Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH2:3][N:4]=[C:5]([NH2:17])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9](S(C)(=O)=O)[N:8]=1.[NH2:20][CH2:21][CH2:22][CH2:23][OH:24].[H-].[Na+]>C(O)(C)(C)C>[F:1][C:2]([F:19])([F:18])[CH2:3][N:4]=[C:5]([NH2:17])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([O:24][CH2:23][CH2:22][CH2:21][NH2:20])[N:8]=1
Reactant: NCCCO
Reactant: CS(=O)(=O)c1nccc(NC(N)=NCC(F)(F)F)n1
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: NCCCOc1nccc(NC(N)=NCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.5 %

Procedure:
4-[2-(2,2,2-Trifluoroethyl)guanidino]-2-methylsulphonylpyrimidine (0.15 g.) was added to a mixture of 3-aminopropanol (0.075 g.), t-butanol (5 ml.) and a 50% w/w dispersion of sodium hydride in mineral oil (0.05 g.) which was stirred under an argon atmosphere. The mixture was stirred at room temperature for 2 hours, heated under reflux for 4 hours and then evaporated to dryness. The residue was partitioned between 2 N aqueous acetic acid and ether, and the aqueous phase basified with 17 N NaOH and extracted three times with ether. The combined ether extracts were dried and evaporated to dryness to give 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-(3-aminopropyloxy)pyrimidine (0.07 g.) which was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([N:21]2[S:25](=[O:27])(=[O:26])[NH:24][C:23](=[O:28])[CH2:22]2)=[C:11]([F:20])[C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[C:14](Br)[CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][C:30]1(C)C(C)(C)OB(C=C)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[CH2:1]([O:8][C:9]1[C:10]([N:21]2[S:25](=[O:27])(=[O:26])[NH:24][C:23](=[O:28])[CH2:22]2)=[C:11]([F:20])[C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[C:14]([CH:29]=[CH2:30])[CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: O=C1CN(c2c(OCc3ccccc3)cc3ccc(Br)cc3c2F)S(=O)(=O)N1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: C=Cc1ccc2cc(OCc3ccccc3)c(N3CC(=O)NS3(=O)=O)c(F)c2c1
Temperature: 110 °C

Procedure:
To a microwave vial is added 5-(3-benzyloxy-7-bromo-1-fluoronaphthalen-2-yl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (340 mg, 0.73 mmol) (intermediate from preparing Example 16), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.24 mL, 1.46 mmol), polystyrene tetrakis(triphenylphosphine)palladium(0) (0.1 mmole/g) (365 mg, 0.0365 mmol), Na2CO3 (2 M, 1.83 mL, 3.65 mmol) and DME (2.5 mL). The mixture is then heated in a microwave at 110° C. for 30 min. The resin is then filtered and the residue is purified quickly by Biotage reverse phase, eluting with 10-90% EtOH/water to give fractions containing the title compound: MS (M+H)+=413. The fractions are combined and used in the next step without concentration.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH:24][C:25]([CH:27]5[CH2:33][CH2:32][CH2:31][CH2:30][N:29]([C:34]6[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=6)[C:28]5=[O:41])=[O:26])=[CH:20][C:19]=4[F:42])=[C:11]3[C:10]([NH:43][CH:44]3[CH2:49][CH2:48][N:47]([CH3:50])[CH2:46][CH2:45]3)=[N:9]2)=CC=1>C(O)(C(F)(F)F)=O>[F:42][C:19]1[CH:20]=[C:21]([NH:24][C:25]([CH:27]2[CH2:33][CH2:32][CH2:31][CH2:30][N:29]([C:34]3[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=3)[C:28]2=[O:41])=[O:26])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:8][N:9]=[C:10]([NH:43][CH:44]3[CH2:49][CH2:48][N:47]([CH3:50])[CH2:46][CH2:45]3)[C:11]=12
Reactant: COc1ccc(Cn2nc(NC3CCN(C)CC3)c3c(Oc4ccc(NC(=O)C5CCCCN(c6ccc(F)cc6)C5=O)cc4F)ccnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC(Nc2n[nH]c3nccc(Oc4ccc(NC(=O)C5CCCCN(c6ccc(F)cc6)C5=O)cc4F)c23)CC1
Yield: 30.3 %

Procedure:
A solution of N-(4-(1-(4-methoxybenzyl)-3-(1-methylpiperidin-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxoazepane-3-carboxamide (20 mg, 0.028 mmol) was heated in TFA (1 mL) at 55° C. for 3 hours. TFA was evaporated and EtOAc was added to dilute the mixture. The mixture washed with saturated aqueous NaHCO3, brine, dry with Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (20% MeOH in CH2Cl2) to afford the product (5 mg, 30% yield) as a white solid. LRMS (APCI pos) m/e 590.1 (M+1). 1H NMR (400 MHz, DMSO-d6): δ 12.15 (s, 1H), 10.20 (s, 1H), 8.10 (s, 1H), 7.82 (d, 1H), 7.18-7.50 (m, 7H), 5.98-6.00 (m, 1H), 5.10-5.20 (m, 1H), 3.90-4.02 (m, 2H), 3.40-3.62 (m, 2H), 2.62-2.80 (m, 1H), 2.15 (s, 3H), 1.90-2.02 (m, 5H), 1.50-1.88 (m, 6H).
Reaction SMILES: [N:1]1[N:10]2[C:4]([CH2:5][NH:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9]2)=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:22]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:23]([C:28]([NH:30][C:31]2[N:36]=[CH:35][C:34]([C:37](Cl)=[O:38])=[CH:33][CH:32]=2)=[O:29])=[CH:24][CH:25]=[CH:26][CH:27]=1>ClCCl.O>[N:1]1[N:10]2[C:4]([CH2:5][N:6]([C:37]([C:34]3[CH:33]=[CH:32][C:31]([NH:30][C:28]([C:23]4[C:22]([C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:29])=[N:36][CH:35]=3)=[O:38])[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9]2)=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)Cn1nccc1CN2
Reactant: O=C(Cl)c1ccc(NC(=O)c2ccccc2-c2ccccc2)nc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2Cc3ccnn3Cc3ccccc32)cn1)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.5 %

Procedure:
To a chilled (0° C.) solution of 0.185 g of 5,10-dihydro-4H-pyrazolo[5,1-c][1,4]benzodiazepine and 417 μl of triethylamine in 3.5 ml of dichloromethane is added 0.35 g of 6-(2-biphenylcarbonyl)aminopyridine-3-carbonyl chloride in 1.5 ml of dichloromethane. The mixture is stirred at room temperature under argon for 16 hours, diluted with 40 ml of dichloromethane and 20 ml of water. The organic layer is separated, washed with 20 ml of brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate. The filtrate is concentrated to dryness under vacuum to give 0.4 g of solid. The solid is purified on silica gel prep-plates with ethyl acetate-hexane (3:1) as eluent to give 170 mg of a brown glass, m.p. 110°-150° C.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:32]=[CH:31][C:6]([O:7][C:8]2[NH:12][N:11]=[C:10]([C:13]3[CH:14]=[C:15]([C:19]4([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:22][O:21][CH2:20]4)[CH:16]=[CH:17][CH:18]=3)[CH:9]=2)=[CH:5][CH:4]=1.Br[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:32]=[CH:31][C:6]([O:7][C:8]2[CH:9]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]4([NH:23][C:24]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:30])[CH2:22][O:21][CH2:20]4)[CH:14]=3)[N:11]([CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[N:12]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)NC1(c2cccc(-c3cc(Oc4ccc(C(F)(F)F)cc4)[nH]n3)c2)COC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cn1nc(Oc2ccc(C(F)(F)F)cc2)cc1-c1cccc(C2(NC(=O)OC(C)(C)C)COC2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
tert-Butyl {3-[3-(5-(4-trifluoromethylphenoxy)-1H-pyrazol-3-yl)phenyl]oxetan-3-yl}carbamate (98 mg, 0.21 mmol), ethyl bromoacetate (80 mg, 0.47 nimbi), and potassium carbonate (67 mg, 0.48 mmol) were combined in 0.5 mL of DMF and the mixture was stirred at ambient temperature under argon atmosphere for 4 h, then warmed to 60° C. for 18 h. The mixture was diluted with EtOAc and washed with water and brine. The organic phase was dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The residue was chromatographed on a 12 g silica gel column using 0-5% MeOH:CHCl3 over 16 min at 30 mL/min. The fractions containing the first-eluting product were combined and evaporated under reduced pressure to give ethyl [3-(4-trifluoromethylphenoxy)-5-(3-{3-[(tert-butyloxycarbonyl)amino]oxetan-3-yl}phenyl)-1H-pyrazol-1-yl]acetate (product A) as an oil, calcd (M+1)+: 562.6. Found: 562.2. 1H NMR (400 MHz, CDCl3) δ 7.6 (m, 5H), 7.50 (t, J=7, 1H), 7.37 (d, J=7, 1H), 7.29 (s, 1H), 5.99 (s, 1H), 5.85 (br s, 1H), 5.00 (d, J=5, 2H), 4.85 (br d, 2H), 4.79 (s, 2H), 4.21 (q, J=7, 2H), 1.27 (t, J=7, 3H). The fractions containing the second-eluting product were combined and evaporated under reduced pressure to give ethyl [5-(4-trifluoromethylphenoxy)-3-(3-{3-[(tert-butyloxycarbonyl)amino]oxetan-3-yl}phenyl)-1H-pyrazol-1-yl]acetate (product B) as an oil, calcd (M+1)+: 562.6. Found: 562.9. 1H NMR (400 MHz, CDCl3) δ 7.88 (br s, 1H), 7.6 (m, 3H), 7.50 (d, J=7, 1H), 7.42 (t, J=7, 1H), 7.32 (d, J=6, 2H), 6.03 (s, 1H), 5.82 (br s, 1H), 5.00 (br s, 2H), 4.90 (overlapping brs s and sharp s, 4H), 4.21 (q, J=7, 2H), 1.25 (t, J=7, 3H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([CH3:27])([S:23]([CH3:26])(=[O:25])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:11][CH:10]=1)C1C=CC=CC=1.C1CCCCC=1>[OH-].[OH-].[Pd+2].C(O)C>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][C:17]([CH3:27])([S:23]([CH3:26])(=[O:25])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:13][CH:14]=1
Reactant: CCOC(=O)C(C)(CCc1ccc(OCc2ccccc2)cc1)S(C)(=O)=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1=CCCCC1
Solvent: CCO
Product: CCOC(=O)C(C)(CCc1ccc(O)cc1)S(C)(=O)=O
Yield: 94.6 %

Procedure:
Pearlman's catalyst (Pd(OH)2/C, 1.19 g, 8.48 mmol) was added to a solution of (+/−)-Ethyl 4-[4-(benzyloxy)phenyl]-2-methyl-2-(methylsulfonyl)butanoate (4.73 g, 12.1 mmol) and cylcohexene (12.3 mL, 121 mmol) in ethanol (50 mL). The mixture was refluxed overnight. The reaction was filtered through celite (˜1 inch), washed with ethanol (100 mL) and ethyl acetate (200 mL), and the combined filtrates were concentrated in vacuo. The crude product was purified via column chromatography using an Analogiz SF15-40 g column and eluting with 500 mL 1:9 EtOAc:Heptane, and 1 L 1:1 EtOAc:Heptane to afford the title compound as a clear liquid (3.44 g, 94.6%) LC-MS m/z 301.1 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.33 (t, J=7.13 Hz, 3H) 1.70 (s, 3H) 2.10-2.24 (m, 1H) 2.37-2.53 (m, 2H) 2.62-2.78 (m, 1H) 3.04 (s, 3H) 4.26 (q, J=7.03 Hz, 2H) 5.77-6.01 (m, 1H) 6.77 (d, J=8.59 Hz, 2H) 7.01 (d, J=8.59 Hz, 2H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([OH:9])[CH2:8][CH2:7][O:6][CH2:5]1.[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][C:17](=O)[O:18]C1C=CC=CN=1>C1COCC1.CCOC(C)=O>[C:17](=[O:18])([O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][N:10]=1)[O:9][C:4]1([CH3:3])[CH2:8][CH2:7][O:6][CH2:5]1
Reactant: O=C(Oc1ccccn1)Oc1ccccn1
Reactant: CC1(O)CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(OC(=O)Oc2ccccn2)CCOC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.8 %

Procedure:
To a suspension of sodium hydride, 60% in mineral oil (185 mg, 4.63 mmol) in THF (20 mL) was added 3-methyltetrahydrofuran-3-ol (394 mg, 3.86 mmol) at 0° C. After stirring 30 min, the solution was transferred to a solution of di(pyridin-2-yl)carbonate (834 mg, 3.86 mmol) in THF (20 mL) through a cannula. The formed slurry was stirred at 0° C. for 30 min. The slurry was warmed to rt and stirred for 2 h. The reaction was diluted with EtOAc, washed with brine, dried over MgSO4, filtered, concentrated to give a residue that was purified by Biotage (5-40% EtOAc:Hex) to afford the desired product 3-methyltetrahydrofuran-3-yl pyridin-2-yl carbonate (334 mg, 38.8% yield) as an oil. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.48-8.29 (m, 1H), 7.91-7.73 (m, 1H), 7.29-7.25 (m, 1H), 7.16-7.12 (m, 1H), 4.23 (d, J=10.3 Hz, 1H), 4.02 (td, J=8.5, 7.2 Hz, 1H), 3.95 (td, J=8.4, 4.5 Hz, 1H), 3.76 (d, J=10.3 Hz, 1H), 2.58-2.47 (m, 1H), 2.11-2.02 (m, 1H), 1.76 (s, 3H).
Reaction SMILES: COCCO[AlH2-]OCCOC.[Na+].[CH3:13][C:14]1([CH3:30])[CH:19]2[CH2:20][CH:16]([CH2:17][CH2:18]2)[CH:15]1[C:21]1([CH:28]=[O:29])[CH2:26][CH2:25][C:24]([CH3:27])=[CH:23][CH2:22]1>C1(C)C=CC=CC=1>[CH3:13][C:14]1([CH3:30])[CH:19]2[CH2:20][CH:16]([CH2:17][CH2:18]2)[CH:15]1[C:21]1([CH2:28][OH:29])[CH2:26][CH2:25][C:24]([CH3:27])=[CH:23][CH2:22]1
Reactant: CC1=CCC(C=O)(C2C3CCC(C3)C2(C)C)CC1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC1=CCC(CO)(C2C3CCC(C3)C2(C)C)CC1
Temperature: 20 °C
Reaction time: 3 h
Yield: 82.8 %

Procedure:
A 1-L reaction flask equipped with a stirrer, a thermometer, a reflux condenser, a heating mantle, and an addition funnel was charged with Vitride (260 g, 0.84 mol) and toluene (260 g). The resulting mixture was stirred at 20° C. The Diels-Alder product containing 1-(3,3-dimethyl-bicyclo[2.2.1]hept-2-yl)-4-methyl-cyclohex-3-enecarbaldehyde (275 g, 1.16 mol, synthesized as above in EXAMPLE V) was added over about 2 hours. The temperature was allowed to rise to 40° C. The reaction mass was aged for 3 hours. The excessive Vitride reagent was quenched with ethyl acetate (22 g), followed by sodium hydroxide (25%, 134 g). The temperature was allowed to rise to 50° C. and stirred for another 0.5 hours. The organic phase was washed with hot water (1 L) twice and concentrated to yield the crude product [1-(3,3-dimethyl-bicyclo[2.2.1]hept-2-yl)-4-methyl-cyclohex-3-enyl]-methanol (250 g, 0.96 mol).
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:8]([CH2:9][O:10]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[O:7][C@@H:6]([N:30]2[CH:37]=[C:36]([CH2:38][CH3:39])[C:34](=[O:35])[NH:33][C:31]2=[O:32])[CH2:5]1)=[N+:2]=[N-:3]>C(O)(=O)C>[N:1]([C@@H:4]1[C@@H:8]([CH2:9][OH:10])[O:7][C@@H:6]([N:30]2[CH:37]=[C:36]([CH2:38][CH3:39])[C:34](=[O:35])[NH:33][C:31]2=[O:32])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: CCc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)c(=O)[nH]c1=O
Solvent: CC(=O)O
Product: CCc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)[nH]c1=O
Reaction time: 0.17 h
Yield: 82.7 %

Procedure:
A mixture of 3'-azido-5-ethyl-5'-O-trityl-2',3'-dideoxyuridine (0.9 g, 1.72 mmole) and 80% acetic acid (25 ml) is heated at 85°-90° C. for 40 minutes, after which acetic acid is evacuated in vacuo to a solid in which water (50 ml) is added, and the mixture is stirred for 10 minutes. The solution is filtered through a celite pad, and then the filtrate is extracted with n-hexane. The water layer is separated, evaporated down to ca. 2 ml, and then the solution is freeze-dried to yield an amorphous powder (400 mg, 83%). Recrystallization from MeOH gives fine needles. m.p. 118°-120° C.
Reaction SMILES: [OH:1][C:2]1[CH:22]=[CH:21][C:5]([CH:6]=[CH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:13][CH:12]=2)=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+:24]>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O-:20])=[O:19])=[CH:13][CH:12]=2)=[O:9])=[CH:21][CH:22]=1.[Na+:24]
Reactant: O=C(O)Cc1ccc(NC(=O)C=Cc2ccc(O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=C([O-])Cc1ccc(NC(=O)C=Cc2ccc(O)cc2)cc1

Procedure:
289 Milligrams of 4-(4'-hydroxycinnamoylamino)phenylacetic acid were dissolved in an alcohol and an equivalent amount of sodium hydroxide was added to the solution. The solution was warmed for 30 minutes and then concentrated under reduced pressure. Ether was added to the residue and the precipitated crystals were collected by filtration to obtain sodium 4-(4'-hydroxycinnamoylamino)phenylacetate.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][C:7]1[C:16]2[C:11](=[C:12]([NH2:17])[CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][N:8]=1.[F:23][CH:24]([F:41])[C:25]1[N:33]=[CH:32][C:31]([CH2:34][NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])=[CH:30][C:26]=1[C:27](O)=[O:28].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[F:41][CH:24]([F:23])[C:25]1[N:33]=[CH:32][C:31]([CH2:34][NH:35][C:36](=[O:40])[CH:37]([CH3:38])[CH3:39])=[CH:30][C:26]=1[C:27]([NH:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[N:10]=[CH:9][N:8]=[C:7]2[O:6][C:5]1[CH:18]=[CH:19][CH:20]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:4]=1)=[O:28]
Reactant: CC(C)C(=O)NCc1cnc(C(F)F)c(C(=O)O)c1
Reactant: Nc1cccc2c(Oc3cccc(C(F)(F)F)c3)ncnc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(=O)NCc1cnc(C(F)F)c(C(=O)Nc2cccc3c(Oc4cccc(C(F)(F)F)c4)ncnc23)c1
Yield: 9.9 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using 4-(3-(trifluoromethyl)phenoxy)quinazolin-8-amine (Intermediate-8, 50 mg, 0.18 mmol), 2-(difluoromethyl)-5-(isobutyramidomethyl)nicotinic acid (Intermediate-66, 56 mg, 0.18 mmol), oxalyl chloride (23 mg, 0.18 mmol), DMF (1 drop) and DIPEA (48 mg, 0.37 mmol) in CH2Cl2 (1.5 mL) to afford 10 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.67 (s, 1H), 8.84-8.82 (d, J=7.8 Hz, 1H), 8.79 (s, 1H), 8.71 (d, J=1.8 Hz, 1H), 8.48 (t, 1H), 8.21-8.19 (d, J=8.4 Hz, 1H), 8.08 (s, 1H), 7.89-7.86 (m, 2H), 7.76 (s, 3H), 7.42-7.06 (t, J=54.6 Hz, 1H), 4.44-4.42 (d, J=5.4 Hz, 2H), 2.44 (m, 1H), 1.05 (d, J=6.6 Hz, 6H); MS [M+H]+: 560.45.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][Si:5]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].[N-:15]=[N+:16]=[N-:17].[Na+]>>[N:15]([CH2:2][CH2:3][CH2:4][Si:5]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8])=[N+:16]=[N-:17]
Reactant: CCO[Si](CCCCl)(OCC)OCC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: CCO[Si](CCCN=[N+]=[N-])(OCC)OCC
Temperature: 140 °C
Reaction time: 3 h

Procedure:
1.0 mole of 3-chloropropyltriethoxysilane (Cl-PTES) and 1.1 moles of sodium azide were heated together in a 500 ml capacity three neck flask made of glass and equipped with reflux condenser and magnetic stirrer and in the presence of 5 mole percent of a catalyst on the basis of a mixture of tris(n-C8 to C10 alkyl)methyl ammonium chloride with stirring for 3 hours at 140° C. The rectification subsequently carried out thereon at reduced pressure gave the 3-azidopropyltriethoxysilane (N3 -PTES) in a yield of 95 weight percent. The N3 -PTES had the following properties:
Reaction SMILES: CC(C)(C)C([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:8][N:7]=1)=O.[OH-].[Na+]>>[F:18][C:15]([F:16])([F:17])[CH2:14][O:13][CH2:12][C:9]1[CH:10]=[CH:11][C:6]([NH2:5])=[N:7][CH:8]=1
Reactant: CC(C)(C)C(=O)Nc1ccc(COCC(F)(F)F)cn1
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc(COCC(F)(F)F)cn1

Procedure:
This material was prepared in analogy to example 86 step B] from 2,2-dimethyl-N-[5-(2,2,2-trifluoro-ethoxymethyl)-pyridin-2-yl]-propionamide (0.56 g) and 3M aqueous NaOH (3.87 mL) as a crystalline white solid (0.123 g). MS (ESI): 207.1 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6]2.[OH-].[K+].[CH:15](=O)[CH2:16][CH2:17][CH3:18].Cl>[Pd].C(O)C>[CH2:15]([CH:7]1[CH2:6][C:5]2[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:8]1=[O:12])[CH2:16][CH2:17][CH3:18]
Reactant: CCCC=O
Reactant: COc1ccc2c(c1)CCC2=O
Agent: [Pd]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: CCCCC1Cc2cc(OC)ccc2C1=O
Reaction time: 3 h
Yield: 53.2 %

Procedure:
A mixture of 5-methoxy-1-indanone (25.0 g, 154 mmol), 85% KOH (2.03 g, 30.8 mmol), 10% palladium on activated carbon (2 g), and ethanol (150 mL) was placed under a hydrogen atmosphere and stirred while butyraldehyde (16.7 mL, 185 mmol) was added over 2 minutes. The mixture warmed during the addition. The resulting mixture was hydrogenated at room temperature for 3 hours, then filtered to remove the catalyst. The filtrate was acidified with 2N HCl (15.4 mL, 30.8 mmol) and evaporated under vacuum. The residue was partitioned between EtOAc (500 mL) and water (500 mL). The organic phase was washed with water (500 mL) and brine (100 mL), dried over MgSO4, filtered, and evaporated under vacuum to an oil (33.5 g). The crude product was purified by column chromatography on EM silica gel 60 (230-400 mesh, 670 g), eluting first with CH2Cl2 and then with 5% EtOAc in CH2Cl2, to afford 2-butyl-5-methoxy-1-indanone (17.9 g) as an oil.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1([C:20]2[C:21](=[O:27])[NH:22][C:23](=[O:26])[NH:24][CH:25]=2)[C:13]2[S:12][C:11]([CH3:14])=[N:10][C:9]=2[CH2:8][CH2:7][C:6]2[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:5]1=2.[CH3:28]I>CN(C)C=O>[CH3:28][N:24]1[CH:25]=[C:20]([C:4]2([OH:3])[C:13]3[S:12][C:11]([CH3:14])=[N:10][C:9]=3[CH2:8][CH2:7][C:6]3[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:5]2=3)[C:21](=[O:27])[NH:22][C:23]1=[O:26]
Reactant: Cc1ccc2c(c1)CCc1nc(C)sc1C2(O)c1c[nH]c(=O)[nH]c1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)CCc1nc(C)sc1C2(O)c1cn(C)c(=O)[nH]c1=O
Reaction time: 0.75 h

Procedure:
Sodium hydride (60% dispersion by wt) (112 mg) was added to a stirred solution of the product from step (v) (1.0 g) in N,N-dimethylformamide (20 ml) at room temperature. After 0.75 h, methyl iodide (0.175 ml) was added and stirring continued for 1 h. The mixture was quenched with water and extracted with ethyl acetate. The organic phase was washed with water, dried (MgSO4) and evaporated under reduced pressure. Purification was by chromatography eluting with 5% methanol in dichloromethane.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH2:19][NH2:20])[CH2:17][NH2:18])=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+].II.[O-]S([O-])=O.[Na+].[Na+]>CC(O)(C)C>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]2[CH2:19][NH:20][C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:18][CH2:17]2)=[CH:14][CH:15]=1
Reactant: NCC(CN)c1ccc(Cl)cc1
Reactant: O=Cc1ccccc1
Agent: II
Agent: O=C([O-])[O-]
Agent: O=S([O-])[O-]
Solvent: CC(C)(C)O
Product: Clc1ccc(C2CN=C(c3ccccc3)NC2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86.4 %

Procedure:
A solution of benzaldehyde (0.0056 mL, 0.056 mmol) and 2-(4-chlorophenyl)propane-1,3-diamine (10.8 mg, 0.059 mmol) in 0.7 mL t-BuOH was heated at 70° C. for 15 min. The reaction mixture was cooled to rt and treated with K2CO3 (38.5 mg, 0.279 mmol) and iodine (17.7 mg, 0.070 mmol). The reaction mixture was stirred for 5 min at rt and then heated to 70° C. for 2.5 hours. The reaction mixture was cooled to rt and saturated aqueous Na2SO3 was added drop-wise until the color changed from orange to yellow. The reaction mixture was partitioned between EtOAc and aqueous Na2CO3 solution, the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and concentrated. The residue was chromatographed using basic aluminum oxide column and eluting with 5% MeOH/CHCl3 to give the title compound as an off-white solid (13.1 mg, 87%). 1H NMR (CDCl3) δ: 7.67-7.70 (m, 2H), 7.36-7.43 (m, 3H), 7.30-7.32 (m, 2H), 7.14-7.18 (m, 2H), 3.70 (dd, J=12.9, 4.4 Hz, 2H), 3.50 (dd, J=13.5, 10.3 Hz, 2H), 3.00 (tt, J=10.0, 4.8 Hz, 1H).