Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:34])([CH3:33])/[CH:3]=[CH:4]/[C@H:5]1[O:10]C(C)(C)[O:8][C@@H:7]([C@@H:13]([O:30][CH3:31])[C:14]([NH:16][CH:17]2[CH2:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[CH2:20][N:19]([CH3:28])[C:18]2=[O:29])=[O:15])[C@H:6]1[OH:32].FC(F)(F)C(O)=O.O1CCCC1.O>ClCCl.CO>[CH3:28][N:19]1[C:18](=[O:29])[CH:17]([NH:16][C:14](=[O:15])[C@H:13]([O:30][CH3:31])[C@H:7]([OH:8])[C@@H:6]([OH:32])[C@H:5]([OH:10])/[CH:4]=[CH:3]/[C:2]([CH3:34])([CH3:33])[CH3:1])[CH2:23][C:22]2[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=2[CH2:20]1
Reactant: CO[C@@H](C(=O)NC1Cc2ccccc2CN(C)C1=O)[C@@H]1OC(C)(C)O[C@H](/C=C/C(C)(C)C)[C@@H]1O
Solvent: C1CCOC1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CO[C@@H](C(=O)NC1Cc2ccccc2CN(C)C1=O)[C@H](O)[C@@H](O)[C@H](O)/C=C/C(C)(C)C
Temperature: 0 °C

Procedure:
24 mg (50 μmol) of product 5, and then 2 ml of a cold trifluoroacetic acid/tetrahydrofuran/water mixture (1.6/1.6/1.0 v/v/v) are successively introduced, at 0° C., into a round-bottomed flask equipped with a magnetic stirrer. This mixture is maintained at 0° C. until the starting material has disappeared on TLC (1 hour) (90/10 v/v dichloromethane/methanol). The solvent is evaporated off under reduced pressure and 2 ml of methanol are added to the residue, which is reevaporated under reduced pressure. This last step is repeated a second time and the residue is dissolved in 5 ml of water in a minimum volume of methanol (0.5 ml). The solution is freeze-dried, giving the expected product Example 1 quantitatively in the form of a foam.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OC([N:26]1[CH2:31][CH2:30][CH:29]([N:32]2[CH:36]=[C:35]([C:37]3[CH:38]=[N:39][C:40]([C:43]4[CH:48]=[CH:47][CH:46]=[C:45]([C:49]5[N:50]=[N:51][N:52]([CH2:54][Si](C)(C)C)[CH:53]=5)[CH:44]=4)=[N:41][CH:42]=3)[CH:34]=[N:33]2)[CH2:28][CH2:27]1)=O)(C)(C)C.CO.[ClH:61].O1CCOCC1>C1COCC1.C([O-])(O)=O.[Na+].C(Cl)Cl>[ClH:61].[CH3:54][N:52]1[CH:53]=[C:49]([C:45]2[CH:44]=[C:43]([C:40]3[N:39]=[CH:38][C:37]([C:35]4[CH:34]=[N:33][N:32]([CH:29]5[CH2:30][CH2:31][NH:26][CH2:27][CH2:28]5)[CH:36]=4)=[CH:42][N:41]=3)[CH:48]=[CH:47][CH:46]=2)[N:50]=[N:51]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(-c4cccc(-c5cn(C[Si](C)(C)C)nn5)c4)nc3)cn2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CO
Product: Cn1cc(-c2cccc(-c3ncc(-c4cnn(C5CCNCC5)c4)cn3)c2)nn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33 %

Procedure:
Tetrabutylammonium fluoride (56 mg; 0.21 mmol; 2.0 eq.) was added to a solution of 4-(4-{2-[3-(1-Trimethylsilanylmethyl-1H-[1,2,3]triazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (60 mg; 0.11 mmol; 1.0 eq.) in THF (1 mL) and the reaction mixture was stirred at RT for 2 h. It was then diluted with a saturated solution of NaHCO3 and extracted with EtOAc (three times). Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude obtained was dissolved in DCM (1 mL) and MeOH (MeOH) and HCl/dioxane (0.4 mL of a 4N solution, 1.6 mmol, 15 eq.) was added. The reaction mixture was stirred at RT for 2 h, concentrated under reduced pressure and purified by autopreparative LC/Ms to give the title compound as a beige solid (15 mg, 33%). 1H NMR (300 MHz, DMSO-d6) δ 9.22 (s, 2H), 9.11 (brs, 1H), 8.94-8.81 (m, 2H), 8.67 (s, 1H), 8.54 (s, 1H), 8.35 (dt, J=7.9 Hz, 1.5 Hz, 1H), 8.22 (s, 1H), 7.96 (dt, J=7.9 Hz, 1.5 Hz, 1H), 7.61 (t, J=7.9 Hz, 1H), 4.61-4.52 (m, 1H), 4.12 (s, 3H), 3.43-3.36 (m, 2H), 3.16-3.06 (m, 2H), 2.28-2.11 (m, 4H). HPLC (Condition A): Rt 2.08 min (purity 98.5%). MS (ESI+): 387.3.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][OH:14])[CH2:11][C@H:10]([O:15][C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[NH:23][C:24]2[C:25]3[C:32]([CH3:33])=[C:31]([C:34](O)=[O:35])[S:30][C:26]=3[N:27]=[CH:28][N:29]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:37]>CO>[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][OH:14])[CH2:11][C@H:10]([O:15][C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[NH:23][C:24]2[C:25]3[C:32]([CH3:33])=[C:31]([C:34]([NH2:37])=[O:35])[S:30][C:26]=3[N:27]=[CH:28][N:29]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3C[C@@H](CO)N(C(=O)OC(C)(C)C)C3)c12
Reactant: N
Solvent: CO
Product: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3C[C@@H](CO)N(C(=O)OC(C)(C)C)C3)c12

Procedure:
Prepared analogously to example 1.4 from 4-[2-((3S,5S)-1-tert-butoxycarbonyl-5-hydroxymethyl-pyrrolidin-3-yloxy)-4-fluoro-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid and ammonia in methanol.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([Si:18]([CH3:26])([CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:12]=1[CH:27]=[CH:28][C:29](OCC)=[O:30]>C1(C)C=CC=CC=1>[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([Si:18]([CH3:26])([CH3:25])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:12]=1[CH:27]=[CH:28][CH2:29][OH:30]
Reactant: CCOC(=O)C=Cc1c(C)ccc(C)c1[Si](C)(C)c1ccccc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: Cc1ccc(C)c([Si](C)(C)c2ccccc2)c1C=CCO
Reaction time: 4 h

Procedure:
A 1M solution of DIBAL in toluene (8.6 ml) was added slowly to the ester product of step (t) above (0.967 g, 2.86 mmol) in 5 ml of toluene at -78°. The reaction was stirred 4 hours with slow warming to 0°. The reaction was then re-cooled (-40°) and quenched with saturated aqueous sodium sulfate. Solid sodium sulfate and celite were added and the mixture was diluted with MTBE, stirred 10 minutes, and then filtered. The filtrate was concentrated to give 0.97 g of a clear oil which was chromatographed on silica gel (230-400 mesh) using a 3"×6.5" column with a 3:1 mixture of hexane and ethyl acetate as the eluent; 602 mg (71%) of refined alcohol product of this step was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[O:5][CH:6]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][NH:22][C:23](=[O:36])[C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)=[CH:26][CH:25]=2)=[CH:15][CH:14]=1)[C:7]([O:9]CC)=[O:8].[OH-].[Na+]>>[F:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[O:5][CH:6]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][NH:22][C:23](=[O:36])[C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)=[CH:26][CH:25]=2)=[CH:15][CH:14]=1)[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)C(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccn3)cc2)cc1)Oc1cccc(F)c1
Agent: [Na+]
Agent: [OH-]
Product: O=C(NCCOc1ccc(CC(Oc2cccc(F)c2)C(=O)O)cc1)c1ccc(-c2ccccn2)cc1
Yield: 86.6 %

Procedure:
In a similar manner to that described in Example 2, ethyl 2-(3-fluorophenoxy)-3-[4-[2-(4-pyridine-2-ylbenzoylamino)ethoxy]phenyl]propionate (500 mg), which is the product of Example 136, was reacted with aqueous sodium hydroxide solution (1N, 2.00 ml) and the reaction mixture was treated to give the title compound (410 mg) as a white powder.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[CH:17]=[CH:16][N:15]=[C:14]([Br:19])[C:13]=3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:20]([N-]C(C)C)(C)C.[Li+].CI>C1COCC1>[C:1]1([S:7]([N:10]2[C:18]3[CH:17]=[CH:16][N:15]=[C:14]([Br:19])[C:13]=3[CH:12]=[C:11]2[CH3:20])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)[N-]C(C)C
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Br)nccc21
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1cc2c(Br)nccc2n1S(=O)(=O)c1ccccc1
Temperature: -35 °C
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
A 50 mL round-bottomed flask, under nitrogen, fitted with a thermometer probe and a condenser/inert gas bubbler (via a Claisen head) was charged with a solution of 1-benzenesulfonyl-4-bromo-1H-pyrrolo[3,2-c]pyridine (0.43 g, 1.27 mmol) in anhydrous THF (8 mL). To the resultant solution, at −35° C., was added dropwise a solution of lithium diisopropylamide (2.0M in heptane/THF/ethyl benzene, 1.27 mL, 2.54 mmol) and the mixture was stirred at −35° C. for 30 min. Methyl iodide (0.48 mL, 7.63 mmol) was added dropwise and solution was allowed to reach room temperature and stirred for 3 h. The reaction was quenched by addition of 1N HCl (3 mL). The solution was diluted with water (7 mL), extracted with EtOAc (2×50 mL). The organic extracts were pooled, was dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, 0-100% EtOAc:cyclohexane) to give the desired product (0.43 g, 96%) as a white powder. LCMS (Method A) RT=4.67 min, [M+H]+ 351 (79Br), 353 (8Br)
Reaction SMILES: [CH3:1][C:2]1([C:6]([OH:8])=O)[CH2:5][O:4][CH2:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:33][C:34]1[N:39]=[C:38]([N:40]2[C:48]3[C:43](=[CH:44][CH:45]=[C:46]([C:49]#[N:50])[CH:47]=3)[CH:42]=[N:41]2)[C:37]([NH2:51])=[CH:36][N:35]=1.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[NH2:33][C:34]1[N:39]=[C:38]([N:40]2[C:48]3[C:43](=[CH:44][CH:45]=[C:46]([C:49]#[N:50])[CH:47]=3)[CH:42]=[N:41]2)[C:37]([NH:51][C:6]([C:2]2([CH3:1])[CH2:5][O:4][CH2:3]2)=[O:8])=[CH:36][N:35]=1
Reactant: CC1(C(=O)O)COC1
Reactant: N#Cc1ccc2cnn(-c3nc(N)ncc3N)c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(C(=O)Nc2cnc(N)nc2-n2ncc3ccc(C#N)cc32)COC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 3-methyloxetane-3-carboxylic acid (17 mg, 0.143 mmol) and HATU (54.5 mg, 0.143 mmol) was added a solution of 1-(2,5-diaminopyrimidin-4-yl)-1H-indazole-6-carbonitrile (30 mg, 0.072 mmol) in DMF (0.5 mL) followed by triethylamine (0.030 mL, 0.215 mmol). The mixture was stirred at RT for 10 min, then diluted with EtOAc (10 mL) and washed with water (2×3 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give the crude compound. The crude product was purified by flash chromatography (Isolute column, 90% EtOAc in heptane to 100% EtOAc and then 0.5% MeOH/EtOAc) to afford the title compound as a pale yellow solid: 1H NMR (250 MHz, DMSO) δ 1.61 (3H, s), 4.31 (2H, d, J=5.94 Hz), 4.83 (2H, d, J=5.94 Hz), 7.20 (2H, br. s.), 7.65-7.92 (1H, m), 8.12 (1H, dd, J=8.22, 0.76 Hz), 8.49 (1H, s), 8.64 (1H, d, J=0.91 Hz), 9.14 (1H, s), 9.70 (1H, s); LC-MS: m/z=+350.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[CH2:19]([NH2:21])[CH3:20]>>[CH2:19]([NH:21][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][N:17]=[CH:18][C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1])[CH3:20]
Reactant: CCN
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Product: CCNC(=O)c1ccncc1Nc1ccc(I)cc1F

Procedure:
N-ethyl-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.34 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.48 mmol of monoethylamine. LC/MS [5.96 min; 386 (M+1)]
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[OH:8][CH2:9][C:10]([C:13]1[CH:17]=[C:16]([NH:18][C:19](=[O:32])[C:20]([CH3:31])([S:22]([CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)(=[O:24])=[O:23])[CH3:21])[O:15][N:14]=1)([CH3:12])[CH3:11].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:11][C:10]([C:13]1[CH:17]=[C:16]([NH:18][C:19](=[O:32])[C:20]([CH3:31])([S:22]([CH:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)(=[O:24])=[O:23])[CH3:21])[O:15][N:14]=1)([CH3:12])[CH2:9][O:8][C:1](=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(CO)c1cc(NC(=O)C(C)(C)S(=O)(=O)C2CCOCC2)on1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCC(C)(C)c1cc(NC(=O)C(C)(C)S(=O)(=O)C2CCOCC2)on1
Temperature: 25 °C
Yield: 81.2 %

Procedure:
Acetic anhydride (24 uL, 0.26 mmol) and a catalytic amount of DMAP are added in sequence to a solution of N-[3-(2-hydroxy-1,1-dimethyl-ethyl)-isoxazol-5-yl]-2-methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionamide (80.0 mg, 0.21 mmol) and pyridine (21 uL, 0.26 mmol) in anhydrous DCM (2.1 mL). The solution is stirred at room temperature until complete consumption of starting material. After removal of the solvent under reduced pressure, the crude is purified by silica gel column chromatography to afford 71 mg of acetic acid 2-methyl-2-{5-[2-methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionylamino]-isoxazol-3-yl}-propyl ester. Yield: 80%; m/z 417 [M+H].
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].C(OCC)(=[O:13])C>ClCCl>[CH3:1][S:2]([C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[O:6])=[O:13]
Reactant: CCOC(C)=O
Reactant: CSc1ccccc1C=O
Solvent: ClCCl
Product: CS(=O)c1ccccc1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a solution of 2-(methylthio)benzaldehyde (500 mg, 3.28 mmol) in 6.6 mL of dichloromethane was added m-chlorobenzoic peracid (0.85 g, 4.9 mmol) at 0° C. After being stirred at room temperature for 1 h, the reaction mixture was diluted with ethyl acetate. The solution was washed with saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/50 to 15/85) to obtain the title compound as a white crystal (493 mg, 89%).
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:13]2[C:8](=[N:9][C:10]([F:14])=[CH:11][CH:12]=2)[N:7]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[N:6]=1)=[N+]=[N-].[H][H]>[Pd]>[NH2:1][CH2:4][C:5]1[C:13]2[C:8](=[N:9][C:10]([F:14])=[CH:11][CH:12]=2)[N:7]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[N:6]=1
Reactant: [H][H]
Reactant: [N-]=[N+]=NCc1nn(C2CCCCO2)c2nc(F)ccc12
Agent: [Pd]
Product: NCc1nn(C2CCCCO2)c2nc(F)ccc12
Reaction time: 0.75 h

Procedure:
Compound 2-4 (135 mg; 0.49 mmol) was hydrogenated in the presence of 10% Pd on carbon catalyst (25 mg) under 1 atmosphere hydrogen pressure (balloon) at room temperature. After 45 minutes LC-MS indicated that the reduction was complete. The reaction mixture was filtered through Celite, and the filtrate concentrated in vacuo to give the title product as a clear oil/solid. MS M+1=251. 1H NMR (CDCl3): 1.61 (m, 1H), 1.78 (m, 2H), 1.92 (dd, 1H), 2.03 (br m, 1H), 2.13 (br m, 1H), 2.60 (br m, 1H), 3.80 (br t, 1H), 4.12 (dd, 1H), 4.22 (br s, 2H), 5.93 (dd, 1H), 6.78 (dd, 1H), 8.21 (t, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][CH2:10][O:11][CH3:12])=[N:6][CH:7]=1.C(N(CC)CC)C>C(O)C.[H][H].[Pt]=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][O:11][CH3:12])=[N:6][CH:7]=1
Reactant: COCC#Cc1ccc(Br)cn1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Solvent: CCN(CC)CC
Product: COCCCc1ccc(Br)cn1
Yield: 69.4 %

Procedure:
5-Bromo-2-(3-methoxypropynyl)pyridine (5.652 g) was dissolved in ethanol (150 ml), followed by the addition of triethylamine (2.5 ml) and platinum oxide (230 mg), and the resulting mixture was stirred in hydrogen atmosphere at room temperature for 5 hr. After the platinum oxide was filtered off, the resulting mixture was evaporated and partitioned between ethyl acetate and water. The resulting organic layer was washed with water, dried (over MgSO4) and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system), to give the title compound as a yellow oil (3.991 g, yield; 68%).
Reaction SMILES: COC(OC)N(C)C.[Br:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[CH3:19])[C:13]([OH:15])=[O:14].[C:20]1([CH3:26])[CH:25]=CC=C[CH:21]=1>>[Br:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[CH3:19])[C:13]([O:15][C:20]([CH3:26])([CH3:25])[CH3:21])=[O:14]
Reactant: Cc1ccccc1
Reactant: Cc1ccc(C(=O)O)cc1Br
Agent: COC(OC)N(C)C
Product: Cc1ccc(C(=O)OC(C)(C)C)cc1Br
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
Dimethylformamide dimethyl acetal (48 mL, 200 mmol) was added dropwise over 15 min to a suspension of 3-bromo-4-methylbenzoic acid (85%; 10.75 g, 42.5 mmol) in toluene (100 mL) at 70° C. The reaction was stirred at 70-80° C. for an additional 0.5 h, then was cooled, washed sequentially with water and 5% sodium bicarbonate, and dried (sodium sulfate). The mixture was filtered through a pad of silica gel, and the filter pad was washed with toluene. The filtrate was concentrated to afford the title compound (8.0 g, 69%) as a yellow oil. TLC (toluene) Rf 0.68.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[C:5]2[C:6]([CH:14]=O)=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.S1(CCCC1)(=O)=O.C([BH3-])#N.[Na+]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[C:5]2[C:6]([CH3:14])=[N:7][N:8]([CH:11]([CH3:12])[CH3:13])[C:9]=2[CH:10]=1
Reactant: COC(=O)c1cc(Br)cc2c1c(C=O)nn2C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: COC(=O)c1cc(Br)cc2c1c(C)nn2C(C)C
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a stirred solution of methyl 6-bromo-3-formyl-1-isopropyl-1H-indazole-4-carboxylate (4.5 g, 13.84 mmol) in DMF (31.5 mL) was added p-toluenesulfonic acid monohydrate (0.342 g, 1.8 mmol), p-toluenesulfonyl hydrazide (3.35 g, 18.0 mmol) followed by sulfolane (31.5 mL), and the reaction mixture was stirred at 100° C. for 1 h. The reaction mixture was cooled to room temperature and sodium cyanoborohydride (3.489 g, 55.0 mmol) was added portion wise over a period of 25 min. The resulting reaction mixture was stirred at 100° C. for 2 h and then at RT for 6 h. The reaction mixture was diluted with water and extracted with ethyl acetate (4×300 mL). The combined organic layers were washed with water, brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude residue (4.4 g) was purified by silica gel chromatography (eluent: 0-5% ethyl acetate: pet ether) to afford the title compound as an off white solid (2.95 g, 68%). 1H NMR (CDCl3, 400 MHz): δ 1.559 (d, J=6.8 Hz, 6H), 2.674 (s, 3H), 3.976 (s, 3H), 4.667-4.767 (m, 1H), 7.715 (d, J=1.6 Hz, 1H), 7.761 (d, J=1.6 Hz, 1H).-LCMS (ES+): 98.63%, 313.06 [M+H] ion present.
Reaction SMILES: CO[C:3](=[O:33])[CH2:4][O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([NH:16][C:17](=[O:32])[C:18]2[CH:23]=[C:22]([N:24]3[CH2:29][CH2:28][CH:27]([CH3:30])[CH2:26][CH2:25]3)[CH:21]=[C:20]([F:31])[CH:19]=2)=[CH:8][CH:7]=1.[NH2:34][NH2:35]>O1CCCC1>[F:31][C:20]1[CH:19]=[C:18]([CH:23]=[C:22]([N:24]2[CH2:25][CH2:26][CH:27]([CH3:30])[CH2:28][CH2:29]2)[CH:21]=1)[C:17]([NH:16][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]([O:5][CH2:4][C:3]([NH:34][NH2:35])=[O:33])=[CH:7][CH:8]=1)=[O:32]
Reactant: COC(=O)COc1ccc(NC(=O)c2cc(F)cc(N3CCC(C)CC3)c2)c2ccccc12
Reactant: NN
Solvent: C1CCOC1
Product: CC1CCN(c2cc(F)cc(C(=O)Nc3ccc(OCC(=O)NN)c4ccccc34)c2)CC1
Temperature: 25 °C

Procedure:
{4-[3-Fluoro-5-(4-methylpiperidin-1-yl)-benzoylamino]-naphthalen-1-yloxy}-acetic acid methyl ester (0.40 g, 0.88 mmol) in a solution of 1M hydrazine in tetrahydrofuran (10 ml) is heated at 80° C. for five hours. After cooling to room temperature the mixture is evaporated to dryness to give 3-fluoro-N-(4-hydrazinocarbonylmethoxy-naphthalen-1-yl)-5-(4-methylpiperidin-1-yl)-benzamide (0.40 g). MS: 451 (M+1).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:37]1[NH:42][CH2:41][C:40](=[O:43])[N:39]2[CH2:44][CH2:45][CH2:46][C@@H:38]12.C(=O)([O-])[O-].[K+].[K+].[NH4+].[Cl-]>CS(C)=O>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:42]3[CH2:41][C:40](=[O:43])[N:39]4[CH2:44][CH2:45][CH2:46][C@@H:38]4[CH2:37]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C1CNC[C@@H]2CCCN12
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc(F)ccc1-c1cc(N2CC(=O)N3CCC[C@@H]3C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 150 °C
Yield: 14.9 %

Procedure:
The title compound was prepared starting from 135 mg (0.253 mmoles) of 2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(4-fluoro-2-methylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide (WO 2005/002577), 70 mg (0.5 mmol) of (8aS)-hexahydropyrrolo[1,2-a]pyrazin-4(1H)-one (EP 300189), 70 mg (0.5 mmol) of potassium carbonate; the reagents were dissolved in 0.8 ml of DMSO. The reaction mixture was heated at 150° C. overnight and then added to a saturated NH4Cl solution and back extracted with DCM; the crude material was purified on SPE cartridge (Silica) eluting with a gradient cyclohexane/ethyl acetate 9:1, to ethyl acetate 100% and affording 24 mg of the title compound as pale yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22](S(C)(=O)=O)[N:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH3:31]>O1CCOCC1>[NH2:31][C:22]1[N:21]=[C:20]([CH2:19][N:13]2[C:14]([CH3:18])([CH3:17])[C:15](=[O:16])[N:11]([C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:6][CH:7]=3)[C:12]2=[O:30])[CH:25]=[CH:24][N:23]=1
Reactant: N
Reactant: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(S(C)(=O)=O)n3)C(C)(C)C2=O)cc1
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(N)n3)C(C)(C)C2=O)cc1

Procedure:
A solution of 0.45 g of 3-(4-tert-butylphenyl)-5,5-dimethyl-1-{[2-(methylsulphonyl)pyrimidin-4-yl]methyl}imidazolidine-2,4-dione obtained in stage e) in 2.1 mL of dioxane and 2.1 mL of 30% aqueous ammonia is heated in a sealed microwave tube at 120° C. for 1 hour. After evaporating off the solvents, 0.38 g of 1-[(2-aminopyrimidin-4-yl)methyl]-3-(4-tert-butylphenyl)-5,5-dimethylimidazolidine-2,4-dione is obtained, the characteristics of which are as follows:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C:6]1([CH2:15][CH2:14][CH:13]([O:16][CH3:17])[CH2:12][CH2:11]1)[C:5]2=[N:18]S(C(C)(C)C)=O.Cl.CCOCC>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8]([CH2:7][C:6]3([CH2:15][CH2:14][CH:13]([O:16][CH3:17])[CH2:12][CH2:11]3)[C:5]2=[NH:18])=[CH:9][CH:10]=1
Reactant: COC1CCC2(CC1)Cc1ccc(Br)cc1C2=NS(=O)C(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: COC1CCC2(CC1)Cc1ccc(Br)cc1C2=N
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of N-(5′-bromo-4-methoxyspiro[cyclohexane-1,2′-indene]-3′(1′H)-ylidene)-2-methylpropane-2-sulfinamide (Example 19 Step 1, mixture of isomers, 2 g, 4.85 mmol) in anhydrous 1,4-dioxane (25 mL) was added 4M HCl in 1,4-dioxane (12.12 mL, 48.50 mmol). A white precipitate was formed immediately and the resulting cloudy mixture was stirred under a nitrogen atmosphere at r.t. for 90 min. Et2O (30 mL) was added and the solid was filtered off and washed with Et2O. The solid was partitioned between DCM (40 mL) and sat. aq. NaHCO3 (40 mL). The phases were separated and the organic layer concentrated. The crude title compound (1.41 g) was used directly in the next step. MS (EI) m/z 307 M+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.[C:10]1([CH:16]([C:22](OCC)=[O:23])[C:17](OCC)=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1(OC2C=CC=CC=2)C=CC=CC=1>[C:10]1([C:16]2[C:17](=[O:18])[NH:9][C:5]3[C:6]([C:22]=2[OH:23])=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Reactant: COc1cccc(N)c1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1ccc2c(O)c(-c3ccccc3)c(=O)[nH]c2c1
Temperature: 25 °C
Yield: 91.9 %

Procedure:
A dark solution of 3-anisidine (5.37 g, 44.8 mmol), diethyl 2-phenylmalonate (10.57 g, 44.8 mmol), and diphenyl ether (50 mL) was heated at 220° C. for 1 h without a reflux condenser to allow ethanol evaporation. The reaction was cooled to rt, and the resultant gray precipitate filtered and washed with diethyl ether and dried to afford 11.0 g 2a (R2=7-OMe in Scheme 1, 92% yield): MS (M+H)+ 269.28.