Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:27]([CH3:28])[CH2:26][CH2:25][N:13]3[C:14](=[O:24])[C:15]=2[O:16]CC2C=CC=CC=2)=[O:9])=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.C(O)C.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:27]([CH3:28])[CH2:26][CH2:25][N:13]3[C:14](=[O:24])[C:15]=2[OH:16])=[O:9])=[CH:29][CH:30]=1
Reactant: [H][H]
Reactant: CN1CCn2c1nc(C(=O)NCc1ccc(F)cc1)c(OCc1ccccc1)c2=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN1CCn2c1nc(C(=O)NCc1ccc(F)cc1)c(O)c2=O
Yield: 82.5 %

Procedure:
A solution of N-(4-fluorobenzyl)-6-(benzyloxy)-1-methyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide (0.202 g, 0.495 mmol) in a mixture of ethyl acetate (150 ml) and ethanol (20 ml) at 25° C. was hydrogenated over 10% palladium on activated carbon (50 mg) and under one atmosphere of hydrogen for one hour to give 0.130 g (83% yield) of the title compound as white needles; mp 212° C. (ethyl acetate). 1HNMR 400 MHz (CDCl3) δ (ppm): 2.93 (3H, s, CH3), 3.63 (2H, t, J=8.6 Hz, CH2), 4.14 (2H, t, J=8.6 Hz, CH2), 4.59 (2H, d, J=6.0 Hz, NCH2), 7.07 (2H, m, aromatics), 7.33 (2H, m, aromatics), 7.89 (1H, broad t, NH), 11.57 (1H, s, OH). HRMS (ESI+) calculated for C15H16FN4O3 [M+H+]: 319.1206. found: 319.1191.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:14]>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH3:14])=[CH:4][CH:3]=1
Reactant: CI
Reactant: Brc1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1ccc2ccc(Br)cc21
Reaction time: 0.33 h
Yield: 90.4 %

Procedure:
A 1-round-bottom flask was charged with 6-bromo-1H-indole (14.88 g, 76 mmol) and THF (150 ml) to give a dark maroon solution. The flask was put under a N2 sweep, and sodium hydride (60 wt %) (3.64 g, 91 mmol) was added in several portions over 15 min. The resulting mixture was stirred for 20 min, then iodomethane (5.94 ml, 95 mmol) was added via syringe. Within a few minutes, an exotherm was observed. After stirring for 20 min, the mixture was concentrated in vacuo, and the residue was taken up in saturated aq. sodium bicarbonate solution and extracted with DCM (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by chromatography on silica gel (0 to 40% EtOAc/Heptane) to afford 6-bromo-1-methyl-1H-indole (14.44 g, 68.7 mmol, 91% yield) as a lightly colored oil. 1H NMR (400 MHz, CDCl3) δ=7.51-7.46 (m, 2 H), 7.24-7.19 (m, 1 H), 7.03 (d, J=3.1 Hz, 1 H), 6.47 (dd, J=0.9, 3.1 Hz, 1 H), 3.77 (s, 3 H).
Reaction SMILES: [CH3:1][C@H:2]([O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[C:12]([O:24]C)[N:13]2[CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]2)=[C:9]([NH2:26])[N:8]=1)[CH2:3][CH2:4][CH3:5].Cl.O1CCOCC1>CO>[NH2:26][C:9]1[N:8]=[C:7]([O:6][C@@H:2]([CH3:1])[CH2:3][CH2:4][CH3:5])[N:15]=[C:14]2[C:10]=1[NH:11][C:12](=[O:24])[N:13]2[CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCCNC3)c2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCC[C@H](C)Oc1nc(N)c2[nH]c(=O)n(CCC3CCCNC3)c2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 63.6 %

Procedure:
To a solution of 2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-9-[2-(3-piperidinyl)ethyl]-9H-purin-6-amine (35 mg, 0.097 mmol) in methanol (4 ml) was added 4M HCl in dioxane (1.5 ml, 6.00 mmol) and the mixture was allowed to stir at room temperature for 1.5 hours. The reaction was then dried under a stream of nitrogen in the Radleys blowdown apparatus to give the crude product. This was redissolved in methanol (˜5 mL) and passed down a 2 g aminopropyl (—NH2) SPE cartridge. The filtrate was dried under a stream of nitrogen in Radleys blowdown apparatus. The sample was dissolved in 1:1 MeOH:DMSO (1 ml) and purified by Mass Directed AutoPrep (Method A). The solvent was dried under a stream of nitrogen in the Radleys blowdown apparatus to give the title compound as an off-white solid (21.5 mg). LCMS (System D): tRET=2.25 min; MH+ 349
Reaction SMILES: B(F)(F)F.CCOCC.C([SiH](CC)CC)C.[Cl:17][C:18]1[C:23](=[O:24])[N:22]([CH3:25])[CH:21]=[C:20]2[C:26](=[O:42])[N:27]([CH2:30][CH2:31][C:32]3[CH:41]=[CH:40][C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:33]=3)[CH:28](O)[C:19]=12>C(Cl)Cl>[Cl:17][C:18]1[C:23](=[O:24])[N:22]([CH3:25])[CH:21]=[C:20]2[C:26](=[O:42])[N:27]([CH2:30][CH2:31][C:32]3[CH:41]=[CH:40][C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:33]=3)[CH2:28][C:19]=12
Reactant: Cn1cc2c(c(Cl)c1=O)C(O)N(CCc1ccc3ccccc3n1)C2=O
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: Cn1cc2c(c(Cl)c1=O)CN(CCc1ccc3ccccc3n1)C2=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 5.7 %

Procedure:
BF3.OEt2 (1.234 ml, 9.73 mmol) and triethylsilane (5.18 ml, 32.4 mmol) were added to a suspension of 7-Chloro-5-methyl-2-(2-quinolin-2-yl-ethyl)-1-hydroxyl-1,2-dihydro-5H-pyrrolo[3,4-c]pyridine-3,6-dione (1.2 g, 3.24 mmol, see Example c3.1)) in DCM (5 ml) at 0° C. and the reaction stirred at 0° C. for 3 h, which was then warmed to r.t. and stirred overnight. The solvent was removed and the resulting mixture was purified via preparative HPLC (Waters 2767 PHW003, eluent: MeCN/aqueous 0.05% solution of ammonium hydrogen carbonate (gradient: 20:80 to 40:60 over 14 min), column: Hanbon Benetnach C18, 10 μm, 20×250 mm) to afford the title compound (65 mg, 6.5% yield).
Reaction SMILES: [C:1](O)(=[O:5])[C:2]([CH3:4])=[CH2:3].C(OC(Cl)=O)C.C(N(CC)CC)C.[NH2:20][C:21]1[CH:29]=[C:25]([C:26]([OH:28])=[O:27])[C:24]([OH:30])=[CH:23][CH:22]=1.Cl>C(#N)C>[C:26]([C:25]1[CH:29]=[C:21]([NH:20][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])[CH:22]=[CH:23][C:24]=1[OH:30])([OH:28])=[O:27]
Reactant: C=C(C)C(=O)O
Reactant: Nc1ccc(O)c(C(=O)O)c1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)Nc1ccc(O)c(C(=O)O)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
Into a 1 liter flask were added 600 ml of acetonitrile, 95.2 g (1.1 mol) of methacrylic acid and 120.1 g (1.1 mol) of chloroformic acid ethyl ester. To this mixture 111.8 g (1.1 mol) of triethylamine was added over a period of 1 hour in a cold bath. Stirring was continued for 1 hour at room temperature and 141.2 g (1 mol) of 5-aminosalicylic acid was added. The mixture was heated for 2 hours at 60° C. The mixture was poured into 5 liter of 1% HCl solution. The deposit was filtered, washed and dried to produce 164.7 g of N-(3-carboxy-4-hydroxyphenyl)methacrylamide.
Reaction SMILES: [CH:1]([N:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]1=[O:16])([CH3:3])[CH3:2].[CH:17]([N-]C(C)C)(C)C.[Li+].CI>O1CCCC1>[CH2:10]([C:9]1[N:4]([CH:1]([CH3:2])[CH3:3])[C:5](=[O:16])[C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:8]=1)[CH3:17]
Reactant: CCOC(=O)c1ccc(C)n(C(C)C)c1=O
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(CC)n(C(C)C)c1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 23 %

Procedure:
To a stirred solution of ethyl 1-isopropyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate as prepared in Example 1(5) (515 mg, 2.0 mmol) in tetrahydrofuran (3 mL) was added a solution of lithium diisopropylamide (2.0M, 1.0 mL, 1.0 mmol) dropwise at −30° C. over 40 min. After addition, the mixture was stirred at 0° C. for 3 h. Then, methyl iodide (426 mg, 3.0 mmol) was added at 0° C., and the mixture was stirred at room temperature for 16 h. The mixture was quenched with water (5.0 mL), and extracted with dichloromethane (30 mL×3). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was purified with plate TLC eluting with n-hexane/ethyl acetate (v/v=2/1) to give 110 mg (23%) of the title compound as yellow oil.
Reaction SMILES: [CH2:1]([C:8]1([CH2:15][CH2:16][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[C:12](=[O:13])[NH:11][NH:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([O:30][CH3:31])(=[O:29])[CH:25]=[CH:26][CH:27]=[CH2:28]>>[CH2:1]([C:8]1([CH2:15][CH2:16][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[C:12](=[O:13])[N:11]2[CH2:28][CH:27]=[CH:26][CH:25]([C:24]([O:30][CH3:31])=[O:29])[N:10]2[C:9]1=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NNC(=O)C1(CCOC1CCCCO1)Cc1ccccc1
Reactant: C=CC=CC(=O)OC
Product: COC(=O)C1C=CCN2C(=O)C(CCOC3CCCCO3)(Cc3ccccc3)C(=O)N12
Yield: 33 %

Procedure:
In a manner analogous to that described in Example 7(B) (b), from 2.7 g of 4-benzyl-4-[2-(tetrahydro-2-pyranyloxy)ethyl]pyrazolidine-3,5-dione and 1.05 g of methyl penta-2,4-dienoate there were obtained 1.2 g (34%) of methyl 2-benzyl-2,3,5,8-tetrahydro-1,3-dioxo-2-[2-(tetrahydro-2-pyranyloxy)ethyl]-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate in the form of a white solid having a melting point of 113°-114° C. (from diethyl ether).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]1[O:21][CH2:20]1>O>[OH:21][CH2:20][CH2:19][N:15]1[CH2:16][CH2:17][CH2:18][CH:14]1[C:11]1[CH:12]=[CH:13][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1
Reactant: C1CO1
Reactant: c1ccc(Oc2ccc(C3CCCN3)cc2)cc1
Solvent: O
Product: OCCN1CCCC1c1ccc(Oc2ccccc2)cc1

Procedure:
12 parts of 2-(4-phenoxyphenyl) pyrrolidine, 2.2 parts of ethylene oxide and 1 part of water were heated at 80° C. for 5 hours. After cooling, there were obtained 8 parts of 1-β-hydroxyethyl-2-(4-phenoxyphenyl) pyrrolidine, B.P./0.3 mm Hg: 179°-180° C.
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10](Cl)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:9])([CH3:8])[CH3:7].CN(C)C=O.[CH2:29]([N:33]1[C:37]([C:38](=[S:40])[NH2:39])=[C:36]([CH2:41][OH:42])[N:35]=[C:34]1[N:43]1[CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45][CH2:44]1)[C:30]#[C:31][CH3:32]>C(OCC)(=O)C>[Si:10]([O:42][CH2:41][C:36]1[N:35]=[C:34]([N:43]2[CH2:44][CH2:45][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:47][CH2:48]2)[N:33]([CH2:29][C:30]#[C:31][CH3:32])[C:37]=1[C:38](=[S:40])[NH2:39])([C:6]([CH3:9])([CH3:8])[CH3:7])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(CO)c1C(N)=S
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1C(N)=S
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.2 %

Procedure:
0.668 g of imidazole and 2.70 g of t-butylchlorodiphenylsilane were added to a 25 ml N,N-dimethylformamide solution of 3.221 g of t-butyl 4-[1-(2-butynyl)-4-hydroxymethyl-5-thiocarbamoyl-1H-imidazol-2-yl]piperazine-1-carboxylate, and the mixture was stirred at room temperature for 16 hours. 300 ml of ethyl acetate was added to the solution, and the organic layer was washed three times with 100 ml of water and then with 100 ml of a saturated sodium chloride solution. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 4.357 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (2:3).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:12]3[N:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]=[C:14]([CH:22]=[O:23])[CH:13]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH3:24][Mg]Br.CCOCC>O1CCCC1>[O:4]1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:12]3[N:17]=[C:16]([C:18]([F:20])([F:21])[F:19])[N:15]=[C:14]([CH:22]([OH:23])[CH3:24])[CH:13]=3)[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: O=Cc1cc(OC2CCC3(CC2)OCCO3)nc(C(F)(F)F)n1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(O)c1cc(OC2CCC3(CC2)OCCO3)nc(C(F)(F)F)n1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
6-(1,4-Dioxaspiro[4.5]dec-8-yloxy)-2-(trifluoromethyl)pyrimidine-4-carbaldehyde (described in Example 1, Step 3) (0.20 g, 0.60 mmol) was dissolved in tetrahydrofuran (6.00 mL) and was cooled to −78° C., then 3.0 M methylmagnesium bromide in ether (0.30 mL, 0.90 mmol) was added. The reaction was stirred at −78° C. for 1 hour at which time LCMS analysis showed that it was mostly done. The reaction was quenched with sat. NH4Cl and was and partitioned between water and EtOAc, the phases were separated and the aqueous phase was washed with additional EtOAc. The combined organic phase was washed with water, then sat. NaCl, dried over MgSO4 and filtered and then the solvent removed in vacuo to leave the crude product. The crude material used in the next reaction without purification. MS: 371 (M+Na+), 349 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]2[CH2:15][CH:14]([O:16][CH3:17])[CH2:13][NH:12]2)=[O:10])=[CH:4][CH:3]=1.[CH3:18][S:19]([C:22]1[N:27]=[C:26]([C:28](Cl)=[O:29])[CH:25]=[CH:24][N:23]=1)(=O)=O.[OH-].[Na+]>ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]2[CH2:15][CH:14]([O:16][CH3:17])[CH2:13][N:12]2[C:28]([C:26]2[CH:25]=[CH:24][N:23]=[C:22]([S:19][CH3:18])[N:27]=2)=[O:29])=[O:10])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1nccc(C(=O)Cl)n1
Reactant: COC1CNN(C(=O)Cc2ccc(F)cc2)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COC1CN(C(=O)Cc2ccc(F)cc2)N(C(=O)c2ccnc(SC)n2)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-(4-Fluorophenyl)-1-(4-methoxy-pyrazolidin-1-yl)-ethanone, 47, (7.67 g, 32.2 mmol) and 2-methylsulfonyl-pyrimidine-4-carbonyl chloride (9.11 g, 48.3 mmol) are dissolved in dichloromethane (150 mL). A 0.5 N aqueous solution of sodium hydroxide (150 mL) is added steadily via addition funnel and the mixture is stirred vigorously at room temperature for 4 hours. The reaction is diluted with 5% aqueous sodium carbonate solution (1 L). The mixture is extracted with dichloromethane (6×200 mL). The combined organic layers are dried over magnesium sulfate, filtered and concentrated to give a red oil. The crude material is purified by over silica (1:1 to 1:3 hexane/ethyl acetate to 100% ethyl acetate) to afford 10.3 g of the desired product as a brown, viscous oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C@H:12]([C:22](OC)=[O:23])[CH:13]([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15])(=[O:10])=[O:9])[S:5][C:6]=1[Cl:7].[BH4-].[Li+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][CH:12]([CH2:22][OH:23])[CH:13]([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15])(=[O:9])=[O:10])[S:5][C:6]=1[Cl:7]
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1cc(Br)c(Cl)s1)C(C(F)(F)F)C(F)(F)F
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=S(=O)(NC(CO)C(C(F)(F)F)C(F)(F)F)c1cc(Br)c(Cl)s1
Temperature: 25 °C
Yield: 82.6 %

Procedure:
To a solution of methyl N-[(4-bromo-5-chloro thien-2-yl)sulfonyl]-4,4,4,4′,4′,4′-hexafluorovalinate (1.45 g, 2.907 mmol) in THF (20 mL) was added lithium borohydride (LiBH4) (5.82 mL, 11.64 mmol) under N2 atmosphere at 0° C. The reaction was allowed to warm to 25° C. for 19 h. The reaction was cooled to 0° C., quenched with 2N HCl (slow addition), diluted in ether (40 mL) and the organic layer washed sequentially with 1N aqueous HCl (10 mL), saturated aqueous NaHCO3 (10 mL) and brine (15 mL), then dried over MgSO4, filtered and concentrated to obtain a crude oil (1.3 g). The crude product was purified by the Biotage Flash™ 40 chromatography system, eluent: 1:6 EtOAc-hexanes, to afford 4-bromo-5-chloro-N-[3,3,3-trifluoro-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide as a white solid (1.13 g, 84.32%). Mass Spectrum (−ESI): 469 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:25]=[CH:24][N:23]=[C:22]([C:26]([OH:28])=O)[CH:21]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:29]=1.[F:30][C:31]1[CH:32]=[C:33]([C@@H:38]2[CH2:43][CH2:42][C:41]([CH3:45])([CH3:44])[CH2:40][NH:39]2)[CH:34]=[C:35]([F:37])[CH:36]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:37][C:35]1[CH:34]=[C:33]([CH:38]2[CH2:43][CH2:42][C:41]([CH3:45])([CH3:44])[CH2:40][N:39]2[C:26]([C:22]2[N:23]=[CH:24][N:25]=[C:20]([N:17]3[CH2:16][CH2:15][CH:14]([N:10]4[CH2:9][CH2:8][C:7]5[CH:29]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=5[NH:12][C:11]4=[O:13])[CH2:19][CH2:18]3)[CH:21]=2)=[O:28])[CH:32]=[C:31]([F:30])[CH:36]=1
Reactant: CC1(C)CC[C@@H](c2cc(F)cc(F)c2)NC1
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)O)ncn3)CC1)C(=O)N2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4CC(C)(C)CCC4c4cc(F)cc(F)c4)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
65 mg (0.16 mmol) 6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid and 70 mg (0.16 mmol) (S)-2-(3,5-difluorophenyl)-5,5-dimethylpiperidine in 0.04 mL (0.72 mmol) DIPEA and 0.80 mL DMF were combined with 65 mg (0.17 mmol) HATU and stirred overnight at RT. Then the reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[CH3:19]O>>[F:6][C:7]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:8]=1[C:9]([O:11][CH3:19])=[O:10]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc([N+](=O)[O-])cc1F

Procedure:
5 ml of concentrated sulfuric acid was added to a methanol (1300 ml) solution of 140 g of 2-fluoro-4-nitrobenzoic acid, and heated under reflux for 48 hours. The solvent was evaporated away under reduced pressure, water was added to the residue, and the formed solid was taken out through filtration. This was dried under reduced pressure to obtain 141 mg of the entitled compound as a yellow solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[C@@H:5]([NH2:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([Cl:26])=[C:21]([CH:25]=1)[C:22](O)=[O:23].Cl>CCOC(C)=O>[CH3:2][O:3][C:4](=[O:15])[C@@H:5]([NH:14][C:22](=[O:23])[C:21]1[CH:25]=[C:17]([NH2:16])[CH:18]=[CH:19][C:20]=1[Cl:26])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Reactant: COC(=O)[C@@H](N)Cc1ccc(Br)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1cc(N)ccc1Cl
Yield: 15.1 %

Procedure:
(S)-2-(5-Amino-2-chloro-benzoylamino)-3-(4-bromo-phenyl)-propionic acid methyl ester (316 mg) was prepared from (S)-2-Amino-3-(4-bromo-phenyl)-propionic acid methyl ester-hydrochloride (1.5 g, 5.1 mmol) and 5-amino-2-chloro-benzoic acid (909 mg, 5.1 mmol) as described in Procedure A, except for an adapted work-up. After reaction completion, the reaction mixture was poured onto 100 mL of 1N HCl and 50 mL of EtOAc. The organic layer was washed with 1N HCl, 10% sodium carbonate, dried over sodium sulfate and evaporated. The crude material was purified over silica gel (DCM-EtOAc, 9-1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([C:12]1[CH:20]=[CH:19][C:15]3[O:16][CH2:17][O:18][C:14]=3[CH:13]=1)=[C:6]([OH:21])[C:5]2=[O:22].[Br:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>N1C=CC=CC=1>[O:16]1[C:15]2[CH:19]=[CH:20][C:12]([C:7]3[O:8][C:9]4[C:4]([C:5](=[O:22])[C:6]=3[OH:21])=[CH:3][C:2]([NH:1][S:30]([C:27]3[CH:28]=[CH:29][C:24]([Br:23])=[CH:25][CH:26]=3)(=[O:32])=[O:31])=[CH:11][CH:10]=4)=[CH:13][C:14]=2[O:18][CH2:17]1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: Nc1ccc2oc(-c3ccc4c(c3)OCO4)c(O)c(=O)c2c1
Solvent: c1ccncc1
Product: O=c1c(O)c(-c2ccc3c(c2)OCO3)oc2ccc(NS(=O)(=O)c3ccc(Br)cc3)cc12
Yield: 91.6 %

Procedure:
100 mg (336 pmol) of 6-amino-2-(benzo[1,3]dioxol-5-yl)-3-hydroxy-4H-chromen-4-one obtained in Example 24 was dissolved in 3 ml of pyridine, and the mixture was reacted with 2 molar equivalents of 4-bromobenzenesulfonylchloride at room temperature for 5 hours. After the reaction was completed, the product was diluted with 10 ml. of water, and the obtained solid was filtered. Then the resulting product was washed with water and ethylether, and dried to give 159 mg of the title compound in a yield of 91.6%.
Reaction SMILES: [C:1]([O:23][CH:24]1[CH2:29][C:28]([CH3:31])([CH3:30])[N:27]([OH:32])[C:26]([CH3:34])([CH3:33])[CH2:25]1)(=[O:22])[C:2]1[CH:21]=[CH:20][CH:19]=[C:4]([C:5]([O:7][CH:8]2[CH2:13][C:12]([CH3:15])([CH3:14])[N:11]([OH:16])[C:10]([CH3:18])([CH3:17])[CH2:9]2)=[O:6])[CH:3]=1.[C:35]([O:39][CH:40]1[CH2:45][C:44]([CH3:47])([CH3:46])[N:43]([O:48][CH3:49])[C:42]([CH3:51])([CH3:50])[CH2:41]1)(=[O:38])[CH:36]=[CH2:37]>>[C:5]([O:7][CH:8]1[CH2:13][C:12]([CH3:14])([CH3:15])[N:11]([O:16][CH2:37][CH2:36][C:35]([O:39][CH:40]2[CH2:41][C:42]([CH3:50])([CH3:51])[N:43]([O:48][CH3:49])[C:44]([CH3:46])([CH3:47])[CH2:45]2)=[O:38])[C:10]([CH3:18])([CH3:17])[CH2:9]1)(=[O:6])[C:4]1[CH:19]=[CH:20][CH:21]=[C:2]([C:1]([O:23][CH:24]2[CH2:25][C:26]([CH3:34])([CH3:33])[N:27]([O:32][CH2:37][CH2:36][C:35]([O:39][CH:40]3[CH2:41][C:42]([CH3:51])([CH3:50])[N:43]([O:48][CH3:49])[C:44]([CH3:46])([CH3:47])[CH2:45]3)=[O:38])[C:28]([CH3:31])([CH3:30])[CH2:29]2)=[O:22])[CH:3]=1
Reactant: C=CC(=O)OC1CC(C)(C)N(OC)C(C)(C)C1
Reactant: CC1(C)CC(OC(=O)c2cccc(C(=O)OC3CC(C)(C)N(O)C(C)(C)C3)c2)CC(C)(C)N1O
Product: CON1C(C)(C)CC(OC(=O)CCON2C(C)(C)CC(OC(=O)c3cccc(C(=O)OC4CC(C)(C)N(OCCC(=O)OC5CC(C)(C)N(OC)C(C)(C)C5)C(C)(C)C4)c3)CC2(C)C)CC1(C)C
Yield: 31 %

Procedure:
The title compound is prepared in a 31% yield as a colorless glass from bis(1-oxyl-2,2,6,6-tetramethylpiperidin-4-yl) isophthalate and 1-methoxy-2,2,6,6-tetramethylpiperidin-4-yl acrylate according to the general procedure of Example 12. The reaction is reduced from five days to 48 hours in this case.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]#[N:9].[CH3:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1>>[C:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[C:14]1[CH:15]=[CH:16][C:11]([CH3:10])=[CH:12][CH:13]=1)#[N:9]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: N#Cc1cnccc1Br
Product: Cc1ccc(-c2ccncc2C#N)cc1

Procedure:
Synthetic Scheme XXVII shows the 5-step preparation of the alkylating reagent 4-(4-bromomethylphenyl)-3-cyanopyridine (73) from 4-bromopyridine (74) (Aldrich). In step 1, the ortho-bromo carbanion was generated with LDA in THF at -78° C. and reacted with anhydrous DMF to give 4-bromo-3-carboxaldehyde 75. In step 2, the aldehyde 75 was reacted with hydroxylamine to give the oxime 76. In step 3, the oxime 76 was dehydrated with 1,1'-carbonyldiimidazole in methylene chloride at reflux to give 4-bromo-3-cyanopyridine (77). In step 4, the nitrile 77 was coupled with 4-methylphenylboronic acid (56) (Scheme XXIV) using Snieckus conditions (Scheme XIII) to give 3-cyano-4-(4-methylphenyl)pridine (78). In step 5, 78 was brominated with NBS/AIBN in carbon tetrachloride at reflux to give the desired alkylating reagent 73. ##STR90##
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH3:11])=[C:4]([N+:12]([O-])=O)[CH:3]=1.[Cl-].[NH4+]>C(O)C.O.[Zn]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH3:11])=[C:4]([CH:3]=1)[NH2:12]
Reactant: CCCSc1ccc(F)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CCO
Product: CCCSc1ccc(F)cc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.7 %

Procedure:
4-Fluoro-2-nitro-1-propylsulfanylbenzene (6.7 g, 31.1 mmol) was dissolved in a mixed solvent of ethanol (40 ml) and water (4 ml). Ammonium chloride (17 g, 0.32 mol) was added to the resulting mixture, and zinc powder (20 g, 0.31 mol) were added little by little. The resulting mixture was then stirred at room temperature for 1 hour. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure to thereby obtain 5.8 g of oily brown 5-fluoro-2-propylsulfanylaniline (yield: 93%).