Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([NH:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11])=O)(C)(C)C.CCOCC.[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]>>[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].[CH2:14]([O:13][NH:12][C:10](=[O:11])[CH2:9][NH2:8])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)NOCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: NCC(=O)NOCc1ccccc1
Temperature: 25 °C

Procedure:
T-Butyloxycarbonyl-O-benzyl glycine hydroxamic acid [(17.5 g, 62.5 mMol) see Step A] was dissolved in trifluoroacetic acid (25 ml), stirred at room temperature thirty minutes, and ether (200 ml) added. The product was filtered and dried to yield: 9.0 g, m.p. 122°-124°.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([O:12][CH2:13][CH3:14])=[CH:5][C:4]=1F)[CH3:2].[CH3:16][S:17]([N:20]1[CH2:25][CH2:24][N:23]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH2:22][CH2:21]1)(=[O:19])=[O:18].C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[CH2:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([O:12][CH2:13][CH3:14])=[CH:5][C:4]=1[N:29]1[CH2:28][CH2:27][CH:26]([N:23]2[CH2:24][CH2:25][N:20]([S:17]([CH3:16])(=[O:19])=[O:18])[CH2:21][CH2:22]2)[CH2:31][CH2:30]1)[CH3:2]
Reactant: CS(=O)(=O)N1CCN(C2CCNCC2)CC1
Reactant: CCOc1cc(F)c(CC)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)c(CC)cc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 33.4 %

Procedure:
A mixture of 1-ethyl-4-(ethyloxy)-2-fluoro-5-nitrobenzene (Example 208, step A) (0.80 g, 3.75 mmol), 1-(methylsulfonyl)-4-(4-piperidinyl)piperazine (0.928 g, 3.75 mmol) and K2CO3 (0.622 g, 4.50 mmol) in DMSO (20 mL) was heated at 90° C. for 48 h. The reaction had not progressed sufficiently so the reaction was then heated at 120° C. for an additional 4 h. The reaction was cooled to rt, poured into H2O and extracted exhaustively with DCM. The combined organics were washed with H2O then dried over MgSO4. The resultant solution was concentrated onto silica and purified by flash chromatography to afford 1-{1-[2-ethyl-5-(ethyloxy)-4-nitrophenyl]-4-piperidinyl}-4-(methylsulfonyl)piperazine (0.551 g, 33%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.75 (s, 1H), 6.74 (s, 1H), 4.19 (q, J=6.93 Hz, 2H), 3.19-3.28 (m, 2H), 3.06-3.14 (m, 4H), 2.87 (s, 3H), 2.52-2.79 (m, 9H), 1.80-1.92 (m, 2H), 1.46-1.67 (m, 2H), 1.33 (t, J=6.97 Hz, 3H), 1.19 (t, J=7.47 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([N:15]4[C:19]([CH3:21])([CH3:20])[CH2:18][NH:17][C:16]4=[O:22])[S:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:23]=1.[H-].[Na+].[CH3:26]I.Cl>O1CCCC1.CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([N:15]4[C:19]([CH3:21])([CH3:20])[CH2:18][N:17]([CH3:26])[C:16]4=[O:22])[S:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:23]=1
Reactant: CI
Reactant: CC1(C)CNC(=O)N1c1nc2c(s1)CCOc1cc(Br)ccc1-2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN1CC(C)(C)N(c2nc3c(s2)CCOc2cc(Br)ccc2-3)C1=O
Reaction time: 0.5 h

Procedure:
A mixture of 0.254 g (0.65 mmol) of 1-(8-bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-2-yl)-5,5-dimethylimidazolidin-2-one from Example 429, and 50.0 mg (1.25 mmol) of 60% sodium hydride dispersion in mineral oil in 2 ml of tetrahydrofuran and 2 ml of dimethylformamide was stirred for 20 min. 0.062 ml (1.00 mmol) of methyl iodide was added in one portion to the above mixture. The mixture was stirred for 30 min and poured into 10 ml of 1 N aq hydrochloric acid. The mixture was extracted with ethyl acetate. The organic extracts were washed with water, brine, dried over magnesium sulfate and concentrated in vacuum. The residue was triturated with hexane and the resulting precipitate was filtered and washed with hexane. Yield 260 mg (98%). MS(ESI+): 408.1
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][C:7]([OH:11])=[CH:6][C:5]=2[C:4]2[CH2:12][CH2:13][C:14](=[N:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]1=2.C(O)(C)C.CO.[BH4-].[Na+]>O>[CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][C:7]([OH:11])=[CH:6][C:5]=2[C:4]2[CH2:12][CH2:13][CH:14]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]1=2
Reactant: Cn1c2c(c3cc(O)ccc31)CCC2=NCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(C)O
Product: Cn1c2c(c3cc(O)ccc31)CCC2NCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 26.4 %

Procedure:
To a stirred solution prepared from 4-methyl-3-phenylmethylimino-1,2,3,4-tetrahydrocyclopent[b]indol-7-ol (16.0 g), isopropanol (200 ml) and methanol (50 ml) was added sodium borohydride (4.8 g) and the mixture was stirred under nitrogen at ambient temperature for 3 hours. The mixture was cooled to 0° C., water was slowly added and the mixture was stirred 0.5 hour. The mixture was extracted with CH2Cl2 (2×200 ml), and the CH2Cl2 extracts were dried (Na2SO4), concentrated and chromatographed on silica gel eluting with 2:1 hexanes/acetone. The product-containing fractions were combined to give 4.25 grams of 4-methyl-3-(phenylmethylamino)-1,2,3,4-tetrahydrocyclopent[b]indol-7-ol.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:27])[NH:10][C:11]([CH3:26])([C:13]1[NH:14][C:15](=[O:25])[CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][N:20]=2)[N:18]=1)[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Li+].[CH3:30]OS(OC)(=O)=O.O>O1CCOCC1>[CH2:1]([O:8][C:9](=[O:27])[NH:10][C:11]([CH3:12])([C:13]1[N:14]([CH3:30])[C:15](=[O:25])[CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][N:20]=2)[N:18]=1)[CH3:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(NC(=O)OCc1ccccc1)c1nc(-c2ccncn2)cc(=O)[nH]1
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1c(C(C)(C)NC(=O)OCc2ccccc2)nc(-c2ccncn2)cc1=O
Temperature: 40 °C
Reaction time: 0.75 h
Yield: 11 %

Procedure:
To a suspension of 0.13 g (0.36 mmol) of [1-Methyl-1-(6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-ethyl]-carbamic acid benzyl ester in 1.5 mL of anhydrous dioxane was added 0.003 g (0.39 mmol) of lithium hydride. The resulting mixture was allowed to stir at 40° C. for 45 minutes. After cooling down to room temperature, 0.058 g (0.46 mmol) of dimethylsulfate was added and reaction mixture was heated at 60° C. for 12 h. After cooling to 0° C., water was added and the mixture extracted with ethyl acetate. The extracts were washed with a saturated aqueous solution of sodium chloride, dried and evaporated. The residue was purified on preparative thin layer chromatography eluting with a mixture of dichloromethane/methanol/aqueous ammonia solution (29%) in the proportions 95/5/0.5 to afford 0.015 g (11%) of the desired compound as a colorless oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([NH:11][C@H:12]([C:20]([NH:22][C@H:23]2[C@H:26](OC(=O)C)[NH:25][C:24]2=[O:31])=[O:21])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Si:32]([O:39][CH2:40][CH:41]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[OH:42])([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].O>C1C=CC=CC=1.C1(C)C=CC=CC=1.O.O.C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[C:1]1([CH2:7][CH2:8][C:9]([NH:11][C@H:12]([C:20]([NH:22][C@H:23]2[C@@H:26]([O:42][CH:41]([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH2:40][O:39][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[NH:25][C:24]2=[O:31])=[O:21])[CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)O[C@@H]1NC(=O)[C@H]1NC(=O)[C@H](Cc1ccccc1)NC(=O)CCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OCC(O)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Solvent: O
Solvent: c1ccccc1
Product: CC(C)(C)[Si](C)(C)OCC(O[C@H]1NC(=O)[C@H]1NC(=O)[C@H](Cc1ccccc1)NC(=O)CCc1ccccc1)c1ccccc1
Yield: 7 %

Procedure:
A mixture of (3S,4S)-3-{N-(3-phenylpropionoyl)-L-phenylalanyl}amino-4-acetoxy-azetidin-2-one (4.36 g, 10.30 mmole), 2-(tert-butyldimethylsilyl)oxy-1-phenylethanol (2.6 g, 10.30 mmole), and zinc acetate dihydrate (2.26 g, 10.30 mmole) in a mixture of benzene (70 ml) and toluene (70 ml) was refluxed overnight using Dean-Stark water separator. After cooling, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water, brine and dried over sodium sulfate. After removal of the solvent, the residue was purified by silica gel column chromatography using ethyl acetate-hexane (4:3) as eluent and (3S,4R)-3-{N-(3-phenylpropionoyl)-L-phenylalanyl}amino-4-{2-(tert-butyidimethylsilyl)oxy-1-phenyl ethoxy}-azetidin-2-one was obtained (440 mg, 7% yield).
Reaction SMILES: [CH:1]1([N:4]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]#[CH:14])[CH:8]=2)[CH3:5])[CH2:3][CH2:2]1.[CH2:15]([O:22][C:23](=[O:33])[CH:24]=[CH:25][C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1)C1C=CC=CC=1.C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.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>[CH3:15][O:22][C:23](=[O:33])/[CH:24]=[CH:25]/[C:26]1[CH:27]=[CH:28][C:29]([C:14]#[C:13][C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([CH2:6][N:4]([CH:1]3[CH2:3][CH2:2]3)[CH3:5])[CH:8]=2)=[CH:30][CH:31]=1
Reactant: O=C(C=Cc1ccc(O)cc1)OCc1ccccc1
Reactant: C#Cc1cccc(CN(C)C2CC2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1ccc(C#Cc2cccc(CN(C)C3CC3)c2)cc1

Procedure:
Following General Procedure B and using cyclopropyl-(3-ethynyl-benzyl)-methyl-amine (Intermediate 91, 0.060 g, 0.32 mmol), methyl-4-iodo-cinnamate (Reagent 4, 0.093 g, 0.32 mmol), triethyl amine (8 mL), copper(I)iodide (0.015 g, 0.08 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.056 g, 0.08 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 5-15% ethyl acetate in hexane as the eluent, the title compound was obtained (0.11 g, 100%).
Reaction SMILES: [CH2:1]([N:4]([C:11]1[CH:12]=[N:13][C:14]([Cl:18])=[C:15]([Cl:17])[CH:16]=1)[CH2:5][CH:6](OC)[O:7]C)[CH:2]=[CH2:3].Cl.ClCCl>O1CCCC1.O>[CH2:1]([N:4]([CH2:5][CH:6]=[O:7])[C:11]1[CH:12]=[N:13][C:14]([Cl:18])=[C:15]([Cl:17])[CH:16]=1)[CH:2]=[CH2:3]
Reactant: C=CCN(CC(OC)OC)c1cnc(Cl)c(Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: C=CCN(CC=O)c1cnc(Cl)c(Cl)c1
Temperature: 15 °C
Reaction time: 4 h

Procedure:
A solution of allyl-(5,6-dichloro-pyridin-3-yl)-(2,2-dimethoxy-ethyl)-amine (57.2 g) in tetrahydrofuran (443 g) was cooled to 10° C. A solution of concentrated hydrochloric acid (136 g) in water (114 g) was slowly added, maintaining the temperature below 20° C. The reaction was then stirred at 15° C. for about 4 hours. Then dichloromethane (570 g) and water (430 g) were added and the layers separated. The organic layer was washed with 5% aqueous sodium bicarbonate (453 g), and then washed twice with water (430 g). The organic layer was concentrated and the residue dissolved in dichloromethane (580 g).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([C@@H:12]3[O:34][C@H:33]([CH2:35][O:36]C(=O)C4C=CC=CC=4)[C@@H:23]([O:24]C(=O)C4C=CC=CC=4)[C@@:13]3([CH3:45])[O:14]C(=O)C3C=CC=CC=3)[C:4]=2[N:5]=[CH:6][N:7]=1.[NH3:46]>O1CCOCC1>[NH2:46][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([C@@H:12]3[O:34][C@H:33]([CH2:35][OH:36])[C@@H:23]([OH:24])[C@@:13]3([CH3:45])[OH:14])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C[C@@]1(OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)O[C@H]1n1cc(I)c2c(Cl)ncnc21
Reactant: N
Solvent: C1COCCO1
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cc(I)c2c(N)ncnc21
Temperature: 120 °C
Reaction time: 10 h
Yield: 69 %

Procedure:
A mixture of compound 10 from Step 1 (200 mg, 0.27 mmol) and aq ammonia (25% w/w, 3 ml) in dioxane (3 ml) was stirred in a sealed tube at 120° C. for 10 h. After cooling the volatiles were evaporated and crude product was purified by chromatography on silica (CHCl3→CHCl3MeOH, 8:2) and then re-purified by reverse phase chromatography (0→100% MeOH in water) to afford title compound 6 as white solid (76 mg, 69%). Compound was recrystallized from MeOH/MeCN. Mp 207° C. [α]20D −39.0 (c 0.274, MeOH). 1H NMR (600 MHz, DMSO-d6): 0.67 (s, 3H, CH3); 3.65 (ddd, 1H, Jgem=12.1, J5′b,OH=4.8, J5′b,4′=2.7, H-5′b); 3.81 (ddd, 1H, Jgem=12.1, J5′a,OH=4.8, J5′a,4′=2.0, H-5′a); 3.79 (ddd, 1H, J4′,3′=9.1, J4,5=2.7, 2.0, H-4′); 3.93 (bd, 1H, J3′,4′=9.1, H-3′); 5.14 (s, 1H, OH-2′); 5.16 (bs, 1H, OH-3′); 5.22 (t, 1H, JOH,5′=4.8, OH-5′); 6.10 (s, 1H, H-1′); 6.67 (bs, 2H, NH2); 7.82 (s, 1H, H-6); 8.10 (s, 1H, H-2). 13C NMR (151 MHz, DMSO-d6): 19.89 (CH3); 51.68 (C-5); 59.46 (CH2-5′); 71.76 (CH-3′); 78.87 (C-2′); 82.39 (CH-4′); 90.71 (CH-1′); 103.11 (C-4a); 126.81 (CH-6); 149.88 (C-7a); 152.23 (CH-2); 157.43 (C-4). IR (Mk): 3474, 3429, 3392, 3366, 1631, 1582, 1553, 1504, 1440, 1343, 1295, 1147, 1128, 1070, 1045, 789. MS (FAB): m/z 407 (M+H). HRMS (FAB) for C12H16H4O4 [M+H] calcd: 407.0216. found: 407.0225. Anal. Calcd for C12H15IN4O4: C, 35.48; H, 3.72; N, 13.79. Found: C, 35.37; H, 3.72; N, 13.39.
Reaction SMILES: [C:1]([Cu])#[N:2].Br[C:5]1[CH:19]=[CH:18][C:8]([C:9]([C:11]2[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=2)=[O:10])=[CH:7][CH:6]=1.[CH3:20][N:21](C=O)C>C(OCC)(=O)C>[C:20]([C:5]1[CH:19]=[CH:18][C:8]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:1]#[N:2])=[CH:13][CH:12]=2)=[O:10])=[CH:7][CH:6]=1)#[N:21]
Reactant: O=C(c1ccc(Br)cc1)c1ccc(Br)cc1
Reactant: N#C[Cu]
Reactant: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(C(=O)c2ccc(C#N)cc2)cc1

Procedure:
8.13 g of CuCN are added to a solution of 5.1 g of 4,4'-dibromobenzophenone in 90 ml of DMF, and the mixture is stirred under reflux for 13 hours. After cooling, the reaction mixture is diluted with ethyl acetate, washed twice with 50% aqueous ethylcnediamine solution, twice with water and then three times with brine, dried and concentrated. Column chromatography (SiO2, toluene to toluene/ethyl acetate 95:5) yields the crystalline title compound; TLC (toluene/ethyl acetate 9:1): Rf =0.34; IR (CH2Cl2): 2220, 1670, 1605, 1405 cm-1.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]([O:13][CH3:14])=[O:12])[CH2:7][CH2:6]1.C(N(CC)CC)C.[C:22]([Si:26]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)Cl)([CH3:25])([CH3:24])[CH3:23].C(=O)(O)[O-].[Na+]>ClCCl.C(OCC)(=O)C>[Si:26]([O:1][CH2:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]([O:13][CH3:14])=[O:12])[CH2:7][CH2:6]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)C1CCC(OCCO)CC1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CCC(OCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The crude product from Example 2A is dissolved in 20 ml of dichloromethane, and 0.83 ml (5.93 mmol) of triethylamine and 1.54 ml (5.93 mmol) of tert-butyldiphenylchlorosilane are added. After addition of 24.2 mg (0.20 mmol) of 4-N,N-dimethylaminopyridine the mixture is stirred at RT for 20 h. In each case 10 ml of ethyl acetate and of saturated aqueous sodium bicarbonate solution are then added. The phases are separated, and the combined organic phases are then dried over magnesium sulfate. The solvent is removed on a rotary evaporator and the residue is purified chromatographically on silica gel 60 (mobile phase: gradient cyclohexane/ethyl acetate 100:1→20:1).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19](Cl)[N:18]=[C:17]([N:31]3[CH2:37][CH2:36][CH2:35][N:34]([CH3:38])[CH2:33][CH2:32]3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:39]([OH:43])[CH2:40][CH2:41][OH:42]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:42][CH2:41][CH2:40][CH2:39][OH:43])[N:18]=[C:17]([N:31]3[CH2:37][CH2:36][CH2:35][N:34]([CH3:38])[CH2:33][CH2:32]3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OCCCO
Reactant: COc1ccccc1Oc1c(Cl)nc(N2CCCN(C)CC2)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCCN(C)CC2)nc1OCCCO

Procedure:
The procedure described in Synthesis Example 3 was repeated by use of 4-t-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(4-methylhomopiperazinyl)-4-pyrimidinyl]benzenesulfonamide and 1,3-propanediol, to thereby obtain the title compound as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:23]([OH:25])=O)=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([Br:22])[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][C:32]=1[N:33]1[CH2:38][C@H:37]([CH3:39])[C@@H:36]([O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[C@H:35]([NH:48][C:49](=[O:55])[O:50][C:51]([CH3:54])([CH3:53])[CH3:52])[CH2:34]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:22][C:17]1[CH:16]=[C:15]2[C:20]([CH:21]=[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:13]([C:23]([NH:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][C:32]=3[N:33]3[CH2:38][C@H:37]([CH3:39])[C@@H:36]([O:40][Si:41]([C:44]([CH3:45])([CH3:46])[CH3:47])([CH3:43])[CH3:42])[C@H:35]([NH:48][C:49]([O:50][C:51]([CH3:52])([CH3:54])[CH3:53])=[O:55])[CH2:34]3)=[O:25])=[N:14]2)=[CH:19][CH:18]=1
Reactant: O=C(Nc1cc2ccc(Br)cc2nc1C(=O)O)OCc1ccccc1
Reactant: C[C@H]1CN(c2ccncc2N)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(Br)ccc3cc2NC(=O)OCc2ccccc2)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.4 %

Procedure:
A mixture of 3-{[(benzyloxy)carbonyl]amino}-7-bromoquinoline-2-carboxylic acid (0.50 g, 1.2 mmol), tert-butyl ((3R,4R,5S)-1-(3-aminopyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate (0.54 g, 1.2 mmol), and HATU (1.2 g, 3.1 mmol) in DMF (4.9 mL) and DIPEA (0.65 mL, 3.7 mmol) was stirred at room temperature for 2 h, then quenched with 50 mL of EtOAc and 30 mL of 1 M NaOH. The resulting layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were concentrated under reduced pressure. The residue was purified by flash chromatography on a 40 g silica gel column, eluting with 0-100% EtOAc in hexanes, to give the sub-title compound (0.565 g, 55%). LCMS calc. for C40H52BrN6O6Si [M+H]+: m/z=919.3. found: 819.4.
Reaction SMILES: [CH2:1]([N:7]1[C:16](=[O:17])[C:15]2[N:14]([CH3:18])[CH:13]=[N:12][C:11]=2[N:10]([CH3:19])[C:8]1=[O:9])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].C[N+]1([O-])CC[O:24]CC1.S(S([O-])=O)([O-])=O.[Na+].[Na+].[OH2:36]>CC(C)=O.C(O)(C)(C)C.[Os](=O)(=O)(=O)=O>[OH:36][CH:5]([CH2:6][OH:24])[CH2:4][CH2:3][CH2:2][CH2:1][N:7]1[C:16](=[O:17])[C:15]2[N:14]([CH3:18])[CH:13]=[N:12][C:11]=2[N:10]([CH3:19])[C:8]1=[O:9]
Reactant: C=CCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Reactant: C[N+]1([O-])CCOCC1
Reactant: O
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CC(C)=O
Product: Cn1cnc2c1c(=O)n(CCCCC(O)CO)c(=O)n2C
Reaction time: 48 h
Yield: 62 %

Procedure:
To 1-(5-hexenyl)-3,7-dimethylxanthine (1.07 g, 4.1 mmol) and 4-methylmorpholine-N-oxide (1.44 g, 12.3 mmol) in water (20 ml) and acetone (10 ml) was added 2.5% solution of osmium tetraoxide in t-butanol (6 drops). After stirring for 48 hours, the mixture was treated with 20% aqueous sodium dithionite solution (20 ml). After 2 minutes, the mixture was extracted with 25% ethanol-dichloromethane (3×30 ml). The combined extracts were dried over magnesium sulfate and the solvents were evaporated under vacuum to give 1-(5,6-dihydroxyhexyl)-3,7-dimethylxanthine (750 mg, 62% yield) as a white powder.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]#[N:28])=[CH:22][CH:21]=1.[CH:29](OCC)=[O:30]>C(O)(=O)C.O1CCCC1>[C:27]([CH:26]([C:23]1[CH:24]=[CH:25][C:20]([O:19][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][O:13]2)=[CH:21][CH:22]=1)[CH:29]=[O:30])#[N:28]
Reactant: CCOC=O
Reactant: N#CCc1ccc(OC2CCCCO2)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: N#CC(C=O)c1ccc(OC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a cold (0° C) solution of 20.2 g. of diisopropylamine in 70 ml. of anhydrous tetrahydrofuran, is added 12.8 g. of n-butyllithium, and 10 g. of 4-tetrahydropyran-2-yloxyphenylacetonitrile, under nitrogen atmosphere, the resulting mixture is stirred at 0° C for 30 minutes and then 7.4 g. of ethyl formate is added. The reaction mixture is stirred for 18 hours at room temperature, under nitrogen atmosphere, poured into ice water and acidified to pH 5 with 10% acetic acid. It is then extracted three times with methylene chloride, the organic extracts are washed with water to neutrality, dried over sodium sulfate and evaporated to dryness under vacuo. The crude residue is treated with dihydropyran in benzene solution, in accordance with the method of Preparation 3, part B, to afford 2-cyano-2-(4-tetrahydropyran-2-yloxyphenyl)acetaldehyde which can be purified by crystallization from acetone-hexane.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[N:11][C:10]2[O:9][CH:8]([CH2:13][CH2:14][Cl:15])[CH2:7][N:6]([CH3:16])[C:5](=O)[C:4]=2[CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:27]2)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:12]=[N:11][C:10]2[O:9][CH:8]([CH2:13][CH2:14][Cl:15])[CH2:7][N:6]([CH3:16])[C:5](=[S:27])[C:4]=2[CH:3]=1
Reactant: CN1CC(CCCl)Oc2ncc(Cl)cc2C1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CN1CC(CCCl)Oc2ncc(Cl)cc2C1=S
Reaction time: 2 h

Procedure:
7-Chloro-2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepine-5(4H)-one, 6.0 g (0.022 mole) was suspended in 200 ml of toluene. To this suspension was added 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diposphetane-2,4-dilsulfide. The mixture was heated to reflux with vigorous stirring for 2 hours. Because the reaction was not complete, an additional amount (3.0 g) of 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide was added and the mixture stirred at reflux for 2 hr and left standing for 56 hr at room temperature. The toluene layer was decanted and washed with 50 ml of dilute aqueous sodium hydroxide and 50 ml of dilute hydrochloric acid. Toluene was removed by rotary evaporation (~80° C., wafter aspirator). The crude oil was recrystallized from isopropyl alcohol giving 3.5 g (54%) of pale yellow crystals, m.p. 125°-127° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:24])[NH:13][C:14](=[O:23])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=2)=[CH:3]1.[OH:25][CH2:26][CH2:27][C:28](=O)[CH3:29].[BH3-]C#N.[Na+]>ClCCl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:24])[NH:13][C:14](=[O:23])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][CH:28]([CH3:29])[CH2:27][CH2:26][OH:25])[CH:17]=2)=[CH:3]1
Reactant: CC(=O)CCO
Reactant: Cn1cc(C2=C(c3cccc(N)c3)C(=O)NC2=O)c2ccccc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Product: CC(CCO)Nc1cccc(C2=C(c3cn(C)c4ccccc34)C(=O)NC2=O)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of 3-(1-methylindol-3-yl)-4-(3-aminophenyl)-1H-pyrrole-2,5-dione (0.2 g, 0.6 mmol) and 4-hydroxy-2-butanone (80 mg, 1.5 eq) in dichloromethane (15 mL) was added NaCNBH3 (56 mg, 1.5 eq) and the reaction mixture was stirred at RT for three days. The product 3-(1-methylindol-3-yl)-4-[3-(3-hydroxy-1-methylpropylamino)phenyl]-1H-pyrrole-2,5-dione separated by preparatory TLC (8.9 mg, 3.6%). LC/mS: M+ 389.