Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CON(C)[C:4](=[O:32])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]2[CH:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)[N:15]=[CH:14][N:13]=2)[CH:6]=1.[CH3:34][C:35](C)=[CH:36][Mg]Br>>[CH3:36][C:35](=[CH2:34])[C:4]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]2[CH:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)[N:15]=[CH:14][N:13]=2)[CH:6]=1)=[O:32]
Reactant: CON(C)C(=O)c1cccc(Nc2cc(Nc3ccc(Oc4ccccc4)cc3)ncn2)c1
Reactant: CC(C)=C[Mg]Br
Product: C=C(C)C(=O)c1cccc(Nc2cc(Nc3ccc(Oc4ccccc4)cc3)ncn2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a N-methoxy-N-methyl-3-(6-(4-phenoxyphenylamino)pyrimidin-4-ylamino)benzamide (0.150 g, 0.340 mmol) at 0° C. was added 2-methylpropenylmagnesium bromide (6.8 mL, 3.4 mmol, 0.5 M solution in THF). The reaction mixture was allowed to stir at room temperature for 30 min. It was quenched with saturated NH4Cl solution (0.5 mL) and was extracted with EtOAc (2×3 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to get a white solid, which was further purified by column chromatography (SiO2, 60-120, product getting eluted in methanol/chloroform: 2/98) to give 2-methyl-1-(3-(6-(4-phenoxyphenylamino)pyrimidin-4-ylamino)phenyl)prop-2-en-1-one (I-83) as a white solid. 1H NMR (DMSO-d6) δ ppm: 1.99 (s, 3H), 5.64 (s, 1H), 6.03 (s, 1H), 6.14 (s, 1H), 6.96-7.02 (m, 4H), 7.10 (t, J=7.6 Hz, 1H), 7.25 (d, J=7.6 Hz, 1H), 7.35-7.43 (m, 3H), 7.56 (d, J=8.8 Hz, 2H), 7.88 (d, J=8 Hz, 1H), 7.92 (s, 1H), 8.29 (s, 1H), 9.21 (s, 1H), 9.38 (s, 1H); LCMS: 423 m/e (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[C:9]1([C:15]2[NH:16][C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].ClC1C=CC=CC=1Cl>[Cu].CCCCCC.C(OCC)(=O)C.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:23]=[C:15]2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: c1ccc(-c2cc3ccccc3[nH]2)cc1
Reactant: Brc1ccc(I)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: Clc1ccccc1Cl
Solvent: CCOC(C)=O
Product: Brc1ccc(-n2c(-c3ccccc3)cc3ccccc32)cc1
Reaction time: 25 h
Yield: 50.1 %

Procedure:
50.0 g (177 mmole) of 4-bromoiodobenzene, 28.5 g (177 mmole) of 2-phenylindole, 30.5 g (221 mmole) of potassium carbonate, 18.7 g of copper powder, and 150 ml of o-dichlorobenzene were put in a 500 ml three-necked flask, and refluxed with stirring for 25 hours under nitrogen flow. Toluene was added to the reaction mixture heated under stirring at 60° C., and insoluble matter was filtered off. The filtrate was vacuum dried. Hexane was added to the residue and deposited crystal was filtered off. The filtrate was condensed, and refined by silica gel column chromatography (eluent:hexane/ethyl acetate: 50/1), recrystallized with a mixed solvent of hexane/ethyl acetate to give 25.7 g of a white crystal of 1-(4-bromophenyl)-2-phenylindole (yield: 50.1%).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:34])[CH2:7][CH:8]([N:12]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH2:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[CH2:30][CH2:29][CH2:28][NH:27][C:26]=4[N:25]=3)=[CH:18][CH:19]=2)[CH:14]=[CH:13]1)[CH2:9][CH2:10][CH3:11])C.Cl>CO.O>[N:25]1[C:26]2[NH:27][CH2:28][CH2:29][CH2:30][C:31]=2[CH:32]=[CH:33][C:24]=1[CH2:23][CH2:22][O:21][C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][CH:18]=1)[N:12]([CH:8]([CH2:9][CH2:10][CH3:11])[CH2:7][C:6]([OH:34])=[O:5])[CH:13]=[CH:14]2
Reactant: CCCC(CC(=O)OCC)n1ccc2cc(OCCc3ccc4c(n3)NCCC4)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCC(CC(=O)O)n1ccc2cc(OCCc3ccc4c(n3)NCCC4)ccc21
Reaction time: 8 h
Yield: 28 %

Procedure:
Sodium hydroxide (0.01 g, 0.23 mmol) was added to a solution of 3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-hexanoic acid ethyl ester (0.02 g, 0.04 mmol) in methanol/water (9/1, 1 mL) and stirred overnight. The reaction was acidified to pH 6 with 1N HCl and the crude product was extracted with ethyl acetate (3×10 mL) and concentrated. The residue was purified by flash chromatography on silica gel (10% methanol in ethyl acetate) to give the title compound (28% yield). 1H NMR (CDCl3) δ 10.4 (bs, 1H), 7.38 (d, 1H, J=8.0 Hz), 7.21 (d, 1H, J=3.2 Hz), 7.14 (d, 1H, J=8.0 Hz), 7.00 (d, 1H, J=2.3 Hz), 6.73 (m, 1H), 6.48 (d, 1H, J=7.3 Hz), 6.32 (d, 2H, J=3.0 Hz), 4.80 (s, 1H), 4.22 (t, 2H, J=7.0 Hz), 3.47 (m, 2H), 2.95 (t, 2H, J=6.8 Hz), 2.68 (m, 4H), 1.88 (m, 4H), 1.15 (m, 2H), 0.81 (t, 3H, J=7.4 Hz). Mass Spectrum (LCMS, ESI) calculated for C24H30N3O3 408.2 (M+H); found 408.3.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[CH:23](C(OCC)=O)[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Li+].O>CS(C)=O.CCOC(C)=O>[CH2:1]([O:8][C:9]([N:11]([CH2:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:12])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc([N+](=O)[O-])cc1CN(C)C(=O)OCc1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)Cc1ccc([N+](=O)[O-])cc1CN(C)C(=O)OCc1ccccc1
Temperature: 130 °C
Reaction time: 3 h
Yield: 91.7 %

Procedure:
15A (2.668 g, 5.82 mmol) was dissolved in DMSO (30 mL), lithium chloride (0.493 g, 11.64 mmol) and water (0.105 mL, 5.82 mmol) were added. The reaction mixture was stirred at 130° C. for 3 h, cooled to rt, diluted with EtOAc (150 mL), washed with water (2×50 mL), brine (1×50 mL) and dried (Na2SO4). EtOAc was removed under reduced pressure and the residue was purified by flash chromatography (0-60% EtOAc/hexanes). Fractions were combined and concentrated under reduced pressure to give 15B (2.062 g, 92% yield) as a yellowish oil. MS (ESI) m/z: 387.2 [M+1]+. 1H NMR: (400 MHz, CDCl3) δ ppm 8.11 (1H, d, J=8.34 Hz), 8.06 (1H, br. s.), 7.28-7.46 (6H, m), 5.20 (2H, br. s.), 4.55-4.69 (2H, m), 4.13 (2H, d, J=6.82 Hz), 3.64-3.86 (2H, m), 2.92 (3H, s), 1.24 (3H, td, J=7.07, 2.53 Hz).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N:11]2[CH2:16][C@@H:15]3[CH2:17][C@H:12]2[CH2:13][N:14]3[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[CH3:29]COCC>CO>[F:1][C:2]1[CH:10]=[C:9]([N:11]2[CH2:16][C@@H:15]3[CH2:17][C@H:12]2[CH2:13][N:14]3[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:27])[F:26])[CH:19]=2)[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:29])=[O:5]
Reactant: CCOCC
Reactant: O=C(O)c1ccc(N2C[C@@H]3C[C@H]2CN3c2cccc(C(F)(F)F)c2)cc1F
Agent: Cl
Solvent: CO
Product: COC(=O)c1ccc(N2C[C@@H]3C[C@H]2CN3c2cccc(C(F)(F)F)c2)cc1F
Yield: 46.3 %

Procedure:
A stirring solution of title compound 225 (250 mg 0.657 mmol), 2N HCl in ether (1 mL, 2.00 mmol) and methanol (25 mL) was refluxed over the weekend. The mixture was concentrated and the residue was purified by chromatography: 20 g SiO2, dry loaded on a samplet, 0% to 50% ethyl acetate in hexanes over 20 minutes to afford title compound 226 (120 mg, 46%) as a white foam. LRMS (ESI): (calc.) 394.13 (found) 395.3 (MH)+. 1H NMR (CDCl3, 400 MHz) δ (ppm): 7.77 (t, J=8.6 Hz, 1H), 7.28 (t, J=7.8 Hz, 1H), 6.92 (d, J=7.6 Hz, 1H), 6.71 (s, 1H), 6.67 (dd, J=8.3, 2.4 Hz, 1H), 6.28 (dd, J=8.9, 2.3 Hz, 1H), 6.17 (dd, J=14.1, 2.3 Hz, 1H), 4.56 (d, J=6.1 Hz, 2H), 3.84 (s, 3H), 3.69 (dd, J=8.7, 1.8 Hz, 1H) 3.63 (dd, J=9.0, 1.8 Hz, 1H), 3.30 (dd, J=9.0, 0.8 Hz, 1H), 3.22 (d, J=8.0 Hz, 1H), 2.20-2.13 (m, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[N:8][O:9][CH2:10][CH2:11][OH:12].O[C:14]1[CH:46]=[CH:45][C:17]([CH2:18][CH:19]2[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]2=[O:44])=[CH:16][CH:15]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCNCC1)=O)=NC(N1CCNCC1)=O>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[N:8][O:9][CH2:10][CH2:11][O:12][C:14]1[CH:46]=[CH:45][C:17]([CH2:18][CH:19]2[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]2=[O:44])=[CH:16][CH:15]=1
Reactant: OCCON=Cc1ccccn1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCNCC1)N1CCNCC1
Product: O=C1SC(Cc2ccc(OCCON=Cc3ccccn3)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 55 %

Procedure:
Following a procedure similar to that described in Example 3(a), but using 498 mg of 2-(2-pyridylmethyleneaminooxy)ethanol (prepared as described in Preparation 4), 1.13 g of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 0.75 ml of tributylphosphine and 693 mg of 1,1'-(azodicarbonyl)dipiperazine, 0.82 g of the title compound was obtained as a foam-like solid.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20](/[CH:22]=[CH:23]/[C:24]([O:26][CH3:27])=[O:25])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:28]=2)=[N:7][C:6]([CH3:29])=[N:5]1)([CH3:3])[CH3:2]>C1COCC1.C(O)C.[Pd]>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:28]=2)=[N:7][C:6]([CH3:29])=[N:5]1)([CH3:2])[CH3:3]
Reactant: COC(=O)/C=C/c1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COC(=O)CCc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2

Procedure:
A solution of 0.11 g (0.28 mmol) of (E)-methyl 3-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)acrylate in 5 ml of THF/ethanol mixture was subjected to hydrogenation over 100 mg of 10% Pd—C for 4 hours. The mixture was filtered through celite; the filtrate was concentrated in vacuum to give Methyl 3-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)propanoate. Yield 96 mg. M/z 396.2, calc. 395.20
Reaction SMILES: [C:1]([Si:5]([CH3:28])([CH3:27])[O:6][CH:7]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)[CH2:8][CH2:9][CH:10]1[NH:14][C:13](=[O:15])[CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:39][O:40][C:41](=[O:52])[C:42]1[CH:47]=[CH:46][C:45]([CH2:48][CH2:49][CH2:50]Br)=[CH:44][CH:43]=1>>[CH3:39][O:40][C:41](=[O:52])[C:42]1[CH:47]=[CH:46][C:45]([CH2:48][CH2:49][CH2:50][N:14]2[C:13](=[O:15])[CH2:12][CH2:11][CH:10]2[CH2:9][CH2:8][CH:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:28])[CH3:27])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:25])([F:26])[F:24])[CH:18]=2)=[CH:44][CH:43]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1)Cc1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(CCCBr)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: COC(=O)c1ccc(CCCN2C(=O)CCC2CCC(Cc2cccc(C(F)(F)F)c2)O[Si](C)(C)C(C)(C)C)cc1
Yield: 84.2 %

Procedure:
Analogous to the procedure described for Compound 1A, Step D, 5-[3-(tert-butyl-dimethyl-silanyloxy)-4-(3-trifluoromethyl-phenyl)-butyl]-pyrrolidin-2-one (250 mg, 0.602 mmol) was alkylated with NaHMDS (1M in THF, 0.72 mL, 0.72 mmol) and 4-(3-bromo-propyl)-benzoic acid methyl ester (170 mg, 0.663 mmol) to yield 4-(3-{2-[3-(tert-butyl-dimethyl-silanyloxy)-4-(3-trifluoromethyl-phenyl)-butyl]-5-oxo-pyrrolidin-1-yl}-propyl)-benzoic acid methyl ester (300 mg). MS 592.1 (M+1).
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=2[C:9]=1[C:10](Cl)=[O:11])[CH2:2][CH2:3][CH3:4].[CH2:17]([NH:24][CH2:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[CH:32]=[C:31]([OH:36])[CH:30]=[CH:29]2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C>[CH2:17]([N:24]([CH2:25][C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([OH:36])[CH:32]=2)[CH:27]=1)[C:10]([C:9]1[C:8]2[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=2[O:6][C:5]=1[CH2:1][CH2:2][CH2:3][CH3:4])=[O:11])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCCCc1oc2ccccc2c1C(=O)Cl
Reactant: Oc1ccc2cc(CNCc3ccccc3)ccc2c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCCc1oc2ccccc2c1C(=O)N(Cc1ccccc1)Cc1ccc2cc(O)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
2-Butyl-benzofuran-3-carbonyl-chloride (3 mmol), prepared in step 2 of Example 3, in 25 mL of anhydrous THF was added under nitrogen dropwise over 1 h to a solution of 6-(benzylamino-methyl)-naphthalen-2-ol (0.71 g, 2.7 mmol), prepared in the previous step, and triethylamine (0.376 mL, 2.7 mmol) in 75 mL of anhydrous THF at room temperature. After the addition the reaction was stirred at room temperature for 20 h (overnight). The solid present was removed by filtration and the filtrate concentrated under reduced pressure to give a brown oil. The oil was dissolved in ethyl acetate and extracted with 1N HCl. The organic layer was dried (MgSO4) and the solvent removed under reduced pressure. Chromatography of the crude oil on 200 g of silica gel (230-400 mesh) using 0%-5% ethyl acetate in methylene chloride as the eluent gave 2-butyl-benzofuran-3-carboxylic acid benzyl-(6-hydroxy-naphthalen-2-ylmethyl)-amide (0.8164 g, 65%) as a light yellow solid, mp 160-164° C.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:23])[C:10]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[C:13]=3[CH3:22])=[C:6]2[N:5]=[C:4]([CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:3]=1.C(N(C(C)C)CC)(C)C>C(O)C.O1CCOCC1.CN(C1C=CN=CC=1)C.C(OCC)(=O)C.Cl.C([Mo](C=O)(C=O)(C=O)(C=O)C=O)=O.[Pd]>[CH3:23][C:9]1[C:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[C:13]=2[CH3:22])=[C:6]2[N:5]=[C:4]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:3]=[CH:2][N:7]2[N:8]=1
Reactant: Cc1nn2c(Cl)cc(C3CCOCC3)nc2c1Cc1cccc(C(F)(F)F)c1C
Agent: O=C[Mo](C=O)(C=O)(C=O)(C=O)C=O
Agent: [Pd]
Agent: CN(C)c1ccncc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1nn2ccc(C3CCOCC3)nc2c1Cc1cccc(C(F)(F)F)c1C
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 20.4 %

Procedure:
To a suspension of 7-chloro-2-methyl-3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-5-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine (85 mg, 0.201 mmol) in ethanol (2 mL) and 1,4-dioxane (2 mL) were added hexaformylmolybdenum (27.1 mg, 0.100 mmol), Pd/C (1.0 mg, mmol) and DMAP (49 mg, 0.4 mmol) and diisopropylethylamine (26 mg, 0.2 mmol). The reaction mixture was irradiated (microwave) and stirred at 150° C. for 15 minutes. Reaction mixture was cooled down, diluted with ethyl acetate (30 mL) and 5% HCl solution. Two layers were separated. Organic layer was dried and concentrated to dryness. The crude product was purified to yield the titled compound (16 mg, 21%); LC/MS: MS (ES+) m/e 390 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.70-1.81 (m, 4H) 2.28 (s, 3H) 2.45-2.49 (m, 3H) 2.96 (s, 1H) 3.37-3.47 (m, 3H) 3.92 (br. s., 2H) 4.10 (s, 2H) 6.89 (d, J=7.33 Hz, 1H) 7.34 (s, 1H) 7.52 (s, 1H) 8.86 (d, J=7.33 Hz, 1H).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][C@@H:8]1[C:12]2[NH:13][C:14](B3OC(C)(C)C(C)(C)O3)=[CH:15][C:11]=2[C:10](=[O:25])[NH:9]1.Br[C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:36]=1[N:35]=[C:34]([NH:37][C:38]([CH3:41])([CH3:40])[CH3:39])[N:33]([CH2:42][C:43]([F:46])([F:45])[F:44])[C:32]2=[O:47]>C(C1C(C(C)(C)C)=C([Pd]Cl)C=CC=1NC)(C)(C)C>[C:38]([NH:37][C:34]1[N:33]([CH2:42][C:43]([F:46])([F:44])[F:45])[C:32](=[O:47])[C:31]2[C:36](=[C:27]([C:14]3[NH:13][C:12]4[C@@H:8]([CH3:7])[NH:9][C:10](=[O:25])[C:11]=4[CH:15]=3)[CH:28]=[CH:29][CH:30]=2)[N:35]=1)([CH3:41])([CH3:39])[CH3:40]
Reactant: C[C@H]1NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)[nH]c21
Reactant: CC(C)(C)Nc1nc2c(Br)cccc2c(=O)n1CC(F)(F)F
Agent: CNc1ccc([Pd]Cl)c(C(C)(C)C)c1C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C[C@H]1NC(=O)c2cc(-c3cccc4c(=O)n(CC(F)(F)F)c(NC(C)(C)C)nc34)[nH]c21
Yield: 26.6 %

Procedure:
2-(tert-Butylamino)-8-((6R)-6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(2,2,2-trifluoroethyl)-4(3H)-quinazolinone (501) as a yellow solid (32 mg, 26%) was prepared according the procedures described for 408, using 1,1-bis[(di-t-butyl-p-methylaminophenyl]palladium(II) chloride (9.8 mg, 0.014 mmol, Sigma Aldrich), K2CO3 (153 mg, 1.111 mmol, Sigma Aldrich), (R)-6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (146 mg, 0.555 mmol, 706), and 8-bromo-2-(tert-butylamino)-3-(2,2,2-trifluoroethyl)quinazolin-4(3H)-one (105 mg, 0.278 mmol, 501d). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.68 (1H, s) 7.89-7.96 (1H, m) 7.83-7.88 (1H, m) 7.59 (1H, s) 7.21 (1H, t, J=7.73 Hz) 6.62 (1H, d, J=1.37 Hz) 6.28 (1H, s) 5.28 (2H, q, J=8.93 Hz) 4.50 (1H, d, J=6.26 Hz) 1.45 (9H, s) 1.36 (3H, d, J=6.65 Hz). m/z (ESI, +ve) 434.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1([F:47])[CH2:5][CH:4]([NH:6][C:7]([NH:9][C@:10]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[C:34](/[CH:39]=C/C3C=CC=CC=3)[CH:33]=2)([C:18]2[CH:23]=[C:22]([O:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27])[CH:21]=[C:20]([F:31])[CH:19]=2)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:8])[CH2:3]1.C[N+]1([O-])CC[O:52]CC1>C(Cl)Cl>[F:1][C:2]1([F:47])[CH2:5][CH:4]([NH:6][C:7]([NH:9][C@:10]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[C:34]([CH:39]=[O:52])[CH:33]=2)([C:18]2[CH:23]=[C:22]([O:24][C:25]([F:29])([F:30])[CH:26]([F:28])[F:27])[CH:21]=[C:20]([F:31])[CH:19]=2)[CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:8])[CH2:3]1
Reactant: C[N+]1([O-])CCOCC1
Reactant: O=C(NC1CC(F)(F)C1)N[C@@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(F)c(/C=C/c2ccccc2)c1
Solvent: ClCCl
Product: O=Cc1cc([C@@](Cc2ccccc2)(NC(=O)NC2CC(F)(F)C2)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Yield: 22.6 %

Procedure:
To a solution of (R,E)-1-(3,3-difluorocyclobutyl)-3-(1-(4-fluoro-3-styrylphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)urea (509 mg, 0.8 mmol) in DCM (10 ml) at 0° C. was added 4-methylmorpholine N-oxide (104 mg, 0.8 mmol). Ozone was bubbled through the resulting yellow solution for 10 min. The reaction solvent was removed and the residue was purified by ISCO chromatography (12 g column, 0-30% EtOAc/hexane) to yield (R)-1-(3,3-difluorocyclobutyl)-3-(1-(4-fluoro-3-formylphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)urea as a colorless oil (106 mg, 23% yield). 1H NMR (400 MHz, CDCl3) δ ppm 10.22 (s, 1H), 8.06 (m, 1H), 7.67 (dd, J=6.19, 2.65 Hz, 1H), 7.16 (m, 4H), 6.85 (m, 3H), 6.69 (m, 3H), 5.85 (m, 1H), 5.40 (d, J=6.57 Hz, 1H), 4.00 (m, 1H), 2.90 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:11][CH:10]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([OH:22])=[CH:7][CH:8]=2)[O:3]1.[H-].[Na+].[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29]Cl>C1(C)C=CC=CC=1.O>[CH3:1][C:2]1([CH3:23])[CH2:11][CH:10]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([O:22][CH2:29][CH2:28][N:27]([CH3:31])[CH3:26])=[CH:7][CH:8]=2)[O:3]1
Reactant: CN(C)CCCl
Reactant: CC1(C)CC(c2cccc3ccccc23)c2ccc(O)cc2O1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CN(C)CCOc1ccc2c(c1)OC(C)(C)CC2c1cccc2ccccc12
Reaction time: 8 h
Yield: 67.2 %

Procedure:
To a stirred solution of 2,2-dimethyl-4-(1-naphthyl)-7-chromanol (7.48 g) in dry toluene (50 ml) was added sodium hydride (1.5 g, ~1.5 eq., 60% dispersion in oil) and the mixture was brought to reflux. To the resulting solution was added dropwise over 10 minutes a solution of 2-dimethylaminoethyl chloride (2.70 g, ~1.1 eq.) in dry toluene (10 ml) and the mixture was stirred under reflux for 2 hours, cooled, diluted with water and left to stand overnight. Next day the toluene layer was separated and evaporated in vacuo. The aqueous layer was extracted with ether and the extract used to dissolve the residue from the toluene evaporation. The organic layer was extracted with 5 N hydrochloric acid (45, 35 and 20 ml respectively), the combined acid extract was basified and extracted into ether. After being dried the ether was removed in vacuo to give a yellow oil (6.2 g) which was chromatographed on alumina in 8% ether--92 % petroleum ether (b.p. 60-80) to give the title compound (4.71 g, 51%) as a colourless oil. The hydrochloric salt had m.p. 178.5°-181.5° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-].[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[S:26][C:25]([CH2:27]Cl)=[N:24][C:23]=2[CH:29]=1>CN(C=O)C.O>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[S:26][C:25]([CH2:27][O:1][C:2]3[CH:7]=[C:6]([CH:5]=[CH:4][N:3]=3)[C:8]#[N:9])=[N:24][C:23]=2[CH:29]=1
Reactant: ClCc1nc2cc(Cl)ccc2s1
Reactant: N#Cc1ccnc(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccnc(OCc2nc3cc(Cl)ccc3s2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 7.5 %

Procedure:
2-Hydroxy-4-cyano-pyridine (240 mg, 2 mmol, 1 equiv.) was dissolved in DMF (6 ml), K2CO3 (415 mg, 3 mmol, 1.5 equiv.) and NaI (60 mg, 0.4 mmol, 0.2 equiv.) were added and the mixture was stirred at r.t. for 10 min. 5-Chloro-2-(chloromethyl)-1,3-benzothiazole (436 mg, 2 mmol, 1 equiv.) was added and the reaction mixture was stirred at 60° C. for 3 h and at r.t. overnight. By addition of H2O, brown solid precipitated, which was filtered, rinsed with H2O, dried and re-crystallised from CH3CN. Yield 280 mg (46%), mp 224-227° C., HPLC-MS (method 1): m/z 302 [M+H]+, Rt=3.80 min. By 13C-NMR analysis it was identified to be the N-alkylated derivative (Scheme 24). The DMF-H2O mother liquors were evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica, eluted with EtOAc/hexane (10%-100% gradient) to give 45 mg (7.5% yield) of a brown solid, HPLC-MS (method 1): m/z 302 [M+H]+, Rt=4.86 min. By 13C-NMR analysis, it was identified to be the desired O-alkylated derivative (Scheme 24).
Reaction SMILES: C1(=O)C2C(=CC=CC=2)CC1.CO[C:13]1[CH:21]=[CH:20][C:19]2[NH:18][C:17]3[C:22]4[C:27]([CH2:28][C:16]=3[C:15]=2[CH:14]=1)=[CH:26][CH:25]=[CH:24][CH:23]=4.C(Cl)(Cl)[Cl:30]>>[Cl:30][C:20]1[C:19]2[NH:18][C:17]3[C:22]4[C:27]([CH2:28][C:16]=3[C:15]=2[CH:14]=[CH:13][CH:21]=1)=[CH:26][CH:25]=[CH:24][CH:23]=4
Reactant: COc1ccc2[nH]c3c(c2c1)Cc1ccccc1-3
Reactant: ClC(Cl)Cl
Agent: O=C1CCc2ccccc21
Product: Clc1cccc2c3c([nH]c12)-c1ccccc1C3
Reaction time: 1 h

Procedure:
The o-chlorophenylhydrazone of 1-indanone (650 mg, 2.5 mmol) was boiled in a chloroform solution of polyphosphonate ester (see the preparation of 5,10-dihydro-8-methoxyindeno[1,2-b]indole) for 30 minutes. The solvent was removed, and the residue stirred in water (75 cm3) for 1 hour. Extraction into diethylether gave a green solution which was washed with water, dried (MgSO4), and evaporated. Purification by column chromatography (Rf [5% EtOAc/petrol (60°-80° C.)]0.5), gave the title compound as a colourless solid. Yield 500 mg, (82%). M.p. 139° C. 1H NMR (CDCl3) δ: 3.72 (2H,s,), 7.0-7.6 (7H, m,), 8.5 (1H, br,).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([CH2:14][S:15]([NH:18][C:19](=[O:25])[C:20](OCC)=[O:21])(=[O:17])=[O:16])[S:12][CH:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].CC(C)([O-])C.[K+]>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:14]3[S:15](=[O:17])(=[O:16])[NH:18][C:19](=[O:25])[C:20]=3[OH:21])[S:12][CH:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)C(=O)NS(=O)(=O)Cc1nc(-c2ccc(Cl)c(Cl)c2)cs1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1NS(=O)(=O)C(c2nc(-c3ccc(Cl)c(Cl)c3)cs2)=C1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of the 2-thiazolylmethyl substituted oxamate intermediate prepared in Step B above (1.0 g., 0.0024 mol) in dimethylformamide (5 ml) was added potassium tert-butoxide (0.55 g, 0.0048 ml) in several portions over 15 minutes. The mixture was stirred at room temperature for 24 hours. After diluting with water (30 ml) and acidifying to congo red indicator paper, a yellow gum (1.1 g.) was obtained. Recrystallization was achieved by dissolving in boiling ether (500 ml), filtering, concentrating to a small volume, and adding petroleum ether. The yield of the title product was 0.3 g., m.p. 250° C. (dec.).