([CH3:12])[CH3:11])[CH:7]=1.[C:22]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:11][CH:10]([CH3:12])[CH:9]([NH:8][C:6]1[CH:7]=[C:2]([N:32]2[CH2:31][CH2:30][N:29]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:34][CH2:33]2)[CH:3]=[CH:4][C:5]=1[N+:19]([O-:21])=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)C(Nc1cc(F)ccc1[N+](=O)[O-])c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)C(Nc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-])c1ccccc1
Yield: 86.9 %

Procedure:
A solution of 5-fluoro-N-(2-methyl-1-phenylpropyl)-2-nitrobenzenamine (1.79 g, 6.2 mmol), N-Boc-piperazine (1.16 g, 6.2 mmol) and N,N-diisopropylethylamine (2.2 mL, 12.4 mmol) in acetonitrile was stirred at reflux for 24 h. The reaction mixture was cooled down and concentrated under reduced pressure. The residue was taken up in dichloromethane, washed with water, dried and concentrated in vacuo to yield 2.45 g of the crude aniline. The crude product was purified by PTLC (15% ethyl acetate in hexanes) to yield 1.75 g (62%) of tert-butyl 4-(3-(2-methyl-1-phenylpropylamino)-4-nitrophenyl)piperazine-1-carboxylate: 1H NMR (400 MHz, CD3OD): δ 9.01 (br d, 1H), 7.96 (dd, 1H), 7.33-7.32 (m, 4H), 7.25-7.24 (m, 1H), 6.27 (br d, 1H), 5.72 (s, 1H), 4.40 (t, 1H), 3.42-3.34 (m, 4H), 3.27-3.23 (m, 2H), 3.16-3.11 (m, 2H), 2.13 (m, 1H), 1.07 (d, 3H), 0.96 (d, 3H). MS (ESI) m/z: Calculated: 454.26; Observed: 477.3 (M++Na).