Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[C:10]([CH3:31])=[C:11]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[C:22]([O:29][CH3:30])[CH:21]=2)=[O:19])[N:12]2[C:17]=1[CH:16]=[CH:15][CH:14]=[CH:13]2)C1C=CC=CC=1>FC(F)(F)C(O)=O>[OH:8][C:9]1[C:10]([CH3:31])=[C:11]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[C:22]([O:29][CH3:30])[CH:21]=2)=[O:19])[N:12]2[C:17]=1[CH:16]=[CH:15][CH:14]=[CH:13]2
Reactant: COc1cc(C(=O)c2c(C)c(OCc3ccccc3)c3ccccn23)ccc1[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)c2c(C)c(O)c3ccccn23)ccc1[N+](=O)[O-]

Procedure:
A solution of 5 g (12 mmol) of [1-(benzyloxy-2-methylindolizin-3-yl](3-methoxy-4-nitrophenyl)methanone, a compound of Example 3, in 30 ml of trifluoroacetic acid, is heated under reflux for 2 hours.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[C:13]1([CH2:19][O:20][C:21](=[O:40])[NH:22][C@@:23]2([CH2:37][CH:38]=[CH2:39])[CH2:28][CH2:27][NH:26][C@@H:25]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=3[CH3:36])[CH2:24]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[F:41][C:42]([F:57])([F:56])[C:43]1[CH:44]=[C:45]([CH2:53][NH:54][CH3:55])[CH:46]=[C:47]([C:49]([F:52])([F:51])[F:50])[CH:48]=1.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[C:13]1([CH2:19][O:20][C:21](=[O:40])[NH:22][C@@:23]2([CH2:37][CH:38]=[CH2:39])[CH2:28][CH2:27][N:26]([C:5]([N:54]([CH2:53][C:45]3[CH:46]=[C:47]([C:49]([F:50])([F:51])[F:52])[CH:48]=[C:43]([C:42]([F:41])([F:56])[F:57])[CH:44]=3)[CH3:55])=[O:11])[C@@H:25]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=3[CH3:36])[CH2:24]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C=CC[C@]1(NC(=O)OCc2ccccc2)CCN[C@@H](c2ccc(F)cc2C)C1
Reactant: CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: C=CC[C@]1(NC(=O)OCc2ccccc2)CCN(C(=O)N(C)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H](c2ccc(F)cc2C)C1
Reaction time: 0.08 h
Yield: 46 %

Procedure:
To a solution of triphosgene (0.714 g, 2.405 mmol) at 0° C. in dry ethyl acetate (5.5 ml) was slowly added a solution of phenylmethyl[(2R,4S)-2-(4-fluoro-2-methylphenyl)-4-(2-propen-1-yl)-4-piperidinyl]carbamate (Intermediate 18, 2 g, 5.23 mmol) and TEA (1.8 ml) in dry ethyl Acetate (10 ml) and the mixture was stirred for 5 minutes at the same temperature. Then a solution of {[3,5-bis(trifluoromethyl)phenyl]methyl}methylamine (WO 2007107818, 27 Sep. 2007) (1.479 g, 5.75 mmol) and TEA (1.63 ml) in dry Ethyl acetate (10 ml) was added in minutes at 0° C. The resulting suspension was refluxed for 5 hours. After cooling, NaHCO3 sat. aq. solution and ethyl acetate were added to the reaction mixture and two phases were separated. The aqueous phase was extracted with ethyl acetate (3×) and the combined organic phases were dried (Na2SO4), filtered and evaporated to dryness. The residue was purified by flash chromatography with Biotage SP1 (from 1:0 to 7:3 Cyclohexane/EtOAc; 40 M) to give two batches of the title compound: 1st batch (1.6 g, 2.40 mmol, 46.0% yield); 1H NMR (500 MHz, DMSO-d6) δ ppm 7.94 (s, 1H) 7.61 (s, 2H) 7.27-7.38 (m, 5H) 7.24 (dd, 1H) 7.18 (br. s., 1H) 6.91 (dd, 1H) 6.76-6.83 (m, 1H) 5.68-5.81 (m, 1H) 5.06-5.18 (m, 2H) 4.88-5.00 (m, 2H) 4.60 (d, 1H) 4.36-4.44 (m, 1H) 4.36 (d, 1H) 3.36-3.47 (m, 1H) 2.94-3.06 (m, 1H) 2.88 (s, 3H) 2.63-2.72 (m, 2H) 2.31 (s, 3H) 1.84-2.05 (m, 3H) 1.64 (t, 1H); UPLC: Rt=1.02 mins; m/z=666 [MH]+. The 2nd batch was purified again by flash chromatography via Biotage SP1 (from 1:0 to 7:3 Cyclohexane/EtOAc; 40 M) to give further two batches of the title compound (0.8 g and 0.15 g).
Reaction SMILES: [F:1][C:2]1[CH:36]=[C:35]([NH:37][C:38]([NH:40][C:41](=[O:49])[CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[S:39])[CH:34]=[CH:33][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[C:16]([CH:30]=[CH:31][CH:32]=3)[CH2:17][N:18]([CH2:26][CH2:27][O:28][CH3:29])C(=O)OC(C)(C)C)[S:13][C:6]=12.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:36]=[C:35]([NH:37][C:38]([NH:40][C:41](=[O:49])[CH2:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[S:39])[CH:34]=[CH:33][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:32]=[CH:31][CH:30]=[C:16]([CH2:17][NH:18][CH2:26][CH2:27][O:28][CH3:29])[CH:15]=3)[S:13][C:6]=12
Reactant: COCCN(Cc1cccc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4F)c3s2)c1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCNCc1cccc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4F)c3s2)c1
Reaction time: 12 h
Yield: 63 %

Procedure:
To a solution of 75 (440 mg, 0.6 mmol) in DCM (10 mL), TFA (145 μL, 1.9 mmol) was added and the reaction was stirred for 12 hours, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluent MeOH/EtOAc (1:10), to afford the title compound 76a (227 mg, 63% yield) as a light yellow solid 1H NMR (DMSO) δ (ppm): 8.54 (d, J=5.5 Hz, 1H), 8.07 (s, 1H), 8.02-8.0 (m, 2H), 7.93 (d-t, J=2.0 Hz, 1H), 7.55-7.53 (m, 4H), 7.34-7.32 (m, 4H), 7.29-7.26 (m, 1H), 6.68 (d, J=5.3 Hz, 1H), 4.19 (s, 2H), 3.81 (s, 1H), 3.57 (t, J=4.9 Hz, 2H), 3.33 (s, 2H), 3.29 (s, 3H), 3.08 (t, J=4.9 Hz, 2H), 2.84 (q, J=2.2 Hz, 4H).
Reaction SMILES: [NH:1]([CH2:3][C:4]([OH:6])=[O:5])[CH3:2].[OH-].[Na+].C(Cl)(Cl)Cl.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>O>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:1]([CH2:3][C:4]([OH:6])=[O:5])[CH3:2])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: CNCC(=O)O
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CN(CC(=O)O)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
4.3 Parts of sarcosine and 4.1 parts of sodium hydroxide are dissolved in 100 parts of water. To the resulting solution, 35 parts of chloroform containing 10 parts of p-chlorobenzenesulfonyl chloride is added, and the resulting mixture is stirred at 60° C for about 2 hours. After the reaction, the aqueous layer is separated and then acidified with hydrochloric acid to precipitate crystals. The crystals are collected by filtration and recrystallized from a mixed solvent comprising acetone and water to obtain 4.6 parts of N-p-chlorobenzenesulfonyl-sarcosine, m.p. 180.5°-182° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.O[CH:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:19][N:16]1[CH2:17][CH2:18][CH:13]([O:1][C:2]2[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=2)[CH2:14][CH2:15]1
Reactant: CC(=O)Nc1cccc(O)c1
Reactant: CN1CCC(O)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc(OC2CCN(C)CC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of N-(3-Hydroxy-phenyl)-acetamide (30.2 g) in anhydrous tetrahydrofuran (600 mL) was treated with 4-hydroxy-N-methylpiperidine (30.54 mL) and triphenylphosphine (68.18 g); a solution of diethylazadicarboxylate in anhydrous tetrahydrofuran (THF) (40.94 mL in 60 mL of THF) was added dropwise and the mixture was stirred at room temperature for 2 hours and then heated to 50° C. overnight. Further amounts of triphenylphosphine (28.00 g) and diethylazadicarboxylate (14 mL) were added and the heating was continued for additional 24 hours.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:13]([CH2:14][CH3:15])=[C:12]([CH2:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][C:18]=3[O:27][CH2:28][CH3:29])[C:11]([CH2:30][CH3:31])=[N:10]2)=[C:4]([CH3:32])[CH:3]=1.C([Li])CCC.CN(C)[CH:40]=[O:41]>C1COCC1>[CH2:28]([O:27][C:18]1[CH:19]=[CH:20][C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17]=1[CH2:16][C:12]1[C:11]([CH2:30][CH3:31])=[N:10][N:9]([C:5]2[C:6]([CH3:8])=[CH:7][C:2]([CH:40]=[O:41])=[CH:3][C:4]=2[CH3:32])[C:13]=1[CH2:14][CH3:15])[CH3:29]
Reactant: CN(C)C=O
Reactant: CCOc1ccc2ccccc2c1Cc1c(CC)nn(-c2c(C)cc(Br)cc2C)c1CC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOc1ccc2ccccc2c1Cc1c(CC)nn(-c2c(C)cc(C=O)cc2C)c1CC
Reaction time: 0.17 h
Yield: 112.1 %

Procedure:
A solution of 1-(4-bromo-2,6-dimethylphenyl)4-(2-ethoxy-naphthalen-1-ylmethyl)-3,5-diethyl-1H-pyrazole (0.400 g, 0.81 mmol) in 2.0 ml anhydrous THF was added dropwise to a dry ice-acetone bath cooled solution of n-butyl lithium (2.5 M solution in hexane, 0.358 ml, 0.90 mmol). After stirring 10 minutes, anhydrous dimethylformamide (0.188 ml, 2.43 mmol) was added. After 30 minutes the cooling bath was removed and the mixture was stirred 1 hour. The reaction was quenched by addition of 0.25 ml of a saturated aqueous ammonium chloride solution. After stirring for 5 minutes, the reaction mixture was well-mixed with ethyl acetate/brine (20 ml of each). The aqueous phase was then twice extracted with equal-volume portions of fresh ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, and concentrated in vacuo to yield an oil (400 mg). Flash chromatography of the entire sample (silica gel, 40 micron mesh; elution with ethyl acetate/hexanes=1:4 in volume) afforded the title compound (100 mg) as an oil.
Reaction SMILES: [C:1]1([CH:7]=[N+]=[N-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CSC.[C:13]1([CH:19]=[CH:20][C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCl.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[C:21]([CH:20]1[CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:19]1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:22])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: [N-]=[N+]=Cc1ccccc1
Reactant: O=C(C=Cc1ccccc1)c1ccccc1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CSC
Product: O=C(c1ccccc1)C1C(c2ccccc2)C1c1ccccc1

Procedure:
Phenyl diazomethane (prepared as in Example 36, 0.5 mmol in 3 ml of t-butyl methyl ether) was added to a stirred solution of dimethylsulphide (7.3 ml; 0.1 mmol), rhodium (II) acetate (2 mg; 0.005 mmol) and chalcone (103 mg; 0.5 mmol) in dichloromethane (2 ml) at room temperature over a period of 24 hours. After the addition was complete the solvent was removed in vacuo and the residue was chromatographed over silica [eluent dichloromethane:petrol (2:3)], to give the title compound as a 4:1 mixture of trans:cis cyclopropanes as a yellowy solid (58 mg; 39%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[C:9](=[C:16]2SCS2)[C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH3:21][CH:22]1[CH2:27][NH:26][CH2:25][CH:24]([CH3:28])[NH:23]1.[NH2:29][NH2:30]>C1(C)C=CC=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:30][N:29]=[C:16]([CH:25]3[CH:24]([CH3:28])[NH:23][CH:22]([CH3:21])[CH2:27][NH:26]3)[C:9]=2[C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(C(=C1SCS1)c1ccncc1)c1ccc(Cl)cc1
Reactant: NN
Reactant: CC1CNCC(C)N1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC1CNC(c2n[nH]c(-c3ccc(Cl)cc3)c2-c2ccncc2)C(C)N1
Reaction time: 1 h

Procedure:
A mixture of 1-(4-chlorophenyl)-2-(1,3-dithietan-2-ylidene)-2-(4-pyridinyl)ethanone (3.2 g, 0.01 mol; prepared as set forth in Step 1 of Example A-341) and 2,6-dimethylpiperazine (3.43 g, 0.03 mol) in 35 mL of toluene was heated at reflux for 12 hours. Toluene and excess 2,6-dimethylpiperazine were then removed under vacuum and the crude thiamide produced was used without purification. A solution of the crude thiamide and anhydrous hydrazine (0.65 g, 0.02 mol) in 40 mL of dry tetrahydrofuran was stirred at room temperature overnight. After the removal of tetrahydrofuran, the residue was stirred with a mixture of ethyl acetate and 5 ammonium hydroxide for one hour. The precipitate was filtered and air dried to give 1.6 g of 2-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-3,5-dimethylpiperazine as a white solid (43% overall yield), mp: 236-238° C. Anal. Calc'd. for C20H22ClN5.0.25H2O: C, 64.51; H, 6.09; N, 18.81; Cl, 9.52. Found; C, 64.28; H, 5.85; N, 18.70; Cl, 9.67.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][C@@H:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[CH3:7])[CH2:3][OH:4].[N:16]#[C:17]Br>>[Cl:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][C@@H:6]([CH3:7])[CH2:5][C@H:2]2[CH2:3][O:4][C:17]([NH2:16])=[N:1]2)=[CH:14][CH:13]=1
Reactant: C[C@@H](C[C@H](N)CO)Oc1ccc(Cl)cc1
Reactant: N#CBr
Product: C[C@@H](C[C@H]1COC(N)=N1)Oc1ccc(Cl)cc1

Procedure:
In analogy to example 1d (2S,4S)-2-amino-4-(4-chloro-phenoxy)-pentan-1-ol was reacted with cyanogen bromide to give (S)-4-[(S)-2-(4-chloro-phenoxy)-propyl]-4,5-dihydro-oxazol-2-ylamine. Light yellow solid. MS (ISP): 257.2 ([{37Cl}M+H]+), 255.2 ([{35Cl}M+M]+).
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:9][CH:10]=2)[N:6]=1.[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][C:16]1=[O:21]>C1COCC1.CCOC(C)=O.Cl>[O:21]=[C:16]1[NH:15][CH2:20][CH2:19][N:18]([C:2]2[O:3][C:4]3[C:5](=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:9][CH:10]=3)[N:6]=2)[CH2:17]1
Reactant: COC(=O)c1cccc2oc(Cl)nc12
Reactant: O=C1CNCCN1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2oc(N3CCNC(=O)C3)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.8 %

Procedure:
A mixture of methyl 2-chlorobenzoxazole-4-carboxylate (750 mg, 3.54 mmol) and piperazin-2-one (780 mg, 7.79 mmol) in THF (60 mL) was stirred at ambient temperature overnight. The reaction mixture was diluted with EtOAc (150 mL) and 1 N HCl (25 ml). The aqueous layer was separated, basified with 1 N NaOH and extracted with EtOAc (6×50 mL). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to give methyl 2-(3-oxopiperazine-1-yl)benzoxazole-4-carboxylate (690 mg, 72%). 1H NMR consistent.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[C:11](=[O:24])[N:12](CC4C=CC(OC)=CC=4)[CH2:13][CH2:14][C:9]=3[C:8]([CH2:25][CH3:26])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.CS(O)(=O)=O.C(Cl)Cl>O>[CH:1]1([N:6]2[C:10]3[C:11](=[O:24])[NH:12][CH2:13][CH2:14][C:9]=3[C:8]([CH2:25][CH3:26])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1nn(C2CCCC2)c2c1CCN(Cc1ccc(OC)cc1)C2=O
Agent: CS(=O)(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CCc1nn(C2CCCC2)c2c1CCNC2=O
Temperature: 70 °C

Procedure:
The reaction mixture from Example 8 was cooled to 55° C. and slowly thereto trifluoroacetic acid (87.3 kg, 764 moles) was added while keeping the temperature between 50-60° C. The first ⅓ of the charge was exothermic and required external cooling. Methanesulfonic acid (6342 ml, 97.7 moles) was added and the reaction was warmed to ˜70° C. for two hours. The reaction was cooled to 20-25° C. and methylene chloride (17 gal, 64 L) was added followed by the slow addition of water (17 gal, 64 L). The layers were separated and the aqueous layer was diluted further with water (6 gal, 22.7 L) and then re-extracted with methylene chloride (6 gal, 22.7 L). The combined methylene chloride layers were mixed with water (29 gal, 110 L) and then brought to pH˜7.0 by the addition of saturated sodium bicarbonate (ca. 45 gal, 170 L). The layers were separated and the methylene chloride atmospherically distilled to about 9 gal (35 L). Ethyl acetate (13 gal, 49 L) was added and the reaction mixture was distilled to about 9 gal (35 L). The resulting slurry was cooled and granulated. The solids were collected by filtration, washed with ethyl acetate and vacuum dried at 40° C. under full vacuum. The yield was 7.91 kg, 71.2%; mp 152-153° C.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Cl[C:10]1[O:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1>>[O:11]1[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=[C:10]1[NH:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: Nc1ccc(Br)cc1
Reactant: Clc1nc2ccccc2o1
Product: Brc1ccc(Nc2nc3ccccc3o2)cc1
Temperature: 100 °C
Yield: 67.8 %

Procedure:
4-Bromoaniline (3.9 g, 0.0227 mol) was added to a solution of 2-chlorobenzoxazole (1.16 g, 0.00755 mol) in xylenes and the reaction mixture was heated at 100° C. for 2 hours. It was cooled to ambient temperature and concentrated under reduced pressure. The residue was partitioned between ethyl acetate (50 mL) and water (50 mL), the organic phase was dried with magnesium sulfate and concentrated under reduced pressure. The residue was triturated in n-heptane and the precipitate collected by filtration and dried to yield N-(1,3-benzoxazol-2-yl)-N-(4-bromophenyl)amine (1.48 g, 0.00512 mol) as a white solid.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:35])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@H:24]([CH2:27][CH:28]([OH:33])[C:29]([F:32])([F:31])[F:30])[CH2:25][CH3:26])[C:5]1=[O:34])[CH:2]=[CH2:3].O.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=[O:39]>C(Cl)Cl>[CH2:1]([C@@:4]1([CH3:35])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@H:24]([CH2:27][C:28]([OH:39])([OH:33])[C:29]([F:30])([F:31])[F:32])[CH2:25][CH3:26])[C:5]1=[O:34])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CC(O)C(F)(F)F)C1=O
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CC(O)(O)C(F)(F)F)C1=O
Reaction time: 8 h

Procedure:
To a solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-6,6,6-trifluoro-5-hydroxyhexan-3-yl)piperidin-2-one prepared above in Step A (100 mg, 0.189 mmol) in DCM (2.1 mL) was added water (17 μL, 0.95 mmol) and Dess-Martin periodinane (161 mg, 0.378 mmol) at rt and the resulting solution was stirred overnight. The reaction was quenched (1 M aq. Na2S2O3), extracted (2×DCM), and washed (2×sat. NaHCO3 and 1×sat. aq. NaCl solution). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to provide the title compound as a colorless film. The product was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([CH3:14])=[N:12][CH:13]=[C:8]2[C:7](I)=[N:6]1.[Cu][C:22]#[N:23].C(OCC)(=O)C>CS(C)=O>[F:1][C:2]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([CH3:14])=[N:12][CH:13]=[C:8]2[C:7]([C:22]#[N:23])=[N:6]1
Reactant: N#C[Cu]
Reactant: Cc1ncc2c(I)nn(Cc3cccc(F)c3F)c2n1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1ncc2c(C#N)nn(Cc3cccc(F)c3F)c2n1
Temperature: 150 °C

Procedure:
1.360 g (3.35 mmol) of 1-(2,3-difluorobenzyl)-3-iodo-6-methyl-1H-pyrazolo[3,4-d]pyrimidine and 330 mg (3.68 mmol) of copper(I) cyanide were initially charged in 10 ml of absolute DMSO and the mixture was heated at 150° C. for 2 h. After cooling, the mixture was added to 200 ml of ethyl acetate and washed with a mixture of concentrated aqueous ammonia solution and semisaturated aqueous ammonium chloride solution (v/v=1:3). The organic phase was washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated on a rotary evaporator. 1.040 g (purity 92%, 100% of theory) of the target compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](C)[C:5](C#N)=[N:6][CH:7]=1.[OH-:11].[Na+].[CH3:13][CH2:14][OH:15]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:5])[C:13]([C:14]([OH:11])=[O:15])=[N:6][CH:7]=1
Reactant: [OH-]
Reactant: CCO
Reactant: Cc1cc(Cl)cnc1C#N
Agent: [Na+]
Product: Cc1cc(Cl)cnc1C(=O)O
Temperature: 90 °C
Yield: 89 %

Procedure:
To a solution of 5-chloro-3-methylpicolinonitrile (24.0 g, 157 mmol) in EtOH (100 mL) was added NaOH 5.0N (110 ml, 550 mmol). The resulting mixture was refluxed at 90° C. for 18 h. After cooling to RT, the reaction mixture was concentrated, diluted with water and the pH of the solution was adjusted to 4 by addition of 5N HCl. The solid that precipitated was filtered and set aside. The filtrate was extracted with EtOAc (2×). The aqueous layer was again acidified with 5N HCl to pH 4 and extracted with EtOAc (2×). The EtOAc extracts were combined, dried, and concentrated. The solid obtained from all the workup steps were combined and dried in a high vac oven at 40° C. for 12 h to give the title compound 5-chloro-3-methylpicolinic acid (24.1 g, 140 mmol, 89% yield). LC/MS (ESI+) m/z=172.0 (M+H); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 11.29 (br. s., 1 H), 8.41 (d, J=1.76 Hz, 1 H), 7.73 (d, J=1.76 Hz, 1 H), 2.75 (s, 3 H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]3[CH:13]=[CH:14][C:15]([N+:17]([O-:19])=[O:18])=[CH:16][C:9]=3[CH2:8][O:7][C:6]=2[CH:20]=1.[N-:21]=[N+:22]=[N-:23].[Na+].[CH:25](OC)(OC)OC.C(O)(=O)C>>[N:1]1([C:2]2[CH:3]=[CH:4][C:5]3[C:11](=[O:12])[C:10]4[CH:13]=[CH:14][C:15]([N+:17]([O-:19])=[O:18])=[CH:16][C:9]=4[CH2:8][O:7][C:6]=3[CH:20]=2)[CH:25]=[N:23][N:22]=[N:21]1
Reactant: COC(OC)OC
Reactant: Nc1ccc2c(c1)OCc1cc([N+](=O)[O-])ccc1C2=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1c2ccc([N+](=O)[O-])cc2COc2cc(-n3cnnn3)ccc21
Temperature: 100 °C

Procedure:
0.50 g (1.85 mmol) of (6) and 0.35 g (5.38 mmol) of sodium azide are suspended in 2.20 g (14.84 mmol) of trimethyl orthoformate at 0° C. 1.20 g (20.00 mmol) of glacial acetic acid are then added to the mixture and the mixture is heated to 100° C. and refluxed for 4 h. After cooling to room temperature, the mixture is concentrated in vacuo and the residue is taken up with EtOAc and dissolved under the influence of heat. The white-grey product precipitates out in the cold. Yield: 0.50 g (83.6%); melting point: 123-126° C.; C15H9N5O4 (Mr=323.27)
Reaction SMILES: [OH-].[K+].[CH:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:11][S:12][CH2:13][CH2:14][CH:15]=[O:16]>CO>[CH3:11][S:12][CH2:13][C:14](=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH:15]=[O:16]
Reactant: O=Cc1ccccc1
Reactant: CSCCC=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CSCC(C=O)=Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.7 %

Procedure:
Into a 100 ml three necked reaction flask equipped with stirrer, thermometer and addition funnel is charged a solution of 0.5 grams of potassium hydroxide in 10 ml methanol. Benzaldehyde (10.0 grams) is added as the mixture is cooled to 5°-10° C. Methional (10.0 grams) is then added dropwise while maintaining the reaction temperature at 5°-10° C. The mixture is then allowed to warm to room temperature and stirred for a period of 1 hour. Most of the solvent is evaporated at reduced pressure and the mixture is partitioned between water and ether. The organic layer is washed several times with water and once with saturated brine. The solvent is evaporated leaving a yellow oil wich is distilled to give 6.1 grams product, boiling point 104°-111° C (0.4 mm Hg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][O:6][C@H:7]1[CH2:11][CH2:10][N:9]([C:12]([CH3:31])([CH3:30])[CH2:13][CH2:14][C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:16]#[N:17])[CH2:8]1.[OH:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1>>[NH3:9].[OH:35][C:36]1[CH:41]=[CH:40][C:39]([C:2]2[CH:34]=[CH:33][CH:32]=[C:4]([CH2:5][O:6][C@H:7]3[CH2:11][CH2:10][N:9]([C:12]([CH3:30])([CH3:31])[CH2:13][CH2:14][C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:16]#[N:17])[CH2:8]3)[CH:3]=2)=[CH:38][CH:37]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: CC(C)(CCC(C#N)(c1ccccc1)c1ccccc1)N1CC[C@H](OCc2cccc(Br)c2)C1
Product: CC(C)(CCC(C#N)(c1ccccc1)c1ccccc1)N1CC[C@H](OCc2cccc(-c3ccc(O)cc3)c2)C1
Product: N

Procedure:
The title compound was prepared from the product of example 55 and 4-hydroxyphenylboronic acid, using the same method as that described for example 56. The crude compound was purified by column chromatography on silica gel, eluting with ethyl acetate. The appropriate fractions were evaporated under reduced pressure and the residue was further purified by column chromatography on silica gel, eluting with dichloromethane:methanol:0.88 ammonia, 98:2:0.2 to 95:5:0.5, to afford the desired compound as a pale brown gum in 78% yield.