Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26]O)=[N+:2]=[N-:3].CCN(S(F)(F)[F:34])CC>C(Cl)Cl>[N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][F:34])=[N+:2]=[N-:3]
Reactant: CCN(CC)S(F)(F)F
Reactant: [N-]=[N+]=NCCOCCOCCOCCOCCOCCOCCOCCO
Solvent: ClCCl
Product: [N-]=[N+]=NCCOCCOCCOCCOCCOCCOCCOCCF
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 24.4 %

Procedure:
23-Azido-3,6,9,12,15,18,21-heptaoxatricosan-1-ol (500 mg, 1.26 mmol) was dissolved in DCM (2 mL) and cooled to −10° C. DAST (482 μL, 3.78 mmol) was added in portions to the cooled solution and the resulting mixture was stirred at −10° C. for 30 minutes then allowed to warm to room temperature and stirred for additional 20 hours. The excess of DAST was quenched with methanol (5 mL) and the solvents were subsequently evaporated at the reduced pressure. The oily residue was dissolved in the water (3 mL) and the pH was adjusted to 5 using NaHCO3. The crude product was purified on semipreparative HPLC (System E) to yield 122 mg (24%) of 4 as a yellowish oil. 1H NMR (500 MHz, CDCl3): δ 3.39 (t, J=5.0 Hz, 2H), 3.65-3.68 (m, 26H), 3.75 (dt, J=4.2 Hz, 29.6 Hz, 2H), 4.56 (dt, J=4.0 Hz, 47.5 Hz, 2H); 13C NMR (125.7 MHz, CDCl3): δ 50.8, 70.1, 70.4, 70.5, 70.7-70.8, 70.9, 83.2 (d, J=169 Hz); 19F NMR (470.6 MHz, CDCl3): 6-225.9; MS ESI (m/z): [M+H]+ calcd. for C16H33FO7N3, 398.2; found 398.0.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]2[NH:12][C:11]3[C:6](=[CH:7][C:8]([NH2:16])=[CH:9][CH:10]=3)[C:5](=[O:17])[C:4]=2[CH:3]=1.[Cl:18][CH2:19][CH2:20][C:21](Cl)=[O:22]>>[Cl:18][CH2:19][CH2:20][C:21]([NH:16][C:8]1[CH:9]=[CH:10][C:11]2[NH:12][C:13]3[C:4](=[CH:3][C:2]([NH:1][C:21](=[O:22])[CH2:20][CH2:19][Cl:18])=[CH:15][CH:14]=3)[C:5](=[O:17])[C:6]=2[CH:7]=1)=[O:22]
Reactant: O=C(Cl)CCCl
Reactant: Nc1ccc2[nH]c3ccc(N)cc3c(=O)c2c1
Product: O=C(CCCl)Nc1ccc2[nH]c3ccc(NC(=O)CCCl)cc3c(=O)c2c1
Yield: 81 %

Procedure:
A suspension of 2,7-diamino-9(10H)-acridone 12 (13.44 g, 60 mmol), in 3-chloropropionyl chloride (3-CPC) (240 mL) was stirred at 90° C. for 4 hr and then heated under reflux for 2 hr. The resultant mixture was cooled to 0° C. after which the product was collected on a glass sinter. The product was washed with acetone (60 mL) followed by toluene (2×60 mL), more acetone (4×60 mL), dry ether (2×60 mL) and finally hexane (2×60 mL). The product was dried over P2O5 under vacuum to yield an olive-green solid (19.68 g, 81%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5](=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:6]([NH:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7].[H][H]>C(O)C.[C].[Pd]>[CH2:17]([CH:5]1[CH2:4][CH2:3][CH2:2][N:8]([NH:9][C:10](=[O:11])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:6]1=[O:7])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)NNC(=O)C(=Cc1ccccc1)CCCCl
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NN1CCCC(Cc2ccccc2)C1=O

Procedure:
10% palladium-carbon powder (50.36% aqueous, 1.92 g) was added to a solution of the (E)/(Z) mixture of tert-butyl N′-[5-chloro-2-(1-phenylmethylidene)pentanoyl]hydrazinecarboxylate obtained in the process of Example 12 in ethanol (20 mL), and the reaction solution was stirred in a hydrogen atmosphere at room temperature for 10 days. Thereafter, the reaction solution was filtered through celite and the solvent was evaporated under reduced pressure. DBU (0.598 mL) was added to a solution of the resulting residue in THF (50 mL) and the mixture was heated under reflux for 44 hours. Thereafter, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 727 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:16])[CH:12]=2)[C:7]1=[O:17])[CH3:2].[CH:19]1(O)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:12]=2)[C:7]1=[O:17])[CH3:2]
Reactant: CCOC(=O)CN1C(=O)c2ccc(O)cc2C1=O
Reactant: OC1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CN1C(=O)c2ccc(OC3CCCCC3)cc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.6 %

Procedure:
To a mixture of (5-hydroxy-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-acetic acid ethyl ester (8.0 g) in anhydrous tetrahydrofuran (160 ml) was added cyclohexanol (3.2 g), diethylazadicarboxylate (6.9 g) and then triphenyl phosphine (12.6 g). Resulting mixture was stirred at room temperature overnight and concentrated. Residue was partitioned between water and ethyl acetate. Aqueous layer was extracted with ethyl acetate. Combined organic layers were washed with brine, dried over magnesium sulfate and filtered. Filtrate was concentrated and purified by silica gel chromatography (eluting with 5% ethyl acetate in methylene chloride) to give the title compound (6.2 g). 1H NMR (200 MHz, CDCl3) δ 7.73 (dd, J=8.2, 0.8 Hz, 1 H), 7.30 (br s, 1 H), 7.12 (m, 1 H), 4.38 (m, 3 H), 4.21 (q, J=7.1 Hz, 2 H), 2.02 (m, 2 H), 1.82-1.25 (m, 13 H).
Reaction SMILES: [CH:1]1([S:6][C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][C:10]3=[C:9]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26]CC)=O)=[CH:19][CH:18]=3)[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH3:29]>CO>[CH:1]1([S:6][C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][C:10]3=[C:9]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][C:24]([NH2:29])=[O:26])=[CH:19][CH:18]=3)[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N
Reactant: CCOC(=O)Cc1ccc(Nc2cc(SC3CCCC3)nc3c2CCC3)cc1
Solvent: CO
Product: NC(=O)Cc1ccc(Nc2cc(SC3CCCC3)nc3c2CCC3)cc1
Yield: 69 %

Procedure:
Following general procedure C, ethyl 2-(4-((2-(cyclopentylthio)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate (0.51 mmol) was reacted with ammonia in methanol (7.0 M, 5 mL) to afford the title compound (0.130 g, 69% over two steps) as an off-white solid. MW=367.51. 1H NMR (DMSO-d6, 300 MHz) δ 8.00 (s, 1H), 7.44 (s, 1H), 7.23 (d, J=8.5 Hz, 2H), 7.10 (d, J=8.5 Hz, 2H), 6.87 (s, 1H), 6.52 (s, 1H), 3.82 (quin, J=7.0 Hz, 1H), 3.33 (s, 2H), 2.84-2.67 (m, 4H), 2.12-1.95 (m, 4H), 1.73-1.39 (m, 6H); APCI MS m/z 368 [M+H]+.
Reaction SMILES: [BH3-]C#N.[Na+].[Cl:5][C:6]1[C:11]([N:12]=[C:13]([C@H:15]2[CH2:20][CH2:19][C@H:18]([CH3:21])[CH2:17][CH2:16]2)[CH3:14])=[C:10]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:9]=[C:8]([Cl:30])[N:7]=1.C(O)(=O)C>C(O)C>[Cl:5][C:6]1[C:11]([NH:12][CH:13]([C@H:15]2[CH2:16][CH2:17][C@H:18]([CH3:21])[CH2:19][CH2:20]2)[CH3:14])=[C:10]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:9]=[C:8]([Cl:30])[N:7]=1
Reactant: CC(=Nc1c(NC(=O)OC(C)(C)C)cc(Cl)nc1Cl)[C@H]1CC[C@H](C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(Nc1c(NC(=O)OC(C)(C)C)cc(Cl)nc1Cl)[C@H]1CC[C@H](C)CC1
Temperature: 50 °C

Procedure:
NaCNBH3 (100 g, 1.59 mol) was added to a mixture of tert-butyl (2,6-dichloro-3-((1-(trans-4-methylcyclohexyl)ethylidene)amino)pyridin-4-yl)carbamate (80 g, 0.2 mol) and acetic acid (60 mL) in ethanol (1.2 L). The mixture was heated to 50° C. for 4 h. TLC (petroleum ether/ethyl acetate=8:1) showed the reaction was complete. The reaction mixture was cooled down, poured into ice water, and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give crude tert-butyl (2,6-dichloro-3-((1-(trans-4-methylcyclohexyl)ethyl)amino)pyridin-4-yl)carbamate, which was used for the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[C:21](=[O:22])[C:20]3=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]3[C:18]2=[O:27])[CH2:13][C:14](O)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].Cl.[CH2:29]([O:36][NH2:37])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1>[CH2:29]([O:36][NH:37][C:14](=[O:15])[CH2:13][CH:12]([C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)[N:17]1[C:18](=[O:27])[C:19]2=[CH:26][CH:25]=[CH:24][CH:23]=[C:20]2[C:21]1=[O:22])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCOc1cc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)ccc1OC
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)NOCc2ccccc2)N2C(=O)c3ccccc3C2=O)ccc1OC
Yield: 93.8 %

Procedure:
N-Benzyloxy-3-(3-ethoxy-4-methoxyphenyl)-3-phthalimidopropionamide was prepared by the procedure of Example 1 from 3-(3-ethoxy-4-methoxyphenyl)-3-phthalimido-propanoic acid (869 mg, 2.36 mmol), N,N′-carbonyldiimidazole (410 mg, 2.53 mmol) and O-benzylhydroxylamine hydrochloride (444 mg, 2.78 mmol) in tetrahydrofuran (6 mL) to afford N-benzyloxy-3-(3-ethoxy-4-methoxyphenyl)-3-phthalimidopropionamide as a white solid (1.05 g, 94% yield): mp, 165.0–166.0° C.; 1H NMR (CDCl3) δ 1.44 (t, J=7.0 Hz, 3H, CH3), 2.95 (dd, J=5.8, 14.0 Hz, 1H, CHH), 3.49 (t, J=12.1 Hz, 1H, CHH), 3.83 (s, 3H, CH3), 4.07 (q, J=7.0 Hz, 2H, CH2), 4.77 (br s, 2H, PhCH2), 5.83 (dd, J=6.0, 10.0 Hz, 1H, NCH), 6.79 (d, J=8.0 Hz, 1H, Ar), 7.06–7.09 (m, 2H, Ar), 7.25–7.85 (m, 5H, Ar), 7.66–7.71 & 7.74–7.79 (2 ms, 4H, Ar), 8.34 (br s, 1H, NH); 13C NMR (CDCl3) δ 14.68, 35.66, 51.54, 55.88, 64.34, 78.13, 111.32, 12.52, 120.08, 123.29, 128.52, 128.67, 129.06, 131.26, 131.76, 133.98, 134.98, 148.31, 149.15, 167.38, 168.26. Anal. Calcd for C27H26N2O6: C, 68.34; H, 5.52; N, 5.90. Found: C, 68.36; H, 5.47; N, 5.74.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[S:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:22][CH2:21]1)[N:14]=2)[C:5](O)=[O:6].[CH3:29][O:30][CH2:31][CH2:32][NH:33][CH3:34]>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[S:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:21][CH2:22]1)[N:14]=2)[C:5]([N:33]([CH2:32][CH2:31][O:30][CH3:29])[CH3:34])=[O:6]
Reactant: CNCCOC
Reactant: O=C(O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Product: COCCN(C)C(=O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1

Procedure:
The title compound was synthesized using the procedure described in Example 105 above, with 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzoic acid (93 mg, 0.238 mmol) and N-(2-methoxyethyl)methylamine (31 μl, 0.286 mmol). MS (ESI) m/z: Calculated: 461.2; Observed: 462.1 (M++1).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]=[CH:9][C:10]([OH:12])=O)=[CH:6][N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.FC1C=CC=CC=1[C:26]1[N:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1>>[CH3:1][C:2]1[C:7]([CH2:8][CH2:9][C:10]([N:31]2[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]2)=[O:12])=[CH:6][N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1
Reactant: Cc1nc(-c2ccccc2)ncc1C=CC(=O)O
Reactant: Oc1ccc(-c2ccccc2F)nc1
Product: Cc1nc(-c2ccccc2)ncc1CCC(=O)N1CCCCC1

Procedure:
The title compound was prepared from 3-(4-methyl-2-phenyl-pyrimidin-5-yl)-acrylic acid analogously as described in Example 15(b) and (c).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:8][C:9]([F:12])([F:11])[CH3:10])[C:4]([O:6][CH3:7])=[O:5].[CH2:13]1[C:17]2([CH2:22][CH2:21][N:20]([S:23](Cl)(=[O:25])=[O:24])[CH2:19][CH2:18]2)[CH2:16][CH2:15][CH2:14]1>C(#N)C>[CH2:13]1[C:17]2([CH2:18][CH2:19][N:20]([S:23]([NH:2][C@@H:3]([CH2:8][C:9]([F:11])([F:12])[CH3:10])[C:4]([O:6][CH3:7])=[O:5])(=[O:25])=[O:24])[CH2:21][CH2:22]2)[CH2:16][CH2:15][CH2:14]1
Reactant: O=S(=O)(Cl)N1CCC2(CCCC2)CC1
Reactant: COC(=O)[C@@H](N)CC(C)(F)F
Agent: Cl
Solvent: CC#N
Product: COC(=O)[C@H](CC(C)(F)F)NS(=O)(=O)N1CCC2(CCCC2)CC1

Procedure:
In a reaction vessel, 100 mg of methyl (S)-2-amino-4,4-difluoropentanoate hydrochloride (0.49 mmol) were admixed with 320 mg of N,O-bis(trimethylsilyl)-acetamide (3.2 eq.) in 3 ml of acetonitrile. The reaction mixture was treated at 100° C. in a microwave for 30 min. 128 mg of 8-azaspiro[4.5]decane-8-sulfonyl chloride (1.1 eq.), dissolved in 2.5 ml of acetonitrile, were then added and the resulting reaction mixture was treated at 100° C. in a microwave for a further 2.5 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC (gradient: acetonitrile/water and addition of 0.05% TFA). Methyl (S)-2-(8-azaspiro[4.5]decane-8-sulfonylamino)-4,4-difluoropentanoate was obtained as a colorless amorphous material.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([C:34]([O:36]C)=O)=[N:14][C:15]=2[NH:19][CH2:20][CH:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[CH2:38]([NH2:41])[CH2:39][NH2:40]>ClCCl>[NH2:40][CH2:39][CH2:38][NH:41][C:34]([C:13]1[N:12]=[C:11]2[C:16]([N:17]=[CH:18][N:10]2[C@H:3]2[C@H:2]([OH:1])[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4]2)=[C:15]([NH:19][CH2:20][CH:21]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:14]=1)=[O:36]
Reactant: NCCN
Reactant: COC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Solvent: ClCCl
Product: NCCNC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 105 °C
Yield: 78.2 %

Procedure:
A mixture of methyl 9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9H-purine-2-carboxylate (Preparation 16) (0.52 g, 1.03 mmol) and 1,2-ethylenediamine (0.6 g, 10 mmol) was heated at 105° C. for 3 hours. The mixture was dissolved in a little dichloromethane and purified by column chromatography on silica gel eluting with dichloromethane:methanol:concentrated aqueous ammonia (85:15:1.5, by volume). After evaporation of appropriate fractions the residue was triturated with diethyl ether, filtered and dried to yield the target compound as a white solid, (0.43 g, 78%).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:31])[N:4]([CH2:19][C:20]2[N:21]=[CH:22][C:23]([C:26](OCC)=[O:27])=[N:24][CH:25]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[OH-:32].[Na+]>>[Cl:1][C:2]1[C:3](=[O:31])[N:4]([CH2:19][C:20]2[CH:25]=[N:24][C:23]([C:26]([N:4]3[CH2:5][CH2:6][CH:7]([OH:32])[CH2:2][CH2:3]3)=[O:27])=[CH:22][N:21]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: CCOC(=O)c1cnc(Cn2c(C)cc(OCc3ccc(F)cc3F)c(Cl)c2=O)cn1
Reactant: [OH-]
Agent: [Na+]
Product: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1Cc1cnc(C(=O)N2CCC(O)CC2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 174.1 %

Procedure:
A mixture of ethyl 5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}pyrazine-2-carboxylate (1.03 g, 2.3 mmol) in 1N NaOH (3.4 ml, 3.45 mmol, EtOH/water 1:1 v/v) stirred at room temperature for 2 hours. The reaction mixture was quenched with 5% citric acid and filtered. The solid was washed with water and dried to afford the desired product (1.011 g, 100%) as a white solid. 1H NMR (CD3OD, 400 MHz) δ 9.02 (s, 1H), 8.60 (s, 1H), 7.60 (m, 1H), 7.04 (m, 2H), 6.55 (s, 1H), 5.50 (s, 2H), 5.30 (s, 2H), 2.52 (s, 3H); ES-HRMS m/z 422.0732 (M+H calculated for C19H15N3O4ClF2 requires 422.0714).
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]1[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C2[O:37]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1.C(Cl)(Cl)Cl>C1COCC1>[F:18][C:14]1([F:17])[CH2:15][CH2:16][C:11]([OH:37])([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:12][CH2:13]1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Reactant: O=C(OCc1ccccc1)C1CCC(F)(F)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)C1(O)CCC(F)(F)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of benzyl-4,4-difluorocyclohexanecarboxylate (6.5 g, 25.56 mmol) in 128 ml of THF was cooled to −78° C. under nitrogen. Potassium bis(trimethylsilyl)amide (76.7 mL of 0.5 M solution in toluene) was added, and the mixture was stirred at −78° C. for one hour. A THF solution (35 mL) of 3-phenyl-2-(phenylsulfonyl)oxaziridine (9.35 g, 35.79 mmol) was added, and the reaction was stirred for 40 minutes. After quenching with a saturated aqueous ammonium chloride solution and warming to room temperature, the reaction mixture was extracted with EtOAc. The combined organic layers were washed with water and brine prior to drying over sodium sulfate. Filtration and removal of solvent provided crude product which was stirred with 100 mL of chloroform, and then filtered to remove the insoluble material. The filtrate was concentrated under vacuum and the residue was subjected to silica gel chromatography eluting with 5 to 20% EtOAc in hexane to afford benzyl 4,4-difluoro-1-hydroxycyclohexanecarboxylate.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]=[C:5]([C:8](Cl)=[O:9])[CH:4]=[CH:3]1.[NH2:11][C:12]1[CH:13]=[C:14]([O:18][C:19]2[N:24]=[CH:23][C:22]3[N:25]=[C:26]([C:30]4[C:31]([NH2:35])=[N:32][O:33][N:34]=4)[N:27]([CH2:28][CH3:29])[C:21]=3[CH:20]=2)[CH:15]=[CH:16][CH:17]=1.O>N1C=CC=CC=1>[NH2:35][C:31]1[C:30]([C:26]2[N:27]([CH2:28][CH3:29])[C:21]3[CH:20]=[C:19]([O:18][C:14]4[CH:13]=[C:12]([NH:11][C:8]([C:5]5[CH:4]=[CH:3][C:2](=[O:1])[NH:7][CH:6]=5)=[O:9])[CH:17]=[CH:16][CH:15]=4)[N:24]=[CH:23][C:22]=3[N:25]=2)=[N:34][O:33][N:32]=1
Reactant: CCn1c(-c2nonc2N)nc2cnc(Oc3cccc(N)c3)cc21
Reactant: O=C(Cl)c1ccc(=O)[nH]c1
Solvent: c1ccncc1
Solvent: O
Product: CCn1c(-c2nonc2N)nc2cnc(Oc3cccc(NC(=O)c4ccc(=O)[nH]c4)c3)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.5 %

Procedure:
The product of Step 1 (93 mg, 0.6 mmol) was added to a solution of the product of Example 3 (200 mg, 0.6 mmol) in pyridine (1 mL) and the resulting mixture was allowed to stir at rt for 30 min. The solution was poured into H2O and the precipitate which formed as filtered, washed with H2O and Et2O and dried to give the title compound as a tan solid (150 mg, 55%). MS (ES+) m/e 459 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].[N:10]([O-])=O.[Na+].[ClH:14]>>[ClH:14].[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][NH2:10])=[CH:4][C:3]=1[CH3:9]
Reactant: O=N[O-]
Reactant: Cc1cc(N)ccc1Br
Agent: Cl
Agent: [Na+]
Product: Cc1cc(NN)ccc1Br
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
4-Bromo-3-methylaniline (10.2 g) was suspended in 6N HCl (85 mL) and cooled to 0° C. A solution of sodium nitrite (4 g in 40 mL H2O) was added over 10 min. The reaction was stirred for 15 min at 0° C. followed by the addition of stannous chloride dihydrate (36 g in 25 mL 12N HCl.) The reaction was stirred for 2 hr at 0° C. The reaction was filtered and the filter cake washed with cold H2O to afford 4-bromo-3-methylphenylhydrazine hydrochloride (Cmpd 9a, 20 g) as a tan solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][C:7](/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:6][C:5]=2[N:4]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:27][CH:26]=2)[N:3]=1>CCO.C1COCC1.[Pd]>[CH3:1][C:2]1[C:10]2[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][C:7]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:6][C:5]=2[N:4]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:29][CH:30]=2)[N:3]=1
Reactant: CCOC(=O)c1cc(/C=C/c2ccccc2)nc2c1c(C)nn2Cc1ccc(Oc2ccccc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1cc(CCc2ccccc2)nc2c1c(C)nn2Cc1ccc(Oc2ccccc2)cc1
Reaction time: 8 h
Yield: 85.1 %

Procedure:
(see, e.g., WO2013039988A1). To a suspension of 10% Pd/C (70 mg) in EtOH (5 mL) was added 52 (186 mg, 0.38 mmol) dissolved in THF (1.5 mL). The suspension was stirred under an atmosphere of hydrogen (ca. 1 atm, balloon) overnight. The suspension was filtered through a pad of celite and the filtrate was concentrated under reduced pressure to provide the title compound (159 mg, 84%) as a light brown oil. Crude was used in the next reaction without further purification. 1H NMR (500 MHz, CDCl3) δ 7.44 (s, 1H), 7.36-7.31 (m, 3H), 7.31-7.26 (m, 3H), 7.26-7.22 (m, 2H), 7.19 (t, J=7.0 Hz, 1H), 7.09 (t, J=7.4 Hz, 1H), 7.00 (d, J=7.9 Hz, 2H), 6.95 (d, J=8.5 Hz, 2H), 5.67 (s, 2H), 4.49 (q, J=7.1 Hz, 2H), 3.35-3.27 (m, 2H), 3.24-3.17 (m, 2H), 2.73 (s, 3H), 1.47 (t, J=7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 165.85, 161.09, 157.08, 156.78, 152.23, 141.30, 140.97, 133.36, 132.21, 129.72, 129.55, 128.49, 128.41, 126.04, 123.30, 118.95, 118.80, 117.33, 109.68, 61.83, 49.83, 39.82, 35.23, 16.31, 14.30. ESI MS: m/z 516.9 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[CH2:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O)[CH3:19]>>[CH2:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1)[CH3:19]
Reactant: CCOc1ccccc1B(O)O
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]cn1
Product: CCOc1ccccc1-n1cnc(-c2c(-c3ccccc3)noc2C)c1
Yield: 12 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (112.6 mg, 0.5 mmol) was converted, using 2-ethoxyphenylboronic acid instead of 4-fluorophenylboronic acid, to the title compound (21 mg, 12%) which was obtained as a white solid. MS (ESI): m/e=346.0 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[CH:29][C:30]([CH3:37])=[C:31]([S:33]([NH2:36])(=[O:35])=[O:34])[CH:32]=1>>[CH3:37][C:30]1[CH:29]=[CH:28][C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)=[CH:32][C:31]=1[S:33]([NH2:36])(=[O:35])=[O:34]
Reactant: Cc1ccc(Br)cc1S(N)(=O)=O
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Cc1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1S(N)(=O)=O

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (156 mg, 0.4 mmol) and 5-Bromo-2-methyl-benzenesulfonamide (example B.18) (124 mg, 0.5 mmol) according to general procedure II. Obtained as an orange solid (22 mg, 10%). MS (ISP) 525.3[(M+H)+]; mp 255-267° C.
Reaction SMILES: N#N.[F:3][C:4]1[CH:5]=[CH:6][C:7]([CH3:12])=[C:8]([CH:11]=1)[C:9]#[N:10].C1C(=O)N([Br:20])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:12][C:7]1[CH:6]=[CH:5][C:4]([F:3])=[CH:11][C:8]=1[C:9]#[N:10]
Reactant: Cc1ccc(F)cc1C#N
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: N#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cc(F)ccc1CBr
Reaction time: 8 h
Yield: 65.9 %

Procedure:
N2 was passed through a mixture of 5-fluoro-2-methylbenzonitrile (28.51 g, 211 mmol), NBS (41.31 g, 232 mmol) and AIBN (2.5 g, 15 mmol) in CCl4 (845 mL) for 10 min after which the reaction was heated at reflux for 8 h. After standing at room temperature overnight, the reaction mixture was filtered and the filter cake washed with CCl4 (500 mL). The combined filtrate was evaporated to give a yellow oil. Flash chromatography (SiO2) using 5-25% ethyl acetate/Hexanes as eluent afforded the title compound (29.74 g, 66% yield) as a pale yellow oil. 1H NMR (500 MHz, CDCl3) &: 7.55 (1H, dd, J=8.6, 5.2 Hz), 7.37 (1H, dd, J=7.9, 2.8 Hz), 7.32-7.28 (1H, m), 4.61 (2H, s).