Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:16]=[N:17][NH:18][CH:19]=2)[CH2:10][C@H:9]1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([CH3:28])[CH:22]=1)=[O:7].Br[CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:35][C:32]([F:34])([F:33])[C:30]1[CH:29]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:36])[F:37])[CH:31]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:19]=[N:18][N:17]([CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH:16]=2)[CH2:10][C@H:9]1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([CH3:28])[CH:22]=1)=[O:7]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1ccc(C[C@@H]2CN(Cc3cn[nH]c3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C[C@@H]2CN(Cc3cnn(CC(=O)OC(C)(C)C)c3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Temperature: 60 °C
Reaction time: 7 h

Procedure:
To a solution of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-(4-pyrazolylmethyl)piperazine (500 mg) and tert-butyl bromoacetate (225 mg) in N,N-dimethylformamide (7.5 ml) was added potassium carbonate (390 mg), and the mixture was stirred at 60° C. for 7 hours. Water was added to the mixture and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, evaporated under reduced pressure, and purified by column chromatography on a silica gel using a mixture of ethyl acetate and hexane (1:1) as eluent to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[[1-(tert-butoxycarbonylmethyl)-1H-pyrazol-4-yl]methyl]-2-(3,4-dimethylbenzyl)piperazine as an oil.
Reaction SMILES: C(N(CC)CC)C.I[C:9]1[CH:18]=[CH:17][C:16]2[NH:15][C:14](=[O:19])[C:13]3[NH:20][CH:21]=[CH:22][C:12]=3[C:11]=2[CH:10]=1.[CH2:23]([C:25]([O-:27])=[O:26])[CH3:24].[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)#[CH:29]>O1CCOCC1.[Cu](I)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>[O:19]=[C:14]1[C:13]2[NH:20][CH:21]=[CH:22][C:12]=2[C:11]2[CH:10]=[C:9]([C:29]#[C:28][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[CH:18]=[CH:17][C:16]=2[NH:15]1.[CH2:23]([C:25]([O-:27])=[O:26])[CH3:24]
Reactant: C#Cc1ccccn1
Reactant: O=c1[nH]c2ccc(I)cc2c2cc[nH]c12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: CCC(=O)[O-]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=c1[nH]c2ccc(C#Cc3ccccn3)cc2c2cc[nH]c12
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 45.2 %

Procedure:
20 mg (0.11 mmol) of copper iodide, 28 mg (0.27 mmol) of triethylamine and 14 mg (0.02 mmol) of dichlorobis(triphenylphosphine)-palladium (II) are added to a suspension of 80 mg (0.21 mmol) of 8-iodo-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in 2.4 ml of anhydrous dioxan, then this mixture is degassed under argon. After 15 minutes, 32 mg (0.31 mmol) of 2-ethynyl-pyridine are added, then the mixture is heated at 100° C. for 3 hours. The raw reaction product is then filtered on celite, the filtrate is evaporated to dryness and the residue is purified by chromatography on silica (eluent ethyl acetate) to give 34 mg (46%) of 4-oxo-8-pyridin-2-ylethynyl-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in the form of a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([OH:13])=O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH3:35][N:36]([C@@H:46]1[CH2:51][CH2:50][CH2:49][NH:48][CH2:47]1)[C:37]1[N:42]=[CH:41][N:40]=[C:39]2[NH:43][N:44]=[CH:45][C:38]=12.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[Cl:8][C:6]1[CH:5]=[C:4]([NH:9][CH2:10][C:11]([N:48]2[CH2:49][CH2:50][CH2:51][C@@H:46]([N:36]([CH3:35])[C:37]3[N:42]=[CH:41][N:40]=[C:39]4[NH:43][N:44]=[CH:45][C:38]=34)[CH2:47]2)=[O:13])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: O=C(O)CNc1cc(Cl)cc(Cl)c1
Reactant: CN(c1ncnc2[nH]ncc12)[C@@H]1CCCNC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(c1ncnc2[nH]ncc12)[C@@H]1CCCN(C(=O)CNc2cc(Cl)cc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 15 %

Procedure:
To a solution of 2-(3,5-dichlorophenylamino)acetic acid (170 mg, 0.77 mmol) in DMF (5 mL) was added HOBt (156 mg, 1.16 mmol) at 0° C. and the reaction mixture was stirred for 10 min, followed by the addition of EDCI (222 mg, 1.16 mmol), (R)—N-methyl-N-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (180 mg, 0.77 mmol) and DIEA (150 mg, 1.16 mmol). The reaction mixture was allowed to warm to rt and was stirred overnight, diluted with EtOAc (50 mL) and washed with water (3×20 mL). The EtOAc layer was dried over Na2SO4 and evaporated in vacuo to give a residue that purified by column chromatography (silica gel, gradient MeOH in DCM) to afford the titled intermediate (50 mg, 14.8%). 1H NMR (400 MHz, DMSO-d6): δ 13.50 (d, J=10.8 Hz, 1H), 8.22 (s, 1H), 8.17 (m, 1H), 6.77 (s, 1H), 6.70 (s, 1H), 6.62 (s, 1H), 6.32 (m, 1H), 4.40 (d, J=12.4 Hz, 1H), 4.00 (m, 3H), 3.28 (s, 3H), 3.02 (t, J=7.8 Hz, 1H), 2.80 (m, 1H), 2.62 (t, J=7.8 Hz, 1H), 2.00 (m, 2H), 1.82 (m, 2H). LC-MS: m/z [M+1]=434.
Reaction SMILES: Cl[C:2]1[C:3]2[C@H:10]([CH3:11])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Br-].[CH2:13]([O:15][C:16]([C:18]1[S:22][C:21]([Zn+])=[CH:20][CH:19]=1)=[O:17])[CH3:14].C1COCC1.O>C(OCC)C.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>[CH3:11][C@H:10]1[C:3]2[C:2]([C:21]3[S:22][C:18]([C:16]([O:15][CH2:13][CH3:14])=[O:17])=[CH:19][CH:20]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH2:8][CH2:9]1
Reactant: C[C@@H]1CCc2ncnc(Cl)c21
Reactant: CCOC(=O)c1ccc([Zn+])s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1ccc(-c2ncnc3c2[C@H](C)CC3)s1
Temperature: 70 °C
Reaction time: 16 h
Yield: 78 %

Procedure:
Pd(PPh3)4 (10 mg, 0.09 mmol) was added to a degassed solution of (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta-[d]-pyrimidine (300 mg, 1.78 mmol) and a 0.5M solution of 5-ethoxycarbonyl-2-thienylzinc bromide in THF (3.6 mL, 1.78 mmol). The reaction mixture was stirred at 70° C. for 16 hours and then it was cooled to room temperature and diluted with diethyl ether (10 mL). Water was added (5 mL) and a precipitate was formed and filtered. The solid was washed with more diethyl ether and the filtrate was concentrated. The resulting oil was purified on silica gel (0%-75% EtOAc/hexanes) to yield (R)-ethyl 5-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)thiophene-2-carboxylate as an oil (400 mg, 78%). m/z: 289 (MH+), 1H NMR (CDCl3): δ (ppm) 8.95 (s, 1H), 7.84-7.82 (m, 1H), 7.70-7.69 (m 1H), 4.39 (dq, 2H, J1=7.2 Hz, J2=1.2 Hz), 3.77 (quint., 1H, J=7.2 Hz), 3.23-1.14 (m, 1H), 3.001-2.95 (m, 1H), 2.42-2.31 (m, 1H), 1.98-1.92 (m, 1H), 1.40 (dt, 3H, J1=7.2 Hz, J2=1.2 Hz), 1.29 (d, 3H, J=7.2 Hz).
Reaction SMILES: [OH:1][C:2]1[C:7]([NH:8]C(=O)OCC2C=CC=CC=2)=[CH:6][N:5]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[N:3]=1.[H][H]>CO.[Pd]>[NH2:8][C:7]1[C:2]([OH:1])=[N:3][C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[N:5][CH:6]=1
Reactant: [H][H]
Reactant: O=C(Nc1cnc(-c2ccccn2)nc1O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: Nc1cnc(-c2ccccn2)nc1O
Yield: 41.1 %

Procedure:
Benzyl 4-hydroxy-2-(pyridin-2-yl)pyrimidin-5-ylcarbamate (10-d) (1 g, 3.1 mmol) in methanol (20 ml) was hydrogenated under 1 atm of hydrogen in the presence of Pd/C (500 mg) overnight. The mixture was filtered and the filtrate was concentrated to provide the crude product, 10-e (240 mg).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[CH2:22](Br)[CH:23]=[CH2:24]>O>[CH2:24]([O:10][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:9][C:6]=1[CH:7]=[O:8])[CH:23]=[CH2:22]
Reactant: C=CCBr
Reactant: O=Cc1cc(F)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1ccc(F)cc1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
To a round bottom flask were added 5-fluorosalicylaldehyde (47c, 4.0 g, 28.5 mmol, 1.0 equiv.), potassium carbonate (4.92 g, 35.6 mmol, 1.25 equiv.), and DMF (20 mL). Allyl bromide (3.7 mL, 42.8 mmol, 1.5 equiv.) was added slowly to the mixture. The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water (2×25 mL), 0.1M KOH (2×25 mL), water (2×25 mL), and brine (2×25 mL), dried over MgSO4, filtered, and concentrated to yield 53b (4.64 g, 90.2%) as a pale yellow liquid. 1H-NMR (500 MHz, CDCl3) δ 10.47 (d, 1H, J=3.0 Hz), 7.50 (dd, 1H, J=3.0, 8.0 Hz), 7.23 (ddd, 1H, J=3.0, 7.5, 11.0 Hz), 6.95 (dd, 1H, J=4.0, 9.0 Hz), 6.06 (tdd, 1H, J=5.0, 10.5, 17.5 Hz), 5.44 (qd, 1H, J=1.5, 17.0 Hz), 5.34 (ddd, 1H, J=1.5, 2.5, 10.5 Hz), 4.64 (td, 2H, J=1.5, 5.0 Hz). 13C-NMR (125 MHz, CDCl3) δ 188.8, 157.4 (d, JC-F=1.9 Hz), 157.2 (d, JC-F=240.5 Hz), 132.4, 126.1 (d, JC-F=5.9 Hz), 122.6 (d, JC-F=23.8 Hz), 118.5, 114.8 (d, JC-F=7.1 Hz), 114.2 (d, JC-F=23.1 Hz), 70.1. 19F-NMR (470 MHz, CDCl3) δ −125.5. HRMS (EI): 180.05789 (M+); calcd. for C10H9FO2: 180.05866.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:21])[C:5]2[C:11](=S)[NH:10][C@@H:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[Br:20])[CH2:8][C:6]=2[N:7]=1.[CH3:22][C:23]1([CH3:32])[O:27][C@@H:26]([CH2:28][CH2:29][O:30][NH2:31])[CH2:25][O:24]1>[Hg](OC(C)=O)OC(C)=O.C1(C)C=CC=CC=1>[CH3:22][C:23]1([CH3:32])[O:27][C@@H:26]([CH2:28][CH2:29][O:30]/[N:31]=[C:11]2\[NH:10][C@@H:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[Br:20])[CH2:8][C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([CH3:21])[C:5]\2=3)[CH2:25][O:24]1
Reactant: Cc1nc(N)nc2c1C(=S)N[C@@H](c1ccc(F)cc1Br)C2
Reactant: CC1(C)OC[C@H](CCON)O1
Agent: CC(=O)O[Hg]OC(C)=O
Solvent: Cc1ccccc1
Product: Cc1nc(N)nc2c1/C(=N/OCC[C@H]1COC(C)(C)O1)N[C@@H](c1ccc(F)cc1Br)C2
Temperature: 100 °C
Yield: 58.7 %

Procedure:
A mixture of (R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidine-5(6H)-thione (31I, 100 mg, 0.3 mmol), (S)—O-(2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)hydroxylamine (194 mg, 1.2 mmol), Hg(OAc)2 (192 mg, 0.6 mmol) and anhydrous toluene (2 mL) was heated at 100° C. for 1 h. LCMS shows completion of the reaction. The mixture was cooled, filtered through celite and washed with ethyl acetate. Filtrate concentrated and the resulting oily residue was purified by preparative LCMS to afford (R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O-2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)ethyl oxime (35A, 87 mg, 65%) as a pale yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 1.35 (s, 3H) 1.40 (s, 3H) 2.01 (qd, J=6.32, 3.03 Hz, 2H) 2.76 (s, 3H) 2.95 (dd, J=16.42, 8.84 Hz, 1H) 3.18 (dd, J=17.18, 5.05 Hz, 1H) 3.56-3.62 (m, 1H) 4.09 (dd, J=7.96, 5.94 Hz, 1H) 4.16-4.28 (m, 2H) 4.98 (ddd, J=8.78, 4.61, 1.52 Hz, 1H) 7.07 (td, J=8.21, 2.53 Hz, 1H) 7.34 (dd, J=8.08, 2.53 Hz, 1H) 7.68 (dd, J=12.00, 6.95 Hz, 1H). MS (ES) [M+H] calculated for C21H26BrFN5O3, 494.11. found 494.00.
Reaction SMILES: Cl.[N:2]1([CH2:7][CH2:8][O:9][CH2:10][C:11]([OH:13])=[O:12])[CH:6]=[CH:5][N:4]=[CH:3]1.O[CH2:15][CH2:16]N1C=CN=C1.[H-].[Na+].ClCC(OCC)=O>CN(C)C=O>[CH2:15]([O:12][C:11](=[O:13])[CH2:10][O:9][CH2:8][CH2:7][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1)[CH3:16]
Reactant: O=C(O)COCCn1ccnc1
Reactant: OCCn1ccnc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(=O)CCl
Solvent: CN(C)C=O
Product: CCOC(=O)COCCn1ccnc1

Procedure:
The 5-(imidazol-1-yl)-3-oxa-pentanoic acid-hydrochloride used as the starting material is prepared in the following manner: 1-(2-hydroxyethyl)imidazole (J. Chem. Soc. 1977, 1272) is reacted in the presence of sodium hydride with ethyl chloroacetate in dimethyl formamide to form 5-(imidazol-1-yl)-3-oxa-pentanoic acid-ethyl ester (oil) and the desired acid is obtained from it by heating with 6 N hydrochloric acid.
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]([CH3:12])[CH:10]=[C:9]([C:13]3[C:18]([CH3:19])=[CH:17][C:16]([O:20][CH3:21])=[CH:15][C:14]=3[CH3:22])[C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.[NH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:37])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1.O>CN1C(=O)CCC1>[CH3:36][O:35][C:32]1[CH:31]=[CH:30][C:29]([CH2:28][C:27]([NH:26][CH2:25][CH2:24][NH:23][C:2]2[C:3]3[N:11]([CH3:12])[CH:10]=[C:9]([C:13]4[C:18]([CH3:19])=[CH:17][C:16]([O:20][CH3:21])=[CH:15][C:14]=4[CH3:22])[C:4]=3[N:5]=[C:6]([CH3:8])[N:7]=2)=[O:37])=[CH:34][CH:33]=1
Reactant: COc1cc(C)c(-c2cn(C)c3c(Cl)nc(C)nc23)c(C)c1
Reactant: COc1ccc(CC(=O)NCCN)cc1
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc(CC(=O)NCCNc2nc(C)nc3c(-c4c(C)cc(OC)cc4C)cn(C)c23)cc1

Procedure:
Heat a solution of 4-chloro-7-(4-methoxy-2,6-dimethyl-phenyl)-2,5-dimethyl-5H-pyrrolo[3,2-d]pyrimidine (120 mg, 0.38 mmol) and N-(2-amino-ethyl)-2-(4-methoxy-phenyl)-acetamide (125 mg) in NMP (2 mL) for 14 h at 130° C. Pour into water (5 mL) and extract with EtOAc (2×10 mL). Dry the combined organic extracts over Na2SO4, filter, and concentrate under reduced pressure to obtain the title compound which is used without further purification.
Reaction SMILES: Cl.[C:2](=[NH:7])(OCC)[CH3:3].[NH2:8][CH2:9][C:10]1[NH:15][C:14](=[O:16])[NH:13][C:12](=[O:17])[C:11]=1[Cl:18]>CN(C)C=O>[ClH:18].[Cl:18][C:11]1[C:12](=[O:17])[NH:13][C:14](=[O:16])[NH:15][C:10]=1[CH2:9][NH:8][C:2](=[NH:7])[CH3:3]
Reactant: CCOC(C)=N
Reactant: NCc1[nH]c(=O)[nH]c(=O)c1Cl
Agent: Cl
Solvent: CN(C)C=O
Product: CC(=N)NCc1[nH]c(=O)[nH]c(=O)c1Cl
Temperature: 25 °C
Reaction time: 13 h
Yield: 52.7 %

Procedure:
To a solution of 705 mg of ethyl acetoimidate hydrochloride in N,N-dimethylformamide (12 ml), 500 mg of 6-aminomethyl-5-chlorouracil wereadded, followed by stirring at room temperature for 13 hours. After the reaction mixture was allowed to cool down, a crystallized matter was collected by filtration and then washed with a 10% solution of hydrochloric acid in methanol, whereby 190 mg of the title compound were obtained (yield: 26%).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]2[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:8]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[N:7][C:6]=12.[C:25]([C:27]1[CH:32]=[CH:31][C:30]([C:33]([OH:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=1)#[CH:26]>>[F:12][C:11]([F:14])([F:13])[C:10]1[N:5]2[N:4]=[CH:3][C:2]([C:26]#[C:25][C:27]3[CH:32]=[CH:31][C:30]([C:33]([OH:36])([CH3:34])[CH3:35])=[CH:29][CH:28]=3)=[C:6]2[N:7]=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:9]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3ncc(I)c3n2)cc1
Reactant: C#Cc1ccc(C(C)(C)O)cc1
Product: CC(C)(O)c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1

Procedure:
The title compound was prepared from 3-iodo-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1 method 2 step 2) (460 g, 1.0 mmol) and 2-(4-ethynyl-phenyl)-propan-2-ol (example D.4) (161 mg, 1.0 mmol) according to general procedure II. Obtained as an orange solid (300 mg, 60%). MS (ISP) 490.2 [(M+H)+]; mp 170–171° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]([CH3:9])[C:6]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.Cl.[CH3:20]O>>[NH2:2][C:3]1[N:8]=[C:7]([CH3:9])[C:6]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([O:16][CH3:20])=[O:15])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: Cc1nc(N)ccc1-c1ccc(C(=O)O)cc1
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc(-c2ccc(N)nc2C)cc1
Yield: 70 %

Procedure:
A stirred suspension of 4-(6-amino-2-methylpyridin-3-yl)benzoic acid hydrochloride (D6, 1.9 g, 8.3 mmole) in methanol (120 ml) was treated with conc. HCl acid (1 ml) and heated under reflux for 2 h. The solution was concentrated in vacuo, the residue treated with excess 10% Na2CO3 solution and extracted with ethyl acetate. The extract was dried (Na2SO4) and concentrated in vacuo to afford the title compound as a pale yellow solid (1.4 g, 70%).
Reaction SMILES: [CH2:1]([C:15]1([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].Br[C:43]([CH3:48])([CH3:47])[C:44](Br)=[O:45].[Cl-].[Cl-].[Cl-].[Al+3]>C(=S)=S>[CH3:47][CH:43]1[C:44](=[O:45])[C:25]2=[CH:26][C:27]3[C:15]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:16]4[C:21]([C:22]=3[CH:23]=[C:24]2[CH2:48]1)=[CH:20][CH:19]=[CH:18][CH:17]=4
Reactant: CCCCCCCCCCCCCCC1(CCCCCCCCCCCCCC)c2ccccc2-c2ccccc21
Reactant: CC(C)(Br)C(=O)Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCCCCCCCCCCCCCC1(CCCCCCCCCCCCCC)c2ccccc2-c2cc3c(cc21)C(=O)C(C)C3
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.1 %

Procedure:
A 5000 mL round flask was charged with 9,9-ditetradecyl-9H-fluorene (30 g, 53.7 mmol) and 2-bromo-2-methylpropanoyl bromide (12.7 g, 55.3 mmol), and then dissolved with 300 mL of carbon disulfide inputted thereto. Then, the reactor was cooled with ice water. Under nitrogen atmosphere, aluminum trichloride (15.7 g, 118.1 mmol) was slowly added thereto in ten lots over 2 hours. The mixture was stirred at room temperature for 8 hours, and then the reaction was terminated by addition of 100 mL of distilled water, followed by washing with 500 mL of distilled water three times. The organic layer was dried over magnesium sulfate, followed by removal of volatile materials and drying, to thereby obtain 30.0 g of 2-methyl-9,9-ditetradecyl-2,3-dihydrocyclopenta[b]fluoren-1(9H)-one (yield: 89.1%) as highly viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:6]2[CH3:12].[H-].[Na+].F[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=1>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)=[C:7]2[C:3]=1[CH:4]=[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:6]2[CH3:12]
Reactant: O=[N+]([O-])c1cccc(F)c1
Reactant: CCOC(=O)c1cc2c(Cl)ccc(O)c2n1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(Cl)ccc(Oc3cccc([N+](=O)[O-])c3)c2n1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.4 %

Procedure:
After 0.50 g (1.97 mmol) of ethyl 4-chloro-7-hydroxy-1-methyl-2-indolecarboxylate was added to a suspension of 0.16 g (3.94 mmol) of 60% sodium hydride and 10 ml of dimethylformamide, the suspension was stirred at room temperature for 30 minutes. Then 0.28 g (1.97 mmol) of 1-fluoro-3-nitrobenzene was added to the solution at room temperature followed by stirring for 3 hours at 150° C. After cooling, the reaction mixture was poured onto ice water. The resulting mixture was then extracted three times with ethyl acetate. The combined extracts were washed with saturated sodium chloride aqueous solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was isolated and purified by silica gel column chromatography to give 0.18 g (24.3%) of ethyl 4-chloro-1-methyl-7-(3-nitrophenoxy)-2-indolecarboxylate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C:14]([OH:16])=O)[CH:8]=[CH:7]2)([O-:3])=[O:2].[CH2:17]([O:19][C:20](=[O:30])[C@H:21]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH2:22])[CH3:18]>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C:14]([NH:22][C@H:21]([C:20]([O:19][CH2:17][CH3:18])=[O:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:16])[CH:8]=[CH:7]2)([O-:3])=[O:2]
Reactant: O=C(O)Cn1ccc2cc([N+](=O)[O-])ccc21
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Product: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)Cn1ccc2cc([N+](=O)[O-])ccc21

Procedure:
Ethyl N-[(5-nitro-1H-indol-1-yl)acetyl]-L-phenylalaninate was prepared from (5-nitro-1H-indol-1-yl)acetic acid and L-phenylalanine ethyl ester following the procedure of Example 10 Step 3: MS (ESI) m/z 396; MS (ESI) m/z 394.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH: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][CH2:25][CH2:26][CH3:27])[C:5]([OH:7])=[O:6].[H-].[Na+].[CH3:30]I>CN(C)P(N(C)C)(N(C)C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH: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][CH2:25][CH2:26][CH3:27])[C:5]([O:7][CH3:30])=[O:6]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OC)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 7.20 g of 3-fluoro-4-(hexadecylamino)-benzoic acid in 25 ml of hexamethylphosphoramide is added to a stirred mixture of 0.800 g of sodium hydride (57% in mineral oil) and 25 ml of hexamethylphosphoramide. The solution which forms after one hour is treated with 11.0 g of methyl iodide and is then stirred at 25° C. for 18 hours. Dilution with water followed by filtration affords a white solid which is crystallized from ethanol to yield methyl 3-fluoro-4-(hexadecylamino)-benzoate as a white solid.
Reaction SMILES: [F:1][CH:2]([F:13])[CH2:3][N:4]1[CH:8]=[C:7]([C:9]([OH:11])=O)[N:6]=[C:5]1[CH3:12].[NH2:14][C@@H:15]([CH3:32])[CH2:16][N:17]1[CH:21]=[CH:20][C:19]([C:22]2[CH:29]=[C:28]([F:30])[C:25]([C:26]#[N:27])=[C:24]([Cl:31])[CH:23]=2)=[N:18]1.C1C=CC2N(O)N=NC=2C=1.CN(C=O)C>O>[Cl:31][C:24]1[CH:23]=[C:22]([C:19]2[CH:20]=[CH:21][N:17]([CH2:16][C@@H:15]([NH:14][C:9]([C:7]3[N:6]=[C:5]([CH3:12])[N:4]([CH2:3][CH:2]([F:1])[F:13])[CH:8]=3)=[O:11])[CH3:32])[N:18]=2)[CH:29]=[C:28]([F:30])[C:25]=1[C:26]#[N:27]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: Cc1nc(C(=O)O)cn1CC(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3cc(F)c(C#N)c(Cl)c3)n2)cn1CC(F)F
Yield: 5.6 %

Procedure:
The title compound was prepared using the procedure described in Example 3(h) using 1-(2,2-difluoro-ethyl)-2-methyl-1H-imidazole-4-carboxylic acid (0.926 mmol, 176 mg), (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzo-nitrile (0.617 mmol, 172 mg) and only a catalytic amount of HOBt (0.062 mmol, 8.34 mg). DMF was used as the solvent. Water was added to the reaction mixture and the mixture was extracted it three times with DCM. The combined organics were washed twice with water. The organic phase was evaporated and the residue was purified by flash chromatography and preparative HPLC, respectively. 15.5 mg of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.07 (d, 3H), 2.36 (s, 3H), 4.23-4.55 (m, 5H), 6.19-6.51 (m, 1H), 7.02 (d, 1H), 7.53 (s, 1H), 7.86 (d, 1H), 7.90-7.95 (m, 1H), 8.00 (s, 1H), 8.12 (d, 1H).