Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[C:17]2[C:12](=[N:13][CH:14]=[N:15][C:16]=2[NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[C:21]([O:33][CH3:34])[CH:20]=2)[NH:11][N:10]=1)(=O)=O.[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH3:34][O:33][C:21]1[CH:20]=[C:19]([NH:18][C:16]2[N:15]=[CH:14][N:13]=[C:12]3[NH:11][N:10]=[C:9]([O:8][CH2:7][CH2:6][N:35]4[CH2:39][CH2:38][CH2:37][CH2:36]4)[C:17]=23)[CH:24]=[CH:23][C:22]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1
Reactant: C1CCNC1
Reactant: COc1cc(Nc2ncnc3[nH]nc(OCCOS(C)(=O)=O)c23)ccc1OCc1ccccn1
Product: COc1cc(Nc2ncnc3[nH]nc(OCCN4CCCC4)c23)ccc1OCc1ccccn1
Yield: 61 %

Procedure:
The procedure described in Example 55 was repeated using 2-[(4-{[3-methoxy-4-(pyridin-2-ylmethoxy)phenyl]amino}-1H-pyrazolo[3,4-d]pyrimidin-3-yl)oxy]ethyl methanesulfonate (prepared as described in Example 18) and pyrrolidine to give the title compound in 61% yield; NMR Spectrum: 1.65 (s, 4H), 2.54 (s, 4H), 2.87 (t, 2H), 3.82 (s, 3H), 4.42 (t, 2H), 5.16 (s, 2H), 7.02 (d, 1H), 7.20 (dd, 1H), 7.36 (t+d, 2H), 7.54 (d, 1H), 7.85 (td, 1H), 8.25 (s, 1H), 8.48 (s, 1H), 8.58 (d, 1H); Mass Spectrum: 462 (MH+).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:35][C:36]([CH3:47])([CH3:46])[CH2:37][O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40].CN(C)C(=O)C>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:35][C:36]([CH3:47])([CH3:46])[CH2:37][O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:40])[CH3:41])[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC(C)(CBr)CO[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(CC(C)(C)CO[Si](C)(C)C(C)(C)C)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 130 °C
Reaction time: 2 h
Yield: 40.4 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), cesium carbonate (4.1 g), (3-bromo-2,2-dimethylpropoxy)(tert-butyl)dimethylsilane (2.36 g) and N,N-dimethylacetamide (10 mL) was stirred at 130° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.63 g, 27%).
Reaction SMILES: [CH2:1]([N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][C:6]([OH:8])=O)[CH:2]=[CH2:3].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.Cl.[CH3:31][NH:32][O:33][CH3:34]>O1CCCC1>[CH2:1]([N:4]([CH2:5][C:6]([N:32]([O:33][CH3:34])[CH3:31])=[O:8])[C:9](=[O:10])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:2]=[CH2:3]
Reactant: C=CCN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: CNOC
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCN(CC(=O)N(C)OC)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 79.4 %

Procedure:
2-(Allyl(tert-butoxycarbonyl)amino)acetic acid (49.6 g, 156 mmol), tetrahydrofuran (600 mL), and triethylamine (36.3 g, 359 mmol) is added to an Erlenmeyer flask and the mixture is cooled to 0° C. Pivaloyl chloride (31 g, 253 mmol) is added drop wise and the reaction is stirred at room temperature for 3 hours and then cooled to 0° C. N,O-dimethylhydroxylamine hydrochloride (28 g, 283 mmol), triethylamine (33 mL, 237 mmol) and tetrahydrofuran (400 mL) are then added. The ice bath is removed and the reaction is stirred at room temperature for 3 hours. The mixture is concentrated under reduced pressure. The resulting residue is dissolved in water (300 mL) and extracted with ethyl acetate (2×300 mL). The organic phases are combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue is purified by silica gel flash chromatography, eluting with hexane/acetone (1:0) to hexane/acetone (1:1) to give the title compound (32 g, 54%). 1H NMR (CDCl3) mixture of two rotamers (60:40) δ 1.42, 1.44 (s, 9H), 3.16, 3.17 (s, 3H), 3.66, 3.69 (s, 3H), 3.88-3.98 (m, 2H), 4.01, 4.11 (s, 2H), 5.10-5.18 (m, 2H), 5.73-5.85 (m, 1H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.Br[C:44]1[CH:45]=[N:46][CH:47]=[N:48][CH:49]=1.[CH3:50][C:51]1[CH:56]=[CH:55][C:54]([N+:57]([O-:59])=[O:58])=[CH:53][C:52]=1[N:60]1[CH2:70][CH2:69][C:63]2[N:64]=[C:65]([NH2:68])[N:66]=[CH:67][C:62]=2[CH2:61]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[CH3:50][C:51]1[CH:56]=[CH:55][C:54]([N+:57]([O-:59])=[O:58])=[CH:53][C:52]=1[N:60]1[CH2:70][CH2:69][C:63]2[N:64]=[C:65]([NH:68][C:44]3[CH:45]=[N:46][CH:47]=[N:48][CH:49]=3)[N:66]=[CH:67][C:62]=2[CH2:61]1
Reactant: Brc1cncnc1
Reactant: Cc1ccc([N+](=O)[O-])cc1N1CCc2nc(N)ncc2C1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1ccc([N+](=O)[O-])cc1N1CCc2nc(Nc3cncnc3)ncc2C1

Procedure:
A mixture of 4,5 Bis(diphenyl-phosphino)-9,9-dimethylxanthene [xanthopos](8.6 mg, 0.01488 mmol) and Tris(dibenzylideneacetone)di-palladium(0)[Pd2(dba)3](6.81 mg, 0.00744 mmol) in dry 1,4-dioxane (5 ml) was stirred vigorously and nitrogen was bubbled through the suspension for 30 minutes. 5-Bromo pyrimidine (19.7 mg, 0.1247 mmol), 6-(2-Methyl-5-nitro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-ylamine (35.57 mg, 0.1247 mmol) and dry cesium carbonate (100 mg, 0.31 mmol) was added. Nitrogen was bubbled through for another 30 minutes; the mixture was allowed to reflux overnight. The mixture was cooled, diluted with ethylacetate, water was added and the layers were separated. The aqueous layer was extracted with ethyl acetate and the two organic extracts were combined. The organics were washed with brine, then dried (sodium sulfate), filtered and concentrated under vacuum. Further purification by silica gel chromatography using 5-10% ethyl acetate/hexane as eluent provided [6-(2-Methyl-5-nitro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-pyrimidin-5-yl-amine [15] as a yellow solid [Yield: 9.75 mg, 21.7%]
Reaction SMILES: Cl[C@H:2]([Br:21])[CH2:3][CH2:4][CH2:5][CH2:6][B:7]([O:9][C:10]12[CH2:18][CH:14]([C:15]1([CH3:17])[CH3:16])[CH2:13][CH2:12][C:11]2([OH:20])[CH3:19])[OH:8].[CH3:22][Mg].[Cl-].[NH4+]>C1COCC1>[C:10]12([OH:9])[CH2:18][CH:14]([C:15]1([CH3:17])[CH3:16])[CH2:13][CH2:12][C:11]2([OH:20])[CH3:19].[Br:21][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([B:7]([O-:8])[O-:9])[CH3:22]
Reactant: C[Mg]
Reactant: CC1(O)CCC2CC1(OB(O)CCCC[C@H](Cl)Br)C2(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(O)CCC2CC1(O)C2(C)C
Product: C[C@H](CCCCBr)B([O-])[O-]
Temperature: -78 °C

Procedure:
In a 500 ml round bottomed flask, 300 ml of anhydrous THF and the crude pinanediol (R)-1-chloro-5-bromopentylboronate from the previous reaction (assuming 89 g; 0.247 moles) were mixed and cooled to -78° C. with stirring under argon. To the solution was added methylmagnesium bromnide (3.26N, 79.6 ml). The solution was warmed to room temperature overnight. Petroleum ether (500 ml) and saturated ammonium chloride (250 ml) were added, forming an emulsion. The aqueous phases were separated. The organic phase was washed with saturated ammonium chloride (2×250 ml), causing the emulsion to disappear. The combined aqueous phases were washed with petroleum ether (2×250 ml). The combined organic phases were dried over sodium sulfate, filtered and evaporated under vacuum to yield 85.85 g of crude pinanediol (R)-5-bromo-1-methylpentylboronate.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[O:11][CH2:10][C:9]([CH3:13])([CH3:12])[O:8][C:6]=2[N:7]=1.[CH3:20][O:21][C:22]1[N:27]=[CH:26][C:25](B(O)O)=[CH:24][N:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:20][O:21][C:22]1[N:27]=[CH:26][C:25]([C:2]2[N:3]=[C:4]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:5]3[O:11][CH2:10][C:9]([CH3:13])([CH3:12])[O:8][C:6]=3[N:7]=2)=[CH:24][N:23]=1
Reactant: COc1ncc(B(O)O)cn1
Reactant: CC1(C)COc2c(nc(Cl)nc2N2CCOCC2)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ncc(-c2nc3c(c(N4CCOCC4)n2)OCC(C)(C)O3)cn1
Temperature: 120 °C

Procedure:
A microwave vial was charged with 2-chloro-7,7-dimethyl-4-morpholin-4-yl-6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidine from Example 104 (50 mg, 0.18 mmol), 2-methoxypyrimidin-5-ylboronic acid (42 mg, 0.27 mmol), Pd(PPh3)2Cl2 (12 mg, 0.02 mmol) and sodium carbonate (0.5 mL, 0.5 mmol, 1M aqueous solution) in acetonitrile (1.5 mL) then evacuated and back filled with nitrogen before being heated at 120° C. using microwave irradiation. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with methanol and the product eluted with 2M ammonia in methanol. The basic fractions were combined and concentrated in vacuo. The resulting residue was purified by trituration with diethyl ether affording 110 as a white solid (30 mg, 17%). LCMS: RT=4.18 min, [M+H]+=360. 1H NMR (400 MHz, CDCl3): δ 9.33 (2H, s), 4.07 (3H, s), 3.92 (2H, s), 3.83 (8H, s), 1.47 (6H, s)
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([S:10][CH3:11])[CH:7]=[C:6]([NH:12][C:13](=[O:18])[CH2:14][CH2:15][CH2:16]Cl)[CH:5]=1.[OH-].[Na+]>CO>[CH3:11][S:10][C:8]1[CH:9]=[C:4]([CH:5]=[C:6]([N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:18])[CH:7]=1)[C:3]([OH:2])=[O:19]
Reactant: COC(=O)c1cc(NC(=O)CCCCl)cc(SC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CSc1cc(C(=O)O)cc(N2CCCC2=O)c1
Reaction time: 4 h
Yield: 100.2 %

Procedure:
To a solution of 3-methylsulfanyl-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid methyl ester (B1) (115 mg, 0.433 mmol, 1 equiv) in MeOH (8 ml) was added 2N aqueous NaOH solution (0.65 ml, 1.3 mmol, 3 equiv). The resulting mixture was stirred for 4 h, 2N aqueous NaOH solution (1 ml, mmol, equiv) was added and the resulting solution was stirred for 16 h then concentrated in vacuo. The residue was diluted with H2O and extracted with Et2O. The aqueous layer was acidified using 2N aqueous HCl solution and the white precipitate formed was extracted twice with AcOEt. The combined organic solutions were dried over Na2SO4 and concentrated in vacuo to give 3-methylsulfanyl-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid (A1) (109 mg, 100%) as a white solid. [M+H]+=252.0, RT=2.61 min
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([C@H:12]1[CH2:16][N:15]([C:17](=S)[CH2:18][C:19](=O)[CH3:20])[C@H:14]([C:23]([O:25][CH3:26])=[O:24])[CH2:13]1)(=[O:11])=[O:10].Cl.[O:28]1[CH2:33][CH2:32][CH:31]([NH:34][NH2:35])[CH2:30][CH2:29]1>>[CH3:26][O:25][C:23]([C@@H:14]1[CH2:13][C@@H:12]([S:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[Cl:1])(=[O:10])=[O:11])[CH2:16][N:15]1[C:17]1[N:34]([CH:31]2[CH2:32][CH2:33][O:28][CH2:29][CH2:30]2)[N:35]=[C:19]([CH3:20])[CH:18]=1)=[O:24]
Reactant: NNC1CCOCC1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2Cl)CN1C(=S)CC(C)=O
Agent: Cl
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2Cl)CN1c1cc(C)nn1C1CCOCC1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-methyl 4-(2-chloro-4-fluorophenylsulfonyl)-1-(3-oxobutanethioyl)pyrrolidine-2-carboxylate was reacted with (tetrahydro-pyran-4-yl)-hydrazine hydrochloride (CAS Reg. No. 116312-69-7) to give the title compound as yellow solid. MS (ESI): m/z=486.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][C:13]3[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=3[C:6]=2[CH:7]=1.[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([S:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)([O-:24])=[O:23].[Na+]>>[N+:22]([C:25]1[CH:26]=[CH:27][C:28]([S:31]([C:2]2[CH:3]=[CH:4][C:5]3[O:14][C:13]4[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=4[C:6]=3[CH:7]=2)(=[O:33])=[O:32])=[CH:29][CH:30]=1)([O-:24])=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCc2oc3ccc(Br)cc3c2C1
Reactant: O=[N+]([O-])c1ccc(S(=O)[O-])cc1
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCc2oc3ccc(S(=O)(=O)c4ccc([N+](=O)[O-])cc4)cc3c2C1
Yield: 25 %

Procedure:
The product of Example 29, step B and sodium 4-nitrobenzenesulfinate were coupled using the procedure of Example 29, step C. Purification by flash column chromatography (SiO2, 3:2 hexane/ethyl acetate) provided tert-butyl 8-(4-nitrophenylsulfonyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (96 mg, 25%) as a pale yellow solid: 1H NMR (CDCl3, 300 MHz) δ 8.08 (s, 1H), 7.83 (dd, J=8.7, 1.8 Hz, 1H), 7.77-7.72 (m, 1H), 7.65 (dt, J=7.8, 2.1 Hz, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.50-7.44 (m, 1H), 7.25-7.20 (m, 1H), 4.58 (s, 2H), 3.84 (t, J=5.7 Hz, 2H), 2.91-2.82 (m, 2H), 1.55 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH2:12][CH2:13][CH3:14])[C:7](=[O:15])[N:6]([CH2:16][CH2:17][CH2:18][CH3:19])[C:5]=2[NH:4][N:3]=1.Br[CH2:21][CH2:22][Cl:23].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[N:3]([CH2:21][CH2:22][Cl:23])[N:4]=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][CH2:13][CH3:14])[C:7](=[O:15])[N:6]2[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCn1c(=O)n(CCC)c(=O)c2c(N)n[nH]c21
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCn1c(=O)n(CCC)c(=O)c2c(N)n(CCCl)nc21
Reaction time: 12 h
Yield: 66 %

Procedure:
A mixture of 3-amino-7-butyl-5-propylpyrazolo[3,4-d]pyrimidine-4,6(5H, 7H)-dione(8 g), 1-bromo-2-chloroethane(3.7 ml) and potassium carbonate(6.2 g) in DMF(100 ml) was stirred at 50°-60° C. for 12 hr. The reaction mixture was concentrated to dryness, and the concentrate was extracted with chloroform/water. The chloroform layer was washed with water, dried and concentrated to obtain a brown syrup, which was purified by flash chromatography(silica gel 100 g, chloroform). The purified syrupy product was crystallized from isopropylether to obtain colorless needles(21.5 g,66%), m.p. 118°-121° C.
Reaction SMILES: O[O:2][S:3]([O-:5])=O.[K+].[CH2:7]([O:9][C:10](=[O:26])/[C:11](/[C:19]1[S:20][C:21](SC)=[CH:22][CH:23]=1)=[CH:12]/[CH2:13][CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[CH3:8].[CH3:27]O>O>[CH2:7]([O:9][C:10](=[O:26])/[C:11](/[C:19]1[S:20][C:21]([S:3]([CH3:27])(=[O:5])=[O:2])=[CH:22][CH:23]=1)=[CH:12]/[CH2:13][CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[CH3:8]
Reactant: CCOC(=O)/C(=C/CC1CCCC1)c1ccc(SC)s1
Reactant: O=S([O-])OO
Reactant: CO
Agent: [K+]
Solvent: O
Product: CCOC(=O)/C(=C/CC1CCCC1)c1ccc(S(C)(=O)=O)s1
Reaction time: 1 h

Procedure:
Add a suspension of oxone® (2.07 g, 3.37 mmol) in water (10 mL) to a solution of (Z)-4-cyclopentyl-2-(5-methylsulfanyl-thiophen-2-yl)-but-2-enoic acid ethyl ester (804 mg, 2.59 mmol) in methanol (14 mL). Stir for 1 h, monitor completion of the reaction by LCMS. Filter the reaction mixture, concentrate the filtrate and extract the residue with dichloromethane. Combine the extracts, wash them with saturated aqueous sodium chloride solution, dry them over sodium sulfate, and remove solvent under vacuum to give 939 mg of the product. MS (m/e): 343.0 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:7][CH2:6][C:5]([C:8]2[C:13]([NH:14][C:15]([C:17]3[NH:18][C:19]([C:22]#[N:23])=[CH:20][N:21]=3)=[O:16])=[CH:12][CH:11]=[C:10]([C:24](O)([CH3:26])[CH3:25])[N:9]=2)=[CH:4][CH2:3]1.[CH2:29]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[CH3:30].S(Cl)(Cl)=O>C(Cl)Cl>[CH3:1][C:2]1([CH3:28])[CH2:7][CH2:6][C:5]([C:8]2[C:13]([NH:14][C:15]([C:17]3[NH:21][CH:20]=[C:19]([C:22]#[N:23])[N:18]=3)=[O:16])=[CH:12][CH:11]=[C:10]([C:24]([N:34]3[CH2:35][CH2:36][N:31]([CH2:29][CH3:30])[CH2:32][CH2:33]3)([CH3:26])[CH3:25])[N:9]=2)=[CH:4][CH2:3]1
Reactant: CC1(C)CC=C(c2nc(C(C)(C)O)ccc2NC(=O)c2ncc(C#N)[nH]2)CC1
Reactant: CCN1CCNCC1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCN1CCN(C(C)(C)c2ccc(NC(=O)c3nc(C#N)c[nH]3)c(C3=CCC(C)(C)CC3)n2)CC1

Procedure:
The title compound is prepared from 5-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-6-(1-hydroxy-1-methyl-ethyl)-pyridin-3-yl]-amide (as prepared in the previous step), N-ethylpiperizine, and thionyl chloride in DCM solvent according to the procedure in Example 14, step (e).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[CH2:18]([N:21]([CH2:30][CH:31]=[CH2:32])[C:22]1([CH3:29])[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]1)[CH:19]=[CH2:20]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:28][CH:25]1[CH2:26][CH2:27][C:22]([N:21]([CH2:18][CH:19]=[CH2:20])[CH2:30][CH:31]=[CH2:32])([CH3:29])[CH2:23][CH2:24]1
Reactant: C=CCN(CC=C)C1(C)CCC(N)CC1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Product: C=CCN(CC=C)C1(C)CCC(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Yield: 47.2 %

Procedure:
Following general procedure B, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (300 mg, 0.966 mmol) was reacted with N1,N1-diallyl-1-methylcyclohexane-1,4-diamine (400 mg, 1.93 mmol) to afford the desired product (220 mg, 47%) as a yellow solid: ESI MS m/z 482 [C26H32BrN3O+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([I:8])=[CH:6][N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:15]1[CH2:18][CH2:17][CH2:16]1>COCCOC>[N:15]1([C:2]2[C:7]([I:8])=[CH:6][N:5]=[CH:4][N:3]=2)[CH2:18][CH2:17][CH2:16]1
Reactant: C1CNC1
Reactant: Clc1ncncc1I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: Ic1cncnc1N1CCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 92.1 %

Procedure:
To a 16×100 mm reaction tube under N2 was added 4-chloro-5-iodopyrimidine (200 mg, 0.832 mmol), cesium carbonate (817 mg, 2.508 mmol) and 1,2-dimethoxyethane (5 mL). The reaction mixture was flushed with nitrogen and then treated with azetidine (112 μL, 1.662 mmol). The reaction mixture was securely capped, stirred at room temperature for 5 min, and then heated at 90° C. for 18 h. The reaction mixture was filtered through a small Celite plug by gravity, washed with dichloromethane (70 mL) and the solvent was evaporated off in vacuo to give 200 mg (92%) of the title compound as a pale yellow solid.
Reaction SMILES: CO[N:3]=[C:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:11][CH:12]=2)[O:7][CH2:6][CH2:5]1.N>CO.[Pd]>[C:14]([C:10]1[CH:9]=[C:8]2[C:13]([CH:4]([NH2:3])[CH2:5][CH2:6][O:7]2)=[CH:12][CH:11]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CON=C1CCOc2cc(C(C)(C)C)ccc21
Agent: [Pd]
Agent: N
Solvent: CO
Product: CC(C)(C)c1ccc2c(c1)OCCC2N
Yield: 104 %

Procedure:
The product of Example 1B (1.53 g) was taken into a solution of 20% ammonia in methanol, and hydrogenated for 4 hours at 60 psi at 50° C. in the presence of 1.55 g of 10% palladium on carbon as catalyst. The reaction mixture was filtered to remove catalyst, and the solvent removed under reduced pressure to give 1.40 g of the title compound (93% for two steps). 1H NMR (300 MHz, CDCl3) δ 7.25 (d, 1H, J=6.8 Hz), 6.96 (dd, 1H, J=2.0 and 8.1 Hz), 6.85 (d, 1H, J=2.0 Hz), 4.18-4.32 (m, 2H), 4.04 (t, 1H), 2.11-2.21 (m, 1H), 1.80-1.90 (m, 1H), 1.29 (s, 9H). MS (DCI) m/e 206 (M+H)+.
Reaction SMILES: Cl[C:2]([CH:4]([CH2:10][CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:3].[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[C:15]([CH3:20])[CH:14]=1.C(N(CC)CC)C>>[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:2]([CH:4]([CH2:10][CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:3])=[C:15]([CH3:20])[CH:14]=1
Reactant: Cc1cc(Br)ccc1N
Reactant: CCOC(=O)C(CC)C(=O)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CC)C(=O)Nc1ccc(Br)cc1C
Yield: 66.7 %

Procedure:
Ethyl 2-(chlorocarbonyl)butanoate (5.8 grams, 0.03 mole), 4-bromo-2-methylaniline (5.0 grams, 0.03 mole) and triethylamine (3.27 grams, 0.03 mole) were reacted under conditions similar to that described for Example I to give 7.4 grams (0.02 mole) of ethyl 2-(4-bromo-2-methylphenylaminocarbonyl)butanoate as a white solid having a melting point of 98° C.-100° C. Elemental analysis of the product indicated the following:
Reaction SMILES: [O:1]([C:13]1[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:14]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][CH:22]=1)[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:36][CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40].O>CN(C)C=O>[O:1]([C:13]1[CH:18]=[C:17]([O:19][CH2:36][CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH:16]=[CH:15][C:14]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][CH:22]=1)[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: CCc1ccc(Cc2ccc(O)cc2O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCOc1ccc(Cc2ccc(CC)cc2)c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a suspension of 2-(4-ethylbenzyl)-5-hydroxyphenyl β-D-glucopyranoside (0.051 g) and cesium carbonate (0.13 g) in N,N-dimethylformamide (2 mL) was added ethyl 4-bromobutyrate (0.028 mL), and the mixture was stirred at 50° C. for 1 hour. The reaction mixture was cooled to ambient temperature, water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel (eluent: dichloromethane/methanol=9/1) to give 5-[3-(ethoxycarbonyl)propyloxy]-2-(4-ethylbenzyl)phenyl β-D-glucopyranoside (0.028 g).
Reaction SMILES: [CH2:1]([C:3]1([CH2:20][CH3:21])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13](=[O:15])[CH3:14])[CH:10]=2)[N:5]([CH:16]([CH3:18])[CH3:17])[C:4]1=[O:19])[CH3:2].[N+:22]([O-:25])([OH:24])=[O:23]>S(=O)(=O)(O)O>[CH2:20]([C:3]1([CH2:1][CH3:2])[C:11]2[C:6](=[CH:7][C:8]([N+:22]([O-:24])=[O:23])=[C:9]([NH:12][C:13](=[O:15])[CH3:14])[CH:10]=2)[N:5]([CH:16]([CH3:17])[CH3:18])[C:4]1=[O:19])[CH3:21].[CH2:20]([C:3]1([CH2:1][CH3:2])[C:11]2[C:6](=[C:7]([N+:22]([O-:25])=[O:23])[CH:8]=[C:9]([NH:12][C:13](=[O:15])[CH3:14])[CH:10]=2)[N:5]([CH:16]([CH3:17])[CH3:18])[C:4]1=[O:19])[CH3:21]
Reactant: O=[N+]([O-])O
Reactant: CCC1(CC)C(=O)N(C(C)C)c2ccc(NC(C)=O)cc21
Agent: O=S(=O)(O)O
Product: CCC1(CC)C(=O)N(C(C)C)c2c([N+](=O)[O-])cc(NC(C)=O)cc21
Product: CCC1(CC)C(=O)N(C(C)C)c2cc([N+](=O)[O-])c(NC(C)=O)cc21
Temperature: 0 °C
Yield: 18 %

Procedure:
To a solution of N-(3,3-diethyl-1-isopropyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (10.4 g, 36.06 mmol) in conc. sulfuric acid (50 ml) was added slowly a mixture of nitric acid (65%, 3.84 g, 2.72 ml, 39.67 mmol) and conc. sulfuric acid (10 ml) at 0° C. After 2 h at room temperature the mixture was poured into ice water. The precipitate was filtered off, washed with water and dried. The crude material was purified by silica gel chromatography (isohexane/ethyl acetate 1:1) to yield 2.2 g N-(3,3-diethyl-1-isopropyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (6.60 mmol, 18%) besides undesired N-(3,3-diethyl-1-isopropyl-7-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (5.5 g).