Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-:1].[Na+].C(N(C(C)C)CC)(C)C.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]([N:21]2[CH2:26][CH2:25][CH2:24]/[C:23](=[CH:27]\[C:28]3[CH:33]=[CH:32][C:31]([N:34]4[CH:38]=[C:37]([CH3:39])[N:36]=[CH:35]4)=[C:30]([O:40][CH3:41])[CH:29]=3)/[C:22]2=[O:42])[CH3:20])=[CH:15][CH:14]=1.[C:43]([O:46][CH2:47]Cl)(=[O:45])[CH3:44]>COCCOC>[I-:1].[C:43]([O:46][CH2:47][N+:36]1[C:37]([CH3:39])=[CH:38][N:34]([C:31]2[CH:32]=[CH:33][C:28](/[CH:27]=[C:23]3/[C:22](=[O:42])[N:21]([C@H:19]([C:16]4[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=4)[CH3:20])[CH2:26][CH2:25][CH2:24]/3)=[CH:29][C:30]=2[O:40][CH3:41])[CH:35]=1)(=[O:45])[CH3:44]
Reactant: CC(=O)OCCl
Reactant: COc1cc(/C=C2\CCCN([C@@H](C)c3ccc(F)cc3)C2=O)ccc1-n1cnc(C)c1
Agent: [I-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(/C=C2\CCCN([C@@H](C)c3ccc(F)cc3)C2=O)ccc1-n1cc(C)[n+](COC(C)=O)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Sodium iodide (54 mg) and IPEA (0.05 mL) were added to a DME solution (2 mL) of (E)-1-[(1S)-1-(4-fluorophenyl)ethyl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidin-2-one (CAS Registry No. 870843-42-8, 100 mg) and chloromethyl acetate (0.03 mL), and the resulting reaction solution was stirred at 80° C. for 1 hr. The reaction solution was allowed to cool to room temperature, and the precipitated solid was collected by filtration. The obtained solid was washed with diethylether and dried in air to give 70 mg of the title compound. The physical property values of this compound were as follows:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[O:12][C:11]([NH:13][C:14]3[CH:19]=[C:18]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH:17]=[CH:16][C:15]=3[O:25][CH3:26])=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:27][C:28]1[CH:29]=[C:30]([Sn](CCCC)(CCCC)CCCC)[CH:31]=[C:32]([F:34])[CH:33]=1>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C.C(OCC)(=O)C>[F:27][C:28]1[CH:29]=[C:30]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[O:12][C:11]([NH:13][C:14]4[CH:19]=[C:18]([S:20]([CH2:23][CH3:24])(=[O:21])=[O:22])[CH:17]=[CH:16][C:15]=4[O:25][CH3:26])=[N:10][CH:9]=3)[CH:3]=2)[CH:31]=[C:32]([F:34])[CH:33]=1
Reactant: CCS(=O)(=O)c1ccc(OC)c(Nc2ncc(-c3cccc(Br)c3)o2)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(F)cc(F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCS(=O)(=O)c1ccc(OC)c(Nc2ncc(-c3cccc(-c4cc(F)cc(F)c4)c3)o2)c1
Temperature: 100 °C
Yield: 63 %

Procedure:
In a pyrex sealed tube, a mixture of the title compound of Example 100 (123 mg, 0.28 mmol), 3,5-difluoro(tributylstannyl)benzene (400 mg, 1 mmol), tetrabutylammonium chloride (170 mg, 0.61 mmol), and tetrakistriphenylphosphine palladium(0) (20 mg, 0.017 mmol) was suspended in dry acetonitrile (10 mL) and stirred at 100° C. After the reaction was determine to be complete by TLC analysis, the reaction was cooled and diluted with ethyl acetate (50 mL), quenched with 1M aqueous potassium fluoride solution (20 mL), and stirred for 3 h. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with hexane:ethyl acetate (1:1) to afford the title compound (83 mg, 63%) as a solid white powder. 1H NMR (400 MHz, d6-DMSO): δ 9.72 (s, 1H), 8.74 (d, J=2.2, 1H), 7.91 (s, 1H), 7.60–7.64 (m, 3H), 7.42–7.53 (m, 4H), 7.23 (d, J=8.6, 1H), 3.94 (s, 3H), 3.16 (q, J=7.3, 2H), 1.07 (t, J=7.3, 3H). MS (ES+, m/z)=471 (m+H)+.
Reaction SMILES: O[C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:13]([N:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].C([O-])([O-])=O.[Cs+].[Cs+].BrC(C)(C)C([NH2:28])=O>O1CCOCC1.CCOC(C)=O.CCCCCC.CN1C(=O)N(C)CCC1.CN1C(=O)CCC1>[NH2:28][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:13]([N:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cccc2cc3ccccc3nc12
Reactant: CC(C)(Br)C(N)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [H-]
Solvent: CN1CCCN(C)C1=O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Nc1cccc2cc3ccccc3nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 18.1 %

Procedure:
To a solution of 4-hydroxyacridine (722 mg, 3.70 mmol) in dioxane (20 mL) was added NaH (Aldrich, dry, 300 mg, 12.2 mmol) and Cs2CO3 (4.00 g, 12.2 mmol). The resulting mixture was stirred at room temperature for about 30 minutes, then 2-bromo-2-methyl-propanamide (2.03 g, 12.2 mmol) was added and the resulting mixture was stirred at reflux for 16 h. After the reflux period, NMP (20 mL), DMPU (2 mL), and NaH (Aldrich, dry, 100 mg, 4.07 mmol) were added. The resulting mixture was stirred at 150° C. for 72 h. The reaction was cooled to room temp., and partitioned between water (50 mL) and EtOAc (100 mL). The aqueous layer was extracted with EtOAc (100 mL) and the combined organics washed with water (2×50 mL), dried (Na2SO4), and concentrated to about 3 g of material. The brown oil was chromatographed on silica (200 mL, 4 cm diam. column), eluting with 1:9 then 3:7 EtOAc/hexane to obtain 4-aminoacridine as a brown solid (130 mg, 0.67 mmol, 18.1% yield).: mp 98-100° C. (lit 105-106° C., Albert, A. et. al., Chemistry and Industry (London), 1941, 60, 122T); 1H NMR (300 MHz, CDCl3) δ8.66 (s, 1 H), 8.23-8.19 (m, 1 H), 7.98-7.95 (m, 1 H), 7.74-7.69 (m, 1 H), 7.53-7.48 (m, 1 H), 7.34 (d, 1 H, J=1.72 Hz), 6.94 (dd, 1 H, J=3.32 Hz), 5.23 (br s, 2 H, N--H2); MS (CI/NH3) 195; IR 3377 (NH).
Reaction SMILES: [BH4-].[Na+].[C:3]1([C:9]2([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[O:13][C:12]3[CH:14]=[CH:15][C:16]([C:18](=[O:34])[CH:19]([N:21]4[CH2:26][CH2:25][C:24]([OH:33])([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH2:23][CH2:22]4)[CH3:20])=[CH:17][C:11]=3[O:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)C>[C:35]1([C:9]2([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[O:13][C:12]3[CH:14]=[CH:15][C:16]([C@@H:18]([OH:34])[C@H:19]([N:21]4[CH2:22][CH2:23][C:24]([OH:33])([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)[CH2:25][CH2:26]4)[CH3:20])=[CH:17][C:11]=3[O:10]2)[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC(C(=O)c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2)N1CCC(O)(c2ccccc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: C[C@H]([C@H](O)c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2)N1CCC(O)(c2ccccc2)CC1
Reaction time: 0.17 h
Yield: 61.6 %

Procedure:
A mixture of sodium borohydride (0.15 g, 3.97 mmol) and ethanol (5 mL) was stirred 10 min and then 1-(2,2-diphenyl-benzo(1,3)dioxol-5-yl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-propan-1-one (1.70 g, 3.36 mmol in 20 mL of ethanol) was added. The reaction was stirred at ambient temperature over the weekend. The white precipitate was collected, rinsed with ethanol and ether, and air dried to afford 1.35 g of crude product. The product was recrystallized from ethanol/ether/hexane and then recrystallized from ethanol/ethyl acetate/methylene chloride to give 1.05 g (61%) of (1R*,2R*)-1-(2,2-diphenyl-benzo(1,3)dioxol-5-yl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-propan-1-ol which had: mp 224-224.5° C. Analysis calculated for C33H33NO4: C, 78.08; H, 6.55; N, 2.76. Found: C, 78.16; H, 6.46; N, 2.72.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]=[C:9]([C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[N:10]([OH:11])[C:5]2=[CH:4][CH:3]=1.[CH3:19][SH:20]>>[CH3:19][S:20][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[N:10]([OH:11])[C:5]2=[CH:4][CH:3]=1
Reactant: CS
Reactant: On1c(C(F)(F)C(F)(F)F)nc2nc(Cl)ccc21
Product: CSc1ccc2c(n1)nc(C(F)(F)C(F)(F)F)n2O

Procedure:
5-Chloro-1-hydroxy-2-(pentafluoroethyl)-1H-imidazo(4,5-b)pyridine is reacted with methanethiol to obtain 5-(methylthio)-1-hydroxy-2-(pentafluoroethyl)-1H-imidazo(4,5-b)pyridine which is subsequently oxidized to obtain the corresponding 5-(methylsulfonyl)-1-hydroxy-2-(pentafluoroethyl)-1H-imidazo(4,5-b)pyridine.
Reaction SMILES: [CH3:1][C:2]1[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:3]=1[CH2:4][O:5][C:6]1[C:11](I)=[CH:10][CH:9]=[CH:8][C:7]=1[C:13]1[N:18]=[C:17]([N:19]2[C:23]([C:24]([F:27])([F:26])[F:25])=[C:22]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:21]=[N:20]2)[CH:16]=[CH:15][CH:14]=1.[CH3:38]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1>[CH3:1][C:2]1[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:3]=1[CH2:4][O:5][C:6]1[C:11]([CH3:38])=[CH:10][CH:9]=[CH:8][C:7]=1[C:13]1[N:18]=[C:17]([N:19]2[C:23]([C:24]([F:27])([F:26])[F:25])=[C:22]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:21]=[N:20]2)[CH:16]=[CH:15][CH:14]=1
Reactant: CB1OB(C)OB(C)O1
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3cccc(I)c3OCc3ccc(C)cc3C)n2)c1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(-c2cccc(-c3cccc(C)c3OCc3ccc(C)cc3C)n2)c1C(F)(F)F
Temperature: 65 °C
Reaction time: 18 h

Procedure:
A vial was charged with the product from Example 15 Step B (40 mg, 0.064 mmol), trimethyl boroxine (49 mg, 50 wt. %, 0.193 mmol), and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (5.3 mg, 0.006 mmol). Sodium carbonate (0.161 mL, 1.0 M aqueous, 0.161 mmol) and THF (0.25 mL) were added, and the resulting suspension was degassed by a nitrogen sparge. The vial was then capped and placed in a pre-heated (65° C.) oil bath. After 18 h, the reaction mixture was allowed to cool to ambient temperature, then was poured into water. The aqueous phase was extracted with EtOAc, and the organic phase was concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 20% EtOAc in hexanes, then 20 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 510.8 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][CH:17]3[CH2:19][O:18]3)[CH:13]=2)[NH:8][C:7]=1[CH3:20])=[O:5])[CH3:2].[N-:21]=[N+:22]=[N-:23].[Na+].[Cl-].[Li+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][C@@H:17]([OH:18])[CH2:19][N:21]=[N+:22]=[N-:23])[CH:13]=2)[NH:8][C:7]=1[CH3:20])=[O:5])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)c1c(C)[nH]c2ccc(OCC3CO3)cc12
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)[nH]c2ccc(OC[C@@H](O)CN=[N+]=[N-])cc12
Temperature: 25 °C
Yield: 38.8 %

Procedure:
A solution of 1.4 g (5.1 mmol) of 2-methyl-5-oxiranylmethoxy-1H-indole-3-carboxylic acid ethyl ester (which was obtained in Example 139), 0.5 g (7.6 mmol) of sodium azide and 0.43 g (10.2 mmol) of lithium chloride in 15 mL anhydrous DMF was heated at 60° C. overnight. The mixture was cooled to room temperature and quenched with water. The aqueous mixture was extracted with ethyl acetate. The organic layer was washed twice with water, dried over sodium sulfate and concentrated in vacuo. The residue was then purified by flash chromatography (10% EtOAc in hexanes to 50% EtOAc in hexanes) to give 0.63 g of the title compound as a yellow solid; mp 75–77° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.34 (t, J=7.1 Hz, 3H), 2.66 (s, 3H), 3.42 (d, 4.6 Hz, 1H), 3.89–3.95 (m, 2H), 4.00–4.06 (m, 1H), 4.26 (q, J=7.1 Hz, 2H), 5.55 (d, J=5.1 Hz, 2H), 6.76 (dd, J=8.7, 2.7 Hz, 1H), 7.24 (d, J=8.7 Hz, 1H), 7.43 (d, J=2.4 Hz, 1H), 11.65 (s, 1H); MS (ES) m/z: 319.0 (MH+); HRMS Calcd. for C15H18N4O4(M+): 318.1328. Found: 318.1334.
Reaction SMILES: [NH2:1][C@@:2]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:19][C@H:20]3[CH2:25][CH2:24][C@H:23]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:22][CH2:21]3)[C:12]=2[CH:16]2C[CH2:17]2)[CH:7]=1)([CH3:5])[CH2:3][OH:4].C([C@H]1CC[C@H](OC2C(C=C)=C3C(=CC=2)C=C([C@]2(C)COC(=O)N2)C=C3)CC1)(C)(C)C>>[NH2:1][C@@:2]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:19][C@H:20]3[CH2:25][CH2:24][C@H:23]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:22][CH2:21]3)[C:12]=2[CH:16]=[CH2:17])[CH:7]=1)([CH3:5])[CH2:3][OH:4]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2C2CC2)CC1
Agent: C=Cc1c(O[C@H]2CC[C@H](C(C)(C)C)CC2)ccc2cc([C@]3(C)COC(=O)N3)ccc12
Product: C=Cc1c(O[C@H]2CC[C@H](C(C)(C)C)CC2)ccc2cc([C@@](C)(N)CO)ccc12

Procedure:
(R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-vinylnaphthalen-2-yl)propan-1-ol was synthesized as per (R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-cyclopropylnaphthalen-2-yl)propan-1-ol (Example 215) in 76% yield using (R)-4-(6-(trans-4-tert-butylcyclohexyloxy)-5-vinylnaphthalen-2-yl)-4-methyloxazolidin-2-one as starting material. MS: m/z=365.48 [M-16]+. 1H NMR (MeOD) δ: 8.29 (d, J=9.0 Hz, 1H), 7.87 (d, J=2.0 Hz, 1H), 7.84 (d, J=9.3 Hz, 1H), 7.55 (dd, J=9.0, 2.3 Hz, 1H), 7.45 (d, J=9.0 Hz, 1H), 7.11 (dd, J=17.9, 11.7 Hz, 1H), 5.66-5.79 (m, 2H), 4.28-4.41 (m, 1H), 3.95 (d, J=11.5 Hz, 1H), 3.84 (d, J=11.5 Hz, 1H), 2.18-2.27 (m, 2H), 1.87-1.95 (m, 2H), 1.80 (s, 3H), 1.41-1.55 (m, 2H), 1.09-1.29 (m, 3H), 0.92 (s, 9H)
Reaction SMILES: C[Si](C)(C)CCOC[N:7]([CH2:50]OCC[Si](C)(C)C)[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:36][CH:35]3[N:37](C(OC(C)(C)C)=O)[CH:31]([CH2:32][O:33][CH2:34]3)[CH2:30]2)[C:9]=1[C:45]([O:47]CC)=[CH2:46]>C(O)(C(F)(F)F)=O>[CH:31]12[NH:37][CH:35]([CH2:36][CH:29]([C:10]3[C:9]4[C:45](=[O:47])[CH2:46][CH2:50][NH:7][C:8]=4[N:13]4[N:14]=[CH:15][C:16]([C:17]5[CH:18]=[N:19][C:20]([C:23]6[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=6)=[CH:21][CH:22]=5)=[C:12]4[N:11]=3)[CH2:30]1)[CH2:34][O:33][CH2:32]2
Reactant: C=C(OCC)c1c(C2CC3COCC(C2)N3C(=O)OC(C)(C)C)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N(COCC[Si](C)(C)C)COCC[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCNc2c1c(C1CC3COCC(C1)N3)nc1c(-c3ccc(-c4ccccc4)nc3)cnn21
Reaction time: 16 h

Procedure:
tert-butyl 7-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-(1-ethoxyvinyl)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate was treated with anhydrous TFA (10 mL) at rt and the mixture was stirred for 16 h. Then the solvent was evaporated off under reduced pressure and the material was lyophilized from acetonitrile:water (3:1) to give compound 5-(3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-3-(6-phenylpyridin-3-yl)-8,9-dihydropyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-6(7H)-one as yellow solid (122 mg) which was used without further purification. HPLC-MS tR=1.16 min (UV254 nm). Mass calculated for formula C26H26N6O2 454.2; observed MH+ (LCMS) 455.2 (m/z).
Reaction SMILES: [F:1][C:2]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH2:19][C:18]([C:24]4[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=4)([C:20]([F:23])([F:22])[F:21])[O:17][N:16]=3)=[CH:11][CH:10]=2)[CH2:5][CH:4]([C:6]([OH:8])=O)[CH2:3]1.CN(C(O[N:41]1N=N[C:43]2C=CC=N[C:42]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.C(N)C>CN(C=O)C.C1COCC1>[CH2:42]([NH:41][C:6]([CH:4]1[CH2:5][C:2]([F:1])([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH2:19][C:18]([C:24]4[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=4)([C:20]([F:21])([F:22])[F:23])[O:17][N:16]=3)=[CH:13][CH:14]=2)[CH2:3]1)=[O:8])[CH3:43]
Reactant: O=C(O)C1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CCN
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCNC(=O)C1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.1 %

Procedure:
To a stirred solution of 3-Fluoro-3-{4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-cyclobutanecarboxylic acid (Preparation 6, 0.2 g, 0.391 mmol) in dry DMF (3 mL) was added HATU (0.223 g, 0.58 mmol), HOBt (0.06 g, 0.43 mmol), DIPEA (0.102 g, 0.79 mmol) and 2M solution of ethyl amine in THF (2 mL) at 0° C. Resulting reaction mixture was stirred at room temperature for 18 hours under nitrogen atmosphere. After complete consumption of starting material, reaction mixture was quenched with water (20 mL), extracted with EtOAc (2×30 mL). Combined organic layer was washed with brine (2×20 mL), saturated solution of lithium chloride (2×20 mL), water (20 mL), dried over sodium sulphate and evaporated in vacuo to get crude. Crude was purified by column chromatography on silica gel (100-200 mesh size). Compound was eluted using 1% methanol in DCM to afford off white solid (0.20 g, 64%). 1H-NMR (400 MHz, CDCl3) δ: 1.15 (t, 3H, J=7.28 Hz), 2.67-2.78 (m, 2H), 2.84-2.96 (m, 2H), 3.22-3.26 (m, 1H), 3.28-3.35 (m, 2H), 3.67 (d, 1H, J=17.24 Hz), 4.07 (d, 1H, J=17.2 Hz), 5.43 (bs, 1H), 7.56 (d, 2H, J=8.36 Hz), 7.64-7.66 (m, 4H); LC-MS (m/z): [M−H] 535.00.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11](Cl)=[O:12])=[C:4]2[N:3]=1.[Cl:14][C:15]1[CH:16]=[C:17]([N:21]2[C:25]([NH2:26])=[CH:24][C:23]([CH3:27])=[N:22]2)[CH:18]=[CH:19][CH:20]=1.C(N(CC)C(C)C)(C)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([NH:26][C:25]3[N:21]([C:17]4[CH:18]=[CH:19][CH:20]=[C:15]([Cl:14])[CH:16]=4)[N:22]=[C:23]([CH3:27])[CH:24]=3)=[O:12])=[C:4]2[N:3]=1
Reactant: Cc1cc(N)n(-c2cccc(Cl)c2)n1
Reactant: O=C(Cl)c1cnn2ccc(Cl)nc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(NC(=O)c2cnn3ccc(Cl)nc23)n(-c2cccc(Cl)c2)n1
Yield: 95.8 %

Procedure:
A solution of 5-chloropyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (150 mg, 0.69 mM, 1.0 equiv), 1-(3-chlorophenyl)-3-methyl-1H-pyrazol-5-amine (140 mg, 0.69 mM, 1.0 equiv, available from Enamine, Ltd, Cincinnati, Ohio Cat# EN300-02447), N,N-diisopropylethylamine (0.18 mL, 1.0 mM, 1.0 equiv), and 15 mL of dichloromethane was stirred at ambient temperature for 3 days. The reaction was partitioned between dichloromethane and water. The dichloromethane phase was dried over sodium sulfate and vacuum filtered through silica gel. The silica gel pad was washed with 95:5 dichloromethane:methanol. The combined filtrates were concentrated to give 250 mg (93%) of 5-chloro-N-(1-(3-chlorophenyl)-3-methyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide which was 74% pure by HPLC and used without further purification. LCMS (ESI) m+H=387.2, (two chlorine isotope pattern).
Reaction SMILES: C[O:2][C@:3]1([C@@H:24]2[CH2:28][S:27][C:26](=[O:29])[N:25]2CC2C=CC(OC)=CC=2)[CH2:20][C@H:19]2[CH2:21][C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:23])=[CH:16][C:17](=[O:22])[O:18]2)[O:4]1.CO[C@]1([C@@H]2CSC(=O)N2CC2C=CC(OC)=CC=2)C[C@H]2C[C@@H](CCCC=CCCC(C)=CC(=O)O2)O1>>[OH:2][C@:3]1([C@@H:24]2[CH2:28][S:27][C:26](=[O:29])[NH:25]2)[CH2:20][C@H:19]2[CH2:21][C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:23])=[CH:16][C:17](=[O:22])[O:18]2)[O:4]1
Reactant: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCCCCCCCCC(C)=CC(=O)O3)O2)cc1
Agent: C/C1=C/C(=O)O[C@@H]2C[C@@H](CCCCCCCCC1)O[C@@](O)([C@@H]1CSC(=O)N1)C2
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCC/C=C\CC/C(C)=C\C(=O)O3)O2)cc1
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCCC=CCCC(C)=CC(=O)O3)O2)cc1
Product: CC1=CC(=O)O[C@@H]2C[C@@H](CCCCCCCCC1)O[C@@](O)([C@@H]1CSC(=O)N1)C2

Procedure:
Application of the method shown in Example 46, with the-modification that (R)-4-((1R, 15R,17R,Z)-17-methoxy-5-methyl-3-oxo-2,16-dioxa-bicyclo[13.3.1]nonadec-4-en-17-yl)-3-(4-methoxybenzyl)thiazolidin-2-one is substituted for (R)-4-((1R,4Z,8Z,13R,15R)-15-methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one, affords the title compound.
Reaction SMILES: Br[C:2]1[C:3](=[O:18])[C:4]([CH3:17])([CH3:16])[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1.CC1(C)C(C)(C)OB([C:27]2[CH:44]=[CH:43][C:30]([O:31][CH2:32][C:33]3[CH:42]=[CH:41][C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:34]=3)=[CH:29][CH:28]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.O>[CH3:16][C:4]1([CH3:17])[C:3](=[O:18])[C:2]([C:27]2[CH:28]=[CH:29][C:30]([O:31][CH2:32][C:33]3[CH:42]=[CH:41][C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:34]=3)=[CH:43][CH:44]=2)=[C:6]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)[O:5]1
Reactant: CC1(C)OB(c2ccc(OCc3ccc4ccccc4n3)cc2)OC1(C)C
Reactant: CC1(C)OC(c2ccc([N+](=O)[O-])cc2)=C(Br)C1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)OC(c2ccc([N+](=O)[O-])cc2)=C(c2ccc(OCc3ccc4ccccc4n3)cc2)C1=O
Yield: 53.6 %

Procedure:
A solution of 4-bromo-2,2-dimethyl-5-(4-nitrophenyl) furan-3(2H)-one (100 mg, 0.32 mmol, 1 eq), 2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)quinoline (115 mg, 0.32 mmol, 1 eq), and Cs2CO3 (521 mg, 1.6 mmol, 5 eq) in toluene (7 mL) and water (2.5 mL) was degassed. Then Pd (dppf)Cl2 (52 mg, 0.06 mmol, 0.2 eq) was added under an inert atmosphere and the solution was again degassed. The reaction mixture was then refluxed for 3 h, filtered through a pad of Celite®, and the filtrate was diluted with EtOAc (30 mL). The combined organic layers were washed with water (20 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography (10% ethyl acetate in hexanes) to afford 2,2-dimethyl-5-(4-nitrophenyl)-4-(4-(quinolin-2-ylmethoxy)phenyl) furan-3(2H)-one (80 mg, 54%) as a solid. 1H NMR (400 MHz, d6-DMSO): δ 8.42 (d, J=8.5 Hz, 1H), 8.27 (d, J=8.5 Hz, 2H), 8.00 (t, J=7.9 Hz, 2H), 7.82-7.76 (m, 3H), 7.68 (d, J=8.5 Hz, 1H), 7.61 (t, J=7.2 Hz, 1H), 7.18 (d, J=8.7 Hz, 2H), 7.10 (d, J=8.7 Hz, 2H), 5.38 (s, 2H), 1.48 (s, 6H). MS: [M+H]: m/z=467.1. HPLC: 89%, Column: Acquity BEH-C-18, 50×2.1 mm, 1.7 um. Mobile Phase: 0.025% TFA in Water (A), AcN (B), Flow rate: 0.5 ml/min (Gradient).
Reaction SMILES: O=C(Cl)[O:3][C:4](Cl)(Cl)Cl.[CH2:9]([O:12][C:13](=[O:16])[CH2:14][NH2:15])[CH2:10][CH3:11].C>O1CCOCC1>[N-:15]=[C:4]=[O:3].[CH2:9]([O:12][C:13](=[O:16])[CH2:14][NH2:15])[CH2:10][CH3:11]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: CCCOC(=O)CN
Solvent: C1COCCO1
Product: [N-]=C=O

Procedure:
0.35 mol diphosgene is added dropwise over 1 hour to a mixture of 0.28 mol of glycine n-propyl ester and 0.4 g activated charcoal in 400 mL dioxane under N2. The reaction mixture is then heated and stirred at reflux for 21/2 hours. The reaction mixture is then cooled, filtered, and concentrated to dryness by rotary evaporator, keeping exposure to moisture to a minimum. The crude product is re-dissolved in 100 mL THF, and the pH of the solution is adjusted to 5.5-6.0 by addition of pyridine. The product mixture is again filtered, and the product is purified by fractional distillation to give glycine n-propyl ester isocyanate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]([CH2:12][CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2].[Na].[CH2:16]([OH:18])[CH3:17]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:18][CH2:16][CH3:17])=[N:8][C:9]([CH2:12][CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCO
Reactant: CCOC(=O)c1cnc(CC)nc1Cl
Agent: [Na]
Product: CCOC(=O)c1cnc(CC)nc1OCC
Reaction time: 0.25 h
Yield: 68 %

Procedure:
To a solution cooled to 0° C. of 64.5 g of 5-ethoxycarbonyl 4-chloro 2-ethyl pyrimidine obtained in the preceding stage, in 200 ml of ethanol, was slowly added a solution of 7.75 g of sodium in 200 ml of ethanol, this being stirred for 15 min. after the addition. Then the solution was acidified to a pH≃3 with hydrochloric ethanol≃6.5 N, and the solvent was evaporated. The residue was diluted in water, extracted with chloroform, dried on sodium sulfate and the solvent evaporated. The residue was distilled and 46.7 g of the expected product were obtained.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[N:13][OH:14])C)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:15][O:16][C:17](=[O:30])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28]Br)=[CH:21][CH:20]=1>>[CH3:15][O:16][C:17](=[O:30])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][O:14][N:13]=[CH:11][C:8]2[CH:7]=[CH:6][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:10][CH:9]=2)=[CH:21][CH:20]=1
Reactant: CC(=NO)c1ccc(C(C)(C)C)cc1
Reactant: COC(=O)Cc1ccc(OCCCBr)cc1
Product: COC(=O)Cc1ccc(OCCCON=Cc2ccc(C(C)(C)C)cc2)cc1

Procedure:
{4-[3-(4-tert-Butyl-benzylideneaminooxy)-propoxy]-phenyl}-acetic acid methyl ester was prepared from 1-(4-tert-butyl-phenyl)-ethanone oxime and [4-(3-bromo-propoxy)-phenyl]-acetic acid methyl ester using a procedure similar to step 2 of example 1. It was used crude in the subsequent reaction. 1H NMR (300 MHz, CDCl3); δ 8.07 (s, 1H), 7.52 (d, 2H), 7.40 (d, 2H), 7.20 (d, 2H), 6.88 (d, 2H), 4.35 (t, 2H), 4.10 (t, 2H), 3.70 (s, 3H), 3.58 (s, 2H), 2.21 (m, 2H), 1.34 (s, 9H).