Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([CH3:10])=[C:8]([CH3:11])[S:7][C:6]1=[NH:12].CCN(CC)CC.[CH3:20][C:21]1([CH3:33])[CH2:25][C:24]2[CH:26]=[CH:27][CH:28]=[C:29]([C:30](Cl)=[O:31])[C:23]=2[O:22]1>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([CH3:10])=[C:8]([CH3:11])[S:7]/[C:6]/1=[N:12]\[C:30]([C:29]1[C:23]2[O:22][C:21]([CH3:33])([CH3:20])[CH2:25][C:24]=2[CH:26]=[CH:27][CH:28]=1)=[O:31]
Reactant: CC1(C)Cc2cccc(C(=O)Cl)c2O1
Reactant: COCCn1c(C)c(C)sc1=N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCn1c(C)c(C)s/c1=N\C(=O)c1cccc2c1OC(C)(C)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.1 %

Procedure:
To a solution of the product of Example 126A (0.20 g, 1.1 mmol) and Et3N (0.45 mL, 3.2 mmol) in 30 mL THF was added 2,2-dimethyl-2,3-dihydro-1-benzofuran-7-carbonyl chloride (Acros, 0.34 g, 1.6 mmol). This mixture was warmed to reflux and allowed to stir for 2 hours. The mixture was then cooled to ambient temperature and concentrated under reduced pressure. The residue was diluted with 10 mL EtOAc and washed with 5 mL saturated, aqueous NH4Cl. The layers were separated and the aqueous layer was extracted 2×5 mL EtOAc. The combined organics were dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure and purified via flash column chromatography (SiO2, 4:1 hexanes:EtOAc) to provide the title compound (0.21 mmol, 0.57 mmol, 53% yield). 1H NMR (300 MHz, CDCl3) δ ppm 1.55 (s, 6H), 2.22 (s, 3H), 2.27 (s, 3H), 3.02 (s, 2H), 3.31 (s, 3H), 3.77-3.89 (m, 2H), 4.33-4.50 (m, 2H), 6.85 (t, J=7.5 Hz, 1H), 7.22 (d, J=7.5 Hz, 1H), 8.00 (d, J=8.1 Hz, 1H); MS (DCI/NH3) m/z 361 (M+H); Anal. calculated for C19H24N2O3S: C, 63.31; H, 6.71; N, 7.77. Found: C, 63.19; H, 6.50; N, 7.66.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[CH3:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:9]=1[OH:17].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[CH3:6][O:5][C:3](=[O:4])[CH2:2][O:17][C:9]1[CH:10]=[CH:11][C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:8]=1[CH3:7]
Reactant: Cc1cc([N+](=O)[O-])ccc1O
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)COc1ccc([N+](=O)[O-])cc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.2 %

Procedure:
A solution of 15.76 ml (171 mmol) of methyl bromoacetate and 25.0 g (163 mmol) of 2-methyl-4-nitrophenol in 300 ml dry acetonitrile was treated with 61.3 g (188 mmol) Cs2CO3 and stirred at RT for 4 h. The mixture was filtered, washed with acetonitrile and evaporated. The residue was suspended in 700 ml CH2Cl2, filtered and evaporated to give 36.4 g of (2-methyl-4-nitro-phenoxy)-acetic acid methyl ester as yellow crystals.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[CH2:14][CH2:15][C:16]([OH:18])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:19]([NH:22][NH:23][C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH3:21])[CH3:20].C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:1]1([O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[CH2:14][CH2:15][C:16]([N:22]([CH:19]([CH3:21])[CH3:20])[NH:23][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)CCc1cc(F)ccc1OC1CCCC1
Reactant: CC(C)NNC(=O)c1ccccc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1cc(F)ccc1OC1CCCC1
Yield: 29.9 %

Procedure:
A solution of 3-(2-cyclopentyloxy-5-fluoro-phenyl)-propionic acid (220 mg, 0.87 mmoles) and benzoic acid N′-isopropyl-hydrazide (130 mg, 0.73 mmoles) in DMF (5mL) was treated with diisopropylethylamine (0.32 mL, 1.81 mmoles), and PyBroP (507 mg, 1.09 mmoles) at room temperature for 48 h. The reaction mixture was partitioned between 1N HCl and ethyl acetate. The organic layer was washed successively with saturated aqueous sodium bicarbonate and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-40% ethyl acetate/hexanes gradient to afford the product as a solid (90 mg, 30%). LC-MS m/e 413.32 (M+H+)
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[F:11].NC(N)=[S:14]>C(O)C>[F:11][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:3]=1[CH2:2][SH:14])[C:7]#[N:8]
Reactant: NC(N)=S
Reactant: N#Cc1ccc(CBr)c(F)c1
Solvent: CCO
Product: N#Cc1ccc(CS)c(F)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 4-(bromomethyl)-3-fluorobenzonitrile (0.8 g, 3.7 mmol) and thiourea (0.57 g, 7.4 mmol) in ethyl alcohol (EtOH; 20 mL) was heated to reflux for 1 h. The progress of the reaction was monitored by TLC; the reaction mixture was cooled to RT and concentrated under reduced pressure. The residue was washed with EtOAc (50 mL), treated with 1.6 N NaOH and stirred for 20 h at RT. The reaction mixture was adjusted to pH˜4 with concentrated HCl and diluted with Et2O (50 mL). The organic layer was washed with H2O (25 mL) and brine (25 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude I-2 (300 mg). The crude material was used without further purification. 1H NMR (500 MHz, CDCl3): δ 7.45 (dd, J=9.5 Hz, 1.5 Hz, 1H), 7.40-7.37 (m, 2H), 3.76 (s, 2H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[N:20]=[C:19]3[S:21][C:22]([NH:24][C:25]([CH:27]4[CH2:29][CH2:28]4)=[O:26])=[N:23][C:18]3=[CH:17][CH:16]=2)[CH:11]=[CH:10][C:9]=1[F:30])(C)(C)C>FC(F)(F)C(O)=O>[NH2:7][C:8]1[CH:13]=[C:12]([CH:11]=[CH:10][C:9]=1[F:30])[O:14][C:15]1[N:20]=[C:19]2[S:21][C:22]([NH:24][C:25]([CH:27]3[CH2:29][CH2:28]3)=[O:26])=[N:23][C:18]2=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F

Procedure:
A solution of tert-butyl(5-{[2-(cyclopropylcarbonyl)amino[1,3]thiazolo[5,4-b]pyridin-5-yl]oxy}-2-fluorophenyl)carbamate (0.78 g, 1.75 mmol) in trifluoroacetic acid (5 mL) was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (100 mL), washed with 0.1N aqueous sodium hydroxide solution (100 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was triturated with diethyl ether to give the title compound (0.60 g, quantitatively) as a white amorphous.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[C:12]([O:18][CH2:19][CH2:20][CH2:21][N:22]1[C:34]2[C:33]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N:27]=[CH:26][C:25]=2[N:24]=[C:23]1[CH2:35][CH2:36][CH2:37][CH3:38])(=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16]>C(Cl)Cl>[C:12]([O:18][CH2:19][CH2:20][CH2:21][N:22]1[C:34]2[C:33]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N+:27]([O-:6])=[CH:26][C:25]=2[N:24]=[C:23]1[CH2:35][CH2:36][CH2:37][CH3:38])(=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCC(=O)OCCCn1c(CCCC)nc2cnc3ccccc3c21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCCC(=O)OCCCn1c(CCCC)nc2c[n+]([O-])c3ccccc3c21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-Chloroperoxybenzoic acid (1.6 g) was added to a solution of the product from step (iii) (2.15 g) in DCM (30 mL) at 5° C. The reaction mixture was allowed to warm to rt, stirred for 18 h and partitioned between DCM/saturated sodium bisulfate solution. The organics were separated washed with saturated NaHCO3 solution, water, dried and evaporated under reduced pressure. Yield 1.77 g
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH3:15])[CH:9]=2)[N:5]=[C:4]2[N:16]([CH3:19])[N:17]=[CH:18][C:3]=12.[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)(=[O:23])=[O:22].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:15][O:14][C:10]1[CH:9]=[C:8]([C:6]2[N:5]=[C:4]3[N:16]([CH3:19])[N:17]=[CH:18][C:3]3=[C:2]([O:30][C:27]3[CH:26]=[CH:25][C:24]([S:21]([CH3:20])(=[O:23])=[O:22])=[CH:29][CH:28]=3)[CH:7]=2)[CH:13]=[CH:12][N:11]=1
Reactant: COc1cc(-c2cc(Cl)c3cnn(C)c3n2)ccn1
Reactant: CS(=O)(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(-c2cc(Oc3ccc(S(C)(=O)=O)cc3)c3cnn(C)c3n2)ccn1
Temperature: 150 °C
Yield: 50.2 %

Procedure:
To 4-chloro-6-(2-methoxypyridin-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine (0.4 g) and 4-(methylsulfonyl)phenol (0.5 g) was added DMF (3.4 mL) and potassium carbonate (1.0 g). Nitrogen was bubbled through the solution for 5 min. The reaction mixture was heated in a microwave reactor for 1 h at 150° C., then purified by reverse phase HPLC to provide 118 (0.3 g). MS (ESI) m/z 411.1 (M+1)+
Reaction SMILES: [Br:1]C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1CC.[CH2:23]([C:25]1[C:26]([NH:33][CH:34]2[C:38]3=[N:39][CH:40]=[CH:41][CH:42]=[C:37]3[CH2:36][CH:35]2[CH2:43][CH3:44])=[N:27][C:28]([CH2:31][CH3:32])=[CH:29][N:30]=1)[CH3:24]>>[Br:1][C:29]1[N:30]=[C:25]([CH2:23][CH3:24])[C:26]([NH:33][CH:34]2[C:38]3=[N:39][CH:40]=[CH:41][CH:42]=[C:37]3[CH2:36][CH:35]2[CH2:43][CH3:44])=[N:27][C:28]=1[CH2:31][CH3:32]
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Reactant: CCc1cnc(CC)c(NC2c3ncccc3CC2CC)n1
Product: CCc1nc(NC2c3ncccc3CC2CC)c(CC)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting N-(3,6-diethylpyrazin-2-yl)-6-ethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ) 8.43, 7.62, 7.19, 5.37, 5.28, 3.11, 3.08, 2.87-2.69, 1.41-1.26, 0.86; HRMS (FAB) calcd for C18H23BrN4+H 375.1185, found 375.1189.
Reaction SMILES: [P:1]([O-:47])([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][N+:43]([CH3:46])([CH3:45])[CH3:44])([O:3][CH2:4][CH:5]([O:26]CC1C=CC=CC=1)[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:2].[H][H]>C(O)(=O)C.[Pd]>[P:1]([O-:47])([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][N+:43]([CH3:46])([CH3:45])[CH3:44])([O:3][CH2:4][CH:5]([OH:26])[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:2]
Reactant: [H][H]
Reactant: CCCCCCCCCCCCCCCCCCOCC(COP(=O)([O-])OCCCCCCCC[N+](C)(C)C)OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCCCCOCC(O)COP(=O)([O-])OCCCCCCCC[N+](C)(C)C
Yield: 28.2 %

Procedure:
290 mg (0.43 mmole) of 2-(benzyloxy)-3-(octadecyloxy)propyl 8-trimethylammoniooctyl phosphate was dissolved in 30 ml of 70% acetic acid, and 0.2 g of 10% Pd-C as a catalyst was added to the mixture. The mixture was stirred at room temperature for 4 hours in a hydrogen atmosphere and filtrated. The filtrate was concentrated to dryness under reduced pressure and the residue was purified by silica gel (3 g, Merck & Co., Art. 7734; eluent: chloroform:methanol:water=65:25:4) column chromatography to give 72 mg (yield: 28.7%) of the above-mentioned compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH3:9][O:10][C:11](=[O:20])[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH3:19])[CH:13]=1.[C:21]([O:25][C:26](=[O:31])[CH2:27][CH2:28][CH2:29]Br)([CH3:24])([CH3:23])[CH3:22]>CC(C)=O>[CH3:9][O:10][C:11](=[O:20])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:29][CH2:28][CH2:27][C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:31])=[C:14]([CH3:19])[CH:13]=1
Reactant: CC(C)(C)OC(=O)CCCBr
Reactant: COC(=O)c1ccc(O)c(C)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCCCC(=O)OC(C)(C)C)c(C)c1
Yield: 76 %

Procedure:
Potassium carbonate (580 mg, 4.20 mmol) and potassium iodide (72 mg, 0.43 mmol) were added to a solution of 4-hydroxy-3-methyl-benzoic acid methyl ester from Example E29 (293 mg, 1.76 mmol) and 4-bromo-butyric acid tert-butyl ester from Example E42.1 (397 mg, 1.78 mmol) in acetone (50 ml). The mixture was heated at reflux for 18 h then the solid was filtered off and the filtrate concentrated in vacuo. The residue was dissolved in EtOAc, washed with water then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 20% EtOAc:80% pet. ether) to yield the title compound (414 mg, 76%).
Reaction SMILES: Cl[C:2]1[N:6]([C:7]2[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=2[C:9]([O:11][CH3:12])=[O:10])[C:5](=[O:17])[N:4]([CH3:18])[N:3]=1.[CH3:19][OH:20].C[O-].[Na+].[Cl-].[NH4+]>COCCOC>[CH3:19][O:20][C:2]1[N:6]([C:7]2[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=2[C:9]([O:11][CH3:12])=[O:10])[C:5](=[O:17])[N:4]([CH3:18])[N:3]=1
Reactant: COC(=O)c1ccccc1-n1c(Cl)nn(C)c1=O
Reactant: CO
Agent: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: COCCOC
Product: COC(=O)c1ccccc1-n1c(OC)nn(C)c1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution containing 10 g of the title compound of Step B dissolved in 110 mL of 1,2-dimethoxyethane and 50 mL of methanol under a nitrogen atmosphere was added dropwise 21.4 L of 30% sodium methoxide. The reaction mixture was stirred at room temperature for approximately 24 h, then heated to 40° C. for 1 h, then heated to 50° C. for 4 h, and finally cooled to 0° C. The reaction was poured into a saturated aqueous solution of ammonium chloride. The organic layer was separated and washed with saturated aqueous ammonium chloride. The organic layer was then dried over magnesium sulfate and filtered, and the filtrate was then evaporated to obtain 7.74 g of the title compound of Step C as a white solid.
Reaction SMILES: C(N(CC)CC)C.C[Si]([C:12]#[C:13][C:14]1[N:15]=[C:16]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[S:17][CH:18]=1)(C)C.Br[C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C)C=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[C:41]1([C:12]#[C:13][C:14]2[N:15]=[C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)[S:17][CH:18]=2)[C:42]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:38]=[CH:39][CH:40]=1
Reactant: Brc1cccc2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C#C[Si](C)(C)C)cs2)CC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(C#Cc3cccc4ccccc34)cs2)CC1
Temperature: 85 °C

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (95 mg), copper(I) iodide (31 mg) and triethylamine (200 mg) are added to a solution of tert-butyl 4-{4-[(trimethylsilyl)ethynyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (XI-1, 600 mg) and 1-bromonaphthalene (375 mg) in degassed N,N-dimethylformamide. After heating to 85° C., tetra-n-butylammonium fluoride (1M in THF, 1.81 ml) is added dropwise. The reaction mixture is then diluted with water and extracted with ethyl acetate. The organic extracts are dried over sodium sulphate and concentrated under reduced pressure. After chromatographic purification, this gives tert-butyl 4-[4-(naphthalen-1-ylethynyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate (576 mg).
Reaction SMILES: Cl.[OH:2][CH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]([C@H:12]2[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]2)=[O:11])[CH2:5][CH2:4]1.Cl[C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][N:20]=1.C(N(CC)C(C)C)(C)C.CN(C)C=O.C(O)(C(F)(F)F)=O>CO>[OH:2][CH:3]1[CH2:4][CH2:5][CH:6]([NH:9][C:10]([C@H:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][N:20]=3)[CH2:13]2)=[O:11])[CH2:7][CH2:8]1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: O=C(NC1CCC(O)CC1)[C@H]1CCCNC1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(N2CCC[C@H](C(=O)NC3CCC(O)CC3)C2)nc1

Procedure:
A mixture of (3S)—N-(4-hydroxycyclohexyl)piperidine-3-carboxamide hydrochloride (19.7 mg, 0.0000750 mol, prepared by using a procedure that was analogous to that described for the synthesis of example 1, steps 1 and 2), methyl 6-chloronicotinate (15.4 mg, 0.0000900 mol) and N,N-diisopropylethylamine (37.5 μL, 0.000216 mol) in N,N-dimethylformamide (0.75 mL, 0.0097 mol) was irradiated under microwave at 200° C. for 15 min. The mixture was adjusted with TFA to pH=2.0 and was diluted with methanol (0.8 mL). The resulting solution was purified by prep.—HPLC to give the desired product. LCMS: m/z 362.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:3]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:13][N:12]([N:21]3[C:30](=[O:31])[C:29]4[C:24](=[CH:25][C:26]([C:32]([O:34]C)=[O:33])=[CH:27][CH:28]=4)[N:23]=[C:22]3[CH3:36])[C:11](=[O:37])[C:5]3=[CH:6][CH2:7][CH2:8][C:9]([CH:10]=1)=[C:4]23.C1COCC1.[OH-].[K+].Cl>O.C(Cl)Cl.CO>[NH2:1][C:2]1[N:3]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:13][N:12]([N:21]3[C:30](=[O:31])[C:29]4[C:24](=[CH:25][C:26]([C:32]([OH:34])=[O:33])=[CH:27][CH:28]=4)[N:23]=[C:22]3[CH3:36])[C:11](=[O:37])[C:5]3=[CH:6][CH2:7][CH2:8][C:9]([CH:10]=1)=[C:4]23
Reactant: COC(=O)c1ccc2c(=O)n(N3C=C(c4ccccc4)n4c(N)cc5c4C(=CCC5)C3=O)c(C)nc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc2cc(C(=O)O)ccc2c(=O)n1N1C=C(c2ccccc2)n2c(N)cc3c2C(=CCC3)C1=O
Temperature: 22.5 °C
Reaction time: 3 h

Procedure:
0.6 g (1.22 mmmol) of the product of Example 28A and 30 ml of THF are introduced into a reactor. After solubilization, a solution of 0.135 g of KOH in 8 ml of water is added and the mixture is kept stirring for 3 h at 20-25° C. The mixture is neutralized with 0.1 N HCl to pH 6.8 and the THF is evaporated off at 50° C. under a vacuum of 20 rnm Hg. The residue is chromatographed, eluting with CH2Cl2 progressively enriched with methanol. The product obtained is crystallized from 10 ml of CH2Cl2 and the precipitate is filtered off. 0.25 g is obtained (Yld=42.7%). M.p.>275° C.—TLC (85/15 CH2Cl2/MeOH): Rf=0.35.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[C:12]([C:15]1[C:27]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C:19]=2[CH:18]=[CH:17][CH:16]=1)(=[O:14])[CH3:13].Cl>ClC(Cl)C>[C:1]([C:23]1[CH:24]=[CH:25][C:26]2[C:27]3[C:19](=[CH:18][CH:17]=[CH:16][C:15]=3[C:12](=[O:14])[CH3:13])[CH2:20][C:21]=2[CH:22]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)c1cccc2c1-c1ccccc1C2
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CC(=O)c1ccc2c(c1)Cc1cccc(C(C)=O)c1-2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Acetic anhydride (17.7 g.) was added to a stirred suspension of aluminium chloride (64 g.) in dichloroethane (100 ml.). The resulting solution was cooled to 0° C and treated dropwise with stirring, below 10° C, with a solution of 4-acetylfluorene (27.86 g.) in dichloroethane (100 ml.). The mixture was stirred at room temperature for 1 hour and then at 40° C for 3 hours, and finally cooled to 0° C and decomposed with 2N hydrochloric acid (200 ml.). The dichloroethane solution was separated and the aqueous portion was extracted with chloroform. The combined organic solution was washed with water and with aqueous sodium bicarbonate, dried over sodium sulphate and evaporated under reduced pressure. The residual solid was twice recrystallised from ethanol to give pure 2,5-diacetylfluorene, m.pt. 128°-129°. A solution of sodium hydroxide (27.2 g.) in water (500 ml.) was cooled to 0° C, stirred, and treated dropwise with bromine (14.8 ml.). 2,5-Diacetylfluorene (5g.) was added, the temperature was raised to 60° C over 3 hours and kept at 60° C for 3 hours. The mixture was cooled and filtered and the filtrate was warmed to 60° C, treated with sodium acetate (230 g.) and then cooled to 0° C for 1 hour. The resulting yellow precipitate was dissolved in water (200 ml.) and the solution was acidified with concentrated hydrochloric acid. After heating on the steam bath for 1 hour the solid was filtered, washed with water and dried in vacuo to give fluorenone-2,5-dicarboxylic acid m.pt. 300° C.
Reaction SMILES: [CH3:1][C:2]([CH3:30])([CH3:29])[C:3](=[O:28])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[S:21][C:20]([S:22]([NH2:25])(=[O:24])=[O:23])=[C:19]([CH3:26])[CH:18]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:27].[CH3:31][O:32][CH2:33][C:34](O)=[O:35]>>[CH3:31][O:32][CH2:33][C:34]([NH:25][S:22]([C:20]1[S:21][C:17]([C:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3](=[O:28])[C:2]([CH3:1])([CH3:29])[CH3:30])=[C:7]([CH3:27])[CH:8]=2)([CH2:13][CH3:14])[CH2:15][CH3:16])=[CH:18][C:19]=1[CH3:26])(=[O:24])=[O:23])=[O:35]
Reactant: COCC(=O)O
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc(C)c(S(N)(=O)=O)s1
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc(C)c(S(=O)(=O)NC(=O)COC)s1
Yield: 84 %

Procedure:
Using a procedure analogous to Example 163, 5-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-thiophene-2-sulfonic acid amide and methoxy-acetic acid give the title compound (84%).
Reaction SMILES: N1(C2CCN(C3S[C:16]([NH:18][C:19]4[N:24]=[C:23]([NH:25][C:26]5[C:31]([O:32][CH3:33])=[N:30][C:29]([P:34]([CH3:37])([CH3:36])=[O:35])=[CH:28][N:27]=5)[C:22]([Cl:38])=[CH:21][N:20]=4)=NN=3)CC2)CCCCC1.[CH3:39][N:40]1[CH2:45][CH2:44][N:43]([C:46]2[O:50][C:49](CN)=[N:48][N:47]=2)[CH2:42][CH2:41]1>>[Cl:38][C:22]1[C:23]([NH:25][C:26]2[C:31]([O:32][CH3:33])=[N:30][C:29]([P:34]([CH3:36])([CH3:37])=[O:35])=[CH:28][N:27]=2)=[N:24][C:19]([NH:18][CH2:16][C:49]2[O:50][C:46]([N:43]3[CH2:44][CH2:45][N:40]([CH3:39])[CH2:41][CH2:42]3)=[N:47][N:48]=2)=[N:20][CH:21]=1
Reactant: CN1CCN(c2nnc(CN)o2)CC1
Reactant: COc1nc(P(C)(C)=O)cnc1Nc1nc(Nc2nnc(N3CCC(N4CCCCC4)CC3)s2)ncc1Cl
Product: COc1nc(P(C)(C)=O)cnc1Nc1nc(NCc2nnc(N3CCN(C)CC3)o2)ncc1Cl

Procedure:
This compound can be prepared as in Example 32 by reacting 2,5-dichloro-N-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]pyrimidin-4-amine (as described in Example 51) with 1-[5-(4-methylpiperazin-1-yl)-1,3,4-oxadiazol-2-yl]methanamine.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([N:10]([C:19]([O:21]CC(Cl)(Cl)Cl)=O)C(OCC(Cl)(Cl)Cl)=O)=[N:2]1.[C:27]1([C:33]2[N:37]=[C:36]([N:38]3[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]3)[S:35][N:34]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([NH:10][C:19]([N:41]2[CH2:42][CH2:43][N:38]([C:36]3[S:35][N:34]=[C:33]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:37]=3)[CH2:39][CH2:40]2)=[O:21])=[N:2]1
Reactant: O=C(OCC(Cl)(Cl)Cl)N(C(=O)OCC(Cl)(Cl)Cl)c1n[nH]c2ccccc12
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: O=C(Nc1n[nH]c2ccccc12)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Yield: 12.2 %

Procedure:
A mixed solution of bis(2,2,2-trichloroethyl) 1H-indazol-3-ylimidodicarbonate (295 mg, 0.61 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (300 mg, 1.22 mmol) and diisopropylethylamine (0.106 ml, 0.610 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 80° C. for 5 hours. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (100% ethyl acetate, followed by ethyl acetate:methanol=1:1) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 30.2 mg (12.2%) of the desired product as a solid.