Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]([NH2:7])=[S:6])(=[O:3])[CH3:2].[CH:8]([O:21][C:22]([C:24]1[N:25]2[CH:28]([S:29][CH2:30][C:31]=1[CH:32](Br)[CH:33]=O)[CH:27]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:26]2=[O:44])=[O:23])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1CCCC1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[C:1]([NH:4][C:5]1[S:6][C:32]([C:31]2[CH2:30][S:29][CH:28]3[N:25]([C:26](=[O:44])[CH:27]3[NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:24]=2[C:22]([O:21][CH:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:23])=[CH:33][N:7]=1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C(Br)C=O)CSC12
Reactant: CC(=O)NC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)Nc1ncc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)OC(C)(C)C)C3SC2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8.9 %

Procedure:
A solution of acetylthiourea (1.8 g) in dry tetrahydrofuran (20 cc) is added, in 5 minutes, to a solution, cooled to 3° C., of the mixture of the epimers of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-(1-bromo-2-oxoethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (5.87 g) in dry tetrahydrofuran (58.7 cc). The reaction mixture is then stirred for 4 hours 30 minutes at 25° C. after which it is diluted with ethyl acetate (150 cc) and saturated sodium bicarbonate solution (150 cc). The organic layer is washed with distilled water (2×100 cc) and then with saturated sodium chloride solution (100 cc) and dried. After evaporation of the solvent under reduced pressure (30 mm Hg; 4 kPa) at 30° C., the residue is chromatographed on a column (height: 30 cm; diameter: 6 cm) of silica (0.04-0.06 mm), elution being carried out under a pressure of 0.4 bar (40 kPa) with a 70:30 (by volume) mixture (1600 cc) of cyclohexane and ethyl acetate and then with a 30:70 (by volume) mixture (2000 cc) of cyclohexane and ethyl acetate, 100 cc fractions being collected. Fractions 27 to 33, containing the pure product, are combined and evaporated to dryness. 3-(2-Acetylamino-thiazol-5-yl)-2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (0.54 g) is obtained in the form of a yellow froth.
Reaction SMILES: I.I.[N:3]1([C:10]2[N:14]([CH2:15][C:16]([F:19])([F:18])[F:17])[C:13]3[CH:20]=[CH:21][CH:22]=[CH:23][C:12]=3[N:11]=2)[CH2:9][CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH:36]=[N:35][N:34]=[N:33]2)=[CH:28][C:27]=1[C:37]([N:39]1[CH2:43][CH2:42][C@:41]([CH2:50][CH2:51]OS(C)(=O)=O)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:40]1)=[O:38].C(N(CC)CC)C>C(#N)C>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH:36]=[N:35][N:34]=[N:33]2)=[CH:28][C:27]=1[C:37]([N:39]1[CH2:43][CH2:42][C@@:41]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([CH2:50][CH2:51][N:6]2[CH2:7][CH2:8][CH2:9][N:3]([C:10]3[N:14]([CH2:15][C:16]([F:19])([F:17])[F:18])[C:13]4[CH:20]=[CH:21][CH:22]=[CH:23][C:12]=4[N:11]=3)[CH2:4][CH2:5]2)[CH2:40]1)=[O:38]
Reactant: FC(F)(F)Cn1c(N2CCCNCC2)nc2ccccc21
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N1CC[C@](CCOS(C)(=O)=O)(c2ccccc2)C1
Agent: I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(-n2cnnn2)cc1C(=O)N1CC[C@](CCN2CCCN(c3nc4ccccc4n3CC(F)(F)F)CC2)(c2ccccc2)C1
Yield: 77 %

Procedure:
Reflux a stirred solution of 2-[1,4]diazepan-1-yl-1-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole dihydroiodide (0.44 g, 0.79 mmol), methanesulfonic acid 2-{(S)-1-[1-(2-methoxy-5-tetrazol-1-yl-phenyl)-methanoyl]-3-phenyl-pyrrolidin-3-yl}-ethyl ester (0.38 g, 0.79 mmol, example 47.2), triethylamine (2.54 mmol) and acetonitrile (11 mL) under argon for 20 hours. Cool and concentrate in vacuo. Dilute with dichloromethane (100 mL), wash the organic phase with NaHCO3 solution (2×20 mL), dry (Na2SO4) the organic phase, filter and evaporate in vacuo. Purify the residue by flash chromatography (silica gel, 7×15 cm) eluting with 10% methanol/0.1% ammonium hydroxide solution in dichloromethane, concentrate the appropriate fractions, and dry the resultant material in vacuo (0.2 Torr) for 2 hours to afford 0.41 g of the title compound as a beige colored foam, Rf=0.39 (silica gel, 10% methanol/0.1% ammonium hydroxide solution in dichloromethane). The compound may be converted to the dihydrochloride salt by methods well known in the art.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([NH2:20])[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[N:21]1[CH:26]=[CH:25][N:24]=[CH:23][C:22]=1[C:27](Cl)=[O:28].C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.CN(C)C(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([NH:20][C:27]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][N:21]=3)=[O:28])[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: O=C(Cl)c1cnccn1
Reactant: Cc1cc(C)cc(-c2nc(N)sc2-c2ccncc2)c1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(C)cc(-c2nc(NC(=O)c3cnccn3)sc2-c2ccncc2)c1
Temperature: 70 °C
Reaction time: 14 h
Yield: 58.8 %

Procedure:
To a solution of [4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]amine (0.50 g, 1.8 mmol) and 4-dimethylaminopyridine (0.06 g, 0.53 mmol) in N,N-dimethylacetamide (5 mL) was added pyrazinecarbonyl chloride (0.44 g, 2.7 mmol) and the mixture was stirred at 70° C. for 14 h. To the reaction mixture was poured aqueous sodium hydrogencarbonate solution and the precipitated solid was collected by filtration. The obtained solid was washed with water and dried. The crude crystals were recrystallized from ethanol to give the title compound (0.41 g, yield 59%).
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[CH:9]([C:11]1[C:12]([O:25][CH2:26][C:27]#[C:28][C:29]2[CH:39]=[CH:38][C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:31][CH:30]=2)=[CH:13][C:14]2[C:15]([CH3:24])([CH3:23])[CH2:16][CH2:17][C:18]([CH3:22])([CH3:21])[C:19]=2[CH:20]=1)=O>CO>[OH:3][N:2]=[CH:9][C:11]1[C:12]([O:25][CH2:26][C:27]#[C:28][C:29]2[CH:39]=[CH:38][C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:31][CH:30]=2)=[CH:13][C:14]2[C:15]([CH3:24])([CH3:23])[CH2:16][CH2:17][C:18]([CH3:22])([CH3:21])[C:19]=2[CH:20]=1
Reactant: NO
Reactant: CCOC(=O)c1ccc(C#CCOc2cc3c(cc2C=O)C(C)(C)CCC3(C)C)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)c1ccc(C#CCOc2cc3c(cc2C=NO)C(C)(C)CCC3(C)C)cc1
Temperature: 50 °C
Reaction time: 11 h
Yield: 62.5 %

Procedure:
0.2 g of hydroxylamine hydrochloride and 0.26 g of sodium acetate were added to 15 ml of a solution of 0.51 g of ethyl 4-[3-(3-formyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoxy)-1-propynyl]benzoate in methanol at room temperature. The obtained mixture was stirred at 50° C. for 11 hours and distilled to remove the methanol, followed by the addition thereto of 20 ml of water. The obtained mixture was extracted with ethyl acetate. The organic phase was washed with a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was purified by silica gel chromatography (developer: 30% diethyl ether/n-hexane) to give 0.33 g of the title compound as a pale-yellow oil. 1H-NMR (400 MHz, CDCl3) δ(ppm); 1.28(s, 6H), 1.30(s, 6H), 1.36(t, J=7.2 Hz, 3H), 1.68(brs, 4H), 4.36(q, J=7.2 Hz, 2H), 4.94(s, 2H), 7.04(s, 1H), 7.47(d, J=8.4 Hz, 2H), 7.68(s, 1H), 7.98(d, J=8.4 Hz, 2H), 8.50(s, 1H)
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:13])[C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.Br[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].[I-].[K+]>C(Cl)(Cl)Cl.[Ag]=O>[O:13]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10](=[O:12])[CH:11]=[C:2]1[O:1][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]
Reactant: O=C1C=C(O)C(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=[Ag]
Agent: [I-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)COC1=CC(=O)c2ccccc2C1=O

Procedure:
a mixture of 2-hydroxynaphthalene-1,4-dione (6, 0.52 g, 3.0 mmol), tert-butyl 2-bromoacetate (0.78 g, 4.0 mmol), silver oxide (0.93 g, 4.0 mmol) and potassium iodide (0.05 g, 0.3 mmol) were refluxed in 10 ml of chloroform overnight under Ar. The reaction mixture was filtered and washed with DCM (3×20 ml), the filtrate was concentrated and purified with flash chromatography to give compound 7c as a light yellow solid, 13%, m.p.=120-122° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19]([OH:21])=O)=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Cl.[CH2:29]([CH2:31][NH2:32])[OH:30]>>[OH:30][CH2:29][CH2:31][NH:32][C:19]([C:17]1[S:18][C:13]2[C:12]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[N:11][C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[CH:3]=[N:2][NH:1]4)=[N:15][C:14]=2[CH:16]=1)=[O:21]
Reactant: NCCO
Reactant: O=C(O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Agent: Cl
Product: O=C(NCCO)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylic acid 13 (30 mg) was coupled to ethanolamine HCl via General Procedure B. The product was purified via reverse phase HPLC to give 6.3 mg of 266. MS (Q1) 424.8 (M)+.
Reaction SMILES: [Na].[CH:2]1([N:7]2[C:11]([NH2:12])=[C:10]([C:13]([NH2:15])=[O:14])[C:9]([CH2:16][CH3:17])=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH2:26][C:27](OCC)=O)[CH:23]=[CH:24][CH:25]=1.Cl>C(O)C.O>[CH:2]1([N:7]2[C:11]3=[N:12][C:27]([CH2:26][C:22]4[CH:23]=[CH:24][CH:25]=[C:20]([O:19][CH3:18])[CH:21]=4)=[N:15][C:13](=[O:14])[C:10]3=[C:9]([CH2:16][CH3:17])[NH:8]2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)Cc1cccc(OC)c1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCc1[nH]n(C2CCCC2)c2nc(Cc3cccc(OC)c3)nc(=O)c1-2
Temperature: 25 °C
Yield: 55.4 %

Procedure:
Sodium (1.19 g) was dissolved in ethanol (85 mL) and 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (5.7 g, 26 mmol) and then ethyl 3-methoxyphenylacetate (10 g) were added. The reaction mixture was refluxed overnight, cooled to room temperature and the solvent was stripped. Water was added to the residue, followed by 2N HCl and the precipitate which formed was collected by filtration and recrystallized from ethyl acetate to afford 5.08 g of 1-cyclopentyl-3-ethyl-6-(3-methoxyphenylmethyl)pyrazolo[3,4-d]pyrimidin-4-one, m.p. 148°-150° C.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13](=[O:22])[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])=[CH:8][CH:7]=1)([OH:3])=[O:2].CO[CH:25](OC)[N:26]([CH3:28])[CH3:27].Cl>CN(C)C=O>[C:1]([CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:13](=[O:22])[C:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:15])=[CH:25][N:26]([CH3:28])[CH3:27])=[CH:8][CH:7]=1)([OH:3])=[O:2]
Reactant: O=C(O)CCc1ccc(CC(=O)C(=O)c2ccccc2)cc1
Reactant: COC(OC)N(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CN(C)C=C(C(=O)C(=O)c1ccccc1)c1ccc(CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75 %

Procedure:
To a solution of 4.44 g of 3-[4-(2-carboxyethyl)phenyl]-1-phenyl-1,2-propanedione in 25 ml of dry dimethylformamide, cooled in an ice-bath, was added 11 ml of dimethylformamide dimethyl acetal. After stirring at room temperature for 15 min., the reaction mixture was poured onto 300 ml of crushed ice and the reaction mixture was acidified with 25 ml of 1N hydrochloride acid. The mixture was extracted with methylene chloride. The layers were separated and the organic phase was washed with water, dried, filtered and evaporated under vacuum. Recrystallization of the residue from methylene chloride-ether gave 3.95 g (75%) of 2-[4-(2-carboxyethyl)phenyl]-1-dimethylamino-4-phenyl-1-butene-3,4-dione as yellow crystals after drying at 50° C. for 3 hrs.
Reaction SMILES: [CH:1]([O:5][C:6](=[O:16])[CH2:7][CH:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])([CH2:3][CH3:4])[CH3:2].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>N1C=CC=CC=1>[CH:1]([O:5][C:6](=[O:16])[CH2:7][CH:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][S:23]([C:20]1[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=1)(=[O:25])=[O:24])([CH2:3][CH3:4])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCC(C)OC(=O)CC(C)CCCCCO
Solvent: c1ccncc1
Product: CCC(C)OC(=O)CC(C)CCCCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C

Procedure:
A mixture of the oily ester, thus obtained, one ml of pyridine and 485 mg of p-toluenesulphonyl chloride was stirred at room temperature for 16 hours. The reaction mixture was poured into ice-water, extracted with ethyl acetate, the extract washed with dilute sulphuric acid, a saturated aqueous solution of sodium bicarbonate, a saturated aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of methylene chloride and ethyl acetate (20:1) as eluent to give 647 mg of the subtitle compound having the following physical characteristics:
Reaction SMILES: C([C:3]([CH2:16][CH3:17])([C:13]([O-:15])=[O:14])[C:4](CC)([C:8]([O-:10])=[O:9])C([O-])=O)C.[CH2:18](Br)[CH2:19][CH2:20]CC>>[CH2:16]([CH:3]([CH2:4][C:8]([OH:10])=[O:9])[C:13]([OH:15])=[O:14])[CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCBr
Reactant: CCC(CC)(C(=O)[O-])C(CC)(C(=O)[O-])C(=O)[O-]
Product: CCCCCC(CC(=O)O)C(=O)O
Reaction time: 19 h
Yield: 153 %

Procedure:
A method similar to that described by Devlin, et al, J. Chem. Soc., Perkin Transactions I, page 830 (1975) was used. Sodium ethoxide was formed by the addition of sodium metal (2.25 g, 91.59 mmol) to anhydrous EtOH (150 ml) under an N2 atmosphere. To the resultant solution was added triethyl-1,1,2-ethanetricaboxylate (obtained from Aldrich; 21 ml, 91.59 mmol) followed by dropwise addition of n-pentyl bromide (11.4 ml, 91.59 mmol). The mixture was brought to reflux and stirred overnight (19 hr). After the reaction had cooled, it was filtered and concentrated. The residue was treated with H2O and extracted with Et2O (three times). The combined organic extracts were dried (MgSO4), concentrated and purified by vacuum distillation (85° C./22.66 Pascals) to yield a colorless liquid (26.37 g, 91% yield).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([I:9])[CH:8]=1)[NH2:5].O.[N:11]([O-])=O.[Na+].Cl[Sn]Cl>Cl>[I:1][C:2]1[CH:3]=[C:4]([NH:5][NH2:11])[CH:6]=[C:7]([I:9])[CH:8]=1
Reactant: Nc1cc(I)cc(I)c1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1cc(I)cc(I)c1
Temperature: -10 °C
Reaction time: 0.67 h

Procedure:
3,5-Diiodoaniline was obtained by the procedure of M. Bérubé (M. Bérubé, et al. Synthesis of Simplified Hybrid Inhibitors of Type 1 17β-Hydroxysteroid Dehydrogenase via the Cross-Metathesis and the Sonogashira Coupling Reactions, Organic Lett. 6 (2004) 3127-3130). 5 g (14.5 mmol) of 3,5-diiodoaniline were stirred with the solution of 5 mL of concentrated hydrochloric acid and 5 mL of water. The mixture was cooled to about −10° C. and 5.5 mL of 20% aqueous solution of NaNO2 was added dropwise with continuous stirring. The suspension was allowed to stir for another 40 minutes. Next, the cooled solution of 10.8 g (47.9 mmol) of SnCl2. 2H2O in 11 mL of concentrated HCl was added dropwise at −10° C. to the suspension of diazocompound. The reaction mixture was kept −10° C. for one hour and at 5° C. overnight. The obtained precipitate of a double salt with tin chloride was filtered off and washed with water. The residue was resuspended in water and added concentrated aqueous solution of NaOH to alkaline medium. The 3,5-diiodophenylhydrazine was extracted with ether, the organic layer was washed in turn with aqueous NaOH, Na2S2O3 and water, and dried with CaCl2. Ether was evaporated to give 4.2 g of 3,5-diiodophenylhydrazine. 1H-NMR (200 MHz, DMSO-d6), δ, ppm: 7.10 (2H, d, 1.2 Hz, arom.), 6.92 (1H, d, 1.2 Hz, arom.), 5.51 (1H, s, NH), 4.12 (2H, broad s, NH2).
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[Br:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1>O>[Br:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][CH:1]=[O:3])=[CH:14][CH:13]=1
Reactant: O=CO
Reactant: Nc1ccc(Br)cc1
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: O=CNc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A stirred solution of formic acid (2.5 mL, 88% in water) is cooled to 0° C., treated with acetic anhydride (0.82 mL, 9.0 mmol) then warmed to RT over 30 minutes. The solution is then cooled to 0° C. and 4-bromoaniline (500 mg, 3.0 mmol) added dropwise over 5 minutes. After stirring a further 16 h at RT, the reaction mixture is diluted with water (20 mL) and extracted into DCM (3×20 mL). The combined DCM phases are washed with 1 M HCl (20 mL) and aqueous NaHCO3 (20 mL), dried over Na2SO4 and reduced in vacuo. Purification by column chromatography (20% EtOAc in heptane) affords the title compound.
Reaction SMILES: [CH3:1][Si:2]([CH3:17])([CH3:16])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[CH:8]1.C([Li])CCC.[I:23]I>C1COCC1>[I:23][C:8]1[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:17])([CH3:16])[CH3:1])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=1
Reactant: C[Si](C)(C)CCOCn1cnc2ccccc21
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c(I)nc2ccccc21
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 63.2 %

Procedure:
A solution of 1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-benzoimidazole (5.029 g, 20.25 mmol) (see Witten et al., J. Org. Chem., 51, 1891-1894 (1986)) in THF (50 mL) was cooled to −78° C. and added dropwise over 12 min via cannula to a flask containing n-butyllithium (2.5 M in hexanes, 12.2 mL) in THF (30 mL) at −78° C., under argon. After stirring for 25 min at −78° C., the flask was warmed to 0° C. for 10 min, then cooled again to −78° C. This solution was then added via cannula to a second flask containing iodine (25.7 g, 101 mmol) in THF (50 mL) at −78° C. Once the addition was complete (˜5 min), the cooling bath was removed, and stirring was continued for 30 min. The reaction mixture was partitioned between ethyl acetate (500 mL) and water (100 mL). The organic layer was washed with saturated aqueous sodium metabisulfite 2×100 mL) to remove the dark iodine color, dried (MgSO4), and concentrated in vacuo. Purification by flash chromatography (10% to 50% ethyl acetate/hexanes) yielded 4.79 g (63%) of pure 2-iodo-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-benzoimidazole as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 7.76-7.72 (m, 1H), 7.54-7.51 (m, 1H), 7.29-7.25 (m, 2H), 5.54 (s, 2H), 3.59 (t, 2H, J=8.1 Hz), 0.92 (t, 2H, J=8.1 Hz), −0.03 (s, 9H). Anal. (C13H19IN2OS) C, H. Calculated: C, 41.71; H, 5.12; L 33.90; N, 7.48. Found: C, 41.90; H, 5.09; L 34.00; N, 7.37.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:13])=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].[Br:14]Br.O>C(O)(=O)C>[Br:14][C:9]1[C:10]([O:11][CH3:12])=[C:2]([Cl:1])[C:3]([OH:13])=[C:4]([CH:8]=1)[C:5]([OH:7])=[O:6]
Reactant: COc1ccc(C(=O)O)c(O)c1Cl
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: COc1c(Br)cc(C(=O)O)c(O)c1Cl
Reaction time: 16 h
Yield: 67.4 %

Procedure:
To a solution of 3-chloro-2-hydroxy-4-methoxybenzoic acid (11.1 g) in acetic acid (275 mL) was added bromine (8.79 g) at room temperature, and the mixture was stirred for 16 hr. To the reaction mixture was added water, and the precipitate was collected by filtration. The precipitate was washed with water, and dissolved in ethyl acetate, and the solution was washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (10.4 g).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]3[CH3:28])[C:16]3[CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[CH3:29][C:30]([CH:33]=O)([CH3:32])[CH3:31]>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]3[CH3:28])[C:16]3[CH2:21][N:20]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2]
Reactant: CC(C)(C)C=O
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CNC3)cc1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(CC(C)(C)C)C3)cc1

Procedure:
Method as described for example 26 using (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (example 7) and pivaldehyde as starting materials. Purified by prep HPLC (low pH).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].Cl.Cl.[CH3:27][N:28]1[CH2:35][CH2:34][NH:33][CH2:32][C:29]21[CH2:31][CH2:30]2>>[OH:14][C:13]1[N:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([N:33]3[CH2:32][C:29]4([CH2:31][CH2:30]4)[N:28]([CH3:27])[CH2:35][CH2:34]3)=[O:21])=[CH:17][N:16]=2)[N:11]=[CH:10][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[CH3:24]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: CN1CCNCC12CC2
Agent: Cl
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N3CCN(C)C4(CC4)C3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 4-methyl-4,7-diazaspiro[2.5]octane dihydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.32 (br. s., 1H) 0.50-0.78 (m, 3H) 2.39 (s, 3H) 2.42 (s, 3H) 2.86 (br. s., 2H) 3.31 (br. s., 1H) 3.41-3.62 (m, 2H) 3.73 (br. s., 1H) 7.63-7.68 (m, 1H) 7.72 (s, 1H) 7.77 (d, J=7.83 Hz, 1H) 8.04 (br. s., 1H) 8.14 (s, 1H) 8.38 (d, J=8.08 Hz, 1H) 8.50 (br. s., 1H) 12.85 (br. s., 1H); ESI-MS m/z [M+H]+ 429.3.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][N:13]1[C:17]2=[N:18][C:19]([C:22]3[CH:23]=[N:24][NH:25][CH:26]=3)=[CH:20][N:21]=[C:16]2[N:15]=[N:14]1.I[CH2:28][CH2:29][OH:30].C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][N:13]1[C:17]2=[N:18][C:19]([C:22]3[CH:26]=[N:25][N:24]([CH2:28][CH2:29][OH:30])[CH:23]=3)=[CH:20][N:21]=[C:16]2[N:15]=[N:14]1
Reactant: OCCI
Reactant: Fc1cc2ncccc2cc1Cn1nnc2ncc(-c3cn[nH]c3)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: OCCn1cc(-c2cnc3nnn(Cc4cc5cccnc5cc4F)c3n2)cn1
Temperature: 120 °C
Yield: 31.7 %

Procedure:
7-fluoro-6-{[6-(1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl]methyl}quinoline (95 mg, 0.274 mmol), 2-iodoethanol (378 mg, 2.198 mmol), K2CO3 (75.8 mg, 0.548 mmol), DMAC 95 ml) were combined and heated in microwave at 120° C. for 4 h. The reaction mixture was concentrated and the resulting residue was purified via flash column chromatography eluted with 0-5% MeOH:CH2Cl2 to give the desired product as a solid (33.9 mg, 31%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:26]=[C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:28]=1[OH:29])[C:8]([O:10][CH2:11][CH2:12][C:13]([O:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([N+:23]([O-])=O)[CH:17]=1)=[O:14])=[O:9])([CH3:4])([CH3:3])[CH3:2]>C(O)(=O)C.O.[Fe]>[C:30]([C:27]1[CH:26]=[C:7]([CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:28]=1[OH:29])[C:8]([O:10][CH2:11][CH2:12][C:13]([O:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([NH2:23])[CH:17]=1)=[O:14])=[O:9])([CH3:32])([CH3:33])[CH3:31]
Reactant: CC(C)(C)c1cc(C(=O)OCCC(=O)Oc2ccc(Cl)c([N+](=O)[O-])c2)cc(C(C)(C)C)c1O
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)c1cc(C(=O)OCCC(=O)Oc2ccc(Cl)c(N)c2)cc(C(C)(C)C)c1O
Reaction time: 3 h
Yield: 93 %

Procedure:
Iron metal powder (13.4 g, 0.24 mole) was added portionwise to a solution of the nitro compound (22.9 g, 0.048 mole) from (b) in acetic acid (110 ml) and water (10 ml), heated on a steam bath. Heating was continued for a further 3 hours, after which the suspension was filtered hot through kieselguhr. The filtrate was poured into a mixture of ice/water (1 liter) with rapid stirring and the precipitate was collected by filtration to give the product as a white solid (20 g, 93%). m.p. 122°-124° C.