Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OP([CH2:9][C:10]([N:12]1[CH2:33][CH2:32][C:15]2[C:16]3[C:21]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([F:29])=[C:25]([Cl:30])[CH:24]=4)=[N:20][CH:19]=[N:18][C:17]=3[S:31][C:14]=2[CH2:13]1)=[O:11])(=O)OCC)C.[H-].[Na+].[CH:36]([C@@H:38]1[CH2:42][CH2:41][CH2:40][N:39]1[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=O.CO>C1COCC1>[Cl:30][C:25]1[CH:24]=[C:23]([NH:22][C:21]2[C:16]3[C:15]4[CH2:32][CH2:33][N:12]([C:10](=[O:11])/[CH:9]=[CH:36]/[C@@H:38]5[CH2:42][CH2:41][CH2:40][N:39]5[C:43]([O:45][C:46]([CH3:47])([CH3:49])[CH3:48])=[O:44])[CH2:13][C:14]=4[S:31][C:17]=3[N:18]=[CH:19][N:20]=2)[CH:28]=[CH:27][C:26]=1[F:29]
Reactant: CCOP(=O)(CC(=O)N1CCc2c(sc3ncnc(Nc4ccc(F)c(Cl)c4)c23)C1)OCC
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1/C=C/C(=O)N1CCc2c(sc3ncnc(Nc4ccc(F)c(Cl)c4)c23)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of diethyl(2-{4-[(3-chloro-4-fluorophenyl)amino]-5,8-dihydropyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-7(6H)-yl}-2-oxoethyl)phosphonate from Example 13A (644 mg, 1.26 mmol) in THF (2.5 mL) was cooled to −78° C. Sodium hydride (60% in mineral oil, 50 mg, 1.26 mmol) was added, and the mixture was stirred for 15 min. Subsequently, a solution of tert-butyl (2S)-2-formylpyrrolidine-1-carboxylate (250 mg, 1.26 mmol) in THF (2.5 mL) was added dropwise. The mixture was slowly warmed to rt and stirred overnight. Methanol was added, and the solvent was removed in vacuo. The crude product was purified by preparative HPLC, and the title compound crystallized from PE/MTBE to yield 397 mg (56%).
Reaction SMILES: [H-].[Na+].[C:3]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[C:17]1[C:18]([CH3:26])=[N:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=1>CN(C=O)C>[CH3:26][C:18]1[C:17]([CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])=[CH:22][CH:21]=[C:20]([N+:23]([O-:25])=[O:24])[N:19]=1
Reactant: CCOC(=O)CC(=O)OC(C)(C)C
Reactant: Cc1nc([N+](=O)[O-])ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])nc1C
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a suspension of NaH (60% in oil, 1.4 g, 36 mmol)) in DMF (50 mL) was added tert-butyl ethyl propanedioate (6.8 g, 36 mmol) at room temperature. The mixture was stirred for 30 min. A solution of 3-chloro-2-methyl-6-nitropyridine (4.8 g, 28 mmol) in DMF (10 mL) was added. The mixture was heated to 80° C. and stirred for 5 h. Cooled to ambient temperature, poured to ice/water, extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated and the residue was purified by column chromatography to give title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:14]=[C:13]([CH2:15][OH:16])[O:12][N:11]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:14]=[C:13]([CH2:15][OH:16])[O:12][N:11]=2)=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(-c2cc(CO)on2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(-c2cc(CO)on2)cc1

Procedure:
[3-(4-nitro-phenyl)-isoxazol-5-yl]-methanol (300 mg, 1.58 mmol) was placed in a 250-ml Parr reactor flask, to which were added 50 ml of ethanol and 10 wt % Pd/C. The mixture was reacted under 40 psi of hydrogen in the Parr reactor for about 1 hour. The completion of the reaction was confirmed by TLC, and then a filtrate by means of a celite placed was distilled under reduced pressure to obtain a yellow solid compound. This was recrystallized from ethyl acetate/hexane (1:2) to obtain [3-(4-amino-phenyl)-isoxazol-5-yl]-methanol in a yellow solid state.
Reaction SMILES: C(N1C=CN=C1)([N:3]1C=CN=C1)=O.[O:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[C:21]([CH2:22][C:23]([OH:25])=O)[C:16]=2[CH:15]=[CH:14]1.N>O1CCCC1>[O:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[C:21]([CH2:22][C:23]([NH2:3])=[O:25])[C:16]=2[CH:15]=[CH:14]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)Cc1cccc2occc12
Agent: N
Solvent: C1CCOC1
Product: NC(=O)Cc1cccc2occc12
Temperature: 20 °C
Reaction time: 4 h

Procedure:
Add 1,1′-carbonyldiimidazole (2.3 g, 14.2 mmol) to a solution of 2-(benzofur-4-yl)acetic acid (2.5 g, 14.2 mmol) in anhydrous tetrahydrofuran (12 mL) under nitrogen and stir at 20° C. for 4 hours. Bubble anhydrous ammonia through the solution, dilute with anhydrous tetrahydrofuran (10 mL) and stir at 20° C. for 18 hours. Concentrate under reduced pressure, wash the solid with aqueous sodium hydrogen sulfate, distilled water, and dry under vacuum to obtain the title compound as a pale yellow solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]([CH3:17])[CH:14]=[C:13]([OH:18])[C:12]2=[O:19].[OH-].[Na+]>O>[CH3:1][S:2]([O:18][C:13]1[C:12](=[O:19])[C:11]2[C:16](=[C:7]([F:6])[CH:8]=[CH:9][CH:10]=2)[N:15]([CH3:17])[CH:14]=1)(=[O:4])=[O:3]
Reactant: Cn1cc(O)c(=O)c2cccc(F)c21
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1cc(OS(C)(=O)=O)c(=O)c2cccc(F)c21
Reaction time: 0.33 h

Procedure:
Methanesulphonyl chloride (1.1 g) d to a solution of 8-fluoro-3-hydroxy-1 -methyl-4-quinolone (1.83 g) and sodium hydroxide (0.6 g) in water (15 ml) and the resultant mixture stirred at 0 to 5° for 3 hours with the pH being adjusted to 9 after 20 minutes using aqueous sodium hydroxide (5M, 2 ml). Further methanesulphonyl chloride (1.1 g) was then added and the mixture stirred for 105 minutes whilst maintaining the pH at 9 by the addition of aqueous sodium hydroxide (5M, 2ml). The resultant solid was collected by filtration, washed with water (20 ml) and crystallised from industrial methylated spirit (100 ml) to give the novel compound 8-fluoro-1-methyl-4-oxo-1,4-dihydroquinol-3-yl methanesulphonate, m.p. 207°-209°.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.C([O-])(O)=O.[Na+].[CH2:43]([O:50][C:51]1[CH:56]=[CH:55][C:54](B(O)O)=[CH:53][CH:52]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>CN(C=O)C>[C:33]([O:32][C:31](=[O:37])[NH:30][C:26]1([C:23]2[CH:24]=[CH:25][C:20]([C:19]3[N:5]4[C:6]5[CH:18]=[CH:17][CH:16]=[N:15][C:7]=5[NH:8][C:9]5[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=5[C:4]4=[N:3][C:2]=3[C:54]3[CH:55]=[CH:56][C:51]([O:50][CH2:43][C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[CH:52][CH:53]=3)=[CH:21][CH:22]=2)[CH2:27][CH2:28][CH2:29]1)([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(Cl)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc(OCc5ccccc5)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 160 °C
Yield: 87.2 %

Procedure:
To a solution of tert-butyl {1-[4-(2-chloro-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (50 mg, 0.097 mmol) in DMF (1 mL) was added saturated NaHCO3, 4-benzyloxyphenylboronic acid (45 mg, 0.20 mmol) and PdCl2(Me2NPhP(tBu)2)2 (7 mg, 0.0097 mmol). The reaction was degassed for 2 minutes and then heated at 160° C., 1 h (microwave reactor). The reaction mixture was cooled to room temperature, then was diluted with EtOAc (15 mL) and washed with brine. The organic phase was dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (SiO2, 10% to 50% EtOAc in hexane) gave the title compound as a yellow solid (56 mg). 1HNMR (CDCl3) 400 MHz δ: 8.17-8.15 (m, 1H), 8.00-7.99 (m, 1H), 7.51 (d, J=8.6 Hz, 2H), 7.48-7.23 (m, 8H), 7.15-7.13 (m, 3H), 6.94 (d, J=7.4 Hz, 1H), 6.89 (d, J=8.6 Hz, 2H), 6.79 (d, J=7.4 Hz, 1H), 6.59 (dd, J=7.7, 4.9 Hz, 1H), 6.30 (s, 1H), 5.12 (br s, 1H), 5.05 (s, 2H), 2.53-2.51 (m, 4H), 2.15-2.12 (m, 1H), 1.93-1.84 (m, 1H), 1.39 (br s, 9H).
Reaction SMILES: [C:1]([Cu])#[N:2].Br[C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:20])[N:12]2[CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:7][CH:6]=1>CN(C=O)C.CCOCC.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:1]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:20])[N:12]2[CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:7][CH:6]=1)#[N:2]
Reactant: N#C[Cu]
Reactant: COC(=O)Cn1c(=O)ccc2ccc(Br)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)Cn1c(=O)ccc2ccc(C#N)cc21
Reaction time: 18 h
Yield: 71.4 %

Procedure:
CuCN (0.211 g, 2.36 mmol) and Pd(PPh3)4 (0.136 g, 0.118 mmol) were added to a solution of methyl 2-(7-bromo-2-oxoquinolin-1(2H)-yl)acetate (0.35 g, 1.18 mmol) in DMF (1 mL) in a screw cap vial. The vial was sealed and placed into a oil bath at 120° C. and the reaction mixture was stirred for 18 h. The resulting mixture was diluted with Et2O and washed with brine. The organic phase was separated, dried (Na2SO4), filtered, concentrated under vacuum and the residue was purified on a silica gel column to give methyl 2-(7-cyano-2-oxoquinolin-1(2H)-yl)acetate (0.204 g, 71%). Retention time (min)=1.464, method [1], MS(ESI) 243.1 (M+H).
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([O:12][CH2:13][C:14]([OH:16])=O)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+]([O-])(O)=O.[O:21]([CH2:25][CH2:26][NH2:27])[N+:22]([O-:24])=[O:23].C(OC(C)C)(C)C>>[O:21]([CH2:25][CH2:26][NH:27][C:14](=[O:16])[CH2:13][O:12][C:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:11][N:10]=1)[N+:22]([O-:24])=[O:23]
Reactant: NCCO[N+](=O)[O-]
Reactant: O=C(O)COc1cc(-c2ccccc2)on1
Solvent: CC(C)OC(C)C
Solvent: O=[N+]([O-])O
Product: O=C(COc1cc(-c2ccccc2)on1)NCCO[N+](=O)[O-]
Yield: 53.2 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.78 g of 5-phenyl-3-isoxazolyloxyacetic acid and 0.60 g of nitroxyethylamine nitrate, 0.58 g of the title compound was obtained as colorless needles (solvent for recrystallization; diisopropyl ether).
Reaction SMILES: [CH2:1]([O:5][C:6]([C@@H:8]1[CH2:13][CH2:12][C@H:11]([C:14](O)=[O:15])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].B>O1CCCC1>[OH:15][CH2:14][C@@H:11]1[CH2:10][CH2:9][C@H:8]([C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:7])[CH2:13][CH2:12]1
Reactant: CCCCOC(=O)[C@H]1CC[C@@H](C(=O)O)CC1
Agent: B
Solvent: C1CCOC1
Product: CCCCOC(=O)[C@H]1CC[C@@H](CO)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of crude cis-4-(butoxycarbonyl)cyclohexanecarboxylic acid (36.5 g) in dry tetrahydrofuran (300 ml) under nitrogen cooled in an ice-bath was added dropwise over 20 minutes 1.0M borane in tetrahydrofuran (150 ml, 150 mmol). The ice-bath was removed and the solution was stirred at ambient temperature for three hours. Water (200 ml) was added dropwise to the stirred solution, the mixture stirred an additional 15 minutes, and potassium carbonate (7.5 g) was added. The mixture was diluted with ether (500 ml) and the layers were separated. The organic layer was washed with brine (100 ml), dried (sodium sulfate), filtered, and the solvent was evaporated under reduced pressure to give crude product (32.38 g) as a pale yellow oil. The crude product was purified by flash column chromatography on silica gel, eluting with ethyl acetate/hexane (10:90 increasing to 50:50). The first compound to elute was dibutyl cis-cyclohexane-1,4-dicarboxylate (MS.: 285.3 (M+1), 3.92 g, 10%), followed by butyl cis-4-(hydroxymethyl)-cyclohexane carboxylate (23.97 g, 75%), as a pale yellow oil: 1H NMR (CDCl3) 4.08 (2H, t, J 7 Hz), 3.50 (1H, t, J 7 Hz), 2.56 (1H, m), 2.02 (2H, m), 1.52-1.65 (7H, m), 1.26-1.41 (5H, m), 0.94 (3H, t, J 7 Hz). MS.: 215.3 (M+1).
Reaction SMILES: [F:1][C:2]1([F:13])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([NH:11]N)[C:4]=2[O:3]1.Cl.[NH:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1.Cl>C(O)C.O1CCOCC1>[F:1][C:2]1([F:13])[O:6][C:5]2[CH:7]=[CH:8][C:9]3[C:17]4[CH2:16][NH:15][CH2:20][CH2:19][C:18]=4[NH:11][C:10]=3[C:4]=2[O:3]1
Reactant: NNc1cccc2c1OC(F)(F)O2
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: FC1(F)Oc2ccc3c4c([nH]c3c2O1)CCNC4
Temperature: 110 °C
Reaction time: 2 h
Yield: 14.6 %

Procedure:
The (2,2-difluoro-benzo[1,3]dioxol-4-yl)-hydrazine (753 mg, 4.00 mmol) and 4-piperidone hydrochloride (543 mg, 4.00 mmol) in ethanol (10 mL) were heated to reflux for 45 min. The 4M HCl in dioxane (2 mL) was added and heating continued for 2 h. A sample was removed and after bubbling HCl gas briefly was heated in the microwave to 110° C. for 10 min. The rest of the material was processed in 5 batches and the combined black reactions filtered, washed with a little water and then precipitation with Et2O:Hexane 1:2 (c.f. 10 mL) before drying the resulting grey solid (147 mg, 13% yield)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:18])[CH2:11][N:12]([CH3:17])[CH2:13][C:14]([OH:16])=O)=[CH:5][CH:4]=1)#[N:2].[CH2:19]([N:21]1[C:33]2[CH:32]=[CH:31][C:30]([NH2:34])=[CH:29][C:28]=2[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH3:20]>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:18])[CH2:11][N:12]([CH3:17])[CH2:13][C:14]([NH:34][C:30]2[CH:31]=[CH:32][C:33]3[N:21]([CH2:19][CH3:20])[C:22]4[C:27]([C:28]=3[CH:29]=2)=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:16])=[CH:7][CH:8]=1)#[N:2]
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: CN(CC(=O)O)CC(=O)Nc1ccc(C#N)cc1
Product: CCn1c2ccccc2c2cc(NC(=O)CN(C)CC(=O)Nc3ccc(C#N)cc3)ccc21

Procedure:
Using the compound obtained in Step 1 and 9-ethyl-9H-carbazol-3-amine, and by the reaction and purification in the same manner as in the method described in Step 2 of Example 3, the title compound was obtained.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1.[C:11]([C:13]1[CH:14]=[C:15]([C:19](=[O:21])[CH3:20])[CH:16]=[CH:17][CH:18]=1)#[CH:12].N>>[N:5]1[CH:6]=[CH:7][N:8]=[CH:9][C:4]=1[C:3]1[CH:12]=[C:11]([C:13]2[CH:14]=[C:15]([C:19](=[O:21])[CH3:20])[CH:16]=[CH:17][CH:18]=2)[O:1][N:2]=1
Reactant: C#Cc1cccc(C(C)=O)c1
Reactant: ON=C(Cl)c1cnccn1
Agent: N
Product: CC(=O)c1cccc(-c2cc(-c3cnccn3)no2)c1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 83D (79 mg, 0.5 mmol) and 1-(3-ethynylphenyl)ethanone (GFS Chemicals, 72 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ 2.70 (s, 3H), 7.55 (s, 1H), 7.71 (t, J=7.8 Hz, 1H), 8.07-8.23 (m, 2H), 8.52 (t, J=1.7 Hz, 1H), 8.70 (d, J=2.7 Hz, 1H), 8.74-8.82 (m, 1H), 9.31 (d, J=1.7 Hz, 1H) ppm; MS (DCI/NH3) m/z 266 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]([NH:22][S:23]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)(=[O:25])=[O:24])=[N:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35][NH2:36]>CN(C=O)C>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([NH:11][C:12]2[C:13]([NH:22][S:23]([C:26]3[CH:27]=[N:28][C:29]([NH:36][CH2:35][CH2:34][N:33]([CH3:37])[CH3:32])=[CH:30][CH:31]=3)(=[O:24])=[O:25])=[N:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2cccnc2)cc(OC)c1
Reactant: CN(C)CCN
Solvent: CN(C)C=O
Product: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2ccc(NCCN(C)C)nc2)cc(OC)c1
Reaction time: 8 h
Yield: 19.1 %

Procedure:
N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)pyridine-3-sulfonamide (100 mg, 0.21 mmol), KHCO3 (40 mg, 0.40 mmol), N1,N1-dimethylethane-1,2-diamine (225 μl, 2.0 mmol) and dry DMF (1.0 mL) were combined and heated to 130 C. with stirring overnight. The reaction mixture was concentrated in vacuo and purified by preparative HPLC to give N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-6-(2-(dimethylamino)ethylamino)pyridine-3-sulfonamide (21.0 mg, 19%). 1H NMR (400 MHz, DMSO-d6) δ 8.76 (br s, 1H), 8.63 (d, 1H), 8.07 (dd, 1H), 7.40 (m, 1H), 7.34 (m, 1H), 7.28 (d, 2H), 7.14 (m, 4H), 6.47 (d, 1H), 6.12 (m, 1H), 3.75 (s, 6H), 3.35 (m, 2H), 3.14 (m, 2H), 2.74 (s, 6H). MS (EI) for C25H29N7O4S: 524.1 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[N:26]=[CH:25][N:24]([CH3:27])[N:23]=2)=[N:10]1.Cl.[NH:29]1[CH2:34][CH2:33][O:32][CH:31]([CH2:35][C:36]([OH:38])=[O:37])[CH2:30]1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[N:26]=[CH:25][N:24]([CH3:27])[N:23]=2)[NH:12][C:13]([CH2:20][N:29]2[CH2:34][CH2:33][O:32][CH:31]([CH2:35][C:36]([OH:38])=[O:37])[CH2:30]2)=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(CBr)NC(c2ncn(C)n2)=NC1c1ccc(F)cc1Br
Reactant: O=C(O)CC1CNCCO1
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOC(CC(=O)O)C2)NC(c2ncn(C)n2)=NC1c1ccc(F)cc1Br
Yield: 41.6 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(1-methyl-1H-1,2,4-triazol-3-yl)-1,4-dihydropyrimidine-5-carboxylate (1 g, 2 mmol) was reacted with 2-(morpholin-2-yl)acetic acid hydrochloride (0.36 g, 2 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.47 g, 42%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[Cl:19])[NH2:15]>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:15][C:14]1[CH:16]=[CH:17][C:18]([Cl:19])=[C:12]([Cl:11])[CH:13]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: Nc1ccc(Cl)c(Cl)c1
Product: Clc1ccc(Nc2nc3ccccc3[nH]2)cc1Cl

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 3,4-dichloroaniline by Procedure A. The product was isolated by filtration to give the title compound as a hydrochloride salt (white solid, mp>270° C.). MS(ES+) m/z 278 (M+, 100).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]=[O:18])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH2:19]([Mg]Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([OH:18])[CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=Cc1ccc2c(cnn2-c2ccc(F)cc2)c1
Reactant: Br[Mg]Cc1ccccc1
Solvent: C1CCOC1
Product: OC(Cc1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To 1-(4-fluorophenyl)-1H-indazole-5-carbaldehyde (240 mg, 1.0 mmol) in anhydrous THF (5 mL) was added benzylmagnesium bromide (19% solution in THF, 3 mL, 3 mmol) dropwise at rt under argon. The reaction mixture was stirred at rt for 30 min and quenched by the slow addition of saturated aqueous ammonium chloride solution (5 mL). The mixture was extracted with ethyl acetate (2×4 mL). The combined ethyl acetate extracts were dried (Na2SO4), concentrated and purified by silica gel flash chromatography to give 1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-phenylethanol (330 mg, 1.0 mmol, 100% yield) as a yellow oil.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[CH:8]=[C:7](Cl)[S:6]1(=[O:13])=[O:12])([CH3:4])([CH3:3])[CH3:2].[Si:14]([O:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>>[C:1]([N:5]1[C:9](=[O:10])[CH:8]=[C:7]([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([O:21][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16])[CH:23]=2)[S:6]1(=[O:13])=[O:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N1C(=O)C=C(Cl)S1(=O)=O
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(B(O)O)c1
Product: CC(C)(C)N1C(=O)C=C(c2cccc(O[Si](C)(C)C(C)(C)C)c2)S1(=O)=O

Procedure:
This compound was prepared according to the procedure of Example 1.1, Step 4, using 9-A and 3-(t-butyldimethylsilyoxy)phenylboronic acid as the starting materials. 1H NMR (500 MHz, CDCl3): δ 7.37–7.36 (m, 2H), 7.25–7.24 (m, 1H), 7.03–7.01 (m, 1H), 6.61 (s, 1H), 1.73 (s, 9H), 0.99 (s, 9H), 0.23 (s, 6H); LCMS found for C19H29NO4SSi (M+H)+: m/z=418.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C(#N)C>[N:14]1([CH:2]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[C:3]([O:5][CH3:6])=[O:4])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C1CCNCC1
Reactant: COC(=O)C(Br)c1ccc(C)cc1
Solvent: CC#N
Product: COC(=O)C(c1ccc(C)cc1)N1CCCCC1
Yield: 10.7 %

Procedure:
To a solution of methyl 2-bromo-2-p-tolylacetate (2.50 g, 10.3 mmol) in acetonitrile, was added piperidine (2.06 ml, 20.6 mmol) and the mixture was reacted for 2 hours at room temperature. The solvent was evaporated and the resulting crude was portioned between water and EtOAc. The aqueous phase was extracted with EtOAc, the organic phases were combined, dried over Na2SO4, filtered and evaporated to dryness. The crude was purified by flash chromatography (petroleum ether/EtOAc=9/1) to obtain methyl 2-(piperidin-1-yl)-2-p-tolylacetate (273 mg, 21% yield) as a colourless oil.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]([CH2:15][OH:16])=[C:13](/[CH:17]=[CH:18]/[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:12][N:11]=2)=[CH:6][CH:5]=1.Cl[C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][N:27]=1>C1COCC1>[CH3:33][O:32][C:30](=[O:31])[C:29]1[CH:34]=[CH:35][C:26]([O:16][CH2:15][C:14]2[C:10]([C:7]3[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=3)=[N:11][O:12][C:13]=2/[CH:17]=[CH:18]/[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[N:27][CH:28]=1
Reactant: OCc1c(-c2ccc(Cl)cc2)noc1/C=C/c1ccccc1
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCc2c(-c3ccc(Cl)cc3)noc2/C=C/c2ccccc2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.5 %

Procedure:
To a suspension of sodium hydride (2.64 g, 60.5 mmol) in THF (100 mL) was added a solution of [3-(4-chloro-phenyl)-5-([E]-styryl)-isoxazol-4-yl]-methanol (17.2 g, 55.0 mmol) in THF (185 mL) at 0° C. The reaction mixture was stirred for 60 min at room temperature. A solution of methyl 6-chloronicotinate (10.6 g, 60.5 mmol) in THF (185 mL) was added at 0° C. The mixture was stirred at room temperature for 2 h and the product was extracted with ethyl acetate/aqueous ammonium chloride and ethyl acetate/brine. Chromatography (silica, ethyl acetate:heptane 2:8 to 7:3) afforded the title compound (15.6 g, 64%) as a white solid. MS: m/e (%)=446 (0.7, M+), 309 (47), 294 (28), 240 (26), 131 (100), 103 (51).
Reaction SMILES: [O-]S(S([O-])=O)=O.[Na+].[Na+].[Br:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([S:17][C:18]2[C:23]([N+]([O-])=O)=[C:22](/[CH:27]=[CH:28]/[N:29](C)C)[N:21]=[C:20]([N:32]([C:40]3[CH:45]=[CH:44][C:43]([C:46]#[N:47])=[CH:42][CH:41]=3)[C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[N:19]=2)=[C:12]([CH3:48])[CH:11]=1>O.C1COCC1>[Br:9][C:10]1[CH:11]=[C:12]([CH3:48])[C:13]([S:17][C:18]2[C:23]3[NH:29][CH:28]=[CH:27][C:22]=3[N:21]=[C:20]([N:32]([C:40]3[CH:45]=[CH:44][C:43]([C:46]#[N:47])=[CH:42][CH:41]=3)[C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[N:19]=2)=[C:14]([CH3:16])[CH:15]=1
Reactant: Cc1cc(Br)cc(C)c1Sc1nc(N(C(=O)OC(C)(C)C)c2ccc(C#N)cc2)nc(/C=C/N(C)C)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Br)cc(C)c1Sc1nc(N(C(=O)OC(C)(C)C)c2ccc(C#N)cc2)nc2cc[nH]c12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of Na2S2O4 (230 mmol) in water (100 ml) is added to a solution of tert-butyl 4-(4-bromo-2,6-dimethylphenylthio)-6-((E)-2-(dimethylamino)vinyl)-5-nitropyrimidin-2-yl4-cyanophenylcarbamate (46 mmol) in THF (300 ml). The mixture is stirred at room temperature for 2 days and then concentrated. The residue is washed with water and extracted with ethyl acetate. The organic layer is concentrated and the product obtained by crystallization from a mixture of water and methanol.