Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:54])[C:3](=[O:53])[C:4]([N:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][NH:14][C@:15]23[CH2:49][CH2:48][C@@H:47]([C:50]([CH3:52])=[CH2:51])[C@@H:16]2[C@@H:17]2[C@@:30]([CH3:33])([CH2:31][CH2:32]3)[C@@:29]3([CH3:34])[C@@H:20]([C@:21]4([CH3:46])[C@@H:26]([CH2:27][CH2:28]3)[C:25]([CH3:36])([CH3:35])[C:24]([C:37]3[CH:45]=[CH:44][C:40]([C:41]([OH:43])=[O:42])=[CH:39][CH:38]=3)=[CH:23][CH2:22]4)[CH2:19][CH2:18]2)[CH2:8][CH2:7]1)=[O:5].O=C(N1CC[CH2:63][CH2:62][CH2:61]1)C(O)=O>>[CH3:33][C@:30]12[C@@:29]3([CH3:34])[C@@H:20]([C@:21]4([CH3:46])[C@@H:26]([CH2:27][CH2:28]3)[C:25]([CH3:36])([CH3:35])[C:24]([C:37]3[CH:38]=[CH:39][C:40]([C:41]([OH:43])=[O:42])=[CH:44][CH:45]=3)=[CH:23][CH2:22]4)[CH2:19][CH2:18][C@@H:17]1[C@H:16]1[C@H:47]([C:50]([CH3:52])=[CH2:51])[CH2:48][CH2:49][C@:15]1([NH:14][CH2:13][CH2:12][N:9]1[CH2:10][CH2:11][N:6]([C:4](=[O:5])[C:3](=[O:53])[N:2]3[CH2:1][CH2:63][CH2:62][CH2:61][CH2:54]3)[CH2:7][CH2:8]1)[CH2:32][CH2:31]2
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCN(C(=O)C(=O)N(C)C)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: O=C(O)C(=O)N1CCCCC1
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCN(C(=O)C(=O)N4CCCCC4)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-(2-(dimethylamino)-2-oxoacetyl)piperazin-1-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid using 2-oxo-2-(piperidin-1-yl)acetic acid as the acid in Step 1. The product was isolated as a white solid (1.1 mg, 18%). LCMS: m/e 781.7 (M+H)+, 1.72 min (method 11). 1H NMR (500 MHz, CHLOROFORM-d) δ 7.99 (d, J=8.4 Hz, 2H), 7.24 (d, J=8.4 Hz, 2H), 5.31 (d, J=4.6 Hz, 1H), 4.77 (s, 1H), 4.65 (s, 1H), 3.84 (dd, J=7.6, 2.7 Hz, 1H), 3.68-3.56 (m, 3H), 3.49 (t, J=4.9 Hz, 2H), 3.43-3.30 (m, 2H), 2.93-2.63 (m, 9H), 2.60-1.05 (m, 28H), 1.72 (s, 3H), 1.17 (s, 3H), 1.04 (s, 3H), 1.00 (s, 3H), 0.97 (s, 3H), 0.97 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:15][CH2:14][C:13]3[N:12]=[C:11]([NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[NH:10][C:9](=[O:23])[C:8]=3[C:7]=2[CH:24]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:15]=[CH:14][C:13]3[N:12]=[C:11]([NH:16][C:17](=[O:22])[C:18]([CH3:20])([CH3:21])[CH3:19])[NH:10][C:9](=[O:23])[C:8]=3[C:7]=2[CH:24]=1
Reactant: COc1ccc2c(c1)-c1c(nc(NC(=O)C(C)(C)C)[nH]c1=O)CC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: c1ccccc1
Product: COc1ccc2ccc3nc(NC(=O)C(C)(C)C)[nH]c(=O)c3c2c1
Yield: 97.4 %

Procedure:
A mixture of N-(1,2,5,6-tetrahydro-9-methoxy-1-oxobenzo[f]quinazolin-3-yl)pivalamide (0.93 g, 2.84 mmoles) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.8 g, 3.5 mmoles) in dry benzene (60 ml) was refluxed under a nitrogen atmosphere for 3 hours. After cooling, benzene was removed under reduced pressure and the residue was purified on a silica gel column eluting with chloroform to give N-(1,2-dihydro-9-methoxy-1-oxobenzo[f]quinazolin-3-yl)pivalamide (0.9 g).
Reaction SMILES: [C:1]([CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([Mg]Br)[CH2:23][CH2:24][CH:25]=[CH2:26]>C1COCC1>[OH:8][C@:1]([CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:26][CH2:25][CH2:24][CH:23]=[CH2:22]
Reactant: C=CCCC[Mg]Br
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)c2ccccc2)C1
Solvent: C1CCOC1
Product: C=CCCC[C@](O)(c1ccccc1)C1CCCN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Yield: 88 %

Procedure:
A stirred solution of tert-butyl 3-benzoylpiperidine-1-carboxylate (160 mg, 0.55 mmol) in dry THF (2 mL) was cooled to −70° C. and 4-pentenylmagnesium bromide in THF (1.8 mL of ˜2.5 M, 2.8 mmol) was added dropwise. The mixture was stirred at −78° C. and allowed to warm to rt overnight. The reaction was quenched with satd aq ammonium chloride. The aqueous layer was extracted with Et2O (3×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The crude material was purified by flash chromatography on a prepacked silica cartridge eluted with an EtOAc/hexanes gradient. tert-Butyl 3-((R)-1-hydroxy-1-phenylhex-5-enyl)piperidine-1-carboxylate (174 mg, 88%) was isolated as an oil. MS ESI+ve m/z 382 (M+Na)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O.C[O:15][C:16](=[O:19])[CH2:17][NH2:18].C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][C:11]([NH:18][CH2:17][C:16]([OH:19])=[O:15])=[O:13]
Reactant: COC(=O)CN
Reactant: O=C(O)CCCNc1ccccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Product: O=C(O)CNC(=O)CCCNc1ccccn1

Procedure:
0.364 g of [4-(pyridin-2-ylamino)butyrylamino]acetic acid [obtained from peptide coupling of 4-(pyridin-2-ylamino)butyric acid with glycine methyl ester in the presence of HOBT/TBTU and subsequent hydrolysis of the methyl ester, in each case under standard conditions] is dissolved in 30 ml of DMF, and 0.3 g of methyl 3-amino-3-(4-trifluoromethoxyphenyl)propionate is added, and the mixture is cooled to −30°. Addition of 0.321 g of TBTU and 0.045 g of HOBT is followed by neutralization with 0.22 ml of N-methylmorpholine (NMM). The reaction mixture is stirred at room temperature for 2 days. After removal of the solvent by distillation, the residue is taken up in ethyl acetate, washed with NaHCO3 and saturated NaCl solution and further worked up as usual. Methyl 3-{2-[4-(4-methylpyridin-2-ylamino)butyrylamino]acetylamino}-3-(4-trifluoromethoxyphenyl)propionate is obtained, FAB-MS (M+H)+ 497.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]1.Br[CH2:16][C:17]1[C:18]([CH3:24])=[N:19][C:20]([Cl:23])=[CH:21][CH:22]=1.Cl>O1CCCC1.O>[Cl:23][C:20]1[N:19]=[C:18]([CH3:24])[C:17]([CH2:16][O:3][CH:4]2[CH2:5][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7]2)=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: Cc1nc(Cl)ccc1CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(Cl)ccc1COC1CN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (170 mg of 60%, 4.26 mmol) was suspended in tetrahydrofuran (12 mL) and cooled to 0° C. tert-Butyl 3-hydroxyazetidine-1-carboxylate (246 mg, 1.420 mmol) was added and the slurry was stirred for 30 minutes at 0° C. 3-(Bromomethyl)-6-chloro-2-methylpyridine (Example 421, Step 2) (313 mg, 1.420 mmol) was added and the solution was heated to 50° C. overnight. The reaction mixture was cooled to ambient temperature, diluted with water, acidified with 1 N hydrochloric acid, and extracted with ethyl acetate (2×). The combined organic layers were dried over magnesium sulfate, filtered, concentrated and purified via silica gel chromatography (0-2% methanol in ethyl acetate) to afford the title compound.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11].[C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:16])[CH:14]=[CH2:15]>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:10]([C:3]1[C:2](/[CH:15]=[CH:14]/[C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[C:7]([F:8])[C:6]([Cl:9])=[CH:5][CH:4]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)c1ccc(Cl)c(F)c1Br
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(Cl)c(F)c1/C=C/C(=O)OC(C)(C)C
Temperature: 90 °C
Reaction time: 8 h
Yield: 50.7 %

Procedure:
To a mixture of Intermediate 12C (50 g, 198 mmol), tert-butyl acrylate (50.9 g, 397 mmol) and TEA (55 mL, 397 mmol) in DMF (500 mL) was added Pd(OAc)2 (8.9 g, 39.7 mmol). The resulting mixture was stirred at 90° C. overnight. The reaction was cooled to rt, filtered, and the filtrate was concentrated. Purification by column chromatography gave Intermediate 12D (30 g, 51%) as a light yellow solid. MS (ESI) m/z: 242.7 (M+H)+.
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.II.[C:23](O)(=[O:25])C>[Cu](Cl)Cl>[CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[C:11]([CH2:12][CH2:13]1)=[CH:10][C:9]([OH:20])=[C:8]([O:25][CH3:23])[CH:7]=3)[CH2:4][CH2:3]2
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Reactant: CC(=O)O
Agent: Cl[Cu]Cl
Agent: II
Product: COc1cc2c(cc1O)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 2 h
Yield: 75 %

Procedure:
To this end, 2-iodo-estrone 49 was prepared by treating oestrone with mercuric acetate and iodine in acetic acid.40 The selective halogenation at position 2 was complete within 2 hours at room temperature with an overall yield of 56% after successive recrystallizations. 2-Iodo-estrone then reacted with a large excess of a freshly prepared solution of sodium methoxyde, in presence of copper chloride in refluxing pyridine41 and gave 2-methoxy-estrone 50 with a yield of 75%. This method has the advantage of not involving any protecting group and gives good overall yield (42%) for the synthesis of 2-methoxy-estrone in two steps from oestrone.
Reaction SMILES: [Cl-:1].[CH3:2][N:3]([CH3:29])[C:4]1[CH:28]=[CH:27][C:7]([CH:8]=[N:9][N+:10]2[CH:14]=[CH:13][N:12]([N:15]=[CH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=3)[C:11]=2[CH3:26])=[CH:6][CH:5]=1.C(O[CH:33](OCC)[N:34]([CH3:36])[CH3:35])C>C(O)CC>[Cl-:1].[CH3:25][N:23]([CH3:24])[C:20]1[CH:21]=[CH:22][C:17]([CH:16]=[N:15][N+:12]2[CH:13]=[CH:14][N:10]([N:9]=[CH:8][C:7]3[CH:6]=[CH:5][C:4]([N:3]([CH3:2])[CH3:29])=[CH:28][CH:27]=3)[C:11]=2[CH:26]=[CH:33][N:34]([CH3:36])[CH3:35])=[CH:18][CH:19]=1
Reactant: CCOC(OCC)N(C)C
Reactant: Cc1n(N=Cc2ccc(N(C)C)cc2)cc[n+]1N=Cc1ccc(N(C)C)cc1
Agent: [Cl-]
Solvent: CCCO
Product: CN(C)C=Cc1n(N=Cc2ccc(N(C)C)cc2)cc[n+]1N=Cc1ccc(N(C)C)cc1

Procedure:
2.05 g of 1,3-bis[[p-(dimethylamino)benzylidene]amino]-2-methylimidazolium chloride and 7.35 g of N,N-dimethylformamide diethyl acetal are stirred at 100° for 45 minutes in 150 ml of 1-propanol. The product is precipitated by the addition of ether. The precipitate is crystallized from dichloromethane/methanol and recrystallized from ethanol. There is obtained 1,3-bis[[p-(dimethylamino)benzylidene]amino]-2-[2-(dimethylamino)vinyl]imidazolium chloride of melting point 246°-248°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:33])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH2:31][CH3:32])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[N:36]1([CH2:42][C:43]([NH2:45])=[O:44])[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:33])[C@:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:21]([N:39]3[CH2:40][CH2:41][N:36]([CH2:42][C:43]([NH2:45])=[O:44])[CH2:37][CH2:38]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH2:31][CH3:32])=[N:9]2)=[CH:4][CH:3]=1
Reactant: NC(=O)CN1CCNCC1
Reactant: CCOc1ccccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1ccccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(N)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 2-piperazin-1-yl-acetamide dihydrochloride (Matrix Scientific) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 35% of 1:1 ethanol/acetonitrile in carbon dioxide). HR-MS (ES, m/z) calculated for C32H36N5O3Cl2 [(M+H)+] 608.2190, observed 608.2190.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]([C:6]1[CH:31]=[CH:30][C:9]([CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:8][CH:7]=1)=[O:5].[Li+].CC([N-]C(C)C)C.[CH3:40][C:41]1([CH3:56])[C:45]([CH3:47])([CH3:46])[O:44][B:43]([C:48]2[CH:49]=[C:50]([CH:53]=[CH:54][CH:55]=2)[CH:51]=O)[O:42]1.O>C1COCC1>[CH3:46][C:45]1([CH3:47])[C:41]([CH3:40])([CH3:56])[O:42][B:43]([C:48]2[CH:49]=[C:50]([CH:53]=[CH:54][CH:55]=2)/[CH:51]=[CH:10]/[C:9]2[CH:8]=[CH:7][C:6]([C:4]([O:3][CH3:2])=[O:5])=[CH:31][CH:30]=2)[O:44]1
Reactant: CC1(C)OB(c2cccc(C=O)c2)OC1(C)C
Reactant: COC(=O)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(/C=C/c2cccc(B3OC(C)(C)C(C)(C)O3)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.2 %

Procedure:
A solution of (4-(methoxycarbonyl)benzyl)triphenylphosphonium bromide (2.9 g, 6 mmol) in 50 mL of THF was added dropwise via syringe to a solution of LDA (5 mL, 10 mmol) in THF at −78° C. under N2 atmosphere. After 30 min at this temperature 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (1.4 g, 6 mmol) in 50 mL of THF was added dropwise via syringe and then stirred at this temperature for 30 min and then allow warm to room temperature over 4 hours, and stirred overnight. The mixture was poured into H2O (300 mL) and then extracted with ethyl acetate (3×100 mL). The combined organic layer was concentrated and purified by silica gel chromatography (eluting with a mixture of petroleum ether and ethyl acetate=50:1) to give (E)-methyl 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)styryl)benzoate (0.9 g, 41%) as a colorless oil. LC-MS: 365 [M+H]+, tR=1.98 min.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:16])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[N:8]([CH2:13][CH3:14])[C:7]2=[O:15].[C:17]([NH2:21])([CH3:20])([CH3:19])[CH3:18]>CN1C(=O)CCC1>[Br:1][C:2]1[C:3]([F:16])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:21][C:17]([CH3:20])([CH3:19])[CH3:18])[N:8]([CH2:13][CH3:14])[C:7]2=[O:15]
Reactant: CC(C)(C)N
Reactant: CCn1c(Cl)nc2c(Br)c(F)ccc2c1=O
Solvent: CN1CCCC1=O
Product: CCn1c(NC(C)(C)C)nc2c(Br)c(F)ccc2c1=O
Yield: 92.6 %

Procedure:
A solution of 8-bromo-2-chloro-3-ethyl-7-fluoroquinazolin-4(3H)-one (512c, 197 mg, 0.645 mmol), tert-butylamine (Aldrich; 1.5 mL, 14.27 mmol), and NMP (0.5 mL) was heated in a sealed microwave vial at 100° C. for 30 min. The reaction mixture was then partitioned between EtOAc (60 mL) and water (40 mL). The organic layer was separated and sequentially washed water (40 mL) and brine (40 mL), then dried over Na2SO4, filtered, and concentrated in vacuo to give as a yellow solid. The combined aqueous layers were subsequently extracted with DCM (2×30 mL), and the combined organic extracts were then sequentially washed with water (2×40 mL) and brine (40 mL), dried over Na2SO4, filtered, and concentrated in vacuo to provide a yellow solid. Combination of the two batches of isolated solids afforded 8-bromo-2-(tert-butylamino)-3-ethyl-7-fluoroquinazolin-4(3H)-one (204.3 mg, 0.597 mmol, 93% yield) as a light-yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.05 (1H, dd, J=8.8, 6.1 Hz), 6.89 (1H, t, J=8.5 Hz), 4.56 (1H, br. s.), 4.05 (2H, q, J=7.2 Hz), 1.62 (9H, s), 1.33 (3H, t, J=7.2 Hz). 19F NMR (376 MHz, CDCl3) δ ppm −96.81 (1F, s). m/z (ESI, +ve) 341.9/343.9 (M+H)+.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][CH2:17][C:18]5[N:23]=[C:22]([CH3:24])[S:21][C:19]=5[C:20]=4[C:11]=3[CH:10]=[N:9]2)=CC=1.O.C(=O)([O-])[O-].[K+].[K+]>FC(F)(F)C(O)=O>[CH3:24][C:22]1[S:21][C:19]2[C:20]3[C:11]4[CH:10]=[N:9][NH:8][C:12]=4[N:13]=[CH:14][C:15]=3[CH2:16][CH2:17][C:18]=2[N:23]=1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CCc2nc(C)sc2-4)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1nc2c(s1)-c1c(cnc3[nH]ncc13)CC2
Yield: 19 %

Procedure:
A solution of 8-(4-methoxybenzyl)-2-methyl-5,8-dihydro-4H-pyrazolo[3,4-c]thiazolo[5,4-f]isoquinoline (0.6 g, 1.65 mmol) in trifluoroacetic acid (4 mL) was heated at 100° C. for 2 hours. The reaction mixture was poured into water (50 mL) and basified with aqueous potassium carbonate to pH of 11. The reaction mixture was then extracted with dichloromethane (3×75 mL). The combined organic extract was dried using sodium sulfate and concentrated under reduced pressure to give dark residue. The crude product was purified by flash column chromatography (SiO2, gradient from 100% chloroform to 2% methanol in chloroform) to give a residue, which was further purified by crystallization from methanol and isopropanol to give the desired product (0.076 g, 13%) as a solid. 1H NMR (DMSO-d6, 400 MHz): δ 13.49 (s, 1H), 8.04 (s, 1H), 8.02 (s, 1H), 3.16 (t, J=7.6 Hz, 2H), 3.0 (t, J=7.6 Hz, 2H), 2.70 (s, 3H); LCMS [M+H]: 243.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[C:12]1[CH:25]=[CH:24][C:15]2[C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][O:18][C:14]=2[CH:13]=1>CCO.O>[NH2:3][C:12]1[CH:25]=[CH:24][C:15]2[C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][O:18][C:14]=2[CH:13]=1
Reactant: CCOC(=O)c1coc2cc(N3C(=O)c4ccccc4C3=O)ccc12
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1coc2cc(N)ccc12
Reaction time: 2 h

Procedure:
A mixture of ethyl 6-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-benzofuran-3-carboxylate (4.7 g, 14.0 mmol) in 200 mL of EtOH was added NH2NH2H2O (6.3 mL, 107.1 mmol, 85% in water) dropwise and the mixture was stired for 2 h at room temperature. The solvent was removed under vacuum and the residue was dissolved in water. The mixture was extracted with EtOAc, and the combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified with silca gel column chromatograph to give ethyl 6-amino-1-benzofuran-3-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C(N(CC)CC)C.[C:21](=S)=[S:22].S(Cl)(C1C=CC(C)=CC=1)(=O)=O>C1COCC1>[N:13]([CH2:12][CH2:11][C:5]1[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[C:21]=[S:22]
Reactant: S=C=S
Reactant: COc1cc(CCN)cc(OC)c1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(CCN=C=S)cc(OC)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 97.7 %

Procedure:
To a solution of 1.0 mL (1.0 g, 5.5 mmol) of 2-(3,5-dimethoxyphenyl)ethanamine (8) in 30 mL of THF was added dropwise 2.5 mL (1.8 g, 18.2 mmol) of triethylamine at 0° C. After stirring for 5 min, a solution of 420 mg (5.52 mmol) of carbon disulfide in 5 mL of THF was added dropwise at 0° C. The resulting solution was slowly warmed to room temperature, stirred for 1.5 h and then cooled to 0° C. To the reaction mixture was added 1.16 g (6.07 mmol) of tosyl chloride in one portion and solution stirred at room temperature for an additional hour. The reaction was quenched by slowly adding 30 mL of saturated NH4Cl(aq). The layers were separated and the aqueous phase was extracted once with ethyl acetate. The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was taken up in methylene chloride and filtered through a plug of silica gel (eluted with methylene chloride) and concentrated in vacuo to afford 1.2 g (100%) of 9 as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 6.37 (s, 3H), 3.80 (s, 6H), 3.71 (t, J=7.0 Hz, 2H), 2.92 (t, J=7.0 Hz, 2H).
Reaction SMILES: Br[C:2]1[C:3]([CH3:12])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH3:13][N:14]1CCCC1=O>[C-]#N.[Zn+2].[C-]#N.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>[C:13]([C:2]1[C:3]([CH3:12])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2)#[N:14]
Reactant: Cc1ccc2cccnc2c1Br
Reactant: CN1CCCC1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1ccc2cccnc2c1C#N

Procedure:
Prepared by reacting 8-bromo-7-methyl-quinoline with zinc cyanide in the presence of tetrakis(triphenylphosphine)palladium in N-methylpyrrolidinone under a protective gas atmosphere at 100-105° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](Br)[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:27][CH2:26][CH2:25][CH:24]1[C:28]1[NH:29][C:30]([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)=[CH:31][N:32]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(COC)OC>C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C.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>[C:16]([O:20][C:21]([N:23]1[CH2:27][CH2:26][CH2:25][CH:24]1[C:28]1[NH:29][C:30]([C:33]2[CH:38]=[CH:37][C:36]([C:13]3[CH:12]=[CH:11][N:10]=[C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:14]=3)=[CH:35][CH:34]=2)=[CH:31][N:32]=1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
Reactant: Brc1ccnc(OCc2ccccc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(-c3ccnc(OCc4ccccc4)c3)cc2)[nH]1
Temperature: 85 °C
Yield: 96.5 %

Procedure:
A mixture of 2-Benzyloxy-4-bromo-pyridine (0.292 g), 2-{5-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (0.533 g, prepared according to WO2008021927 A2) and Pd(PPh3)4 (0.064 g) in aq. K2CO3 solution/dimethoxyethane (1.82 mL/5.0 mL) was heated at 80-90° C. for 8 hours. Reaction mixture was cooled, diluted with ethyl acetate, washed with brine, dried (MgSO4) and concentrated. The residue was purified by flash column chromatography (silica gel, 20 to 80% ethyl acetate/hexanes) to give 2-{5-[4-(2-Benzyloxy-pyridin-4-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (0.530 g): LCMS-ESI+: calc'd for C30H33N4O3: 497.6 (M+H+). Found: 497.0 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[C@H:6]([O:7][C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])[C@@H:5]([O:13][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])[C:4](=O)[O:3]1.[NH2:20][OH:21]>C(OCC)(=O)C>[OH:21][N:20]1[C:2](=[O:1])[C@H:6]([O:7][C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])[C@@H:5]([O:13][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])[C:4]1=[O:3]
Reactant: NO
Reactant: CC(C)C(=O)O[C@H]1C(=O)OC(=O)[C@@H]1OC(=O)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)C(=O)O[C@H]1C(=O)N(O)C(=O)[C@@H]1OC(=O)C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.7 %

Procedure:
To a stirred solution of compound (27) (5.98 g, 22 mmol) in ethyl acetate (50 mL) at 0° C. was added a 50% aqueous solution of hydroxylamine (1.75 g, 26.4 mmol). The resulting mixture was stirred at room temperature for 3 h and washed successively with aqueous citric acid solution and brine, then dried over anhydrous sodium sulfate. After filtration and concentration in vacuo, the residue was suspended in toluene and the reaction mixture heated under reflux for 5 h, with the azeotropically liberated water being collected in a Dean-Stark apparatus. Toluene was removed in vacuo to afford the title compound (28) (6.3 g, quantitative yield). 1H-NMR (400 MHz, CDCl3): δ 1.22 (d, J=6.8 Hz, 12H), 2.69 (hept, J=6.8 Hz, 2H), 5.48 (s, 2H).