Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:5][C@@H:4]2[C@H:6]([OH:9])[CH2:7][O:8][C@@H:3]2[C@@H:2]1[OH:10].[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.[OH-].[K+]>C(Cl)(Cl)(Cl)Cl.ClCCl.O>[CH3:21][C:11]1[CH:16]=[CH:15][C:14]([S:17]([O:10][C@@H:2]2[CH2:1][O:5][C@@H:4]3[C@H:6]([OH:9])[CH2:7][O:8][C@H:3]23)(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)cc1
Temperature: 0 °C

Procedure:
Isomannide (40) (10 g, 68.49 mmol) and p-toluenesulphonyl chloride (6.53 g, 34.25 mmol) were dissolved in a mixture of carbon tetrachloride (50 mL), dichloromethane (5 mL) and water (40 mL). The flask was cooled to 0° C. and a solution of potassium hydroxide (1.92 g, 34.25 mmol) in water (5 mL) added dropwise over 30 minutes with stirring. The resulting biphasic mixture was stirred at 0° C. for 7 hours. Then off-white precipitate was collected by filtration in vacuo then partitioned between dichloromethane (30 mL) and water (10 mL). The organic phase was washed with brine (2×10 mL) then dried (Na2SO4), filtered and reduced in vacuo to leave a colourless solid. Recrystallisation from carbon tetrachloride gave monotosylate (50) as colourless granules (3.92 g, 38%). TLC (Rf=0.11, EtOAc:heptane 1:1); analytical HPLC main peak, Rt=10.692 min; HPLC-MS 318.2, 323.1 [M+Na]+, 623.2 [2M+Na]+; [□]D18+72.2° (c=5.4, CHCl3); δH (500 MHz, CDCl3) 2.44 (3H, s, CH3), 3.54 (1H, dd, 7.23 Hz, OCH2CHOH), 3.78 (1H, dd, 7.59 Hz, OCH2CHOTs), 3.95 (1H, dd, 6.45 Hz, OCH2CHOH), 4.01 (1H, dd, J=9.33 and 6.64 Hz, OCH2CHOTs), 4.26 (1H, m, CHOH), 4.42 and 4.48 (each 1H, brt, J=5.03 and 5.00 Hz respectively, CHCHCHOH and CHCHCHOTs), 4.90 (1H, dd, 6.84 Hz, CHOTs), 7.37 (2H, d, J=8.13 Hz, aromatic CH3CCH), 7.82 (2H, d, J=8.20 Hz, aromatic OSO2CCH); δC (125 MHz, CDCl3) 21.69 (CH3), 70.03 (CH2CHOTs), 72.29 (CHOTs), 74.02 (CH2CHOH), 80.00 (CH2CHOH), 81.36 (CHCHOTs), 81.76 (CHCHOH), 128.00 and 129.89 (aromatic CH), 133.04 (CHOSO2C quaternary), 145.26 (CH3C quaternary).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:23][C@@H:24]([OH:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:9][C@H:10]([NH:12]C(=O)OCC1C=CC=CC=1)[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[OH-].[Pd+2].[OH-].[C]>[NH2:12][C@H:10]([CH3:11])[CH2:9][N:8]([CH2:23][C@@H:24]([OH:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: C[C@H](CN(C[C@@H](O)c1ccccc1)C(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: C[C@@H](N)CN(C[C@@H](O)c1ccccc1)C(=O)OC(C)(C)C
Yield: 95 %

Procedure:
2.85 g of (R)-benzyl 1-[tert-butoxycarbonyl{(S)-2-hydroxy-2-phenylethyl}amino]propan-2-ylcarbamate was dissolved in 40 mL of methanol. To the solution, 1.42 g of 20% palladium hydroxide-carbon was added, and the mixture was vigorously stirred at room temperature for 14 hours in a hydrogen gas atmosphere. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (dichloromethane:methanol=4:1) to obtain 1.86 g of the title compound as a colorless oil (96%).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:15])([CH3:14])[O:8][SiH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[S:4][C:3]=1[CH:16]=O.[C:18](=[N:31][NH2:32])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[C:18](=[N:31][N:32]=[CH:16][C:3]1[S:4][C:5]([C:7]([CH3:15])([CH3:14])[O:8][SiH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:6][C:2]=1[Br:1])([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cc(Br)c(C=O)s1
Reactant: NN=C(c1ccccc1)c1ccccc1
Solvent: CCO
Product: CC(C)(C)[SiH2]OC(C)(C)c1cc(Br)c(C=NN=C(c2ccccc2)c2ccccc2)s1
Yield: 89.7 %

Procedure:
To a solution of 3-bromo-5-(tert-butyl-dimethyl-silanyloxymethyl)-thiophene-2-carbaldehyde [30.1 g, 89.7 mmol, Intermediate (68)] in ethanol (350 mL) was added benzophenone hydrazone (20 g, 104.7 mmol). The resulting yellow solution was stirred at reflux for 6 hours. The solvent was then removed and the residue was chromatographed through silica gel (n-heptane/dichloromethane, 20/80 as eluant) to produce N-benzhydrylidene-N′-[1-[3-bromo-5-(tert-butyl-dimethyl-silanyloxymethyl)-thiophen-2-yl]-methylidene]-hydrazine [41.3 g, Intermediate (69)]. LC/MS: 515.1 (M+H), (2 isomers detected) RT=4.17 minutes and 4.34 minutes.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])=[N:6][CH:7]=1.[C:13](Cl)(Cl)=[S:14].C(=O)([O-])[O-].[K+].[K+]>O.C(Cl)(Cl)Cl>[CH2:9]([N:8]([CH2:11][CH3:12])[C:5]1[CH:4]=[CH:3][C:2]([N:1]=[C:13]=[S:14])=[CH:7][N:6]=1)[CH3:10]
Reactant: CCN(CC)c1ccc(N)cn1
Reactant: S=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCN(CC)c1ccc(N=C=S)cn1
Yield: 19.1 %

Procedure:
Using procedures similar to those employed in Step A of Example 8, the reaction of 15.9 g (0.096 mole of 5-amino-2-diethylaminopyridine with 22.2 g (0.193 mole) of thiophosgene and 5.0 g (0.036 mole) of potassium carbonate in 50 ml of water and 150 ml of chloroform yielded 3.8 g of (2-diethylaminopyridin-5-yl) isothiocyanate as a solid. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35](=[O:40])[CH2:36][C:37](=O)[CH3:38])=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([C:35](=[O:40])/[CH:36]=[C:37](\[NH:1][C@@H:2]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]3[N:17]=[C:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:19][C:20]=3[CH3:21])=[CH:9][CH:8]=2)[C:3]([OH:5])=[O:4])/[CH3:38])=[CH:33][CH:34]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Reactant: CC(=O)CC(=O)c1ccc(Cl)cc1
Product: C/C(=C/C(=O)c1ccc(Cl)cc1)N[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared (as described above for the preparation of Example 2) from 100 mg (0.27 mmol) of Intermediate 45 and 54 mg (0.27 mmol) of Intermediate 28 to yield 76 mg of Example 24: TLC (DCM/MeOH (4:1): Rf=0.52; 1H NMR (DMSO-d6, 300 MHz) δ11.52 (d, 1H, J=9.6), 7.97 (m, 2H), 7.87 (d, 2H, J=8.6), 7.55 (m, 5H), 7.18 (d, 2H, J=8.5), 6.86 (d, 2H, J=8.5), 5.59 (s, 1H), 4.21 (t, 2H, J=6.1), 4.09 (m, 1H), 3.22 (m, 1H), 2.96 (t, 2H, J=6.1), 2.78 (dd, 1H, J=13.9, 9.4), 2.39 (s, 3H), 1.73 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.Br[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:1]=2)[CH:4]=1
Reactant: Nc1ccc(Br)cn1
Reactant: O=C(CBr)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: FC(F)(F)c1cn2cc(Br)ccc2n1
Yield: 98 %

Procedure:
To a mixture of 2-amino-5-bromo-pyridine o (11.6 mmol, 2.0 g) in ethanol (50 ml) was added 3-bromo-1,1,1-trifluoroacetone (2.1 equiv., 24.3 mmol, 4.64 g) and potassium carbonate (1.5 equiv., 17.3 mmol, 2.40 g). The mixture was heated at reflux for 24 hours and evaporated under reduced pressure. The residue was partitioned between a diluted aqueous sodium bicarbonate solution (100 ml) and dichloromethane (100 ml). The organic layer was dried (MgSO4) and evaporated under reduced pressure. The residue was triturated with diisopropylether (20 ml) and filtered. The filtrate was evaporated under reduced pressure and the residue was triturated with petroleum ether (20 ml). The solids were isolated by filtration affording 6-bromo-2-trifluoromethyl-imidazo[1,2-a]pyridine p (3.0 g, yield=98%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:15])([CH3:14])[CH2:4][CH2:5][CH:6]1[CH2:11][C:10]([CH3:12])=[CH:9][C:8](=[O:13])[CH2:7]1.[H][H]>CO.[Pd]>[CH3:1][O:2][C:3]([CH3:14])([CH3:15])[CH2:4][CH2:5][CH:6]1[CH2:11][CH:10]([CH3:12])[CH2:9][C:8](=[O:13])[CH2:7]1
Reactant: COC(C)(C)CCC1CC(=O)C=C(C)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(C)(C)CCC1CC(=O)CC(C)C1

Procedure:
A solution of 3-(3-methoxy-3-methylbut-1-yl)-5-methylcyclohex-5-en-1-one (30.0 g, 0.14 mol) in methanol (150 mL) was placed in a thick walled bottle. Palladium on charcoal (5%, 2.0 g) was added and the mixture was shaken under 53.5 psi of hydrogen. When the theoretical amount of hydrogen had been consumed, workup yielded 3-(3-methoxy-3-methylbut-1-yl)-5-methylcyclohexan-1-one as a mixture of two diastereoisomers bp0.5 104-107~C (27.6 g, ratio 69:93.1); NMR(CDC13)δ1.0(d,3H), 1.1(s,6H), 1.3-1.5(m,6H), 1.6-2.0(m,4H), 2.2-2.4(m,2H),3.1(s,3H). IR(neat) 2970, 2925, 1720, 1360, 1090 cm-1 ; MS(m/e) 41, 73, 124, 147, 165, 180, 197.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N+:19]([O-:21])=[O:20])[C:11]=1[NH:12][C:13](=O)C(F)(F)F)[C:5]([O:7][CH3:8])=[O:6].C([O-])([O-])=O.[Cs+].[Cs+].CI>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N+:19]([O-:21])=[O:20])[C:11]=1[NH:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Br)c(NC(=O)C(F)(F)F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CI
Product: CNc1c(Br)cc(C(=O)OC)cc1[N+](=O)[O-]
Temperature: 45 °C
Reaction time: 0.33 h

Procedure:
To methyl 3-bromo-5-nitro-4-(2,2,2-trifluoroacetamido)-benzoate (9.69 g, 26.1 mmol) in 250 mL acetonitrile was added Cs2CO3 (10.2 g, 31.3 mmol) and methyliodide (3.3 mL, 52.2 mmol). The mixture was heated to 45° C. for 2 h. The solvent was removed in vac. Water and methanol were added and stirred for 20 minutes. The solid was filtered and washed with methanol.
Reaction SMILES: [CH2:1]([C:3]1[C:4]2[CH:5]=[CH:6][C:7]([O:26][CH3:27])=[C:8]([O:24][CH3:25])[C:9]=2[CH2:10][NH+:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][C:15]4[O:23][CH2:22][O:21][C:16]=4[CH:17]=3)[C:12]=12)[CH3:2].[I-].[C:29]([Mg]Br)([CH3:31])=[CH2:30].O1CCCC1>C(OCC)C>[CH2:1]([C:3]1[C:4]2[CH:5]=[CH:6][C:7]([O:26][CH3:27])=[C:8]([O:24][CH3:25])[C:9]=2[CH:10]([C:29]([CH3:31])=[CH2:30])[N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][C:15]4[O:23][CH2:22][O:21][C:16]=4[CH:17]=3)[C:12]=12)[CH3:2]
Reactant: CCC1=C2c3cc4c(cc3CC[NH+]2Cc2c1ccc(OC)c2OC)OCO4
Reactant: C=C(C)[Mg]Br
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=C(C)C1c2c(ccc(OC)c2OC)C(CC)=C2c3cc4c(cc3CCN21)OCO4
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 12 %

Procedure:
To a suspension of 13-ethyl-9,10-dimethoxy-5,6-dihydro-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinolin-7-ylium; iodide (300 mg, 0.61 mmol) in anhydrous diethyl ether (100 mL) at 0° C. was added a solution of isopropenylmagnesium bromide in tetrahydrofuran (0.5 M, 18.4 mL, 9.2 mmol) dropwise. After stirring at 0° C. for 30 min, the reaction was quenched by adding saturated aqueous ammonium chloride solution (20 mL). The mixture was extracted with diethyl ether (2×50 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was re-crystallized from diethyl ether to afford 13-ethyl-8-isopropenyl-9,10-dimethoxy-5,8-dihydro-6H-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinoline (32 mg, 12%). LC/MS m/e calcd for C25H27NO4 (M+H)+: 406.50, observed: 406.2; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.16 (t, J=7.20 Hz, 3 H) 1.53 (s, 3 H) 2.57-2.64 (m, 1 H) 2.64-2.71 (m, 1 H) 2.64-2.71 (m, 1 H) 2.71-2.78 (m, 1 H) 2.95-3.04 (m, 1 H) 3.15-3.22 (m, 1 H) 3.72 (s, 3 H) 3.81 (s, 3 H) 4.60 (s, 1 H) 4.72 (s, 1 H) 5.08 (s, 1 H) 6.04 (d, J=4.55 Hz, 2 H) 6.86 (s, 1 H) 6.89 (s, 1 H) 6.96 (s, 2 H).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:37]1[CH:42]2[CH2:43][NH:44][CH2:45][CH2:46][N:41]2[CH2:40][CH2:39][S:38]1(=[O:48])=[O:47].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O.C(OCC)(=O)C>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:44]3[CH2:45][CH2:46][N:41]4[CH:42]([CH2:37][S:38](=[O:48])(=[O:47])[CH2:39][CH2:40]4)[CH2:43]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=S1(=O)CCN2CCNCC2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1cc(F)ccc1-c1cc(N2CCN3CCS(=O)(=O)CC3C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 150 °C
Reaction time: 18 h
Yield: 49.3 %

Procedure:
A 8 ml sealed vial was charged with 180 mg (0.31 mmol) of 2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(4-fluoro-2-methylphenyl) -3-pyridinyl]-N,2-dimethylpropanamide (WO 2005/002577); 168 mg (0.62 mmol) of octahydropyrazino[2,1-c][1,4]thiazine 2,2-dioxide (D19), 128 mg (0.701 mmol) of potassium carbonate; the reagents were dissolved in 1 ml of DMSO and stirred at 150° C. for 18 h. The reaction mixture was diluted with water and ethyl acetate and the aqueous phase was extracted with ethyl acetate. The combined organic fractions were dried and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography (silica, cyclohexane/EtOAc 50/50 to EtOAc) affording the title compound as a white solid 105 mg.
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3][OH:4].CC([O-])(C)C.[K+].F[C:13]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C1COCC1.O>[F:1][CH:2]([F:5])[CH2:3][O:4][C:13]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: OCC(F)F
Reactant: CCOC(=O)c1cc([N+](=O)[O-])ccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cc([N+](=O)[O-])ccc1OCC(F)F
Reaction time: 0.08 h

Procedure:
A mixture of 2,2-difluoroethanol (0.178 mL, 2.82 mmol) and KOtBu (0.319 g, 2.70 mmol) in 10 mL THF was stirred for 5 min, then ethyl 2-fluoro-5-nitrobenzoate (0.500 g, 2.35 mmol) was added and it was stirred at rt overnight. Additional 60 μL 2,2-difluoroethanol and 110 mg KOtBu were added and it was stirred for 2 h. The mixture was diluted with H2O, concentrated i.vac. and extracted 2× with EtOAc. The combined organic layers were dried with Na2SO4 and concentrated to furnish the subtitle compound. Yield: 0.52 g (81%); TLC: Rf=0.85 (silica gel, DCM:EtOH 99:1).
Reaction SMILES: [CH3:1][CH:2]([NH:9][C:10](=[O:25])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]#[C:20][C:21]#[C:22][CH2:23][OH:24])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[N+:33]([C:36]1[CH:41]=[C:40]([N+:42]([O-:44])=[O:43])[CH:39]=[CH:38][C:37]=1F)([O-:35])=[O:34].C(=O)(O)[O-].[K+]>CS(C)=O.O>[CH3:1][CH:2]([NH:9][C:10](=[O:25])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]#[C:20][C:21]#[C:22][CH2:23][O:24][C:37]1[CH:38]=[CH:39][C:40]([N+:42]([O-:44])=[O:43])=[CH:41][C:36]=1[N+:33]([O-:35])=[O:34])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Reactant: CC(NC(=O)CCCCCCCCC#CC#CCO)c1ccccc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: CC(NC(=O)CCCCCCCCC#CC#CCOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-])c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.9 %

Procedure:
To a solution of 220 mg (0.65 mmol) of N-(α-methylbenzyl)-14-hydroxy-10,12-tetradecadiynamide in 10 ml DMSO was added 506 mg (5.00 mmol) of triethylamine. To the solution was then added 130 mg (0.70 mmol) of 2,4-dinitrofluorobenzene. The resulting red solution was stirred 16 hours at ambient temperature, and 25 ml of saturated aqueous potassium bicarbonate solution was then added. After stirring 15 minutes, the mixture was poured into 100 ml of water and the resulting solution was extracted with 100 ml portions of ethyl acetate. The combined organic extracts were washed with three 50 ml portions of water and three 50 ml portions of saturated aqueous sodium bicarbonate solution and dried over (MgSO4). Evaporation gave 312 mg of a red oil. NMR indicated no starting alcohol was present. The product was purified by passing it through silica gel (ether as eluent); crystallization from ether petroleum ether gave white crystals, m.p. 59°-60° C. NMR (CDC13): 9.42-7.30, m, 8H aryl H's; 6.00, br s, 1H, N--H; 5.10, br s 2H, O--CH3C=C and m, 1H, CHCH3 ; 2.30, m, 4H, C=CH2CH2 and --CH2CO--; 1.55, d, J=7 Hz, 3H, CH3 and 170--1.20, m, 12 H, other CH2.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9])=[O:4].[CH2:23]([CH2:25][NH2:26])O.O>CS(C)=O>[Cl:20][C:17]1[CH:18]=[CH:19][C:6]2[NH:5][C:3](=[O:4])[N:26]3[CH2:25][CH2:23][O:9][C:8]3([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:7]=2[CH:16]=1
Reactant: NCCO
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1NC(=O)C(Cl)(Cl)Cl
Solvent: O
Solvent: CS(C)=O
Product: O=C1Nc2ccc(Cl)cc2C2(c3ccccc3)OCCN12
Yield: 66.3 %

Procedure:
To a solution of 1.89 g of 2-trichloroacetamido-5-chlorobenzophenone in 40 ml of dimethylsulfoxide was added 3.05 g of monoethanolamine, and the resultant mixture was heated at about 90°C for 3 hours. After cooling, the reaction mixture was poured into 300 ml of water and extracted with chloroform. The extract was washed twice with water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was chromatographed on silica gel using chloroform as an eluent to give 1.0 g of 9-chloro-2,3,6,10b-tetrahydro-10b-phenyl-5H-oxazolo[3,2-C]quinazolin-5-one. Recrystallization from ethanol gave pale yellow prisms, having a melting point of 219° - 220°C.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=1[Cl:13])(=[O:3])[CH3:2].[C:14](=O)([O-])[O-].[K+].[K+].IC.O>CN(C)C=O>[C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:10][CH3:14])=[O:9])=[CH:6][C:5]=1[Cl:13])(=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1ccc(C(=O)O)cc1Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COC(=O)c1ccc(C(C)=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a solution of 4-acetyl-3-chlorobenzoic acid (synthesized by the method of Tetrahedron 1988, 44, 1631, 700 mg, 3.52 mmol) in N,N-dimethylformamide (4 mL) were added potassium carbonate (974 mg, 7.05 mmol) and iodomethane (658 μL, 10.57 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added water, and the mixture was extracted with ethyl acetate three times. The organic layer was combined, filtered through Phase-separator (Varian Inc.), and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→75:25) to give methyl 4-acetyl-3-chlorobenzoate (707 mg, 94%) as a pale yellow powder.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][C:3]=1[F:26].[CH3:27][NH:28][C:29]([C:31]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][N:32]=1)=[O:30].C(=O)([O-])[O-].[K+].[K+].ClCCl>O1CCOCC1.O>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:2]([C:34]4[CH:35]=[CH:36][C:31]([C:29]([NH:28][CH3:27])=[O:30])=[N:32][CH:33]=4)=[C:3]([F:26])[CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)[N:15]=1
Reactant: CNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CN1CCN(c2cc(N3CCc4cc(F)c(Br)cc4C3)nc(N)n2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CNC(=O)c1ccc(-c2cc3c(cc2F)CCN(c2cc(N4CCN(C)CC4)nc(N)n2)C3)cn1
Temperature: 120 °C

Procedure:
A mixture of 4-(7-bromo-6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (0.025 g, 0.060 mmol), N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxamide (0.0140 g, Frontier, Cat. No. M10074) in 1,4-dioxane (0.36 mL) was stirred at r.t. for 10 min. Potassium carbonate (37.8 mg, 0.274 mmol) in water (0.18 mL) was added. The mixture was degassed and refilled with nitrogen three times [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (3.0 mg, 0.0036 mmol) was added and the mixture was degassed and refilled with nitrogen three times and then heated at 120° C.) (oil bath temperature) for 3 h. After cooling, the mixture was diluted with methanol, and filtered. The filtrate was purified on RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=477.2.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:36])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][N:21]=[N+:22]=[N-:23])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:24])[C:12]=2[C@H:25]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[C:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[CH2:45][OH:46])#[CH:38].CCN(C(C)C)C(C)C>C1COCC1.CCOCC.[Cu]I>[CH2:1]([O:4][C:5]1([CH3:36])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][N:21]4[CH:38]=[C:37]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=5[CH2:45][OH:46])[N:23]=[N:22]4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:24])[C:12]=2[C@H:25]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C#Cc1ccccc1CO
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CN=[N+]=[N-])nn23)CC1
Agent: [Cu]I
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(Cn4cc(-c5ccccc5CO)nn4)nn23)CC1
Reaction time: 48 h
Yield: 43.4 %

Procedure:
To a stirred clear solution of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(azidomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.0946 g, 0.189 mmol), (2-ethynylphenyl)methanol (0.125 g, 0.947 mmol) and DIEA (0.165 ml, 0.947 mmol) in THF (5 mL) was added CuI (0.072 g, 0.379 mmol) at rt. After 48 h, the reaction mixture was diluted with Et2O (50 mL), washed with 1% NH4OH (2×10 mL), brine (10 mL), dried (MgSO4), filtered and concentrated to give yellow solid which was purified by prep-HPLC to afford (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-((4-(2-(hydroxymethyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.0521 g, 0.082 mmol, 43.6% yield) as off-white solid. 1H NMR (500 MHz, CDCl3) δ 8.02 (s, 1H), 7.51-7.55 (m, 1H), 7.45-7.49 (m, 1H), 7.33-7.38 (m, 2H), 6.54 (s, 1H), 5.96-6.05 (m, 1H), 5.89 (br. s., 1H), 5.82 (s, 2H), 5.45 (d, J=16.87 Hz, 1H), 5.26-5.38 (m, 1H), 5.18 (qd, J=1.58, 10.40 Hz, 1H), 4.64 (s, 2H), 4.13-4.28 (m, 2H), 4.00 (d, J=5.2 Hz, 2H), 2.62 (s, 3H), 1.83-2.04 (m, 3H), 1.65-1.73 (m, 1H), 1.31 (s, 3H), 1.22-1.26 (m, 12H). LCMS (M+H)=632.7.