Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH:17]([C:18]2[NH:19][C:20]([C:23]3[CH:24]=[CH:25][C:26]4[C:30]5[CH:31]=[CH:32][C:33](Br)=[CH:34][C:29]=5[O:28][C:27]=4[CH:36]=3)=[CH:21][N:22]=2)[CH2:16][C:13]2([CH2:15][CH2:14]2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:37]([O:41][C:42]([N:44]1[CH:49]([C:50]2[NH:54][C:53]3[CH:55]=[C:56](B4OC(C)(C)C(C)(C)O4)[CH:57]=[CH:58][C:52]=3[N:51]=2)[CH:48]2[CH2:68][CH:45]1[CH2:46][CH2:47]2)=[O:43])([CH3:40])([CH3:39])[CH3:38].C(=O)([O-])[O-].[K+].[K+]>COCCOC.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:37]([O:41][C:42]([N:44]1[CH:49]([C:50]2[NH:54][C:53]3[CH:55]=[C:56]([C:33]4[CH:32]=[CH:31][C:30]5[C:26]6[CH:25]=[CH:24][C:23]([C:20]7[NH:19][C:18]([CH:17]8[CH2:16][C:13]9([CH2:14][CH2:15]9)[CH2:12][N:11]8[C:9]([O:8][CH2:1][C:2]8[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=8)=[O:10])=[N:22][CH:21]=7)=[CH:36][C:27]=6[O:28][C:29]=5[CH:34]=4)[CH:57]=[CH:58][C:52]=3[N:51]=2)[CH:48]2[CH2:68][CH:45]1[CH2:46][CH2:47]2)=[O:43])([CH3:39])([CH3:38])[CH3:40]
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1c1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2[nH]1
Reactant: O=C(OCc1ccccc1)N1CC2(CC2)CC1c1ncc(-c2ccc3c(c2)oc2cc(Br)ccc23)[nH]1
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: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1C2CCC(C2)C1c1nc2ccc(-c3ccc4c(c3)oc3cc(-c5cnc(C6CC7(CC7)CN6C(=O)OCc6ccccc6)[nH]5)ccc34)cc2[nH]1
Yield: 87.6 %

Procedure:
To the solution of 6-[5-(7-bromo-dibenzofuran-3-yl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carboxylic acid benzyl ester (150 mg, 0.28 mmol) and 3-[6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (160 mg, 0.36 mmol) in DME (2.25 ml) and water (0.75 ml) was added potassium carbonate (78 mg, 0.56 mmol), followed by Pd(PPh3)4 (15 mg) and PdCl2(dppf)CH2Cl2 (15 mg). The mixture was heated at 90 C for 16 hours. The mixture was diluted with EtOAc, and was washed with water and brine, and was dried with sodium sulfate. Concentration and purification by flash column chromatography (hexanes/EtOAc) gave 3-(6-{7-[2-(5-benzyloxycarbonyl-5-aza-spiro[2.4]hept-6-yl)-3H-imidazol-4-yl]-dibenzofuran-3-yl}-1H-benzoimidazol-2-yl)-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (190 mg). m/z: 775.2 (M+1), 773.3 (M−1), 338.2 (M+2)/2.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:7]([C:8]2[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[N:9]=2)[N:6]=[CH:5][C:4]=1[C:16](=O)[CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)[CH2:21][CH2:20]1.C(O)C.B.[Na].Cl.C(O)C>O1CCCC1>[ClH:31].[CH3:2][C:3]1[N:7]([C:8]2[N:9]=[C:10]([CH3:15])[CH:11]=[C:12]([CH3:14])[N:13]=2)[N:6]=[CH:5][C:4]=1/[CH:16]=[CH:17]/[CH2:18][N:19]1[CH2:20][CH2:21][N:22]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)[CH2:23][CH2:24]1
Reactant: Cc1cc(C)nc(-n2ncc(C(=O)CCN3CCN(c4ccc(Cl)c(Cl)c4)CC3)c2C)n1
Agent: B
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(C)nc(-n2ncc(/C=C/CN3CCN(c4ccc(Cl)c(Cl)c4)CC3)c2C)n1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 115.6 %

Procedure:
1.0 g of 1-[5-methyl-1-(4,6-dimethyl-2-pyrimidinyl)-4-pyrazolyl]-3-[4-(3,4-dichlorophenyl)-1-piperazinyl]-1-propanone hydrochloride was dissolved in a solvent mixture comprising 50 ml of ethanol and 50 ml of tetrahydrofuran. After cooling with ice to 0° C., 500 mg of sodium boron hydride was added and the mixture was stirred at the same temperature for 45 minutes. Further, 50 mg of sodium boron hydride was added and the mixture was stirred for additional 2 hours. Then it was neutralized by adding a 1N hydrochloric acid/ethanol solution. After evaporating the ethanol, chloroform was added to the concentrated residue. Then it was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. After evaporating the solvent, 50 ml of dioxane, 50 ml of tetrahydrofuran and 220 mg of p-toluenesulfonic acid monohydrate were added to the obtained residue. Then the resulting mixture was heated under reflux for 5 hours. After evaporating the solvent, chloroform was added to the residue. Then it was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (chloroform:methanol=30:1), converted into hydrochloride by adding a 1N hydrochloric acid/ethanol solution and recrystallized from ethanol to thereby give 560 mg of the title compound.
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:16]3[CH:17]=[CH:18][C:19]([CH3:21])=[CH:20][C:15]=3[N:14]=[C:13]2[CH:22]([CH3:24])[CH3:23])[CH:8]([O:25][CH3:26])[CH2:7]1)=O)C>[OH-].[K+].CCO>[CH:22]([C:13]1[N:12]([CH:9]2[CH2:10][CH2:11][NH:6][CH2:7][CH:8]2[O:25][CH3:26])[C:16]2[CH:17]=[CH:18][C:19]([CH3:21])=[CH:20][C:15]=2[N:14]=1)([CH3:24])[CH3:23]
Reactant: CCOC(=O)N1CCC(n2c(C(C)C)nc3cc(C)ccc32)C(OC)C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COC1CNCCC1n1c(C(C)C)nc2cc(C)ccc21
Yield: 17.5 %

Procedure:
A solution of 4-(2-isopropyl-5-methyl-benzoimidazol-1-yl)-3-methoxy-piperidine-1-carboxylic acid ethyl ester (465 mg, 1.37 mmol) in a 1/1 1N KOH/EtOH solution (10 mL) was heated to 80° C. overnight. The mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (15/1 CH2Cl2/CH3OH) to yield 2-isopropyl-1-(3-methoxy-piperidin-4-yl)-5-methyl-1H-benzoimidazole (69 mg, 18%) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH:3]([CH2:20][CH3:21])[CH:4]([C:10]1[CH:19]=[CH:18][C:13]2[N:14]=[C:15](N)[S:16][C:12]=2[CH:11]=1)[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.[BrH:23].N([O-])=O.[Na+]>O>[Br:23][C:15]1[S:16][C:12]2[CH:11]=[C:10]([CH:4]([N:5]3[CH:9]=[CH:8][N:7]=[CH:6]3)[CH:3]([N:2]([CH3:22])[CH3:1])[CH2:20][CH3:21])[CH:19]=[CH:18][C:13]=2[N:14]=1
Reactant: CCC(C(c1ccc2nc(N)sc2c1)n1ccnc1)N(C)C
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCC(C(c1ccc2nc(Br)sc2c1)n1ccnc1)N(C)C
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To a mixture of 6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-amine (4.75 g, 15.06 mmol) and water (46 mL) at 0° C. was added aqueous HBr (18.5 mL) and the mixture was cooled to −10° C. A cold (−10° C.) solution of sodium nitrite (1.3 g) in water (15 mL) was added to the reaction mixture over a period of 10 min while maintaining the temperature below −5° C. and the reaction was stirred at −10° C. for 15 min. To the reaction mixture was added a cold (−10° C.) solution of CuBr2 in water (46 mL), cooling bath was removed and stirred for 3 h. The reaction was basified using aqueous sodium carbonate, filtered through a pad of celite and extracted with DCM. The DCM extract was washed with water, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography using 0 to 2% methanol in DCM as eluent to afford 1-(2-bromobenzo[d]thiazol-6-yl)-1-(1H-imidazol-1-yl)-N,N-dimethylbutan-2-amine. MS ESI: m/z 400.9 [M+Na+].
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[OH-].[Na+].[CH3:17]O>CCOC(C)=O.O>[CH3:17][O:8][C:7]([C:5]1[S:6][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:9]
Reactant: O=C(O)c1ccc(Br)s1
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Br)s1

Procedure:
To a solution of 5-bromo-thiophene-2-carboxylic acid (1.04 g, 5.0 mmol) in 15 mL of methanol, add concentrated sulfuric acid (0.5 ml, 10 mmol). After heating to reflux for an hour, cool the reaction to room temp, and dilute with EtOAc/H2O=50/50. Then, neutralize with 1.0 N NaOH to pH=7, extract the aqueous solution with ethyl acetate (30 ml×3), and dry the combined organic layers over sodium sulfate. Purify the crude material via flash chromatograpgy on sila gel to give the title compound 0.62 g. GC/MS (m/z) 222 (M+1), 191 (M—OMe+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[OH2:18].CC(C)=[O:21]>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:11]2[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=2)([CH3:10])[CH3:9])=[CH:6][CH:7]=1.[CH3:10][C:8]([C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)([CH3:9])[C:11]([OH:21])=[O:18]
Reactant: CC(C)=O
Reactant: O
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Product: CC(C)(C(=O)O)c1ccc(O)cc1

Procedure:
A solution of 28.5 g Bisphenol-A (IX) (0.12 moles) and 36.4 g acetone (0.63 moles) is pumped into a CO pressurized reactor containing 92 g HF (4.6 moles) and 10 g H2O (0.56 moles). At a starting pressure of 1530 psig and 72°-75° C., the (IX) and acetone reactants are pumped in 64 minutes to a final pressure of 1760 psig. After a total reaction time of 293 minutes, maintaining pressures of 1930-2210 psig, a 98% (IX) conversion yields 20.3 g or 44% selectivity to (I).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][N:22]=3)[CH2:17][CH2:16]2)=[O:14])=[C:6]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:7]=1.[CH3:29][C@@H:30]1[CH2:34][O:33][C:32](=[O:35])[NH:31]1>>[CH3:27][C:26]1[C:21]([N:18]2[CH2:19][CH2:20][N:15]([C:13]([C:5]3[CH:4]=[CH:3][C:2]([N:31]4[C@H:30]([CH3:29])[CH2:34][O:33][C:32]4=[O:35])=[CH:7][C:6]=3[NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[O:14])[CH2:16][CH2:17]2)=[N:22][CH:23]=[C:24]([CH3:28])[CH:25]=1
Reactant: C[C@@H]1COC(=O)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3NS(C)(=O)=O)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C)cc3NS(C)(=O)=O)CC2)c(C)c1
Yield: 8.5 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using [N-{5-bromo-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}methanesulfonamide (234 mg) described in Preparation Example 123 and (R)-4-methyloxazolidin-2-one (50.6 mg) described in Preparation Example 25, the title compound (20.8 mg) was obtained.
Reaction SMILES: [CH:1]1([O:5][C:6]2[C:15]([C:16]3[N:17]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:18]([C:21]4[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH:26]=4)=[CH:19][N:20]=3)=[CH:14][CH:13]=[C:12]3[C:7]=2[CH2:8][CH2:9][C@H:10]([CH3:47])[N:11]3[C:42]([CH:44]2[CH2:46][CH2:45]2)=[O:43])[CH2:4][CH2:3][CH2:2]1>[Pd].CO>[CH:1]1([O:5][C:6]2[C:15]([C:16]3[N:17]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:39])([CH3:40])[CH3:41])[C:18]([CH:21]4[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:32])([CH3:33])[CH3:31])=[O:28])[CH2:23][CH2:22]4)=[CH:19][N:20]=3)=[CH:14][CH:13]=[C:12]3[C:7]=2[CH2:8][CH2:9][C@H:10]([CH3:47])[N:11]3[C:42]([CH:44]2[CH2:45][CH2:46]2)=[O:43])[CH2:2][CH2:3][CH2:4]1
Reactant: C[C@H]1CCc2c(ccc(-c3ncc(C4=CCN(C(=O)OC(C)(C)C)CC4)n3COCC[Si](C)(C)C)c2OC2CCC2)N1C(=O)C1CC1
Agent: [Pd]
Solvent: CO
Product: C[C@H]1CCc2c(ccc(-c3ncc(C4CCN(C(=O)OC(C)(C)C)CC4)n3COCC[Si](C)(C)C)c2OC2CCC2)N1C(=O)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101 %

Procedure:
A mixture of tert-butyl 4-[2-[(2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-imidazol-5-yl]-1,2,3,6-tetrahydropyridine-1-carboxylate (0.094 g, 0.14 mmol) and palladium on carbon (10 wt %, 0.047 g) in methanol (4 mL) stirred under a hydrogen atmosphere at room temperature for 30 minutes. The reaction mixture was filtered, and the filtrate was concentrated under vacuum to afford tert-butyl 4-(2-((S)-5-cyclobutoxy-1-(cyclopropanecarbonyl)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)piperidine-1-carboxylate (0.094 g, 100%) as a light yellow solid. MS (ESI, pos. ion) m/z 665 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]2[C:14](=[O:15])[C:13]3[CH:16]=[CH:17][C:18]([OH:20])=[CH:19][C:12]=3[O:11]2)[CH:6]=[CH:7][CH:8]=1.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(OCC)(=O)C>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]2[C:14](=[O:15])[C:13]3[CH:16]=[CH:17][C:18]([O:20][C:21](=[O:28])[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:19][C:12]=3[O:11]2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1cccc(C=C2Oc3cc(O)ccc3C2=O)c1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1cccc(C=C2Oc3cc(OC(=O)c4ccccc4)ccc3C2=O)c1
Temperature: 25 °C

Procedure:
After 2-[(3-methoxyphenyl)methylene]-6-hydroxy-3(2H)-benzofuranone 0.5 g was dissolved in pyridine 5 ml, benzoyl chloride 0.282 ml was added, and the mixture was refluxed for 1.5 hours. The reaction mixture was cooled to room temperature, ethyl acetate 50 ml was added, and the mixture was washed with 2N-hydrochloric acid 50 ml once and with saturated sodium bicarbonate solution 50 ml. The ethyl acetate solution was dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting powder was dissolved in hexane 10 ml and ethyl acetate 5 ml, and the precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 221.5 mg.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=[C:4]2[N:3]=1.CC1(C)C(C)(C)OB([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])O1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.[Cu]I>[N:3]1[C:4]2[N:5]([C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=2)[CH:6]=[CH:7][C:2]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1B1OC(C)(C)C(C)(C)O1
Reactant: Brc1ccn2c(n1)nc1ccccc12
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccccc1-c1ccn2c(n1)nc1ccccc12
Temperature: 120 °C
Yield: 44.8 %

Procedure:
1,1′ Bis(diphenylphosphino)ferrocnee]dichloropalladium(II),w/DCM (0.033 g, 0.040 mmol) was added to a solution containing 2-bromobenzo[4,5]imidazo[1,2-a]pyrimidine (0.2 g, 0.806 mmol), tert-butyl (2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (0.386 g, 1.209 mmol), Copper(I) iodide (0.015 g, 0.081 mmol), and Potassium carbonate (0.806 ml, 1.612 mmol) in DMF. The solution was heated in the microwave for 15 minutes at 120° C. The reaction was cooled to room temperature. Diluted with water, extracted with ethyl acetate, combined organics, dried, filtered and concentrated. Purified by Combiflash column using 0% to 80% ethyl acetate in hexanes to afford tert-butyl (2-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)phenyl)carbamate (0.13 g, 0.361 mmol, 44.7% yield).
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:22][CH2:23]Br)[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[NH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1>CN(C=O)C>[CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:22][CH2:23][NH:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=3)[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCCOc1cccc2c1c1ccccc1n2Cc1ccccc1
Reactant: NCc1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: c1ccc(Cn2c3ccccc3c3c(OCCNCc4ccccn4)cccc32)cc1
Yield: 80.9 %

Procedure:
A mixture of 9-benzyl-4-(2-bromoethoxy)-9H-carbazole (0.0622 g, 0.1635 mmol), diisopropylethylamine (0.0211 g, 0.1635 mmol), 2-(2-aminomethylpyridine (0.0531 g, 0.4907 mmol), and DMF (0.5 mL) is stirred at 100° C. for 30 min. After cooling, the solvent is removed and the residue partitioned between CH2Cl2 and aq. sodium bicarbonate. The organic layers are dried over sodium sulfate; chromatography on silica gel (40 mL) using CH3OH—CH2Cl2 (2/98) gave 0.0539 g (81%) of the title compound; IR (drift) 1586, 1457, 1342, 1269, 1237, 1153, 1145, 1118, 1047, 782, 776, 753, 745, 718, 710 cm−1; 1H NMR (CDClCH3) δ3.32, 4.13, 4.44, 5.51, 6.70, 6.99, 7.12, 7.2-7.4, 7.66, 8.39, 8.60. Anal. Calcd for C27H25N3O: C, 79.58; H, 6.18; N, 10.31. Found: C, 79.66; H, 6.41; N, 10.28.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:32])[C:6]2[CH:11]=[C:10]([N:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]4([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=5[OH:28])[CH2:21][CH2:20]4)[C:13]3=[O:29])[C:9]([CH3:30])=[CH:8][C:7]=2[F:31])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:40][CH2:41][Cl:42]>C(#N)C>[Cl:42][CH2:41][CH2:40][O:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]1([NH:18][C:14]2[C:13](=[O:29])[N:12]([C:10]3[C:9]([CH3:30])=[CH:8][C:7]([F:31])=[C:6]([CH:11]=3)[C:5]([NH:4][CH:1]3[CH2:2][CH2:3]3)=[O:32])[CH:17]=[CH:16][N:15]=2)[CH2:21][CH2:20]1
Reactant: ClCCBr
Reactant: Cc1cc(F)c(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3O)CC2)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(F)c(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3OCCCl)CC2)c1=O
Temperature: 95 °C

Procedure:
To a solution of N-cyclopropyl-2-fluoro-5-[3-{[1-(2-hydroxyphenyl)cyclopropyl]amino}-2-oxopyrazin-1(2H)-yl]-4-methylbenzamide (Example 318g, 1.189 g) in acetonitrile (30 mL) was added potassium carbonate (3.78 g) followed by 1-bromo-2-chloroethane (4.54 mL). The reaction was heated at 95° C. for 32 h under nitrogen. The reaction was cooled to room temperature, filtered through celite, and the cake washed with further acetonitrile. The filtrate was collected and the solvents removed in vacuo to give the subtitle compound (1.368 g).
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]([CH2:11][CH2:12][OH:13])[CH:9]=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.CC1(C)N([O])C(C)(C)CCC1.[O-:25]Cl=O.[Na+]>C(#N)C.P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].O>[F:1][C:2]1[C:7]2[N:8]([CH2:11][C:12]([OH:25])=[O:13])[CH:9]=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: [O-][Cl+][O-]
Reactant: OCCn1cnc2cccc(F)c21
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C(O)Cn1cnc2cccc(F)c21
Temperature: 35 °C
Reaction time: 6 h

Procedure:
2-(7-fluoro-1H-benzimidazol-1-yl)ethanol (706 mg, 3.92 mmol) is suspended in 20 mL of acetonitrile and 15 mL of sodium phosphate buffer 1M (pH 6.5). The mixture is heated to 35° C. TEMPO (43 mg, 0.27 mmol) is added, followed by NaClO2 (80%, 887 mg, 7.84 mmol) dissolved in 4 mL of water and diluted bleach (2 ml of a 0.4% aqueous solution). The reaction mixture turns red-brown after the bleach addition. To drive the reaction to completion, if needed, more TEMPO (22 mg), NaClO2 (440 mg in 2 mL of water) and diluted bleach (1 mL) are added and the mixture stirred 6 hours at 35° C. After cooling at room temperature, the reaction is quenched by addition of saturated aqueous Na2SO3 (5 mL). The brown-red color disappears. The pH is adjusted to 8-9 by addition of NaOH 2M and the mixture is washed with ethyl acetate (2×). The organic layer is discarded and the aqueous phase is acidified with HCl 1M (up to pH 3). The desired product is crystallized in the aqueous phase as a white solid (537 mg, 70%). TLC: dichloromethane/methanol 10:1+5% triethylamine, Rf=0.33 (s.m.: Rf=0.56)
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:12])[C:5]2[S:10][C:9](=[O:11])[NH:8][C:6]=2[N:7]=1.C[Si](C)(C)Cl.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(O[CH:34]1[O:40][C@@H:39]([CH2:41][O:42][C:43](=[O:50])[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C@:37]([C:51](=[O:58])[C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)([OH:38])[C@:35]1([C:59](=[O:66])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[OH:36])(=O)C.C(=O)(O)[O-].[Na+]>C(#N)C.C[Si](C)(C)N[Si](C)(C)C.C(OCC)(=O)C.O>[NH2:1][C:2]1[NH:3][C:4](=[O:12])[C:5]2[S:10][C:9](=[O:11])[N:8]([C@H:34]3[O:40][C@@H:39]([CH2:41][O:42][C:43](=[O:50])[C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[C@:37]([C:51](=[O:58])[C:52]4[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=4)([OH:38])[C@:35]3([C:59](=[O:66])[C:60]3[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=3)[OH:36])[C:6]=2[N:7]=1
Reactant: Nc1nc2[nH]c(=O)sc2c(=O)[nH]1
Reactant: CC(=O)OC1O[C@@H](COC(=O)c2ccccc2)[C@@](O)(C(=O)c2ccccc2)[C@@]1(O)C(=O)c1ccccc1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1nc2c(sc(=O)n2[C@H]2O[C@@H](COC(=O)c3ccccc3)[C@@](O)(C(=O)c3ccccc3)[C@@]2(O)C(=O)c2ccccc2)c(=O)[nH]1
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
5-Aminothiazolo[4,5-d]pyrimidine-2,7(6H)-dione 32 (400 mg, 2.71 mmol) was suspended in acetonitrile (16 mL) and hexamethyldisilazane (0.96 mL), and trimethylchlorosilane (0.55 mL) and trimethylsilyl triflate (0.9 mL) added. The mixture was stirred under reflux for 3.5 h. A solution of trimethylsilyl triflate (0.45 mL) in acetonitrile (1.0 mL) was added dropwise and stirring and heating was continued for additional 30 min. A slurry of 1-O-acetyl-2,3,5-O-tribenzoyl-L-ribofuranose (1.22 g, 2.28 mmol) in acetonitrile (4.1 mL) was added and the mixture stirred under reflux for 30 min. The reaction mixture was cooled and slowly poured into a vigorously stirred mixture of sodium bicarbonate (2.81 g) and water (96 mL), which produced a stick solid. Ethyl acetate was added, the mixture stirred until the solid dissolved. The aqueous layer was extracted with ethyl acetate twice and the combined organic layer washed with sodium bicarbonate, dried (Na2SO4), and concentrated. The crude was purified by chromatography on silica with 5% Et3N and 5% ethanol in methylene chloride to give 1.10 g of 5-amino-3-(2′,3′,5′-O-tribenzoyl-β-L-ribofuranosyl)thiazolo[4,5-d]pyrimidine-2,7(6H)-dione 33 as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([C:9]1[CH:10]=[C:11]([S:16]([N:19]([C:27]2[N:28]=[CH:29][S:30][CH:31]=2)[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:18])=[O:17])[CH:12]=[CH:13][C:14]=1F)#[N:8].[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[C:35]([I:40])[CH:34]=1>CN(C)C=O.C(OCC)(=O)C>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][C:14]2[CH:13]=[CH:12][C:11]([S:16]([N:19]([C:27]3[N:28]=[CH:29][S:30][CH:31]=3)[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:18])=[O:17])=[CH:10][C:9]=2[C:7]#[N:8])=[C:35]([I:40])[CH:34]=1
Reactant: Oc1ccc(Cl)cc1I
Reactant: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1ccc(F)c(C#N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1ccc(Oc2ccc(Cl)cc2I)c(C#N)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a suspension of potassium carbonate (0.0549 g, 0.000397 mol) in N,N-dimethylformamide (3.0 mL) was added tert-butyl [(3-cyano-4-fluorophenyl)sulfonyl]1,3-thiazol-4-ylcarbamate (Preparation 250, 0.1004 g, 0.000167 mol) and stirred at room temperature under nitrogen for 10 minutes. 4-chloro-2-iodophenol (0.067 g, 0.000263 mol) was added and stirred at room temperature for 16 hours. The reaction was diluted with ethyl acetate (10.0 mL). The organic phase was washed saturated aqueous sodium chloride solution (2×10.0 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound as a yellow oil, 162 mg, 100% yield.
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:9]([N+:10]([O-])=O)=[CH:8][C:7]2[C:13]3([CH2:20][O:21][C:6]=2[CH:5]=1)[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)#N.O.C(O)(=O)C>[Pd].C(O)C>[CH3:19][N:16]1[CH2:17][CH2:18][C:13]2([C:7]3[CH2:8][C:9]4[C:4]([CH:3]=[CH:1][N:10]=4)=[CH:5][C:6]=3[O:21][CH2:20]2)[CH2:14][CH2:15]1
Reactant: CN1CCC2(CC1)COc1cc(CC#N)c([N+](=O)[O-])cc12
Agent: [Pd]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CN1CCC2(CC1)COC1=C2CC2=NC=CC2=C1
Yield: 6.9 %

Procedure:
6-(Cyanomethyl)-2,3-dihydro-1'-methyl-5-nitrospiro[benzofuran-3,4'-piperidine] (D6, 0.35 g, 1.2 mmol) was hydrogenated at 50 psiH2 over 10% palladium on charcoal (0.30 g) in a mixture of ethanol (18 ml), water (2 ml) and acetic acid (0.15 ml) for 24 h. Catalyst was filtered off onto kieselguhr, and the filtrate was evaporated to dryness. Chromatography on silica gel, eluting with 0-12% methanol/chloroform (gradient) gave the title compound (0.020 g, 10%) as a pale orange solid.