Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:39][CH2:40][OH:41])[C:9]1[C:10]2[CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28][C:11]=2[N:12]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[CH:25][N:24]=[C:23]3[CH3:27])=[CH:18][CH:17]=2)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO>[CH2:1]([N:8]([C:9]1[C:10]2[CH2:31][NH:30][CH2:29][CH2:28][C:11]=2[N:12]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[CH:25][N:24]=[C:23]3[CH3:27])=[CH:18][CH:17]=2)[N:14]=1)[CH2:39][CH2:40][OH:41])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(N(CCO)Cc4ccccc4)n2)CN(C(=O)OC(C)(C)C)CC3)cc1
Agent: Cl
Solvent: CO
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(N(CCO)Cc4ccccc4)n2)CNCC3)cc1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
tert-Butyl 4-(benzyl(2-hydroxyethyl)amino)-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (121 mg, 0.22 mmol) was dissolved methanol (2 mL). Hydrochloric acid (0.018 mL, 0.22 mmol) was added and the reaction was stirred at 75° C. for 1 h. The solvent was evaporated under reduced pressure and the crude 2-(benzyl(2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)ethanol (95 mg, 96%) was used as such in the subsequent step. MS (ES+) m/z 456.3 (M+H)+
Reaction SMILES: P(Br)(Br)([Br:3])=O.[CH2:6]([C:11]1[CH:12]=[CH:13][C:14](=O)[NH:15][N:16]=1)[CH2:7][CH2:8][CH2:9][CH3:10].[OH-].[Na+].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.O>[Br:3][C:14]1[N:15]=[N:16][C:11]([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:12][CH:13]=1
Reactant: CCCCCc1ccc(=O)[nH]n1
Reactant: O=P(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCc1ccc(Br)nn1
Temperature: 65 °C
Reaction time: 18 h
Yield: 144 %

Procedure:
A solution of 18.6 g of phosphorus oxybromide in 18.6 g of absolute toluene was diluted with 100 ml of absolute toluene in a sulphonation flask under nitrogen, heated to 65° C. and treated dropwise within 1.5 hours with a solution of 21.6 g of 6-pentyl-3(2H)-pyridazinone (prepared according to Example 3) in 100 ml of absolute toluene. A grey coloured difficultly stirrable suspension formed occasionally. For the completion of the reaction, the mixture was stirred at 65° C. overnight (18 hours), then cooled to room temperature, poured into 250 ml of water and stirred well. The aqueous phase was neutralized with 28% (wt./vol.) sodium hydroxide solution and with sodium hydrogen carbonate. The organic phase was separated and the aqueous phase was back-extracted with 100 ml of tert.butyl methyl ether. The combined organic phases were washed with 100 ml of water, dried over sodium sulphate and evaporated on a rotary evaporator. The brown coloured crude product was subsequently distilled in a high vacuum, there being obtained 21.4 g (72%) of 3-bromo-6-pentylpyridazine in the form of a brown oil (b.p. 99°-108° C./0.04-0.06 Torr) which crystallized upon cooling. Recrystallization of a sample from methyl formate at -20° C. gave white crystals of melting point 31°-32° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]([OH:15])=O)[CH:9]=2)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH:22]([N:25]([CH3:36])[C:26]1[S:27][C:28]2[CH:34]=[C:33]([NH2:35])[CH:32]=[CH:31][C:29]=2[N:30]=1)([CH3:24])[CH3:23]>>[CH:22]([N:25]([CH3:36])[C:26]1[S:27][C:28]2[CH:34]=[C:33]([NH:35][C:13]([C:10]3[CH:9]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[O:12][N:11]=3)=[O:15])[CH:32]=[CH:31][C:29]=2[N:30]=1)([CH3:24])[CH3:23]
Reactant: CC(C)N(C)c1nc2ccc(N)cc2s1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)on1
Agent: O=C(Cl)C(=O)Cl
Product: CC(C)N(C)c1nc2ccc(NC(=O)c3cc(-c4ccc(Cl)cc4)on3)cc2s1
Yield: 36.2 %

Procedure:
Prepare according to Method C (Example 9), using 5-(4-chlorophenyl)isoxazole-3-carboxylic acid (39 mg, 0.174 mmol), oxalyl chloride (300 μL, 3.44 mmol), and N2-isopropyl-N2-methyl-benzothiazole-2,6-diamine (33 mg, 0.149 mmol) to afford the title compound (23 mg, 36%). mass spectrum (m/e): 427.0 [M+H]. 1H NMR (400 MHz, DMSO-d6) δ 10.76 (s, 1H), 8.24 (d, 1H, J=2.2 Hz), 8.01 (d, 2H, J=8.8 Hz), 7.66 (d, 2H, J=8.4 Hz), 7.60 (dd, 1H, J=8.8, 2.2 Hz), 7.54 (s, 1H), 7.41 (d, 1H, J=8.4 Hz), 4.34 (m, 1H), 2.98 (s, 3H), 1.23 (d, 6H, J=6.6 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([NH2:14])=[N:12][C:11]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)=[N:10]1.[Cu][C:29]#[N:30].O>CN(P(N(C)C)(N(C)C)=O)C>[NH2:14][C:13]1[N:9]([C:3]2[CH:4]=[CH:5][C:6]([C:29]#[N:30])=[CH:7][C:2]=2[F:1])[N:10]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[N:12]=1
Reactant: Nc1nc(Nc2ccc(N3CCOCC3)cc2)nn1-c1ccc(I)cc1F
Reactant: N#C[Cu]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: N#Cc1ccc(-n2nc(Nc3ccc(N4CCOCC4)cc3)nc2N)c(F)c1
Temperature: 55 °C
Yield: 10.6 %

Procedure:
A mixture of 1-(2-fluoro-4-iodo-phenyl)-N3-(4-morpholino-phenyl)-1H-[1,2,4]triazole-3,5-diamine (0.48 g, 0.99 mmol) and copper (I) cyanide (0.09 g, 0.99 mmol) in HMPA (3 mL) was heated at 55° C. for 2 h, then poured into water (75 mL) and filtered, washing with water. The filter cake was suspended in chloroform (100 mL) and methanol (5 mL), was refluxed for 2 h, cooled, filtered and evaporated. Purification by semi-preparative HPLC provided the title compound (0.04 g, 9% yield) as a pale tan lyophilate.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11](O)[CH:10]([CH2:15][OH:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CS(Cl)(=O)=O.[H-].[Na+]>C(Cl)Cl.C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C@@H:11]2[C@@H:10]([CH2:15][O:16]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCC1CN(Cc2ccccc2)CCC1O
Agent: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: c1ccc(CN2CC[C@H]3OC[C@H]3C2)cc1
Temperature: 2.5 °C
Reaction time: 1.5 h

Procedure:
To a solution of above crude cis and trans mixture of 1-benzyl-3-(hydroxymethyl)piperidin-4-ol (2.69 g, 12.16 mmol) in DCM (60 mL) was added DIPEA (3.39 mL, 24.31 mmol) and MsCl (0.947 mL, 12.2 mmol) dropwise at 0° C. The reaction mixture was further stirred for 1.5 h at 0-5° C. and then quenched with saturated aqueous NaHCO3. The aqueous phase was extracted with DCM. The combined organic phases were dried over Na2SO4, filtered and concentrated to afford a mixture of mono- and bi-mesylated compounds. The crude was then dissolved in THF (250 mL) and added NaH (1.05 g, 43.8 mmol, 60% in mineral oil) portionwise at room temperature. After being stirred for 40 min at room temperature, the reaction mixture was then heated to 65° C. for 4.5 h. The reaction mixture was cooled to room temperature, then quenched with water and concentrated in vacuo. The residue was dissolved in EtOAc, washed with saturated aqueous NH4Cl, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (0-100% EtOAc/heptanes) to provide racemic (cis)-3-benzyl-7-oxa-3-azabicyclo[4.2.0]octane as a colorless oil. 1H NMR (400 MHz, CD2Cl2) δ ppm 7.32-7.41 (m, 5H), 4.97 (ddd, J=3.03, 4.42, 6.19 Hz, 1H), 4.68 (t, J=5.68 Hz, 1H), 4.07-4.13 (m, 1H), 3.53-3.60 (m, 2H), 2.90-2.98 (m, 1H), 2.82-2.90 (m, 1H), 2.52-2.59 (m, 2H), 2.49 (dd, J=6.32, 11.37 Hz, 1H), 1.83-1.87 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[CH:7]=[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:5]2=[O:24].[CH3:25][Si:26]([C:29]#[CH:30])([CH3:28])[CH3:27].C(N(CC)CC)C>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.[Cu]I.CN(C=O)C>[F:18][C:15]1[CH:16]=[CH:17][C:12]([N:8]2[C:9]3[C:4](=[CH:3][C:2]([C:30]#[C:29][Si:26]([CH3:28])([CH3:27])[CH3:25])=[CH:11][CH:10]=3)[C:5](=[O:24])[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:7]2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2)c2ccc(Br)cc2c1=O
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(-c2ccc(F)cc2)c2ccc(C#C[Si](C)(C)C)cc2c1=O
Reaction time: 1 h
Yield: 43.7 %

Procedure:
Compound D (450 mg, 1.15 mmol), trimethylsilylacetylene (179 μL, 1.27 mmol), PdCl2(PPh3)2 (40.5 mg, 0.058 mmol), CuI (22 mg, 0.12 mmol), triethylamine (321 μL, 2.31 mmol) and DMF (5.8 mL) were added to a microwave vial. The vial was capped and place in a microwave reactor at 150° C. for one hour. The reaction was washed with water and brine and extracted with EtOAc (2×). The organics were combined, dried (MgSO4), and concentrated to dryness. Purification by flash chromatography on silica gel afforded 205 mg (44%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.45 (s, 1H), 8.24 (d, J=1.84 Hz, 1H), 7.76-7.73 (m, 2H), 7.68 (dd, J=8.8 Hz, 1H), 7.52 (t, J=8.64, 8.72 Hz, 2H), 6.93 (d, J=8.8 Hz, 1H), 4.22 (q, J=7.08 Hz, 2H), 1.25 (t, J=7.12, 7.04 Hz, 3H), 0.24 (s, 9H); ES-MS [M+1]+: 408.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([N+:19]([O-:21])=[O:20])=[C:13]([OH:18])[CH:14]=2)[CH:9]1[CH2:22][C:23]1[CH:28]=[C:27]([Br:29])[C:26]([O:30][CH3:31])=[C:25]([Br:32])[CH:24]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH3:39][O:40][C:41]1[CH:48]=[CH:47][C:44]([CH2:45]Cl)=[CH:43][CH:42]=1>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([N+:19]([O-:21])=[O:20])=[C:13]([O:18][CH2:45][C:44]3[CH:47]=[CH:48][C:41]([O:40][CH3:39])=[CH:42][CH:43]=3)[CH:14]=2)[CH:9]1[CH2:22][C:23]1[CH:24]=[C:25]([Br:32])[C:26]([O:30][CH3:31])=[C:27]([Br:29])[CH:28]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1ccc(CCl)cc1
Reactant: COc1c(Br)cc(CC2c3cc([N+](=O)[O-])c(O)cc3CCN2C(=O)OC(C)(C)C)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(COc2cc3c(cc2[N+](=O)[O-])C(Cc2cc(Br)c(OC)c(Br)c2)N(C(=O)OC(C)(C)C)CC3)cc1
Temperature: 100 °C

Procedure:
A mixture of 1-(3,5-dibromo-4-methoxy-benzyl)-6-hydroxy-7-nitro-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester (0.002 mol), K2CO3 (0.331 g, 0.0024 mol) and 4-methoxybenzyl chloride (0.376 g, 0.0024 mol) in 10 mL of DMF was heated for 4 h at 100° C. 0.17 g (0.00109 mol) of 4-methoxybenzyl chloride was added additionally. The reaction mixture was heated for 5 h at 100° C., cooled, poured in water, cooled, filtered and dried in vacuum. The residue was dissolved in ethyl acetate and filtered through silica gel. The solution was concentrated. The residue was crystallized from chloroform-hexanes mixture. Yield 0.96 g (72%).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35]([N:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:43][C:44]1([CH3:56])[O:48][C@H:47]([CH2:49][CH2:50]OS(C)(=O)=O)[CH2:46][O:45]1.CC1(C)O[C@H](CCO)CO1.CS(Cl)(=O)=O.C(N(C(C)C)CC)(C)C>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35]([N:37]3[CH2:42][CH2:41][N:40]([CH2:50][CH2:49][C@@H:47]4[CH2:46][O:45][C:44]([CH3:56])([CH3:43])[O:48]4)[CH2:39][CH2:38]3)=[O:36])[C@@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C@@:17]([C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)N1CCNCC1
Reactant: CC1(C)OC[C@@H](CCOS(C)(=O)=O)O1
Agent: CC1(C)OC[C@@H](CCO)O1
Agent: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC[C@@H]2COC(C)(C)O2)CC1
Temperature: 180 °C

Procedure:
The mixture of [2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazol-1-yl]-piperazin-1-yl-methanone (80 mg, 0.13 mmol), methanesulfonic acid 2-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethyl ester (437 mg, 1.95 mmol, prepared from 2-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethanol and methanesulfonyl chloride in the present of triethylamine) and diisopropylethylamine (110 uL, 0.65 mmol) in dry dimethylformamide (3 mL) was heated in the microwave at 180° C. for 20 min. Upon cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water (5×) and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification of the crude residue by flash column chromatography (silica gel, eluting with ethyl acetate and hexane) gave rac-[(4S*,5R*)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazol-1-yl]-{4-[2-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethyl]-piperazin-1-yl}-methanone (45 mg).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1.[C:13]([N:16]1[CH2:21][CH2:20][CH:19]([C:22](Cl)=[O:23])[CH2:18][CH2:17]1)(=[O:15])[CH3:14]>CCCCC>[F:5][C:6]1[CH:7]=[C:8]([F:12])[CH:9]=[CH:10][C:11]=1[C:22]([CH:19]1[CH2:18][CH2:17][N:16]([C:13](=[O:15])[CH3:14])[CH2:21][CH2:20]1)=[O:23]
Reactant: Fc1cccc(F)c1
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCC
Product: CC(=O)N1CCC(C(=O)c2ccc(F)cc2F)CC1
Temperature: 100 °C
Yield: 47 %

Procedure:
To a rapidly stirred slurry of aluminum chloride (3.3 g, 24.7 mmol) and 1,3-difluorobenzene (10 mL) at ambient temperature was added 1-acetylpiperidine-4-carbonyl chloride (2.5 g, 13.2 mmol). The reaction mixture was heated at reflux (100° C.) for 1.5 hours and then poured into 30 mL of ice water, the mixture was extracted with DCM (50 ml) and the organic layer was washed with water and dried over Na2SO4. The solvent was removed in vacuo to give an oil. Trituration of the oil with pentane gave the title product (1.75 g, 6.22 mmol, 47%) as a white solid. MS (ESI) m/z 268.3 (M+H+); HPLC (Novapak 150×3.9 mm C-18 column: mobile phase: 35-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 2 min.) t 1.04 min.
Reaction SMILES: [C:1]1([C:6]2[NH:7][C:8]3[C:13]([CH:14]=2)=[C:12]([O:15][Si](C(C)C)(C(C)C)C(C)C)[CH:11]=[CH:10][CH:9]=3)[CH2:5][CH2:4][CH2:3][CH:2]=1.[F-].[Cs+].[CH2:28]([O:30][C:31](=[O:34])[CH2:32]Br)[CH3:29]>C(C#N)(C)=O.C(Cl)Cl>[CH2:28]([O:30][C:31](=[O:34])[CH2:32][O:15][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:13]=1[CH:14]=[C:6]([C:1]1[CH2:5][CH2:4][CH2:3][CH:2]=1)[NH:7]2)[CH3:29]
Reactant: CCOC(=O)CBr
Reactant: CC(C)[Si](Oc1cccc2[nH]c(C3=CCCC3)cc12)(C(C)C)C(C)C
Agent: CC(=O)C#N
Agent: [Cs+]
Agent: [F-]
Solvent: ClCCl
Product: CCOC(=O)COc1cccc2[nH]c(C3=CCCC3)cc12
Temperature: 50 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
To 300 mg (0.845 mmol) of 2-cyclopent-1-enyl-4-triisopropylsilyloxy-1H-indole (14d step 1) in 3 mL AcCN was added 154 mg (1.01 mmol, 1.2 eq) of CsF and 282 μL (2.54 mmol, 3 eq) ethylbromoacetate and the reaction was stirred at 50° C. overnight. The reaction was diluted with CH2Cl2 and filtered through celite. The CH2Cl2 layer was washed with 2N Na2CO3 solution, H2O, aqueous NaCl solution, dried (Na2SO4), and concentrated in vacuole to yield 239 mg (99%) of (2-cyclopent-1-enyl-1H-indol-4-yloxy)-acetic acid ethyl ester as a dark oil.
Reaction SMILES: [O:1]=[C:2]([C:14]1[O:18][C:17](/[CH:19]=[CH:20]/[C:21]([OH:23])=[O:22])=[CH:16][CH:15]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[OH-].[K+:25]>CO>[O:1]=[C:2]([C:14]1[O:18][C:17](/[CH:19]=[CH:20]/[C:21]([O-:23])=[O:22])=[CH:16][CH:15]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[K+:25]
Reactant: CCCCCCCCCCCC(=O)c1ccc(/C=C/C(=O)O)o1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCCC(=O)c1ccc(/C=C/C(=O)[O-])o1
Reaction time: 1 h

Procedure:
A mixture of 5.0 g (0.0156 mole) of (E)-3-[5-(1-oxododecyl)-2-furanyl]-2-propenoic acid, 1.0 g of potassium hydroxide and 100 ml of methanol is heated with stirring on a steam bath for 1 hour. The methanol is distilled off to 50 ml and the mixture cooled. The solid is separated by filtration to give potassium (E)-3-[5-(1-oxododecyl)-2-furanyl]-2-propenoate, m.p. 220°-230° C. (decomposition).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH2:7][CH2:8][NH:9][C:10](=O)[CH3:11])=[CH:4][CH:3]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[CH3:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][N:9]=[C:10]([CH3:11])[C:4]=2[CH:3]=1
Reactant: CC(=O)NCCc1ccc(C)s1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CC1=NCCc2sc(C)cc21

Procedure:
In close analogy to the procedure described above, N-[2-(5-Methyl-thiophen-2-yl)-ethyl]-acetamide is reacted with phosphorus pentoxide to provide the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][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)=[CH:15][CH:14]=2)[N:3]=1.F[B-](F)(F)F.[C:37]([C:39]1[CH:44]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:42]=[CH:41][C:40]=1[CH2:49][C:50]([O:52][CH3:53])=[O:51])#[CH:38].CN(C=O)C>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.[Cu]I.CCN(CC)CC>[CH3:53][O:52][C:50](=[O:51])[CH2:49][C:40]1[CH:41]=[CH:42][C:43]([C:45]([F:47])([F:46])[F:48])=[CH:44][C:39]=1[C:37]#[C:38][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][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)=[CH:15][CH:14]=2)[N:3]=1
Reactant: C#Cc1cc(C(F)(F)F)ccc1CC(=O)OC
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(C(F)(F)F)cc1C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Temperature: 120 °C

Procedure:
A stirred suspension of tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (K5) (0.200 g, 0.438 mmol), PdCl2(PPh3)2 (0.031 g, 0.044 mmol), t-Bu3PH.BF4 (0.013 mg, 0.044 mmol), CuI (0.008 g, 0.044 mmol) and methyl 2-(2-ethynyl-4-(trifluoromethyl)phenyl)acetate (A59) (0.212 g, 0.875 mmol) in anhydrous, degassed DMF (6 mL) and Et3N (6 mL) was heated at 120° C. for 20 minutes under nitrogen. The volatiles were evaporated under reduced pressure then the residue adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound A60 as a brown solid (0.176 g, 61%); 1H NMR (400 MHz, CDCl3) δ 8.64 (s, 1H), 7.93 (d, J=0.8 Hz, 1H), 7.67 (dd, J=8.2, 1.3 Hz, 1H), 7.56 (d, J=8.5 Hz, 2H), 7.51-7.49 (m, 2H), 7.23 (d, J=8.5 Hz, 2H), 4.36-4.18 (m, 2H), 4.01 (s, 2H), 3.72 (s, 3H), 2.91-2.74 (m, 2H), 2.72-2.58 (m, 1H), 1.83 (d, J=12.6 Hz, 2H), 1.64-1.56 (m, 2H), 1.50 (s, 9H). LCMS-A: rt 7.227 min; m/z 661 [M−H]−.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:11]2([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:16][CH2:15][C:14](=O)/[C:13](=[CH:18]/[N:19](C)C)/[CH2:12]2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].O.[NH2:31]N>C(O)C>[C:1]([C:5]1[CH:6]=[C:7]([C:11]2([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])[CH2:16][CH2:15][C:14]3[C:13](=[CH:18][NH:19][N:31]=3)[CH2:12]2)[CH:8]=[CH:9][CH:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CN(C)/C=C1\CC(NC(=O)OC(C)(C)C)(c2cccc(C(C)(C)C)c2)CCC1=O
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(c2cccc(C(C)(C)C)c2)CCc2n[nH]cc2C1
Reaction time: 3 h
Yield: 67 %

Procedure:
To a stirred solution of (E)-tert-butyl 1-(3-tert-butylphenyl)-3-((dimethylamino) methylene)-4-oxocyclohexylcarbamate (801 mg, 2.0 mmol) in 6 mL of ethanol was added hydrazine monohydrate (150 μL, 3.0 mmol). The reaction was allowed to stir for 3 h. The reaction was concentrated and purified using a biotage 40S column eluting with DCM/MeOH (95:5) to afford 500 mg (67% yield) of an off white foam. LCMS corresponded to the desired material: retention time (min)=2.45 (method [8]); MS (ESI) 370.0.
Reaction SMILES: CS(C)=O.F[C:6]1[CH:29]=[CH:28][C:9]([C:10]([C:12]2[CH:27]=[CH:26][C:15]([O:16][C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([OH:22])=[O:21])=[CH:14][CH:13]=2)=[O:11])=[CH:8][CH:7]=1.[NH2:30][C:31]1[CH:32]=[C:33]([OH:37])[CH:34]=[CH:35][CH:36]=1>CN(C)C=O>[NH2:30][C:31]1[CH:32]=[C:33]([CH:34]=[CH:35][CH:36]=1)[O:37][C:28]1[CH:29]=[CH:6][CH:7]=[CH:8][C:9]=1[C:10]([C:12]1[CH:27]=[CH:26][C:15]([O:16][C:17]2[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=2)[C:20]([OH:22])=[O:21])=[CH:14][CH:13]=1)=[O:11]
Reactant: O=C(O)c1cccc(Oc2ccc(C(=O)c3ccc(F)cc3)cc2)c1
Reactant: Nc1cccc(O)c1
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: Nc1cccc(Oc2ccccc2C(=O)c2ccc(Oc3cccc(C(=O)O)c3)cc2)c1

Procedure:
As shown by reaction (1), 4,-4-difluorobenzophenone is reacted with 3-hydroxybenzoic acid to obtain 3-[4-(4-fluorobenzoyl)phenoxy]benzoic acid. The reaction is carried out in a suitable aprotic solvent, such as dimethylsulfoxide or N,N-dimethylformamide, under an inert atmosphere, at an elevated temperature of about 100° to 140° C. for about 8 to 64 hours. The 3-[4-(4-fluorobenzoyl)phenoxy]benzoic acid (A) is then reacted with 3-aminophenol, as shown by reaction (2) to obtain 3-[4-(3-aminophenoxybenzoyl)phenoxy]benzoic acid (B). This reaction is carried out in a suitable aprotic solvent, under an inert atmosphere, at an elevated temperature of about 100° to 140° C. for about 8 to 64 hours. At the end of the reaction period, the reaction mixture is cooled, then poured into water, which is then neutralized to precipitate the monomer (B). If desired, the crude monomer can be purified by recrystallization or by dissolving it in a suitable solvent and precipitating it from solution into a suitable non-solvent.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[C:19]1[N:24]=[C:23]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:22]=[C:21]([N:31]2[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[N:33]=[C:32]2[CH:40]([F:42])[F:41])[N:20]=1>C1COCC1.C(O)(=O)C.O>[F:42][CH:40]([F:41])[C:32]1[N:31]([C:21]2[N:22]=[C:23]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[N:24]=[C:19]([NH:1][C:2]3[CH:7]=[CH:6][N:5]=[CH:4][N:3]=3)[N:20]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: Nc1ccncn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: FC(F)c1nc2ccccc2n1-c1nc(Nc2ccncn2)nc(N2CCOCC2)n1
Reaction time: 0.33 h
Yield: 6.1 %

Procedure:
To a solution of 0.214 g (2.25 mmol) of 4-aminopyrimidine in THF (4.5 mL) at 0° C. was added 1.25 mL of NaHMDS (2 M solution in THF), and the mixture stirred for 20 min. A solution of 0.282 g (0.77 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole in THF (6 mL) was added and the resulting mixture was stirred for 1 hr at RT. After neutralization with acetic acid, the mixture was diluted with water and extracted with EtOAc. The organic layer was washed sequentially with water and aq. NH3, dried and concentrated. Chromatography on alumina, eluting with CH2Cl2/EtOAc (1:3) gave a white powder. Recrystallization from ethanol gave 0.020 g (6% yield) of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-(4-pyrimidinyl)-1,3,5-triazin-2-amine: mp 233-235° C.; 1H NMR (CDCl3) δ8.92 (d, J=1.4 Hz, 1H), 8.67 (d, J=5.8 Hz, 1H), 8.39 (dd, J=6.8, 1.7 Hz, 1H), 8.22 (dd, J=5.8, 1.3 Hz, 1H), 8.01 (s, 1H), 7.92 (dd, J=6.8, 1.7 Hz, 1H), 7.56 (t, JHF=53.5 Hz, 1H), 7.49-7.43 (m, 2H), 3.98-3.96 (m, 4H), 3.86-3.85 (m, 4H); Anal. Calcd. for C19H17F2N9O: C, 53.65; H, 4.1; N, 29.6. Found: C, 53.35; H, 4.2; N, 29.4%.