Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](OC)(OC)[CH2:4][CH2:5][CH2:6][CH3:7].Cl.N1C=CC=CC=1.[NH2:19][C:20]1[CH:21]=[N:22][C:23]2[C:28]([C:29]=1[NH:30][CH2:31][C:32]1([OH:38])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)=[CH:27][CH:26]=[CH:25][CH:24]=2>C1(C)C=CC=CC=1>[CH2:4]([C:3]1[N:30]([CH2:31][C:32]2([OH:38])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[C:29]2[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N:22]=[CH:21][C:20]=2[N:19]=1)[CH2:5][CH2:6][CH3:7]
Reactant: Nc1cnc2ccccc2c1NCC1(O)CCOCC1
Reactant: CCCCC(OC)(OC)OC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCc1nc2cnc3ccccc3c2n1CC1(O)CCOCC1
Temperature: 25 °C

Procedure:
Trimethylorthovalerate (1.8 mL, 10.4 mmol) and pyridine hydrochloride (92 mg, 0.8 mmol) were added to a suspension of 4-[(3-aminoquinolin-4-ylamino)methyl]tetrahydropyran-4-ol (8.0 mmol) in toluene (40 mL). The reaction mixture was heated at reflux for 2.5 hours and then cooled to ambient temperature. A precipitate was isolated by filtration and dried to provide 4-[(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydro-2H-pyran-4-ol as a white solid, mp 180-181° C. MS (ESI) m/z 340 (M+H)+; Anal. calcd for C20H25N3O2: C, 70.77; H, 7.42; N, 12.38. Found: C, 70.58; H, 7.53; N, 12.40.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8]([CH3:11])(=O)=O)[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[C:20]1(S)[CH:25]=[CH:24]C=[CH:22][CH:21]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]([C:12]#[N:13])=[C:6]([S:8][C:11]2[CH:24]=[CH:25][CH:20]=[CH:21][CH:22]=2)[N:7]=1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccccc2)c1C#N
Reactant: Sc1ccccc1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(Sc2ccccc2)nc(N)nc1-c1ccccc1

Procedure:
From 2-amino-4-methanesulfonyl-6-phenyl-pyrimidine-5-carbonitrile, thiophenol and DBU in DME. EI-MS m/e (%): 304 (M+, 76), 303 ([M—H]+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[N:17]=[C:16]([CH2:18]O)[C:15]([CH3:20])=[N:14]1.[BrH:21].S(=O)(=O)(O)O>O>[Br:21][CH2:18][C:16]1[C:15]([CH3:20])=[N:14][N:13]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][C:4]=2[Cl:12])[N:17]=1
Reactant: Br
Reactant: Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1CO
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1CBr

Procedure:
A mixture of this product (38.5 g) and caesium carbonate (32.6 g) in tetrahydrofuran (1000 ml) was stirred at room temperature for 1 hour. The mixture was stirred at room temperature for 11/2 hours. The solvent was evaporated under reduced pressure and the residue taken up in ether. The extract was washed with water, dried and evaporated. The residue was triturated with light petroleum (bp 40°-60°) and filtered to give 2-(2,6-dichloro-4-trifluoro-methylphenyl)-2H-1,2,3-triazole-4-carboxaldehyde oxime. A mixture of 2-(2,6-dichloro-4-trifluoromethylphenyl)-5-methyl-2H-1,2,3-triazol-4-ylmethanol (4.1 g). hydrobromic acid (10 ml of 48%) and concentrated sulphuric acid (1ml) was heated under reflux for 10 minutes. The mixture was added to water and extracted with ether. The extract was worked up to give 4-bromomethyl-2-(2,6-dichloro-4-trifluoromethylphenyl)-5-methyl-2H-1,2,3-triazole, m.p. 98°-100°. Compound 6 (5 g), isopropanol (50 ml) and methanol (20 ml) was added sodium borohydride (0.67 g), portionwise. The mixture was stirred at room temperature overnight. Water was added and the mixture made acidic with hydrochloric acid. The mixture was extracted with ether and the extract washed with brine dried and evaporated to give [2-(2,6-dichloro-4-trifluoromethylphenyl)-2H-1,2,3-triazol-4-yl]methanol, mp 87°-88°.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=3[CH3:20])=[C:10]([C:21]([NH2:23])=[O:22])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[I:24]N1C(=O)CCC1=O.O>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=3[CH3:20])=[C:10]([C:21]([NH2:23])=[O:22])[C:9]=2[I:24])[CH:5]=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1ccc(Cl)cc1-c1[nH]c(-c2ccnc(N)n2)cc1C(N)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(Cl)cc1-c1[nH]c(-c2ccnc(N)n2)c(I)c1C(N)=O
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 42.9 %

Procedure:
5-(2-Amino-pyrimidin-4-yl)-2-(5-chloro-2-methyl-phenyl)-1H-pyrrole-3-carboxamide (1.1 g, 3.36 mmol) in dry DMF (6 mL) was treated with solid N-iodosuccinimide (830 mg, 3.69 mmol), stirred at room temperature for 4.5 h and poured into iced water (150 mL). The solid was then filtered with suction, washed thoroughly with water, dried in an oven under vacuum at 50° C. and purified by flash chromatography over silica gel (DCM/MeOH/7 N NH3 in MeOH 95/5/0.5) to afford the title compound (654 mg, 43%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH2:23])=[C:16]2[N:15]=1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][C:34]([CH3:40])([C:37](O)=[O:38])[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH:23][C:37]([C:34]3([CH3:40])[CH2:35][CH2:36][N:31]([C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])[CH2:32][CH2:33]3)=[O:38])=[C:16]2[N:15]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(=O)O)CC1
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3Cl)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(C)(C(=O)Nc2cnn3ccc(N4CCC[C@@H]4c4cc(F)ccc4Cl)nc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (R)-5-(2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (Example 8, Step A; 25 mg, 0.075 mmol), 1-(tert-butoxycarbonyl)-4-methylpiperidine-4-carboxylic acid (22 mg, 0.090 mmol), and HATU (34 mg, 0.090 mmol) was added 0.6 mL DMF to make a solution. After cooling in an ice bath for 10 minutes, DIEA (0.039 mL, 0.23 mmol) was added to the reaction dropwise. The reaction was allowed to warm up to ambient temperature and stirred overnight. The reaction mixture was directly purified by reverse-phase column chromatography, eluting with 5 to 80% acetonitrile/water to yield the final product as a yellowish powder (28 mg, 67% yield). MS (apci) m/z=557.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[OH:21])[CH:12]=[C:11]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=2)[C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].N1C=CC=CC=1.[O:35]=[C:36]1[O:40][CH:39]([C:41](Cl)=[O:42])[CH2:38][CH2:37]1>C1COCC1>[NH2:1][C:2]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[OH:21])[CH:12]=[C:11]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][C:41]([CH:39]3[CH2:38][CH2:37][C:36](=[O:35])[O:40]3)=[O:42])[CH:23]=2)[C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: O=C1CCC(C(=O)Cl)O1
Reactant: CC(C)(C)OC(=O)c1c(-c2cccc(N)c2)cc(-c2ccccc2O)nc1N
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1c(-c2cccc(NC(=O)C3CCC(=O)O3)c2)cc(-c2ccccc2O)nc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.4 %

Procedure:
To a cold (0° C.) solution of tert-butyl 2-amino-4-(3-aminophenyl)-6-(2-hydroxyphenyl)nicotinate (starting compound 6, 0.626 g, 1.659 mmol) in THF (7 mL) including pyridine (0.148 mL, 1.824 mmol) was added a solution of 5-oxotetrahydro-2-furancarbonyl chloride (0.271 g, 1.824 mmol) in THF (3 mL). After 1 hr., the mixture was allowed to warm to room temperature and the stirring was continued for 2 hrs. The mixture was partitioned between ethyl acetate and water. The separated organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica-gel (hexane:ethyl acetate, 1:4-1:19) to give tert-butyl 2-amino-6-(2-hydroxyphenyl)-4-(3-{[(5-oxotetrahydro-2-furanyl)carbonyl]amino}-phenyl)-nicotinate as a pale yellow foam (0.677 g, yield 83%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[N:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:1][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[N:7][CH:8]=3)[N:3]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Nc1ccc2cnccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(Nc1ccc2cnccc2n1)c1ccc(Cl)cc1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 19.1 %

Procedure:
2-Amino-1,6-naphthyridine (200 mg, Production Example 25b) was dissolved in dichloromethane (6.0 ml), to which were then added triethylamine (0.20 ml) and 4-chlorobenzenesulfonyl chloride (0.31 g), followed by stirring at 40° C. for 1.5 hours. An aqueous saturated sodium bicarbonate was added thereto, followed by extracting with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column, to give the title compound (84 mg, 21.44%) as pale yellow crystals.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.C([O-])([O-])=O.[K+].[K+].[OH:12][CH2:13][C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1.CCOCC>CN(C)C=O>[Br:1][CH2:2][CH2:3][CH2:4][O:20][C:16]1[CH:15]=[C:14]([CH2:13][OH:12])[CH:19]=[CH:18][CH:17]=1
Reactant: OCc1cccc(O)c1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: OCc1cccc(OCCCBr)c1
Temperature: 65 °C
Reaction time: 0.08 h

Procedure:
1,3-dibromopropane (23 mL, 0.22 mol) is gradually added to a suspension of K2CO3 (3.2 g, 23 mmol) and 3-(hydroxymethyl)phenol (5 g, 40.3 mmol) in dimethylformamide (DMF) (30 mL) stirred beforehand for 5 min at 65° C. The reaction medium is maintained under stirring for 45 min at the same temperature. After cooling to room temperature (RT), Et2O (150 mL) is added and the organic phase is extracted 4 times with a saturated NaCl aqueous solution. The organic phase is dried on Na2SO4. After evaporation of the solvent under reduced pressure, a viscous colorless oil is obtained (6.7 g, 68%) which gradually crystallizes.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[S:10]1[CH:14]=[CH:13][N:12]=[CH:11]1.C([O-])(=O)C.[K+]>CC(N(C)C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:10]1[C:14]([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[CH:13][N:12]=[CH:11]1
Reactant: O=Cc1ccc(Br)cc1
Reactant: c1cscn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=Cc1ccc(-c2cncs2)cc1

Procedure:
In a bomb tube, a mixture of 3.7 g (20 mmol) of 4-bromo-benzaldehyde, 6.64 ml (93 mmol) of thiazole, 2.94 g of potassium acetate and 1.16 g (1 mmol) of Pd(PPh3)4 is stirred in 50 ml of dimethylacetamide at 150° C. for 12 hours. The reaction mixture is concentrated by evaporation; water is added to the residue and the mixture is extracted three times with methylene chloride. The organic phases are filtered through cotton wadding, concentrated by evaporation and chromatographed (SiO2; hexane/ethyl acetate=1:2): 4-(Thiazol-5-yl)-benzaldehyde is obtained; HPLC:tRet(grad20-100/20)=11.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[CH:22])=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:23].Br[C:25]1[CH:26]=[C:27]([S:31]([NH2:34])(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:15])([F:17])[F:16])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[C:22][C:25]4[CH:26]=[C:27]([S:31]([NH2:34])(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=4)=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:23]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)c(C)c3)nc12
Reactant: NS(=O)(=O)c1cccc(Br)c1
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C#Cc4cccc(S(N)(=O)=O)c4)c3n2)ccc1Cl

Procedure:
The title compound was prepared from 5-(4-chloro-3-methyl-phenyl)-3-ethynyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (example C.11) (168 mg, 0.5 mmol) and commercially available 3-bromo-benzenesulfonamide (118 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (114 mg, 46%). MS (ISN) 489.2 [(M−H)−]; mp 234° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH2:14][CH:13]([CH2:15][CH2:16][CH:17]=O)[O:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:19]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH2:14][CH:13]([CH2:15][CH2:16][CH2:17][N:28]3[CH2:29][CH2:30][N:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:26][CH2:27]3)[O:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=CCCC1CC(c2cccc([N+](=O)[O-])c2)=NO1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(C2=NOC(CCCN3CCN(c4ccccc4)CC3)C2)c1
Yield: 58.5 %

Procedure:
3-[3-(3-Nitrophenyl)-4,5-dihydroisoxazol-5-yl]propanal (33.7 mg, 0.135 mmol), 1-phenylpiperazine (20.0 mg, 0.123 mmol), molecular sieve (5 beads) and NaBH(OAc)3 (78.4 mg, 0.369 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 28.4 mg (58.4%) of the target compound was obtained.
Reaction SMILES: O1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([CH3:28])([CH3:27])[CH2:11][C:12](=[O:26])[C:13](NC3C=CC=C4C=3C=CC=N4)=[O:14])[C:4]=2OC1.CC(C1C=CC=CC=1)(C)CC(=O)C(N)=[O:34]>>[CH3:27][C:10]([C:9]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)([CH3:28])[CH2:11][C:12](=[O:26])[C:13]([OH:14])=[O:34]
Reactant: CC(C)(CC(=O)C(=O)Nc1cccc2ncccc12)c1cccc2c1OCO2
Reactant: CC(C)(CC(=O)C(N)=O)c1ccccc1
Product: CC(C)(CC(=O)C(=O)O)c1ccccc1

Procedure:
According to the instructions for 4-(1,3-benzodioxol-4-yl)-N-(quinolin-5-yl)-4-methyl-2-oxopentanamide (Example 12) after chromatography on silica gel, 370 mg of N-(quinolin-5-yl)-)-4-methyl-2-oxo-4-phenylpentanamide is obtained from 515 mg of 4-methyl-2-oxo-4-phenylpentanoic acid (WO98/54159). Flash point: 98–99° C.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1.C(OO)(=[O:17])C.C(O)(C)C>C(O)(=O)C>[Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][C:5]1[CH:6]=[N+:7]([O-:17])[CH:8]=[CH:9][CH:10]=1
Reactant: CC(=O)OO
Reactant: Clc1ccccc1Oc1cccnc1
Solvent: CC(C)O
Solvent: CC(=O)O
Product: [O-][n+]1cccc(Oc2ccccc2Cl)c1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A solution of 74.3 g of 3-(o-chlorophenoxy)pyridine [Agr. Biol. Chem. 34, 68 (1970)] in 75 ml of glacial acetic acid at 35° C. is treated with 76 g of 40% peractic acid in acetic acid in three equal portions. The mixture is held at 35° C. for 16 hours, refluxed 1 hour, cooled to 60° C. and 75 ml of isopropanol is added. The mixture is refluxed for 1 hour, cooled and concentrated at reduced pressure. The oil is dissolved in 700 ml of dichloromethane, washed with excess 25% sodium hydroxide solution, concentrated at reduced pressure and distilled to yield 3-(o-chlorophenoxy)pyridine N-oxide, bp 150°-155° C. at 0.15 mm.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[F:5][C:6]([F:16])([F:15])[C:7]1[CH:14]=[CH:13][C:10]([CH2:11]Br)=[CH:9][CH:8]=1>CS(C)=O.C(OCC)(=O)C>[N:1]([CH2:11][C:10]1[CH:9]=[CH:8][C:7]([C:6]([F:5])([F:15])[F:16])=[CH:14][CH:13]=1)=[N+:2]=[N-:3]
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium azide (2.30 g, 35.4 mmol) was added to a solution of 4-(trifluoromethyl)benzyl bromide (4.26 g, 17.8 mmol) dissolved in dimethyl sulfoxide (15 mL) and stirred at ambient temperature overnight. The mixture was diluted with ethyl acetate, washed with water and brine, and dried over sodium sulfate. After filtration, the solvent was removed under reduced pressure to afford the title compound. The crude product was used in the next step without further characterization.
Reaction SMILES: CC1C=C(C)N([C:8]([CH:10]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:17][C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])N=1.[CH:24]1([CH2:27][C:28]2[O:32][C:31]([NH2:33])=[N:30][N:29]=2)[CH2:26][CH2:25]1>>[CH:24]1([CH2:27][C:28]2[O:32][C:31]([NH:33][C:8]([CH:10]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=4[O:17][C:18]4[C:19]3=[CH:20][CH:21]=[CH:22][CH:23]=4)=[O:9])=[N:30][N:29]=2)[CH2:26][CH2:25]1
Reactant: Nc1nnc(CC2CC2)o1
Reactant: Cc1cc(C)n(C(=O)C2c3ccccc3Oc3ccccc32)n1
Product: O=C(Nc1nnc(CC2CC2)o1)C1c2ccccc2Oc2ccccc21

Procedure:
The title compound, white solid, m.p. 234-236° C. and MS: m/e=347.1(M+H+) was prepared in accordance with the general method of example 48a from (3,5-dimethylpyrazol-1-yl)-(9H-xanthen-9-yl)-methanone and 5-cyclopropylmethyl-[1,3,4]oxadiazol-2-ylamine.
Reaction SMILES: [O:1]1[CH:5]=[C:4]([CH2:6][N:7]2[C:11]([O:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)=[CH:10][C:9]([C:23]3[CH:24]=[C:25]([C:29]4([NH2:33])[CH2:32][O:31][CH2:30]4)[CH:26]=[CH:27][CH:28]=3)=[N:8]2)[N:3]=[CH:2]1.[F:34][C:35]([F:42])([F:41])[CH2:36][S:37](Cl)(=[O:39])=[O:38].O>C(Cl)Cl>[F:22][C:19]([F:20])([F:21])[C:16]1[CH:17]=[CH:18][C:13]([O:12][C:11]2[N:7]([CH2:6][C:4]3[N:3]=[CH:2][O:1][CH:5]=3)[N:8]=[C:9]([C:23]3[CH:24]=[C:25]([C:29]4([NH:33][S:37]([CH2:36][C:35]([F:42])([F:41])[F:34])(=[O:39])=[O:38])[CH2:32][O:31][CH2:30]4)[CH:26]=[CH:27][CH:28]=3)[CH:10]=2)=[CH:14][CH:15]=1
Reactant: NC1(c2cccc(-c3cc(Oc4ccc(C(F)(F)F)cc4)n(Cc4cocn4)n3)c2)COC1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Solvent: O
Solvent: ClCCl
Product: O=S(=O)(CC(F)(F)F)NC1(c2cccc(-c3cc(Oc4ccc(C(F)(F)F)cc4)n(Cc4cocn4)n3)c2)COC1
Reaction time: 0.5 h

Procedure:
A stirred solution of 3-{3-[1-(1,3-oxazol-4-ylmethyl)-5-(4-trifluoromethylphenoxy)-1H-pyrazol-3-yl]phenyl}oxetan-3-amine (35 mg, 0.077 mmol) in 1 mL of CH2Cl2 was cooled in an ice bath. To the solution was added TEA (21 uL, 0.15 mmol) and 2,2,2-trifluoroethylsulfonyl chloride (12 uL, 0.12 mmol) and the solution was stirred for 30 min. Water was added and the organic phase was washed with brine, died over Na2SO4, 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. Product containing fractions were combined and the solvent was removed under reduced pressure to give N-(3-{3-[5-(4-trifluoromethylphenoxy)-1-(1,3-oxazol-4-ylmethyl)-1H-pyrazol-3-yl]phenyl}oxetan-3-yl)-2,2,2-trifluoroethanesulfonamide as a foam. Calcd (M+1)+: 603.1131. found 603.1153. 1H NMR (400 MHz, CDCl3) δ 7.80 (s, 1H), 7.78 (d, J=7, 1H), 7.65 (d, J=7, 2H), 7.61 (s, 1H), 7.49 (1, J=7, 1H), 7.37 (d, J=7, 2H), 7.28 (d, J=7, 2H), 7.09 (s, 1H), 6.08 (s, 1H), 6.05 (s, 1H), 5.44 (s, 2H), 5.23 (d, J=7, 2H), 5.05 (d, J=7, 2H), 3.03 (q, J=9, 2H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:11]=[CH:10][O:9][CH:8]=1.[CH3:12][C:13]1[C:17]2[CH2:18][CH2:19][CH2:20][C:21](=[O:22])[C:16]=2[O:15][N:14]=1.[Cl-].[NH4+]>CCCCCC.CCOCC>[O:9]1[CH:10]=[CH:11][C:7]([C:21]2([OH:22])[C:16]3[O:15][N:14]=[C:13]([CH3:12])[C:17]=3[CH2:18][CH2:19][CH2:20]2)=[CH:8]1
Reactant: Brc1ccoc1
Reactant: Cc1noc2c1CCCC2=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCCCCC
Product: Cc1noc2c1CCCC2(O)c1ccoc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96.3 %

Procedure:
To a solution of 4 ml (0.04 mol) of 10M n-butyllithium in hexane cooled to -78° C. was added 3.59 ml (0.04 mol) of 3-bromofuran in 100 ml of ether and the mixture was stirred for 10 min. To the above cooled solution was added 5.49 g (0.036 mol) 4,5,6,7-tetrahydro-3-methyl-benzisoxazol-7-one and the mixture was allowed to warm to room temperature, and then stirred for 1 h. To the mixture was added saturated ammonium chloride solution and the resulting mixture was extracted with ethyl acetate (3×100 ml), and the organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo to afford 7.6 g (96%) of 7-(3-furyl)-3-methyl-4,5,6,7-tetrahydrobenzisoxazol-7-ol, as a brown oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH:15]=[CH2:16])[CH:12]=[CH:11][C:10]=1[N:17]1[S:21](=[O:23])(=[O:22])[N:20]([CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:19](=[O:30])[CH2:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[N-]>C(Cl)Cl.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2]>[CH2:37]([O:36][C:34]([CH:33]1[CH2:16][CH:15]1[C:13]1[CH:12]=[CH:11][C:10]([N:17]2[CH2:18][C:19](=[O:30])[N:20]([CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[S:21]2(=[O:23])=[O:22])=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:14]=1)=[O:35])[CH3:38]
Reactant: C=Cc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CCOC(=O)C1CC1c1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1

Procedure:
To a solution of 5-(2-benzyloxy-4-vinylphenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (Example 81, step A) (75 mg, 0.17 mmol) in methylene chloride is added rhodium acetate dimer (cat.). Ethyl diazoacetate (0.024 mL, 0.17 mmol) in methylene chloride (0.2 mL) is added dropwise via syringe pump over 4 h. The solvent is removed under reduced pressure and the crude material purified on silica gel using a gradient of 0-40% EtOAc/hexanes to give the title compound as a mixture of isomers (cis:trans 1:2) as a colorless oil: (M+H)+=548.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1Cl)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:32]2[CH:33]=[C:34]([N:38]3[CH2:41][CH2:40][CH2:39]3)[CH:35]=[CH:36][CH:37]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1COCC1>O>[N:38]1([C:34]2[CH:33]=[C:32]([C:13]3[C:14]4[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:20]=[C:21]([CH3:22])[C:12]=3[C@H:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:37]=[CH:36][CH:35]=2)[CH2:41][CH2:40][CH2:39]1
Reactant: CC1(C)OB(c2cccc(N3CCC3)c2)OC1(C)C
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2ccccc2c1Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2ccccc2c1-c1cccc(N2CCC2)c1
Temperature: 110 °C

Procedure:
A Smith process vial was charged with (S)-ethyl 2-tert-butoxy-2-(1-chloro-3-methylnaphthalen-2-yl)acetate (60.5 mg, 0.181 mmol), 1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)azetidine (93.7 mg, 0.361 mmol), chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]Pd(II)methyl-t-butyl ether adduct (12.2 mg, 0.0181 mmol) and potassium phosphate (153 mg, 0.543 mmol), THF (2 mL) and water (1 mL) was added and mixture sparged with nitrogen for 10 minutes and then heated in microwave at 110° C. for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with brine, dried (MgSO4), filtered, concentrated and purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to the desired product containing some impurities that was used in the next step without further purification.