Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([C:6](=[C:11]([NH:17][CH2:18][CH:19]=[CH2:20])[CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:7]([O:9][CH3:10])=[O:8])(=[O:5])[CH3:4].[CH3:21]I>>[C:3]([C:6](=[C:11]([NH:17][CH2:18][CH:19]=[CH2:20])[CH:12]([CH3:21])[C:13]([O:15][CH3:16])=[O:14])[C:7]([O:9][CH3:10])=[O:8])(=[O:5])[CH3:4]
Reactant: CI
Reactant: C=CCNC(CC(=O)OC)=C(C(C)=O)C(=O)OC
Agent: [H-]
Agent: [Na+]
Product: C=CCNC(=C(C(C)=O)C(=O)OC)C(C)C(=O)OC

Procedure:
In the same manner as in Reference Example 4-2-(1) but using 60 % sodium hydride (0.8 g; 20 mmole), dimethyl 2-acetyl-3-allylamino-2-pentenedioate (2.55 g; 10 mmole) and methyl iodide (2.84 g; 20 mmole), there was produced dimethyl 2-acetyl-3-allylamino-4-methyl-2-pentenedioate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10](OS(C)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](OS(C)(=O)=O)C1
Product: CC(C)(C)OC(=O)N1CC[C@@H](NCc2ccccc2)C1
Yield: 97.1 %

Procedure:
A solution of (S)-3-methanesulfonyloxypyrrolidine-1-carboxylic acid tert-butyl ester (16.9 g, 57 mmol) and benzylamine (18.3 g, 171 mmol) was stirred for 4 hours at 95° C. The remaining benzylamine was evaporated off under reduced pressure and the residue was purified by silica gel column chromatography (eluent; ethyl acetate) to afford (R)-3-benzylaminopyrrolidine-1-carboxylic acid tert-butyl ester (15.3 g, 97%) as pale yellow oil.
Reaction SMILES: [NH2:1][CH:2]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27]C)=[C:23]([F:29])[CH:22]=1)[CH2:3][NH:4][C:5]1[S:6][C:7]([C:10]2[CH:19]=[CH:18][C:13]3[NH:14][C:15](=[O:17])[O:16][C:12]=3[CH:11]=2)=[CH:8][N:9]=1.B(Br)(Br)Br>C(Cl)Cl>[NH2:1][CH:2]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([F:29])[CH:22]=1)[CH2:3][NH:4][C:5]1[S:6][C:7]([C:10]2[CH:19]=[CH:18][C:13]3[NH:14][C:15](=[O:17])[O:16][C:12]=3[CH:11]=2)=[CH:8][N:9]=1
Reactant: COc1ccc(CC(N)CNc2ncc(-c3ccc4[nH]c(=O)oc4c3)s2)cc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: NC(CNc1ncc(-c2ccc3[nH]c(=O)oc3c2)s1)Cc1ccc(O)c(F)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 34.4 %

Procedure:
To a 25 mL round-bottomed flask was added 6-(2-(2-amino-3-(3-fluoro-4-methoxyphenyl)propylamino)thiazol-5-yl)benzo[d]oxazol-2(3H)-one (Example 129) (60 mg, 145 μmol) and 3 mL of DCM. The solution was cooled to −78° C., and treated dropwise with boron tribromide, 1.0 M in DCM (497 μL, 2895 μmol) via a syringe. The solution was stirred at −78° C. for 1 hour and then allowed to warm to room temperature overnight. The reaction mixture was concentrated, and 2 mL of MeOH was added dropwise. The reaction mixture was purified by preparative LC to give 6-(2-(2-amino-3-(3-fluoro-4-hydroxyphenyl)propylamino)thiazol-5-yl)benzo[d]oxazol-2(3H)-one (20 mg, 35% yield). MS m/z: 401 (M+1). 1H NMR (400 MHz, CD3OD) δ ppm 2.85-2.98 (m, 2H), 3.47-3.53 (m, 1H), 3.62-3.71 (m, 2H), 6.92-6.97 (m, 2H), 7.05-7.10 (m, 2H), 7.26 (dd, J=8.02, 1.57 Hz, 1H), 7.37 (s, 1H), 7.38 (d, J=1.37 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]([CH:4]1[CH2:9][O:8][CH2:7][CH2:6][N:5]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=O.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[C:2]([CH:4]1[CH2:9][O:8][CH2:7][CH2:6][N:5]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])#[N:1]
Reactant: CC(C)(C)OC(=O)N1CCOCC1C(N)=O
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCOCC1C#N
Reaction time: 3.5 h

Procedure:
A solution of the product of Step 2 (1 eq.) and triethylamine (2.1 eq.) in CH2Cl2 (0.1 M) was cooled to 0° C. and trifluoroacetic anhydride (1.1 eq.) added dropwise under nitrogen. Stirring was continued 3.5 hours more at room temperature and volatiles removed in vacuo. Residues taken in EtOAc were washed with water, brine and dried over Na2SO4. Evaporation gave the title compound as a brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[C:6]=1[CH:7]=O.[CH3:17][CH:18]([CH3:34])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:23]=1)=[O:20]>>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[C:6]=1[CH2:7][N:31]1[CH2:32][CH2:33][CH:28]([C:24]2[CH:23]=[C:22]([NH:21][C:19](=[O:20])[CH:18]([CH3:17])[CH3:34])[CH:27]=[CH:26][CH:25]=2)[CH2:29][CH2:30]1
Reactant: O=Cc1c(Br)cnn1Cc1ccc(Cl)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3c(Br)cnn3Cc3ccc(Cl)cc3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 4-bromo-1-(4-chlorobenzyl)-1H-pyrazole-5-carbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 529.1 (M+H)+.
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[CH:11][C:10]([C:13]([O:15]C)=O)=[CH:9][N:8]=1.[CH:18]1([C:21]2[CH:22]=[C:23]([CH3:33])[C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[N:25][CH:26]=2)[CH2:20][CH2:19]1>>[CH:18]1([C:21]2[CH:22]=[C:23]([CH3:33])[C:24]([N:27]3[CH2:28][CH2:29][N:30]([C:13]([C:10]4[CH:11]=[N:12][C:7]([N:3]5[CH2:4][CH2:5][CH2:6][S:2]5(=[O:1])=[O:17])=[N:8][CH:9]=4)=[O:15])[CH2:31][CH2:32]3)=[N:25][CH:26]=2)[CH2:20][CH2:19]1
Reactant: COC(=O)c1cnc(N2CCCS2(=O)=O)nc1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2cnc(N3CCCS3(=O)=O)nc2)CC1
Yield: 6.8 %

Procedure:
Using methyl 2-(1,1-dioxo-1λ6-isothiazolidin-2-yl)pyrimidine-5-carboxylate (85 mg) described in Preparation Example 231 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (72 mg) described in Preparation Example 83 and by the reaction and treatment in the same manner as in Example 109, the title compound (10 mg) was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[N:10]([C@H:12]1[CH2:17][CH2:16][C@@H:15]([OH:18])[CH2:14][CH2:13]1)[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K+].[Br-].C([O-])(O)=O.[Na+].[O-]Cl.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.O.CC1(C)N([O])C(C)(C)CCC1>[CH2:1]([O:8][C:9](=[O:19])[N:10]([CH3:11])[CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C(=O)OCc1ccccc1)[C@H]1CC[C@@H](O)CC1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Solvent: O
Product: CN(C(=O)OCc1ccccc1)C1CCC(=O)CC1
Reaction time: 1 h
Yield: 98.3 %

Procedure:
A solution of 2.63 g (10 mmol) of cis-(4-Hydroxy-cyclohexyl)-methyl-carbamic acid benzyl ester in 16 ml CH2Cl2 was treated with a solution 0.24 g (2 mmol) of KBr and 0.28 g (3.33 mmol) of NaHCO3 in 5 ml of water. The suspension was cooled (0-5° C.) and 8 mg (0.05 mmol) of TEMPO and then 5.7 ml (12.5 mmol) of NaOCl (13%, 2.18 M in water) were added during 20 min. After 1 h at this temperature, again 8 mg (0.05 mmol) of TEMPO and then 2.85 ml (6.25 mmol) of NaOCl (13%, 2.18 M in water) were added. After 1 h, 5 ml of 1M sodium thiosulfat solution was added. The aqueous phase was extracted with CH2Cl2(2×), the organic phase was dried (Na2SO4), filtered and evaporated to give 2.57 g (99%) of Methyl-(4-oxo-cyclohexyl)-carbamic acid benzyl ester, MS: 261 (M).
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[C:13]([CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:12][NH:11][C:10]=1[CH3:21])C1C=CC=CC=1.[CH2:22](OC1C(=O)C(C(OC)C(F)(F)F)=CNC=1C)C1C=CC=CC=1>>[OH:8][C:9]1[C:14](=[O:15])[C:13]([CH2:16][C:17]([F:18])([F:19])[F:20])=[CH:12][N:11]([CH3:22])[C:10]=1[CH3:21]
Reactant: COC(c1c[nH]c(C)c(OCc2ccccc2)c1=O)C(F)(F)F
Reactant: Cc1[nH]cc(CC(F)(F)F)c(=O)c1OCc1ccccc1
Product: Cc1c(O)c(=O)c(CC(F)(F)F)cn1C

Procedure:
To a clear solution of 3-benzyloxy-5-(1-chloro-2,2,2-trifluoro-ethyl)-2-methyl-1H-pyridin-4-one hydrochloric acid salt (2.03 g, 5.50 mmol) in methanol (70 mL) was added sodium borohydride (1.25 g, 33.0 mmol) in several portions. The reaction was completed within 20 min. The reaction mixture was quenched with deionized water (80 mL). The volume of the resulting clear solution was reduced to about 10 mL by evaporation under reduced pressure to give a solid/liquid mixture. Another 50 mL of deionized water was added. The aqueous solution was extracted with dichloromethane (3×50 mL). The combined organic fractions was dried over Na2SO4, filtered, then concentrated in vacuo to give an oil (1.3 g), which solidified upon standing. HPLC analysis (HPLC Method 1, Example 24) of the crude solid material indicated presence of a mixture of the desired compound 3-benzyloxy-2-methyl-5-(2,2,2-trifluoro-ethyl)-1H-pyridin-4-one (RT=14.7 min, peak percent area=80.6%) and 3-benzyloxy-2-methyl-5-(2,2,2-trifluoro-1-methoxy-ethyl)-1H-pyridin-4-one (RT=15.7 min, peak percent area=16.2%) in about 5/1 ratio. Purification of the solid by column chromatography on silica gel (methanol/dichloromethane 2/100 to 3/100 v/v as eluant) afforded the title compound (0.9 g, 56% yield, HPLC purity (peak percent area): 98% at λ=280 nm). 1H NMR (DMSO-d6) δ ppm: 11.47 (br s, 1H), 7.60 (s, 1H), 7.37 (m, 5H), 5.06 (s, 2H), 3.41 (q, J=11.5 Hz, 2H), 2.06 (s, 3H); MS-ESI (m/z) 298.2 [M+1]+, 91.1 (100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[C:12](OCC)(=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14].N12CCCN=C1CCCCC2>COC(C)(C)C.O.C(O)(=O)C>[CH2:16]([O:15][C:13](=[O:14])[C:12](=[O:18])[CH2:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=1)[CH3:17]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Solvent: COC(C)(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(=O)O
Product: CCOC(=O)C(=O)Cc1cc(Cl)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Route B: To a solution of 2-chloro-4-methyl-5-nitropyridine (1.0 g, 5.8 mmol) in diethyl oxalate (4.23 g, 29 mmol) under an argon atmosphere was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.95 mL, 6.4 mol). The mixture was stirred at rt for 1.5 h then diluted with t-butyl methyl ether (40 mL), water (30 mL) and acetic acid (1 ml). The organic layer was separated, washed with water, dried (MgSO4) and evaporated to dryness. The resultant damp red solid residue was finally dried under high vacuum at 40–50° C. to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]3=[N:16][CH:17]=[C:18]([C:19]4[CH:20]=[N:21][C:22]([N:29]5[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=4)[N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:35]CN(CC)CC.C=O.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]3=[N:16][CH:17]=[C:18]([C:19]4[CH:20]=[N:21][C:22]([N:29]5[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]5)=[C:23]([C:25]([F:27])([F:28])[F:26])[CH:24]=4)[N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2nn3c(-c4cnc(N5CCNCC5)c(C(F)(F)F)c4)cnc3s2)cc1OC
Reactant: CCN(CC)CC
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(-c2nn3c(-c4cnc(N5CCN(C)CC5)c(C(F)(F)F)c4)cnc3s2)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.8 %

Procedure:
To a mixture of 2-(3,4-Dimethoxy-phenyl)-5-(6-piperazin-1-yl-5-trifluoromethyl-pyridin-3-yl)-imidazo[2,1-b][1,3,4]thiadiazole (105 mg, 0.199 mmol, 1 eq), Et3N (0.056 mL, 0.399 mmol, 2 eq), formaldehyde (0.180 mL, 2.39 mmol, 12 eq) and acetic acid (0.02 mL, 0.239 mmol, 1.2 eq) in MeOH (4 mL) was added Sodium cyanoborohydride (0.175 g, 2.79 mmol, 14 eq). The reaction mixture was stirred at rt for 2 h. Solvents were evaporated to dryness and the residue was dissolved in sat NaHCO3/EtOAc. Layers were separated and the aqueous layer was extracted once with EtOAc. The combined organic layers were dried, filtered and evaporated. The residue was purified on silica gel (isolute flash Si II, 10 g, 96:4 DCM/7N NH3 in MeOH) to give the desired product (50 mg, 50%). HPLC-MS: (5-100% B in 8 min, 0.8 mL/min, 50° C.): tR=3.47 min, [M+H]+ m/z 505.3; 1H NMR (300 MHz, CDCl3) δ 8.92 (s, 1H), 8.49 (d, J=1.9 Hz, 1H), 7.52 (s, 1H), 7.42 (d, J=1.7 Hz, 1H), 7.36 (dd, J=8.3, 2.0 Hz, 1H), 6.90 (d, J=8.4 Hz, 1H), 3.94 (s, 3H), 3.88 (s, 3H), 3.41 (m, 4H), 2.57 (m, 4H), 2.34 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:29])[C:5]2[N:10]=[C:9]([C:11]3[N:15]([C:16]4[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=4)[N:14]=[C:13]([C:23]([F:26])([F:25])[F:24])[CH:12]=3)[O:8][C:7](=[O:27])[C:6]=2[CH:28]=1.[CH:30]([NH2:33])([CH3:32])[CH3:31]>O1CCCC1>[Cl:1][C:2]1[CH:28]=[C:6]([C:7]([NH:33][CH:30]([CH3:32])[CH3:31])=[O:27])[C:5]([NH:10][C:9]([C:11]2[N:15]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=3)[N:14]=[C:13]([C:23]([F:26])([F:24])[F:25])[CH:12]=2)=[O:8])=[C:4]([CH3:29])[CH:3]=1
Reactant: CC(C)N
Reactant: Cc1cc(Cl)cc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Solvent: C1CCOC1
Product: Cc1cc(Cl)cc(C(=O)NC(C)C)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reaction time: 0.08 h

Procedure:
To a solution of 6-chloro-2-[1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-8-methyl-4H-3,1-benzoxazin-4-one (i.e. the benzoxazinone product of Step D) (5.0 g, 11.3 mmol) in tetrahydrofuran (35 mL) was added dropwise isopropylamine (2.9 mL, 34.0 mmol) in tetrahydrofuran (10 mL) at room temperature. The reaction mixture was then warmed until all solids had dissolved and stirred an additional five minutes, at which point thin layer chromatography on silica gel confirmed completion of the reaction. The tetrahydrofuran solvent was evaporated under reduced pressure, and the residual solid was purified by chromatography on silica gel, followed by trituration with ether/hexane to afford the title compound, a compound of the present invention, as a solid (4.6 g), melting at 195-196° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:13])=[CH:4][C:5]([OH:12])=[C:6]([C:8](=[O:11])[CH2:9][CH3:10])[CH:7]=1.[Br:14]N1C(=O)CCC1=O>C(O)(=O)C>[Br:14][C:4]1[C:5]([OH:12])=[C:6]([C:8](=[O:11])[CH2:9][CH3:10])[CH:7]=[C:2]([Cl:1])[C:3]=1[CH3:13]
Reactant: CCC(=O)c1cc(Cl)c(C)cc1O
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Product: CCC(=O)c1cc(Cl)c(C)c(Br)c1O
Temperature: 65 °C

Procedure:
The 1-(5-chloro-2-hydroxy-4-methylphenyl)propan-1-one (1.6 g, 8.0 mmol) was dissolved in acetic acid (20.0 mL) and N-bromosuccinimide (1.7 g, 9.7 mmol) was added. The reaction was warmed in an oil bath to 65° C. and monitored by LC/MS. After heating for 3 h the reaction was complete. This was allowed to cool to room temperature and was concentrated in vacuo. The residue was diluted with EtOAc and washed with water (twice), brine, dried over magnesium sulfate and concentrated to give 1-(3-bromo-5-chloro-2-hydroxy-4-methylphenyl)propan-1-one as an amber oil. This oil was dissolved in DMF (10.0 mL) and potassium carbonate (3.3 g, 24 mmol) and methyl iodide (0.75 mL, 12 mmol) were added. The reaction was stirred at 65° C. for 18 hours. The reaction was complete, and the reaction mixture was diluted with EtOAc, washed with water, brine, dried over magnesium sulfate and concentrated to give the crude product as a dark oil. The product was purified by chromatography on silica gel eluting with a hexane: EtOAc gradient to give 1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)propan-1-one as an oil (1.8 g, 81%). LCMS calculated for C11H13BrClO2 (M+H)+: m/z=290.9, 292.9. found: 290.8, 292.9.
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)[CH2:6][O:5][C:4]([NH2:7])=[N:3]1>CCO.CCCCCCC>[CH3:1][C@:2]1([C:8]2[CH:9]=[CH:10][C:11]([O:14][C:15]([F:18])([F:16])[F:17])=[CH:12][CH:13]=2)[CH2:6][O:5][C:4]([NH2:7])=[N:3]1
Reactant: CC1(c2ccc(OC(F)(F)F)cc2)COC(N)=N1
Solvent: CCO
Solvent: CCCCCCC
Product: C[C@]1(c2ccc(OC(F)(F)F)cc2)COC(N)=N1

Procedure:
((RS)-4-Methyl-4-(4-trifluoromethoxy-phenyl)-4,5-dihydro-oxazol-2-ylamine was sepa-rated by chiral HPLC (Chiralpak AD, EtOH/heptane 10:90) to give (S)-4-methyl-4-(4-trifluoromethoxy-phenyl)-4,5-dihydro-oxazol-2-ylamine. (+)-Enantiomer. Viscous colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([OH:18])=O)=[CH:4][CH:3]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C1(C)C(C)=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:16](=[O:18])[C:6]=2[CH:7]=1
Reactant: Cc1ccc(OCc2ccccc2C(=O)O)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Cc1ccccc1C
Product: Cc1ccc2c(c1)C(=O)c1ccccc1CO2

Procedure:
To a stirred suspension of 24.0 g. (0.5 mole) of a 50% dispersion of sodium hydride in mineral oil in 150 ml. of dimethylformamide under nitrogen was added dropwise 50.4 g. (0.5 mole) of 4-methylphenol in 100 ml. of dimethylformamide. The mixture was stirred until the evolution of hydrogen ceased. A solution of 67.1 g. (0.5 mole) of phthalide in 100 ml. of dimethylformamide was added and the mixture was refluxed two hours then stirred at 25° C. for sixteen hours. The mixture was poured into ice-water and acidified. The precipitated solid was filtered, dried and recrystallized from ethanol to give 2-carboxybenzyl 4-methylphenyl ether. The ether (22.6 g., 0.1 mole) was refluxed in dry xylene with a mixture of 65 g. of Super-cel and 65 g. of phosphorus pentoxide for seventeen hours. The reaction mixture was filtered. The filter cake was washed with xylene and ether. The combined filtrates were concentrated to give a solid which was recrystallized from ethanol to afford crystals of 2-methyldibenzo[b,e]oxepin-11-one, m.p. 100°-103° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[C:9]2=[N:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=[C:8]2[NH:7][CH:6]=1)[CH3:4].[NH4+:18].[Cl-]>CN(C=O)C>[CH2:3]([C:5]1[C:9]2=[N:10][C:11]([C:14]([F:16])([F:17])[F:15])=[CH:12][CH:13]=[C:8]2[N:7]([NH2:18])[CH:6]=1)[CH3:4]
Reactant: CCc1c[nH]c2ccc(C(F)(F)F)nc12
Reactant: [NH4+]
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1cn(N)c2ccc(C(F)(F)F)nc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
A suspension of NaH (4.65 g, 116 mmol, 60% in mineral oil) in DMF (40 mL) at 0° C. is treated with 3-ethyl-5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridine (2 g, 7.75 mmol) and stirred at 0° C. for 1 h. The mixture is treated with HOSA (4.4 g, 38.8 mmol) portion wise and warmed to rt over 2 h. The mixture is then poured over ice, treated with solid NH4Cl (3 g), and filtered through a pad of Celite. The filtrate is extracted with Et2O (3×150 mL). The combined organic layer is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 30%-50% EtOAc in heptane to afford 3-ethyl-5-trifluoromethyl-pyrrolo[3,2-b]pyridin-1-ylamine (1.5 g, 84%). MS: 230 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 7.97 (d, 1H), 7.59 (d, 1H), 7.54 (s, 1H), 6.12 (s, NH2, 2H), 2.78 (q, 2H), 1.28 (t, 3H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][C:5]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][N:7]=1.[CH3:16][N:17]=[C:18]=[O:19]>C(OCC)(=O)C>[CH3:16][NH:17][C:18]([N:2]([CH3:1])[C:3]1[S:4][C:5]([S:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:6][N:7]=1)=[O:19]
Reactant: CNc1nnc(SCc2ccccc2)s1
Reactant: CN=C=O
Solvent: CCOC(C)=O
Product: CNC(=O)N(C)c1nnc(SCc2ccccc2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-methylamino-5-benzylthio-1,3,4-thiadiazole (4.0 g) in ethyl acetate (100 ml) was added 1.5 g of methyl isocyanate. The reaction was stirred at room temperature for 2 hrs then heated at reflux for an additional 2 hrs. The product, 1,3-dimethyl-3-(5-benzylthio-1,3,4-thiadiazol-2-yl)urea, crystallized upon the addition of petroleum ether, was collected, washed with ether and dried to give 4.7 g, MP 139°-142° C.
Reaction SMILES: C(O[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[N:18]=[C:19]([C:24]#[C:25][C@@H:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH3:27])[N:20]=[CH:21][C:22]=3[N:23]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[N+](C1C=CC(S([O:48][CH2:49][C@H:50]2[CH2:52][C:51]2([F:54])[F:53])(=O)=O)=CC=1)([O-])=O>>[F:54][C:51]1([F:53])[CH2:52][C@@H:50]1[CH2:49][O:48][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[O:16][C:17]3[N:18]=[C:19]([CH2:24][CH2:25][C@@H:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH3:27])[N:20]=[CH:21][C:22]=3[N:23]=2)=[CH:13][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@H]2CC2(F)F)cc1
Reactant: C[C@@H](C#Cc1ncc2nc(-c3ccc(OCc4ccccc4)cc3)oc2n1)NC(=O)OC(C)(C)C
Product: C[C@@H](CCc1ncc2nc(-c3ccc(OC[C@H]4CC4(F)F)cc3)oc2n1)NC(=O)OC(C)(C)C

Procedure:
Using tert-butyl ((2S)-4-(2-(4-(benzyloxy)phenyl) [1,3]oxazolo[5,4-d]pyrimidin-5-yl)but-3-yn-2-yl)carbamate and ((1R)-2,2-difluorocyclopropyl)methyl 4-nitrobenzenesulfonate, and in the same manner as in Step A of Example 4 and Example 5, the title compound was obtained.
Reaction SMILES: [CH2:1]([N:3](C(C)C)C(C)C)C.[CH3:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[O:27][CH:26]([CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)[CH2:25][C:24]=3[CH:34]=2)=[CH:16][CH:15]=1)(=[O:13])=[O:12].Cl.C(N(C(C)C)C(C)C)C>ClCCl.O1CCCC1.O.C(OCC)(=O)C>[CH3:10][S:11]([C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[O:27][CH:26]([CH:28]4[CH2:33][CH2:32][N:31]([C:1]#[N:3])[CH2:30][CH2:29]4)[CH2:25][C:24]=3[CH:34]=2)=[CH:18][CH:19]=1)(=[O:12])=[O:13]
Reactant: CCN(C(C)C)C(C)C
Reactant: CS(=O)(=O)c1ccc(-c2ccc3c(c2)CC(C2CCNCC2)O3)cc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2ccc3c(c2)CC(C2CCN(C#N)CC2)O3)cc1
Temperature: 25 °C

Procedure:
Ethyldiisopropylamine (0.96 mL) and bromonitirile (175 mg) are added to a solution of 4-[5-(4-methanesulfonyl-phenyl)-2,3-dihydro-benzofuran-2-yl]-piperidine (400 mg) in dichloromethane (10 mL) and tetrahydrofuran (10 mL), and the reaction mixture is stirred over night at room temperature. Dichloromethane and water are added and the organic phase is separated and washed with water, 10% NH4Cl solution, and brine, and dried over MgSO4. The solvent is evaporated and the residue is triturated with diethyl ether to give a brownish solid. Since this material still contains ethyldiisopropylamine hydrochloride, ethyl acetate and water are added. The organic phase is separated, dried over MgSO4 and concentrated in vacuo. The residue is again triturated with diethyl ether to afford the title compound. LC (method 2): tR=1.18 min; Mass spectrum (ESI+): m/z=383 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:35]=[CH:34][C:5]([C:6]([N:8]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25](=[O:33])[C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:21][CH2:20]2)[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>>[C:36]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25](=[O:33])[C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[CH2:21][CH2:20]2)[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=2)=[O:7])=[CH:34][CH:35]=1)(=[O:38])[CH3:37]
Reactant: Cc1ccc(N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)C(=O)c2ccc(N)cc2)cc1C
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(C(=O)N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c2ccc(C)c(C)c2)cc1
Yield: 99.7 %

Procedure:
Using 4-amino-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(3,4-dimethylphenyl)benzamide (333.1 mg, 0.70 mmol) and acetic anhydride (0.080 ml, 0.85 mmol), the procedure of Inventive Example 94 was repeated to obtain 359.9 mg (99.7%) of the title compound in a light brown amorphous form.