Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1)=[O:2].Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2([CH2:24][CH3:25])[O:23][CH2:22][CH2:21][O:20]2)=[CH:15][C:14]=1[CH3:26].C(=O)([O-])[O-].[K+].[K+]>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>[CH2:24]([C:19]1([C:16]2[CH:17]=[CH:18][C:13]([C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([CH:1]=[O:2])[CH:8]=3)=[C:14]([CH3:26])[CH:15]=2)[O:23][CH2:22][CH2:21][O:20]1)[CH3:25]
Reactant: CCC1(c2ccc(Br)c(C)c2)OCCO1
Reactant: O=Cc1cccc(B(O)O)c1
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+]
Product: CCC1(c2ccc(-c3cccc(C=O)c3)c(C)c2)OCCO1

Procedure:
In a manner similar to that of Example 1(h), by reaction of 6.6 g (44 mmol) of 3-formylbenzeneboronic acid and 10 g (37 mmol) of 2-(4-bromo-3-methylphenyl)-2-ethyl-[1,3]dioxolane with 45 mL of 2.0M potassium carbonate and 2.14 g of tetrakis(triphenylphosphine)palladium, the desired product is obtained in the form of a thick oil (m=9.1 g; Y=84%).
Reaction SMILES: Br[C:2]1[C:3]([O:28][CH3:29])=[C:4]([CH:10]([NH:12][C:13]2[N:21]=[CH:20][N:19]=[C:18]3[C:14]=2[N:15]=[CH:16][N:17]3[CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[CH3:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[C:32]1[C:45]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46].C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>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.O>[Cl:9][C:6]1[C:7]([CH3:8])=[C:2]([C:34]2[CH:33]=[C:32]([C:45]([O:47][CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)=[O:46])[N:31]([CH3:30])[CH:35]=2)[C:3]([O:28][CH3:29])=[C:4]([CH:10]([NH:12][C:13]2[N:21]=[CH:20][N:19]=[C:18]3[C:14]=2[N:15]=[CH:16][N:17]3[CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH3:11])[CH:5]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc1C(=O)OCc1ccccc1
Reactant: COc1c(C(C)Nc2ncnc3c2ncn3C2CCCCO2)cc(Cl)c(C)c1Br
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1c(C(C)Nc2ncnc3c2ncn3C2CCCCO2)cc(Cl)c(C)c1-c1cc(C(=O)OCc2ccccc2)n(C)c1
Temperature: 95 °C

Procedure:
A mixture of N-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (0.032 g, 0.066 mmol, from Example 113, Step 2, Chiral intermediate), benzyl 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylate (0.027 g, 0.080 mmol), sodium carbonate (0.16 mL, 0.17 mmol), 1,4-dioxane (0.6 mL)/water (0.2 mL) and tetrakis(triphenylphosphine)palladium(0) (4.6 mg, 0.0040 mmol) was degassed with N2 for 5 minutes, then heated at 95° C. overnight. The mixture was diluted with EtOAc, washed with sat. NaHCO3, water, brine, and dried over Na2SO4 and concentrated. The crude product (20 mg, 50%) was purified by chromatography eluting with 0 to 40% EtOAc in CH2Cl2. LCMS calculated for C33H36ClN6O4 (M+H)+: m/z=615.2. found: 615.2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C@H:13]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]Br)=[CH:27][CH:26]=3)[C@H:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1>>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C@H:13]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][N:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)=[CH:27][CH:26]=3)[C@H:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCCCCCCCCCCOc1ccc([C@H]2c3ccc(OCc4ccccc4)cc3OC[C@H]2c2ccccc2)cc1
Reactant: C1COCCN1
Product: c1ccc(COc2ccc3c(c2)OC[C@@H](c2ccccc2)[C@H]3c2ccc(OCCCCCCCCCCN3CCOCC3)cc2)cc1

Procedure:
From (+,−) cis 7-Benzyloxy-4-[4-(bromodecyloxy)-phenyl]-3-phenylchroman (300 mg, 0.48 mmol) and morpholine (208 mg, 2.4 mmol).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=[O:8])=[C:5]([CH3:9])[CH:4]=[C:3]1[C:10]([O:12][CH3:13])=[O:11].[Mn]([O-])(=O)(=O)=[O:15].[K+].S([O-])([O-])=O.[Na+].[Na+].[Mn]([O-])(=O)(=O)=O>CC(C)=O.O.O.CC(C)=O>[C:7]([C:6]1[N:2]([CH3:1])[C:3]([C:10]([O:12][CH3:13])=[O:11])=[CH:4][C:5]=1[CH3:9])([OH:15])=[O:8]
Reactant: COC(=O)c1cc(C)c(C=O)n1C
Reactant: O=[Mn](=O)(=O)[O-]
Agent: O=S([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1cc(C)c(C(=O)O)n1C
Reaction time: 1.5 h
Yield: 61.3 %

Procedure:
To a solution of methyl 1,4-dimethyl-5-formylpyrrole-2-carboxylate (0.3 g, 0.0016 m) in acetone (10 ml) at room temperature was added over 15 minutes a solution of potassium permanganate (0.52 g, 0.0033 m) in 1:1 water-acetone (10 ml), and the resulting mixture allowed to stir for 1.5 hours. The reaction mixture was then diluted with water (100 ml), treated with enough sodium sulfite to reduce the excess permanganate, filtered, and the filtrate acidified with dilute hydrochloric acid. The resulting precipitate was filtered, washed well with water and dried to give 0.20 g (64%) of methyl 5-carboxy-1,4-dimethylpyrrole-2-carboxylate.
Reaction SMILES: Cl.O[NH2:3].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH:19]3[CH2:20][CH2:21][CH2:22][CH:15]2[C:16](=[CH:24]O)[C:17](=[O:23])[CH2:18]3)(=[O:13])=[O:12])=[CH:7][CH:6]=1>>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH:19]3[CH2:20][CH2:21][CH2:22][CH:15]2[C:16]2[CH:24]=[N:3][O:23][C:17]=2[CH2:18]3)(=[O:13])=[O:12])=[CH:7][CH:6]=1
Reactant: NO
Reactant: O=C1CC2CCCC(C1=CO)N2S(=O)(=O)c1ccc(Cl)cc1
Agent: Cl
Product: O=S(=O)(c1ccc(Cl)cc1)N1C2CCCC1c1cnoc1C2

Procedure:
Prepared as described in Example 5 using hydroxyamine hydrochloride and 9-(4-chlorophenylsulfonyl)-2-(hydroxymethylene)-9-azabicyclo[3.3.1]nonan-3-one which was prepared as described in Example 34.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([OH:14])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.Cl.[CH3:44][NH:45][O:46][CH3:47]>C(Cl)Cl>[CH3:44][N:45]([O:46][CH3:47])[C:12](=[O:14])[CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1ccc(CC(=O)O)cc1OC
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CC(=O)N(C)OC)cc1OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 66.1 %

Procedure:
(3,4-Dimethoxyphenyl)acetic acid (13.0 g, 66.4 mmol) was suspended in anhydrous CH2Cl2 followed by addition of EDCI (15.3 g, 79.7 mmol), HOBt (20.6 g, 152 mmol), triethylamine (8.06 g, 79.7 mmol), and N,O-dimethylhydroxylamine hydrochloride (6.48 g, 66.4 mmol). The reaction was stirred 3 days at ambient temperature after which the solvent was evaporated at reduced pressure. The residue was partitioned between EtOAc and water. The organic layer was washed with aq. HCl, sat NaHCO3, brine, dried (Na2SO4), and concentrated in vacuo to give 10.5 g (66%) of N-methyl-N-methoxy-(3,4-dimethoxyphenyl)acetamide as a pale brown oil.
Reaction SMILES: Br[C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]3[CH2:21][CH2:20][N:19]([S:22]([CH2:25][CH2:26][CH3:27])(=[O:24])=[O:23])[CH2:18][CH2:17]3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:30]([S:33]([N:36]1[CH2:41][CH2:40][N:39]([CH2:42][C:43]2[CH:48]=[CH:47][C:46]([NH:49][C:50](=[O:66])[C:51]3[CH:56]=[CH:55][C:54](B4OC(C)(C)C(C)(C)O4)=[CH:53][CH:52]=3)=[CH:45][CH:44]=2)[CH2:38][CH2:37]1)(=[O:35])=[O:34])[CH2:31][CH3:32].C([O-])(O)=O.[Na+]>COCCOC.O>[CH2:25]([S:22]([N:19]1[CH2:20][CH2:21][N:16]([CH2:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]([C:5]3[CH:28]=[CH:29][C:2]([C:54]4[CH:55]=[CH:56][C:51]([C:50]([NH:49][C:46]5[CH:47]=[CH:48][C:43]([CH2:42][N:39]6[CH2:40][CH2:41][N:36]([S:33]([CH2:30][CH2:31][CH3:32])(=[O:34])=[O:35])[CH2:37][CH2:38]6)=[CH:44][CH:45]=5)=[O:66])=[CH:52][CH:53]=4)=[CH:3][CH:4]=3)=[O:7])=[CH:10][CH:11]=2)[CH2:17][CH2:18]1)(=[O:24])=[O:23])[CH2:26][CH3:27]
Reactant: CCCS(=O)(=O)N1CCN(Cc2ccc(NC(=O)c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)cc2)CC1
Reactant: CCCS(=O)(=O)N1CCN(Cc2ccc(NC(=O)c3ccc(Br)cc3)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCCS(=O)(=O)N1CCN(Cc2ccc(NC(=O)c3ccc(-c4ccc(C(=O)Nc5ccc(CN6CCN(S(=O)(=O)CCC)CC6)cc5)cc4)cc3)cc2)CC1
Temperature: 80 °C
Yield: 15.2 %

Procedure:
A mixture containing 5 (88.8 mg, 0.18 mmol), 6 (101.4 mg, 0.19 mmol), Pd(TPP)4 (9.1 mg, 0.008 mmol), and NaHCO3 (57.1 mg, 0.68 mmol) in DME/H2O (4.5:1 v/v, 7 mL) was heated at 80° C. for 19 h, allowed to cool to rt, and evaporated to dryness. The remaining crude product was washed with H2O (3×10 mL) and dried, then a portion (60.5 mg of the 178.1 mg isolated) was purified by PTLC to give the title product (21.9 mg). Rf 0.38 (100:10:1 v/v CHCl3/MeOH/NH4OH (28%)). HPLC: tR 1.68 min (method 1). LC-MS m/z calcd for C42H52N6O6S2 ([M]+), 800. found, 801 ([M+H]+). 1H NMR (DMSO-d6): δ 0.92 (t, J=7.5 Hz, 3H), 1.62 (m, 2H), 2.38 (m, 4H), 2.95 (m, 2H), 3.10 (m, 4H), 3.44 (br s, 2H), 7.23 (m, 2H), 7.70 (m, 2H), 7.87 (m, 2H), 8.03 (m, 2H), 10.25 (s, 1H).
Reaction SMILES: [ClH:1].[C:2]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:14][S:13][C:12]3=[N:15][CH:16]=[C:17]([C:18]([OH:20])=O)[N:11]23)=[CH:6][CH:5]=1)#[N:3].[C:21]1([S:27][CH2:28][CH2:29][NH2:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>>[ClH:1].[C:21]1([S:27][CH2:28][CH2:29][NH:30][C:18]([C:17]2[N:11]3[C:12]([S:13][CH2:14][CH:10]3[C:7]3[CH:6]=[CH:5][C:4]([C:2]#[N:3])=[CH:9][CH:8]=3)=[N:15][CH:16]=2)=[O:20])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: N#Cc1ccc(C2CSc3ncc(C(=O)O)n32)cc1
Reactant: NCCSc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(C2CSc3ncc(C(=O)NCCSc4ccccc4)n32)cc1
Reaction time: 0.25 h

Procedure:
The carboxylic acid from Step D, Example 1 (20.0 mg, 0.0625 mmol), 2-aminoethyl phenyl sulfide (9.6 mg, 0.0625 mmol), EDC hydrochloride (14.4 mg, 0.0751 mmol), HOBT (10.1 mg, 0.0751 mmol), and N,N-diisopropylethylamine (0.044 mL, 0.250 mmol) were stirred in dry, degassed DMF (1 mL) at 25° C. for 16 hours. The crude product was purified by preparative HPLC using a gradient of 5%-95% acetonitrile/0.1% TFA; 95%-5%/0.1% aqueous TFA over 15 min. The title compound was isolated after conversion to the HCl salt. MS (es) m+1=407. 1H-NMR (CD3OD): δ7.77 (s, 1H); 7.74 (d, 2H, J=8.3 Hz); 7.25-7.33 (m, 6H); 7.18 (t, 2H, J=7.2 Hz); 6.44 (bd, 1H, J=8.6 Hz); 4.77 (dd, 1H, J=11.8, 8.9 Hz); 3.91 (d, 1H, J=11.8 Hz), 3.40 (ddd, 2H, J=13.6, 6.8, 4.3 Hz); 3.00 (t, 2H, J=6.8 Hz).
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.[OH-].[Na+].[CH2:20](Br)[CH3:21]>CO.O>[CH2:20]([O:1][C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1)[CH3:21]
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1O
Reactant: CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCOc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reaction time: 16 h
Yield: 52 %

Procedure:
The 2'-deoxy-5-hydroxyuridine (244 mg.,1mmol) was suspended in a mixture of methanol (10ml) and water (5ml) at room temperature, and 1 ml of 1.0N sodium hydroxide solution (1mmol) was added to generate the monoanion. Ethyl bromide (0.312ml, 4mmol) was added, and the reaction mixture was stirred for 16 hours. The solvent was removed in vacuo, and ethanol was added to and evaporated from the residue. The desired 5-ethoxy product was separated from small amounts of the 3 ethyl-5-ethoxy dialkyl byproduct by chromatography on a silica gel column using chloroform-methanol (9:1, v/v) as the solvent. Following crystallization from absolute ethanol, 5-ethoxy-2'-deoxyuridine was obtained in 52% yield (140 mg); mp 179°-181° C.; 1H NMR (methyl sulfoxide-d6),δ11.38 (1H, br s, NH), 7.58 (1H, s, H-6), 6.18 (1H, t, H-1'), 5.19 (1H, d, 3'-OH), 5.09 (1H, t, 5'-OH), 4.25 (1H, m, H-3'), 3.79 (3H, m. H4'and OCH2CH3 ), 3.59 (2H, br s,H-5'and H-5"), 2.10 (2H, m, H-2'and H-2") and 1.23ppm (3H, t, OCH2CH3). Anal. Calcd. for C11H16N2O6C, 48.53; H, 5.92; N, 10.29. Found: C, 48.69; H, 6.0-1; N, 10.36.
Reaction SMILES: B.[C:2]1([CH:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])C(O)=O)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[O:22]1CCC[CH2:23]1>O>[C:2]1([CH2:8][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:23][OH:22])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: CCCCCCCCCC(C(=O)O)c1ccccc1
Agent: B
Agent: Cl
Solvent: O
Product: OCCCCCCCCCCCc1ccccc1
Reaction time: 5.5 h

Procedure:
To 200 ml. of 1 M borane in tetrahydrofuran, cooled in an ice bath under nitrogen, is added dropwise over 35 minutes, a solution of 52.5 g. of phenylundecanoic acid in 150 ml. of tetrahydrofuran. The solution is allowed to stand at room temperature for 5.5 hours and poured onto ice. To the mixture is added 8 ml. of concentrated hydrochloric acid and the mixture is diluted with water to 2.2 liters. The mixture is extracted with ether (ca 500 ml.) and the extracts dried over magnesium sulfate. Concentration in vacuo gives a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:15])=[C:11]([CH3:14])[N+:12]=2[O-])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:18])=O.N>C(Cl)(Cl)Cl>[Cl:18][CH2:14][C:11]1[N:12]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[O:9][C:10]=1[CH3:15]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1oc(-c2ccc(Cl)cc2)[n+]([O-])c1C
Agent: N
Solvent: ClC(Cl)Cl
Product: Cc1oc(-c2ccc(Cl)cc2)nc1CCl
Temperature: 0 °C

Procedure:
1.00 g (4.47 mmol) of the compound from Example 31A are initially charged in 15 ml of chloroform, and 1.5 ml (16.10 mmol) of phosphoryl chloride are added carefully. With stirring, the reaction mixture is heated at reflux for 30 min. The mixture is then cooled to 0° C. and made weakly basic by addition of ammonia. The mixture is extracted three times with in each case 20 ml of ethyl acetate. The combined organic phases are washed twice with in each case 5 ml of water and then dried over magnesium sulfate. The solvent is removed on a rotary evaporator. The residue is used without further purification in the subsequent steps.
Reaction SMILES: [C:1]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.ClC1C=C(C=CC=1)C(OO)=[O:14]>C(Cl)(Cl)Cl>[O:14]1[CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][C:1]12[CH2:7][OH:8]
Reactant: OCC1=CCCCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: OCC12CCCCC1O2
Temperature: 25 °C

Procedure:
A stirred solution of 1-cyclohexenemethanol in 220 ml of chloroform was cooled to 0°-5° and 35.9 g of m-chloroperoxybenzoic acid (41.6 g of 85% pure material) in 355 ml of chloroform was added dropwise during three hours. The temperature of the reaction mixture was maintained at 0°-5° throughout the addition. Upon completion of the addition the reaction mixture was allowed to warm to ambient temperature during 24 hours. The reaction mixture was evaporated under reduced pressure to one-half the original volume and filtered. The filtrate was washed with three portions of 150 ml each of an aqueous solution saturated with sodium bicarbonate; then with three portions of 150 ml each of an aqueous solution saturated with sodium chloride. The chloroform layer was dried with sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to a residue. The residue was distilled using a Vigreux column to give 10.8 g of 1,2-epoxycyclohexanemethanol; bp 51°-52°/0.08-0.085 mm; nD25 =1.4738. The nmr and the ir spectra were consistent with the assigned structure.
Reaction SMILES: C([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH2:23][C@H:24]([OH:27])[CH2:25][OH:26])(OCC1C=CC=CC=1)=O>CO.[Pd]>[OH:27][C@H:24]([CH2:25][OH:26])[CH2:23][O:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][CH2:14][CH2:13][CH2:12][NH2:11]
Reactant: O=C(NCCCCc1ccccc1OC[C@H](O)CO)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NCCCCc1ccccc1OC[C@H](O)CO
Reaction time: 2 h
Yield: 91.3 %

Procedure:
To a vigorously stirred solution of 69 (2 g, 5.4 mmol) in methanol (60 mL) under nitrogen was added Pd/C (10% wet, 0.5 g). The mixture was stifled 2 h at room temperature under an atmosphere of hydrogen then the pressure was released and the mixture was filtered through a pad of silica gel. The solvent was removed and the residue was purified by column chromatography (silica gel, 2:1:0.2 chloroform/ethanol/concentrated ammonium hydroxide) to provide 70 (1.18 g, 92%) as a white solid. 1H NMR (300 MHz, DMSO-d6) d 1.32 (m, 2H), 1.54 (m, 2H), 2.55 (m, 2H), 3.45 (m, 2H), 3.82 (m, 3H), 3.94 (m, 2H), 6.83 (d, 2H), 7.08 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][NH:12][CH2:11][CH:10]2[N:14]([CH3:25])[C:15](=[O:24])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[O:26]=[S:27]1(=[O:37])[CH2:32][CH2:31][N:30]([CH2:33][C:34](O)=[O:35])[CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][N:12]([C:34](=[O:35])[CH2:33][N:30]3[CH2:31][CH2:32][S:27](=[O:37])(=[O:26])[CH2:28][CH2:29]3)[CH2:11][CH:10]2[N:14]([CH3:25])[C:15](=[O:24])[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)CN1CCS(=O)(=O)CC1
Reactant: CN(C(=O)Cc1ccc(F)cc1)C1CNCC1c1ccc(Cl)c(Cl)c1
Product: CN(C(=O)Cc1ccc(F)cc1)C1CN(C(=O)CN2CCS(=O)(=O)CC2)CC1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 87 (step c), the title compound N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[2-(1,1-dioxo-1lambda*6*-thiomorpholin-4-yl)-acetyl]-pyrrolidin-3-yl}-2-(4-fluoro-phenyl)-N-methyl-acetamide was prepared from N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-N-methyl-acetamide using (1,1-Dioxo-1lambda*6*-thiomorpholin-4-yl)-acetic acid instead of 1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid and was obtained as a colorless oil. MS m/e: 556.1 [M]+.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[CH2:15][N:16]([CH2:25][CH3:26])[CH2:17][CH2:18][CH2:19]OS(C)(=O)=O)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[CH2:27]([O:29][CH2:30][CH2:31][CH2:32][NH2:33])[CH3:28]>C(#N)C>[CH:11]1[C:12]2[C:7](=[CH:6][C:5]3[C:14]([C:13]=2[CH2:15][N:16]([CH2:25][CH3:26])[CH2:17][CH2:18][CH2:19][NH:33][CH2:32][CH2:31][CH2:30][O:29][CH2:27][CH3:28])=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:8]=[CH:9][CH:10]=1
Reactant: CCOCCCN
Reactant: CCN(CCCOS(C)(=O)=O)Cc1c2ccccc2cc2ccccc12
Solvent: CC#N
Product: CCOCCCNCCCN(CC)Cc1c2ccccc2cc2ccccc12
Temperature: 75 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
The mesylate 17 (584 mg, 1.57 mmol) and 3-ethoxypropylamine (649 mg, 6.30 mmol) were dissolved in acetonitrile (30 mL). The mixture was then stirred at 75° C. under a N2 atmosphere overnight. After the confirmation of the disappearance of the mesylate by TLC, the solution was concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (25 mL) and washed three times with aqueous sodium carbonate. The organic layer was separated, dried with anhydrous Na2SO4, filtered and concentrated under vacuum. Flash column chromatography of the residue gave 19 as a light yellow oil. Yield 60%; Rf=0.35 (0.5:4:85.5 NH4OH:MeOH:CH2Cl2); 1H NMR (CDCl3) δ 8.43 (d, 2H), 8.29 (s, 1H), 7.89 (d, 2H), 7.40 (m, 4H), 4.38 (s, 2H), 3.35 (q, 2H), 3.25 (t, 2H), 2.62 (q, 2H), 2.44 (t, 2H), 2.27 (t, 2H), 2.23 (t, 2H), 1.54 (q, 2H), 1.41 (q, 2H), 1.14 (m, 6H); 13C NMR (CDCl3) δ 131.3, 131.2, 130.6, 128.9, 127.2, 125.4, 125.0, 124.7, 69.1, 66.0, 50.7, 50.6, 48.2, 47.5, 47.2, 30.1, 27.1, 15.4, 11.9.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14](S(C)(=O)=O)=[N:15][CH:16]=2)[N:11]([CH3:23])[C:10]1=[O:24].[CH3:25][N:26]([CH3:37])[CH2:27][CH2:28][O:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([NH:34][C:33]3[CH:32]=[CH:31][C:30]([O:29][CH2:28][CH2:27][N:26]([CH3:37])[CH3:25])=[CH:36][CH:35]=3)=[N:15][CH:16]=2)[N:11]([CH3:23])[C:10]1=[O:24]
Reactant: CN1C(=O)N(c2c(Cl)cccc2Cl)Cc2cnc(S(C)(=O)=O)nc21
Reactant: CN(C)CCOc1ccc(N)cc1
Product: CN(C)CCOc1ccc(Nc2ncc3c(n2)N(C)C(=O)N(c2c(Cl)cccc2Cl)C3)cc1
Temperature: 160 °C
Yield: 13.8 %

Procedure:
A mixture of 200 mg (0.52 mmol) of 3-(2,6-dichlorophenyl)-7-methanesulfonyl-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one and 140 mg (0.8 mmol) of 4-[2-(dimethylamino)ethoxy]aniline was heated at 160° C. for 2 hours and then cooled. The residue was chromatographed on silica gel using firstly dichloromethane/methanol/acetic acid/water (240:24:3:2) and then dichloromethane/methanol/acetic acid/water (90:18:3:2) for the elution. Product-containing fractions were combined and evaporated. The residue was evaporated with toluene and then dissolved in 40 ml of dichloromethane, washed with 40 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to give 35 mg (23%) of 3-(2,6-dichlorophenyl)-7-[4-[2-(dimethylamino)ethoxy]anilino]-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 173-174° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10](=[O:15])[C:11](Br)([CH3:13])[CH3:12])[CH3:8].[F:16][C:17]1[CH:18]=[C:19]([OH:26])[CH:20]=[CH:21][C:22]=1[N+:23]([O-:25])=[O:24].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O.CCOC(C)=O>[CH2:7]([O:9][C:10](=[O:15])[C:11]([O:26][C:19]1[CH:20]=[CH:21][C:22]([N+:23]([O-:25])=[O:24])=[C:17]([F:16])[CH:18]=1)([CH3:13])[CH3:12])[CH3:8]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)Oc1ccc([N+](=O)[O-])c(F)c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 23 %

Procedure:
Potassium carbonate (3.96 g, 29 mmol) and 2-bromo-2-methylpropanoic acid ethyl ester (4.47 g, 23 mmol; CAS Reg. No. 600-00-0) were added to a solution of 3-fluoro-4-nitrophenol (3 g, 19 mmol; CAS Reg. No. 394-41-2) in DMSO (50 ml). The mixture was stirred for 18 h at 100° C. 10% aqueous citric acid and EtOAc were added and the layers were separated. The organic layer was washed with brine and dried over MgSO4. The solid was filtered off and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, EtOAc/heptane) to obtain the title compound (1.19 g, 4.4 mmol; 23%) as yellow oil.