Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.C[O-].[Na+].[O-]S(C(F)(F)F)(=O)=O.F[N+:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CO>[Br:1][C:2]1[N:6]=[CH:5][N:4]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=2)[N:3]=1
Reactant: F[n+]1ccccc1
Reactant: Brc1nc[nH]n1
Agent: C[O-]
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Solvent: CO
Product: Brc1ncn(-c2ccccn2)n1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
3-Bromo-1H-1,2,4triazole (1.9 g, 12.8 mmol) was dissolved in anhydrous methanol (20 mL). NaOMe (51 mL of a 0.5 M solution in methanol, 25.6 mmol) was then added to the stirred solution and the resulting reaction mixture was cooled to −78° C. in an argon blanketed flask. 1-Fluoropyridinium triflate (4.9 g, 15 mmol) in anhydrous methanol (20 mL) was added dropwise to this stirred solution. The resulting yellow mixture was stirred at −78° C. for 1 h under argon atmosphere, then allowed to reach ambient temperature. The mixture was stirred for 16 h at ambient temperature, after which time it was concentrated in vacuo. The resulting residue was dissolved in EtOAc (100 mL), the EtOAc solution washed with H2O (100 mL), then brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane:EtOAc (90:10) to afford 2-(3-bromo-1H-1,2,4-triazol-1-yl)pyridine as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14](S(C)(=O)=O)=[N:15][CH:16]=2)[N:11]([CH:23]2[CH2:28][CH2:27][CH2:26][CH:25]=[CH:24]2)[C:10]1=[O:29].[CH2:30]([N:32]([CH2:43][CH3:44])[CH2:33][CH2:34][O:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1)[CH3:31]>ClCCl.CO.C(O)(=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([NH:40][C:39]3[CH:38]=[CH:37][C:36]([O:35][CH2:34][CH2:33][N:32]([CH2:43][CH3:44])[CH2:30][CH3:31])=[CH:42][CH:41]=3)=[N:15][CH:16]=2)[N:11]([CH:23]2[CH2:28][CH2:27][CH2:26][CH:25]=[CH:24]2)[C:10]1=[O:29]
Reactant: CCN(CC)CCOc1ccc(N)cc1
Reactant: CS(=O)(=O)c1ncc2c(n1)N(C1C=CCCC1)C(=O)N(c1c(Cl)cccc1Cl)C2
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: CCN(CC)CCOc1ccc(Nc2ncc3c(n2)N(C2C=CCCC2)C(=O)N(c2c(Cl)cccc2Cl)C3)cc1
Temperature: 180 °C
Yield: 5.7 %

Procedure:
A mixture of 70 mg (0.15 mmol) of 3-(2,6-dichlorophenyl)-1-[2-cyclohexen-1(RS)-yl]-7-methanesulfonyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one and 150 mg (0.7 mmol) of 4-[2-(diethylamino)ethoxy]aniline was heated at 180° C. for 35 minutes and then cooled. The residue was subjected to column chromatography on silica gel using dichloromethane/methanol/acetic acid/water (240:24:3:2) for the elution. Product-containing fractions were combined and evaporated and the residue was evaporated with toluene. The residue was then dissolved in 30 ml of dichloromethane, washed twice with 20 ml of saturated aqueous sodium bicarbonate solution each time, dried over magnesium sulfate, filtered and evaporated to give 5 mg (22%) of 3-(2,6-dichlorophenyl)-1-[2-cyclohexen-1(RS)-yl]-7-[4-[2-(diethylamino)ethoxy]anilino]-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one as an orange colored gum. [Mass spectrum (ESI) MH+ =581].
Reaction SMILES: Cl.Cl.C(OC([N:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:22][N:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)[CH:19]=2)[CH2:14]1)=O)C1C=CC=CC=1.[H][H]>CCO.[Pd]>[CH3:29][N:26]1[CH2:27][CH2:28][N:23]([CH2:22][C:18]2[CH:19]=[C:20]3[C:15](=[CH:16][CH:17]=2)[CH2:14][NH:13][CH2:21]3)[CH2:24][CH2:25]1
Reactant: [H][H]
Reactant: CN1CCN(Cc2ccc3c(c2)CN(C(=O)OCc2ccccc2)C3)CC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CN1CCN(Cc2ccc3c(c2)CNC3)CC1
Reaction time: 1 h
Yield: 95 %

Procedure:
To a degassed solution of 5-(4-Methyl-piperazin-1-ylmethyl)-1,3-dihydro-isoindole-2-carboxylic acid benzyl ester (Step 9, 1.3 Kg, 3.55 mol) dissolved in EtOH (13 L) was added 10% Pd/C (0.065 Kg). Hydrogen was passed through the mixture at 30° C. for 4 h or until complete by NMR. The solution was then stirred for 1 h under an atmosphere of N2 and then filtered to remove the catalyst through a GF/F filter followed by filtration through a Cuno filter. The filtrate was evaporated to a small volume, azeotroped with toluene (3.9 L) and dried to constant weight yielding the title compound as a red/black oily solid (0.78 Kg) which was stored under nitrogen until required.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][N:11]=1)[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:43][O:44][C:45]1[C:46]2[N:59]=[C:58]([NH2:60])[S:57][C:47]=2[C:48]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[N:49][CH:50]=1>C1COCC1>[CH3:43][O:44][C:45]1[C:46]2[N:59]=[C:58]([NH:60][C:6](=[O:8])[C:5]3[CH:9]=[CH:10][N:11]=[C:3]([CH3:2])[CH:4]=3)[S:57][C:47]=2[C:48]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[N:49][CH:50]=1
Reactant: COc1cnc(-c2ccccc2)c2sc(N)nc12
Reactant: Cc1cc(C(=O)O)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1cnc(-c2ccccc2)c2sc(NC(=O)c3ccnc(C)c3)nc12

Procedure:
From 2-methyl-isonicotinic acid hydrochloride, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-phenyl-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 377 (M+H+, 100).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:12]=[CH:13][CH:14]=1.[Br:22]N1C(=O)CCC1=O.O>O1CCCC1>[Br:22][C:12]1[N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:10]([C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[CH:14][CH:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)n1cccc1-c1nc2ccccc2s1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)n1c(Br)ccc1-c1nc2ccccc2s1
Temperature: 0 °C
Reaction time: 14 h
Yield: 88.6 %

Procedure:
t-Butyl 2-(1,3-benzothiazol-2-yl)-1H-pyrrole-1-carboxylate (490 mg, 1.63 mmol) synthesized in Example (4a) was dissolved in tetrahydrofuran (20 mL), and cooled to 0° C. N-Bromosuccinimide (290 mg, 1.63 mmol) was added, and stirring was carried out at room temperature for 14 hours under nitrogen atmosphere. Water (20 mL) was added, and extraction was carried out with diethyl ether (20 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=0%-16%) to afford the desired compound (548 mg, yield 89%) as a pale yellow solid.
Reaction SMILES: [C:1]([O-:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].FC(F)(F)C1C=C([Zn+:16])C=CC=1.[Zn]>>[C:1]([O-:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Zn+2:16].[C:1]([O-:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: FC(F)(F)c1cccc([Zn+])c1
Agent: CC(C)(C)C(=O)[O-]
Agent: [Zn]
Product: [Zn+2]
Reaction time: 0.25 h

Procedure:
The 3-(trifluormethyl)phenylzinc pivalate (1d) product can be stored under inert gas atmosphere at ambient temperature for one week without any loss of activity (entry 1, Table 1 below). After 5 minutes of storage in air, 95% of active zinc species could be determined by titration (Table 1, entry 2). After 15 minutes, the activity is reduced to 58% (Table 1, entry 3) and after 30 and 45 minutes, activities of 43% and 40% are obtained (Table 1, entries 4-5). After storage on air for 60 minutes, active zinc species cannot be detected (Table 1, entry 6).
Reaction SMILES: C([CH:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])[C:4](=[O:12])[CH2:5][CH2:6][C:7]([O:9]CC)=[O:8])#N>Br>[CH3:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:3][C:4](=[O:12])[CH2:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)CCC(=O)C(C#N)c1ccccc1C
Agent: Br
Product: Cc1ccccc1CC(=O)CCC(=O)O

Procedure:
Undistilled ethyl 5-cyano-4-oxo-5-(2-methylphenyl)pentanoate (prepared by the procedure described above; 773 g.) was heated under reflux with hydrobromic acid (48-50%; 1550 ml.) for 3 hours. On cooling, the reaction mixture separated into two layers. The lower, aqueous phase was separated and extracted with chloroform (3 × 500 ml.). The chloroform extract was added to the upper, organic layer of the reaction mixture. The chloroform solution (about 2 liters) thus obtained was washed with water (3 × 200 ml.) and evaporated to give 5-(2-methylphenyl)-4-oxopentanoic acid (535 g.) in the form of a dark coloured oil.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][C:17]=2[NH:22][C:23]([C:25]2[N:26]=[C:27](Br)[S:28][C:29]=2[NH:30]C(=O)OC(C)(C)C)=[O:24])[CH2:12][CH2:11]1)=O)CCC.[F:39][C:40]1[CH:41]=[CH:42][C:43]([OH:49])=[C:44](B(O)O)[CH:45]=1>>[NH2:30][C:29]1[S:28][C:27]([C:42]2[CH:41]=[C:40]([F:39])[CH:45]=[CH:44][C:43]=2[OH:49])=[N:26][C:25]=1[C:23]([NH:22][C:17]1[CH:18]=[N:19][N:20]([CH3:21])[C:16]=1[N:13]1[CH2:12][CH2:11][CH:10]([CH2:9][NH2:8])[CH2:15][CH2:14]1)=[O:24]
Reactant: CCCCOC(=O)NCC1CCN(c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC1
Reactant: OB(O)c1cc(F)ccc1O
Product: Cn1ncc(NC(=O)c2nc(-c3cc(F)ccc3O)sc2N)c1N1CCC(CN)CC1
Yield: 20 %

Procedure:
Following the procedure for Example 278 starting with tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamate and 5-fluoro-2-hydroxyphenylboronic acid gave 297 as an off-white solid (18 mg, 20%). 1H NMR (400 MHz, d4-MeOD) δ 7.64 (dd, J=9.6, 3.1 Hz, 1H), 7.49 (s, 1H), 6.96 (td, J=4.8, 3.1 Hz, 1H), 6.90 (dd, J=9.6, 4.8 Hz, 1H), 3.74 (s, 3H), 3.27-3.12 (m, 4H), 2.66 (d, J=6.5 Hz, 2H), 1.86 (d, J=12.5 Hz, 2H), 1.69-1.42 (m, 1H), 1.45-1.36 (m, 2H). LCMS (ES+) m/z 446 (M+1).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:38])=[C:9]([CH2:11][O:12][C:13]2[CH:35]=[CH:34][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:25]/[CH:26]=O)=[CH:22][N:21]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:20]=3)=[CH:15][C:14]=2[O:36][CH3:37])[N:10]=1.[CH2:39]([P:48](=[O:55])([O:52][CH2:53][CH3:54])[O:49][CH2:50][CH3:51])P(=O)(OCC)OCC.CN(C)C=O.[H-].[Na+]>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:38])=[C:9]([CH2:11][O:12][C:13]2[CH:35]=[CH:34][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:25]/[CH:26]=[CH:39]/[P:48](=[O:55])([O:49][CH2:50][CH3:51])[O:52][CH2:53][CH3:54])=[CH:22][N:21]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:20]=3)=[CH:15][C:14]=2[O:36][CH3:37])[N:10]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/C=O)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(/C=C/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1)OCC
Reaction time: 15 h
Yield: 82.3 %

Procedure:
To a mixture of (2E)-3-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-2-propenaldehyde (0.51 g), tetraethyl methylenediphosphonate (0.32 g) and N,N-dimethylformamide (10 mL) was added sodium hydride (60% in oil, 0.050 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give diethyl (1E,3E)-4-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-1,3-butadienylphosphonate as colorless crystals (0.53 g, yield 82%) from a fraction eluted with ethyl acetate-hexane (8:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 143-144° C.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:27][CH2:26][CH:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:24][CH2:23]2)=[C:4]([C@H:10]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].[F:34][C:35]1[CH:52]=[CH:51][C:38]([CH2:39][CH2:40][O:41][C:42]2[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=2)=[CH:37][CH:36]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.CCOC(C)=O.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:18]([O:17][C@@H:10]([C:4]1[C:5]([CH3:9])=[N:6][C:7]([CH3:8])=[C:2]([C:45]2[CH:44]=[CH:43][C:42]([O:41][CH2:40][CH2:39][C:38]3[CH:37]=[CH:36][C:35]([F:34])=[CH:52][CH:51]=3)=[CH:47][CH:46]=2)[C:3]=1[N:22]1[CH2:23][CH2:24][CH:25]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:26][CH2:27]1)[C:11]([O:13][CH:14]([CH3:15])[CH3:16])=[O:12])([CH3:20])([CH3:19])[CH3:21]
Reactant: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)OC(C)C)c(N2CCC(c3ccccc3)CC2)c1Br
Reactant: OB(O)c1ccc(OCCc2ccc(F)cc2)cc1
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: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)OC(C)C)c(N2CCC(c3ccccc3)CC2)c1-c1ccc(OCCc2ccc(F)cc2)cc1
Temperature: 90 °C
Reaction time: 4 h
Yield: 51.8 %

Procedure:
The Pd(Ph3P)4 (33.5 mg, 0.029 mmol) was added to a nitrogen purged and degassed solution of (S)-isopropyl 2-(5-bromo-2,6-dimethyl-4-(4-phenylpiperidin-1-yl)pyridin-3-yl)-2-(tert-butoxy)acetate (150 mg, 0.29 mmol), (4-(4-fluorophenethoxy)phenyl)boronic acid (83 mg, 0.32 mmol), and sodium carbonate (184 mg, 1.74 mmol) in dioxane (4.5 mL) and water (0.9 mL) and stirred in a screw-capped pressure vessel for 4 h at 90° C. The reaction was allowed to cool, diluted with EtOAc, and the organic layer was washed with brine and dried (Na2SO4). The crude product was charged (DCM) to a 24 g ISCO silica gel cartridge and gradient elution (5-65% EtOAc/hexanes) using an Isolera chromatography station gave (S)-isopropyl 2-(tert-butoxy)-2-(5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethyl-4-(4-phenylpiperidin-1-yl)pyridin-3-yl)acetate 98 mg (52%) as a mixture of diastereomers. 1H NMR (500 MHz, DMSO-d6) δ 7.42-7.39 (m, 2H), 7.29-7.23 (m, 3H), 7.17-7.13 (m, 5H), 7.06-7.02 (m, 3H), 6.07 (s, 1H), 4.98-4.93 (m, 1H), 4.25 (t, J=7.0 Hz, 2H), 3.08 (t, J=6.2 Hz, 2H), 2.78-2.72 (m, 1H), 2.62-2.58 (m, 1H), 2.47 (br. s, 1H), 2.46 (s, 3H), 2.28 (br. s, 1H), 2.05 (s, 3H), 1.94-1.90 (m, 1H), 1.77-1.66 (m, 2H), 1.57 (br. s, 2H), 1.18 (br. s, 12H), 1.14 (d, J=5.5 Hz, 3H). UPLC (M+H)=653.5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.Br[C:11]([CH3:18])([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:11]([CH3:18])([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:4]([F:9])[CH:3]=1
Reactant: Oc1ccc(Cl)cc1F
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(Cl)cc1F
Temperature: 55 °C
Reaction time: 18 h

Procedure:
A mixture of 4-chloro-2-fluorophenol (11.280 g, 77 mmol), ethyl 2-bromoisobutyrate (12.61 mL, 85 mmol) and cesium carbonate (37.6 g, 115 mmol) in N,N-dimethylformamide (100 mL) was stirred at 55° C. for 18 hours. The reaction mixture was poured into brine, and extracted with ethyl acetate (2×250 mL). The combined organic phases were washed with brine, dried (MgSO4) and concentrated. The crude product was used in the next step without additional purification. MS (DCI+) m/z 278 (M+NH4)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]=1[C:14]#[N:15].[Li+].CC([N-]C(C)C)C.[I:24]I.[O-]S([O-])=O.[Na+].[Na+]>C1COCC1>[F:1][C:2]1[C:7]([I:24])=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]=1[C:14]#[N:15]
Reactant: II
Reactant: N#Cc1c(F)cccc1-c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: O=S([O-])[O-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1c(-c2ccccc2)ccc(I)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of Example 243A (6.8 g, 34.5 mmol) in THF (110 mL) at −78° C. under nitrogen atmosphere was treated dropwise with LDA (2.0 M solution in THF) and stirred for 1 h, then a solution of iodine in THF (30 mL) was added via cannula over about 10 min. The thick mixture was allowed to warm to rt and stirred for 1 h, then treated with saturated aqueous Na2SO3 solution (10 mL). The mixture was concentrated to remove the THF, then H2O was added and the mixture was extracted with EtOAc. The extracts were washed with brine, dried (MgSO4) and concentrated. The residue was purified by flash chromatography on silica gel, eluting with EtOAc/hexanes (1:7), and the resulting solid was triturated with hexanes and EtOAc to give the desired product (6.8 g). Rf=0.44 (7:1 hexane:EtOAc)
Reaction SMILES: [CH:1]([N:4]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:5](=[O:28])[CH2:6][N:7]1[C:16](=[O:17])[CH2:15][C:14]2[N:10]([C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:12][N:13]=2)[C:9]2[CH:24]=[CH:25][CH:26]=[CH:27][C:8]1=2)([CH3:3])[CH3:2].[C:35]([O:39][C:40]([N:42]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:44]([CH2:51]Br)=[N:43]1)=[O:41])([CH3:38])([CH3:37])[CH3:36]>>[C:35]([O:39][C:40]([N:42]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:44]([CH2:51][CH:15]2[C:14]3[N:10]([C:11]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[N:12][N:13]=3)[C:9]3[CH:24]=[CH:25][CH:26]=[CH:27][C:8]=3[N:7]([CH2:6][C:5](=[O:28])[N:4]([CH:1]([CH3:3])[CH3:2])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:16]2=[O:17])=[N:43]1)=[O:41])([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2ccccc21
Reactant: CC(C)N(C(=O)CN1C(=O)Cc2nnc(-c3ccccc3)n2-c2ccccc21)c1ccccc1
Product: CC(C)N(C(=O)CN1C(=O)C(Cc2nn(C(=O)OC(C)(C)C)c3ccccc23)c2nnc(-c3ccccc3)n2-c2ccccc21)c1ccccc1
Yield: 63 %

Procedure:
Following the procedure described for Example 3(A), Step A, N-isopropyl-2-(5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-N-phenyl-acetamide (Preparation 7(A)) (411.7 mg, 0.9118 mmol) was alkylated with 3-bromomethyl-indazole-1-carboxylic acid tert-butyl ester (309 mg, 0.993 mmol). Purification by medium pressure chromatography eluting with a solvent gradient (EtOAc to 5% MeOH in EtOAc) provided 391.9 mg of 3-{6-[(isopropyl-phenyl-carbamoyl)-methyl]-5-oxo-1-phenyl-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulen-4-ylmethyl}-indazole-1-carboxylic acid tert-butyl ester. 1H NMR (CD3OD) δ 7.99 (m, 2H), 7.22-7.66 (m, 15H), 7.01 (dd, 1H), 4.53-4.81 (m, 3H), 3.88-4.21 (M, 3H), 1.65 (m, 9H), 0.94 (m, 6H).
Reaction SMILES: [I-].[K+].CS(O[CH2:8][CH2:9][O:10][C:11]1[C:19]2[C:14](=[N:15][CH:16]=[N:17][C:18]=2[NH:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:29]=[N:30][C:31]([CH3:34])=[CH:32][CH:33]=3)=[C:23]([F:35])[CH:22]=2)[NH:13][N:12]=1)(=O)=O.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[F:35][C:23]1[CH:22]=[C:21]([NH:20][C:18]2[N:17]=[CH:16][N:15]=[C:14]3[NH:13][N:12]=[C:11]([O:10][CH2:9][CH2:8][N:40]4[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]4)[C:19]=23)[CH:26]=[CH:25][C:24]=1[O:27][C:28]1[CH:29]=[N:30][C:31]([CH3:34])=[CH:32][CH:33]=1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCOS(C)(=O)=O)c34)cc2F)cn1
Reactant: CN1CCNCC1
Agent: [I-]
Agent: [K+]
Product: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCN5CCN(C)CC5)c34)cc2F)cn1
Yield: 54 %

Procedure:
The procedure described in Example 23 was repeated (except that potassium iodide was not used) using 2-{[4-({3-fluoro-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]oxy}ethyl methanesulfonate and N-methylpiperazine to give the title compound in 54% yield; NMR Spectrum: 2.11 (s, 3H), 2.44 (s, 8H), 2.08 (t, 2H), 3.31 (hidden by water, 3H), 4.46 (t, 2H), 7.26 (m, 3H), 7.55 (dd, 1H), 8.01 (dd, 1H), 8.24 (d, 1H), 8.36 (s, 1H), 8.60 (br s, 1H); Mass Spectrum: 479 (MH+).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]1([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=O)[CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(OCC)C.C1COCC1>[C:7]1([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C1CC(c2ccccc2)c2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C1=CC(c2ccccc2)c2ccccc21
Yield: 50 %

Procedure:
Keeping the temperature at -5° C., to a suspension of 5.0 g (0.131 moles) of LiAlH4 in 300 ml of ethyl ether, 35 g (0.168 moles) is added of 3-phenyl-1-indanone dissolved in 50 ml of THF. The oil obtained by evaporating ether (40 g), is dissolved in 300 ml of toluene containing 20 g of Sio2 and kept refluxing for 2 hours, with formed water being distilled off. The resulting mixture is filtered, the solvent is evaporated and by distillation 18 g is obtained (yield of 50%) of 1-phenylindene boiling at 95-100° C./0.2 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[CH:14]=[C:13]([C:15]([OH:17])=O)[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:18][C:19]1[S:20][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][N:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[CH:14]=[C:13]([C:15]([NH:18][C:19]3[S:20][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][N:23]=3)=[O:17])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)c1cnc(N)s1
Reactant: O=C(O)c1cn(Cc2ccc(Cl)c(Cl)c2)nn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(NC(=O)c2cn(Cc3ccc(Cl)c(Cl)c3)nn2)s1
Temperature: 40 °C
Reaction time: 72 h
Yield: 43.4 %

Procedure:
A mixture of 1-[(3,4-dichlorophenyl)methyl]-1H-1,2,3-triazole-4-carboxylic acid (Intermediate 11) (1 g, 3.6 mmol), methyl 2-amino-1,3-thiazole-5-carboxylate (0.58 g, 3.6 mmol), HATU (1.82 g, 1.3 eq) and DIPEA (0.9 mL, 1.3 eq) in DMF (50 mL) was stirred at 40° C. for 3 days. The solvent was evaporated and the residue was washed with water and extracted with DCM. A precipitate was formed, filtered and triturated with a mixture of methanol/acetonitrile. After filtration, the yellow solid was dried to give the title compound as a pale yellow solid (644 mg, 44%). LC/MS: m/z 412 (M+H)+. Rt: 3.21 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([CH2:13][OH:14])=[C:11]([CH3:15])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Cl[C:19]1[CH:20]=[CH:21][C:22]2[N:23]([CH:25]=[N:26][N:27]=2)[N:24]=1.O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([CH2:13][O:14][C:19]3[CH:20]=[CH:21][C:22]4[N:23]([CH:25]=[N:26][N:27]=4)[N:24]=3)=[C:11]([CH3:15])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1onc(-c2cccc(F)c2)c1CO
Reactant: Clc1ccc2nncn2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1onc(-c2cccc(F)c2)c1COc1ccc2nncn2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 51.2 %

Procedure:
To a solution of [3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol (100 mg, 0.48 mmol) in DMF (2 mL) was added sodium hydride (55% dispersion in mineral oil, 23.2 mg, 0.53 mmol). The mixture was stirred at room temperature for 15 min. After addition of a solution of 6-chloro-1,2,4-triazolo[4,3-b]pyridazine (82 mg, 0.53 mmol) in DMF (3 mL) the mixture was stirred at room temperature overnight. Then the mixture was poured into water, extracted (ethyl acetate/water) and the organic phase was dried with sodium sulfate and concentrated. Chromatography (SiO2, heptane:ethyl acetate=100:0 to 9:1) afforded the title compound (80 mg, 51%) as a white solid. MS: m/e=326.0 [M+H]+.