Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]([F:14])([F:13])[F:12])[NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[O:15][CH3:16].O([CH2:25][C:26]([F:29])([F:28])[F:27])S(C(F)(F)F)(=O)=O>>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]([F:12])([F:13])[F:14])[N:7]([CH2:25][C:26]([F:29])([F:28])[F:27])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: COc1ccc2[nH]c(C(F)(F)F)nc2c1Cl
Product: COc1ccc2c(nc(C(F)(F)F)n2CC(F)(F)F)c1Cl

Procedure:
Synthesized as described in Example 195D from 4-chloro-5-(methyloxy)-2-(trifluoromethyl)-1H-benzimidazole and trifluoroethyl triflate: MS (ESI) m/z 333 (M+1).
Reaction SMILES: [OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C:5]3=[O:12])[CH2:3]1)[CH2:9]2.[O:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1.CO>C1COCC1>[O:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[C:22]1[CH:29]=[CH:28][C:25]([CH2:26][O:1][C:2]23[CH2:11][CH:6]4[CH2:7][CH:8]([CH2:10][CH:4]([C:5]4=[O:12])[CH2:3]2)[CH2:9]3)=[CH:24][CH:23]=1
Reactant: BrCc1ccc(-c2nc3ccccc3o2)cc1
Reactant: O=C1C2CC3CC1CC(O)(C3)C2
Solvent: C1CCOC1
Solvent: CO
Product: O=C1C2CC3CC1CC(OCc1ccc(-c4nc5ccccc5o4)cc1)(C3)C2
Reaction time: 1 h

Procedure:
To KH (35%; 1.38 g; 0.012 mole) in THF (20 ml) under N2 and cooled to 0° C. is added 5-hydroxytricyclo[3.3.1.13,7 ]decan-2-one (2 g; 0.012 mole) all at once. The reaction mixture is stirred for 5 min. in an ice bath and 1 hr. at room temperature. To the reaction mixture is then added 4-(benzoxazol-2-yl)benzyl bromide (3.4 g; 0.012 mole) dissolved in THF (60 ml) at a fast drip rate. A bright yellow mixture forms and the mixture is stirred overnight at room temperature. The mixture is next cooled in an ice bath, MeOH added to quench any KH and filtered. The filtercake is washed with THF and evaporated to dryness. The product is purified using a gradient flash chromatography (eluting with 10%-25% ethyl acetate/hexane) to obtain 5-[4-(benzoxazol-2-yl)benzyloxy]tricyclo[3.3.1.13,7 ]decan-2-one (m.p. 159°-160° C.) which is used directly in Step C.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[F:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:13]=1[C:14](O)=O.N>>[F:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:13]=1[C:14]1[O:1][N:2]=[C:3]([C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[N:10]=1
Reactant: O=C(O)c1c(F)cccc1F
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: Fc1cccc(F)c1-c1nc(-c2cccnc2)no1

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 2,6-difluorobenzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.29 (t, J=8.6 Hz, 2H), 7.65 (ddd, J=8.0, 4.9, 1.0 Hz, 1H), 7.77 (tt, J=8.6, 6.1 Hz, 1H), 8.57 (ddd, J=8.3, 1.9, 1.7 Hz, 1H), 8.75 (dd, J=4.7, 1.7 Hz, 1H), 9.30 (dd, J=2.2, 0.8 Hz, 1H) ppm; MS (DCl/NH3) m/z 260 (M+H)+.
Reaction SMILES: [CH2:1]([C:6](=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17])[CH2:7]Br)[CH2:2][CH2:3][CH2:4][CH3:5].[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1>C(Cl)(Cl)Cl>[CH2:1]([C:6](=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17])[CH2:7][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: C1CCNC1
Reactant: CCCCCC(=Cc1ccc(Cl)cc1Cl)CBr
Solvent: ClC(Cl)Cl
Product: CCCCCC(=Cc1ccc(Cl)cc1Cl)CN1CCCC1
Temperature: 150 °C
Yield: 39.1 %

Procedure:
A mixture of 50 g of (III) and 31.7 g of pyrrolidine was heated for 5 hours at 150° C. in an oil bath. The crude product was cooled, and dissolved in CHCl3, and the solution was washed with dilute NaOH and then several times with water. The organic phase was dried over Na2SO4 and concentrated. Distillation of the residue gave 19 g of (IV) of boiling point 148°-150° C./0.1 mbar.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C=O)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
To a solution of 3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (3.07 g), 4-hydroxybenzaldehyde (2 g) and triphenylphosphine (4.51 g) in tetrahydrofuran (50 ml) was added diethyl azodicarboxylate (2.7 ml), and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was evaporated and the obtained residue was purified by silica gel column chromatography (hexane:acetone=5:1) and dried under reduced pressure to give the title compound (3.2 g).
Reaction SMILES: CO[C:3]1[CH2:8][CH2:7][N:6]([CH3:9])[C:5](=[O:10])[C:4]=1[C:11]([O:13]CC)=O.[Cl:16][C:17]1[CH:18]=[C:19]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][C:22]1=[O:27]>C(O)CO.CO>[Cl:16][C:17]1[CH:18]=[C:19]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:20][N:21]1[CH2:26][CH2:25][N:24]2[C:3]3[CH2:8][CH2:7][N:6]([CH3:9])[C:5](=[O:10])[C:4]=3[C:11]([OH:13])=[C:23]2[C:22]1=[O:27]
Reactant: CCOC(=O)C1=C(OC)CCN(C)C1=O
Reactant: O=C1CNCCN1Cc1ccc(F)c(Cl)c1
Solvent: OCCO
Solvent: CO
Product: CN1CCc2c(c(O)c3n2CCN(Cc2ccc(F)c(Cl)c2)C3=O)C1=O
Temperature: 250 °C

Procedure:
A mixture of ethyl 4-methoxy-1-methyl-2-oxo-1,2,5,6-tetrahydropyridine-3-carboxylate (0.27 g, 1.27 mmol) and 1-(3-chloro-4-fluorobenzyl)piperazin-2-one (0.92 g, 3.80 mmol) in ethylene glycol (2.5 mL) was heated in a sealed tube at 250° C. in a microwave reactor for 20 minutes with stirring. The resultant solution was diluted with methanol (2.5 mL) and cooled to 0° C. The white solid precipitate was filtered, washed successively with cold methanol and diethyl ether, and then dried under vacuum to provide the title compound.
Reaction SMILES: [I-].C[N+]1(C)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.[C:11]([NH2:15])([CH3:14])([CH3:13])[CH3:12]>O.CO>[C:11]([N:15]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)N
Reactant: C[N+]1(C)CCC(=O)CC1
Agent: [I-]
Solvent: O
Solvent: CO
Product: CC(C)(C)N1CCC(=O)CC1
Yield: 4.6 %

Procedure:
A suspension of 64.5 g (253 mmol) of 1,1-dimethyl-4-oxo-piperidinium iodide in 50 mL of water and 90 mL (860 mmol) of tert-butylamine was stirred for 15 min when 1.0 mL of 40% Triton B in MeOH was added. The mixture was refluxed for 2 hr under N2, and then it was extracted with Et2O (4×100 mL). The aqueous phase was basified with 20 g of NaOH in 20 mL of water, and then it was extracted further with Et2O (4×100 mL). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated. The residual oil was shaken with 1.5 L of petroleum ether, which was decanted and concentrated. The residue was distilled under vacuum to provide 1.8 g of 1-tert-butyl-piperid-4-one.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[N:19]=[C:18]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH2:28][C:29]([NH2:31])=[O:30])[C:17]([C:32]([F:35])([F:34])[F:33])=[CH:16][N:15]=2)=[CH:9][CH:8]=1.C=O.[C:38](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(Cl)Cl>[CH3:38][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[N:19]=[C:18]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH2:28][C:29]([NH2:31])=[O:30])[C:17]([C:32]([F:35])([F:33])[F:34])=[CH:16][N:15]=2)=[CH:9][CH:8]=1
Reactant: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCCCN3)cc2)ncc1C(F)(F)F
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CN1CCCCC1c1ccc(Nc2ncc(C(F)(F)F)c(CCc3ccccc3CC(N)=O)n2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 92.1 %

Procedure:
To a suspension of 2-(2-(2-(2-((4-piperidin-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (8) (0.023 g, 0.048 mmol) in anhydrous methanol (1.5 mL) were added a 37% aq. solution of formaldehyde (0.014 mL, 0.19 mmol) and sodium triacetoxyborohydride (0.050 g, 0.24 mmol) under an atmosphere of nitrogen. The reaction was stirred at room temperature for 2.5 hours, the volatiles were removed in vacuo and the residue was diluted with EtOAc (15 mL) and sat. aq. NaHCO3 (10 mL). The layers were separated and the aqueous layer was extracted with EtOAc (10 mL), the combined organic layers were washed with water (10 mL), brine (10 mL), dried (MgSO4), filtered and concentrated in vacuo to give a solid which was taken up in DCM (˜10 mL) and methanol (˜1 mL) and concentrated in vacuo. The process was repeated with only DCM twice after which the sample was further dried on high-vacuum to give the title compound (9) (0.022 g, 91% yield) as an off-white solid; 1H NMR (400 MHz, d6-DMSO) δ 10.17 (s, 1H), 8.66 (s, 1H), 7.68 (d, J=8.6 Hz, 2H), 7.43 (s, 1H), 7.27-7.13 (m, 6H), 6.92 (s, 1H), 3.49 (s, 2H), 3.15-2.98 (m, 4H), 2.97-2.90 (m, 1H), 2.75-2.69 (m, 1H), 2.07-1.97 (m, 1H), 1.90 (s, 3H), 1.73 (d, J=12.8 Hz, 1H), 1.66-1.54 (m, 3H), 1.50-1.38 (m, 1H), 1.36-1.27 (m, 1H). LCMS Method C: rt 4.88 min; m/z 498.3 [M+H]+.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[CH3:20])=[O:11])[CH2:3]1.[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31](Cl)(=[O:33])=[O:32])(=[O:24])=[O:23]>>[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:7]1[C@@H:2]([CH3:1])[CH2:3][N:4]([CH2:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[CH3:20])=[O:11])[CH2:5][C@H:6]1[CH3:8])(=[O:33])=[O:32])(=[O:24])=[O:23]
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Reactant: Cc1c(F)cccc1NC(=O)CN1C[C@@H](C)N[C@@H](C)C1
Product: Cc1c(F)cccc1NC(=O)CN1C[C@@H](C)N(S(=O)(=O)c2ccccc2S(C)(=O)=O)[C@@H](C)C1

Procedure:
The title compound was prepared from the product of Example 60 step (i) (0.503 mmol) and 2-methanesulphonylbenzenesulphonyl chloride (0.503 mmol) by the method of Example 58 step (ii) as a white solid. Yield: 17 mg
Reaction SMILES: Br[CH2:2][C:3]([C:5]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:7][CH2:6]1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1>CC(C)=O>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:2][C:3]([C:5]2([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:7][CH2:6]2)=[O:4])=[CH:22][CH:21]=1
Reactant: CCOC(=O)C1(C(=O)CBr)CC1
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1(C(=O)COc2ccc(Cl)cc2)CC1
Yield: 69 %

Procedure:
47.2 g (0.2 mol) of ethyl 1-(bromoacetyl)-cyclopropanecarboxylate are added to a suspension of b 28 g (0.2 mol) of potassium carbonate and 26 g (0.2 mol) of 4-chlorophenol in 300 ml of acetone and the mixture is heated under reflux for 6 hours. Inorganic salts are then filtered off, the filtrate is concentrated under reduced pressure and the residue is distilled in vacuo. 39 g (69% of theory) of ethyl 1-(4-chlorophenoxyacetyl)-cyclopropanecarboxylate are obtained. B.P. 148°-150° C./0.45 mbar.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:29])[C:9]([C:11]1[S:28][C:14]2[C:15]3[CH:23]=[CH:22][C:21]([C:24](OC)=[O:25])=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10].[NH2:30][CH2:31][C@@H:32]([OH:34])[CH3:33]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:29])[C:9]([C:11]1[S:28][C:14]2[C:15]3[CH:23]=[CH:22][C:21]([C:24]([NH:30][CH2:31][C@@H:32]([OH:34])[CH3:33])=[O:25])=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10]
Reactant: COC(=O)c1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2
Reactant: C[C@H](O)CN
Product: C[C@H](O)CNC(=O)c1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2

Procedure:
Following Example 47 and General Procedure C, methyl 2-((2-chlorophenyl)(methyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylate 138 and (S)-(+)-1-amino-2-propanol gave 177. MS: (ESI+) 471.0
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[NH3:11]>CO>[NH2:11][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1
Reactant: N
Reactant: N#Cc1ccc(CBr)cc1
Solvent: CO
Product: N#Cc1ccc(CN)cc1
Yield: 16.8 %

Procedure:
Stir 4-bromomethyl-benzonitrile (2.0 g, 0.010 mmoles) in sealed vessel in a solution of 2N ammonia in methanol at 80° C. until completion. Reduce solvent in volume. Dissolve residue in ethyl acetate and wash with 1N HCl. Basify aqueous layer with 5N NaOH. Extract aqueous layer into dichloromethane. Dry organic layer over MgSO4 and reduce in volume to isolate 0.223 g. Yield=16.8%. Mass Spectrum (m/e): (M−).
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=3)=[O:18])[CH2:13][CH2:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[NH:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>C(Cl)Cl>[CH:1]([NH:4][C:5]1[C:6]([N:11]2[CH2:12][CH2:13][N:14]([C:17]([C:19]3[CH:20]=[CH:21][C:22]([C:23]([N:42]4[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]4)=[O:24])=[CH:26][CH:27]=3)=[O:18])[CH2:15][CH2:16]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:2])[CH3:3]
Reactant: C1CNCCN1
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cc2)CC1
Agent: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)N3CCNCC3)cc2)CC1
Temperature: 5 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
4-[1-[3-(Isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]benzoic acid (1.5 g) was dissolved in methylene chloride (50 ml) and then, triethylamine (0.7 ml) was added and cooled. Pivaloyl chloride (0.58 ml) was added slowly to the solution at 0~5° C. and the mixture was stirred at 5° C. for 2 hours. With the addition of piperazine (0.9 g), the solution was stirred at 5~10° C. for 3 hours. The reaction mixture was washed with water and aqueous sodium bicarbonate and the solvent was concentrated under reduced pressure. The concentrated residue was crystallized by treatment with ether and further recrystallized using isopropanol and ether. The recrystallized product was filtered and dried to give 1.48 g (yield: 83%) of the desired compound as white crystal.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#[N:5].[H-].[Na+].[CH3:16][N:17]1[CH2:21][CH2:20][C@H:19]([OH:22])[CH2:18]1>O1CCCC1>[CH3:16][N:17]1[CH2:21][CH2:20][C@H:19]([O:22][C:2]2[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=2[C:4]#[N:5])[CH2:18]1
Reactant: N#Cc1cc(C(F)(F)F)ccc1F
Reactant: CN1CC[C@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CC[C@H](Oc2ccc(C(F)(F)F)cc2C#N)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.3 %

Procedure:
To a solution of 2-fluoro-5-(trifluoromethyl)benzonitrile (8.0 g, 42.3 mmol, Aldrich) in tetrahydrofuran (50 mL) were added sodium hydride (1.9 g, 46.5 mmol, 60% in mineral oil) and (S)-1-methylpyrrolidin-3-ol (4.7 mL, 46.5 mmol, Aldrich). After stirring at room temperature for 3 hours, the reaction mixture was quenched with saturated NaHCO3 (30 mL). The aqueous layer was extracted with ethyl acetate (3×30 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 10.9 g of the title compound. MS (ESI+) m/z 271 (M+H)+.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:28]=[CH:27][C:21]([C:22]([O:24]CC)=[O:23])=[CH:20][CH:19]=3)[CH:14]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].O1CCCC1.[OH-].[Na+].Cl>C(O)C>[CH2:1]([O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:27][CH:28]=3)[CH:14]=2)=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCOc1ccc(-c2cc(-c3ccc(C(=O)OCC)cc3)no2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCCOc1ccc(-c2cc(-c3ccc(C(=O)O)cc3)no2)cc1
Temperature: 0 °C
Yield: 98.9 %

Procedure:
To a solution of Ethyl 4-[5-(4-n-pentyloxyphenyl)-isoxazol-3-yl]benzoate (6.33 g) in ethanol 60 ml) and tetrahydrofuran (90 ml) was added 2N sodium hydroxide aqueous solution (12.5 ml) at 80° C. The mixture was refluxed for 1 hour and poured into ice-water. The suspension was adjusted to pH 2.0 with 1N HCl. The precipitate was collected by filtration, washed with water and dried to give 4-[5-(4-n-pentyloxyphenyl)isoxazol-3-yl]benzoic acid (5.80 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[C:14]([O:20]C)[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.N1C=CC=CC=1>O>[Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[C:14]([OH:20])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: COc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1C#N
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: N#Cc1ccc(-c2ncc(C(F)(F)F)cc2Cl)cc1O

Procedure:
5.0 g of 3-chloro-2-(4-cyano-3-methoxyphenyl)-5-trifluoromethylpyridine and 5.5 g of pyridine hydrochloride were stirred for 2 hours at 200° C. After cooling, the reaction mixture was thoroughly stirred with 100 ml of water. The solid portion was then separated off and purified by means of column chromatography on silica gel (cyclohexane/methyl tert-butyl ether (2:1) as eluent). Yield: 3.4 g (71%) of white crystals having a melting point of 155°-157° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([O:15][Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])=[C:11]([CH2:13][OH:14])[CH:12]=2)[N:5]=[C:4]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:3]=1.[OH-].[Na+].[Cl:32][C:33]([Cl:40])([Cl:39])[CH2:34][O:35][C:36](Cl)=[O:37]>CCOC(C)=O.O>[Cl:32][C:33]([Cl:40])([Cl:39])[CH2:34][O:35][C:36](=[O:37])[NH:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([O:15][Si:16]([CH:20]([CH3:21])[CH3:22])([CH:23]([CH3:25])[CH3:24])[CH:17]([CH3:18])[CH3:19])=[C:11]([CH2:13][OH:14])[CH:12]=2)[N:5]=[C:4]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:3]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC(C)[Si](Oc1ccc(-n2nc(C(C)(C)C)cc2N)cc1CO)(C(C)C)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)[Si](Oc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1CO)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
To a solution of Intermediate 61c (0.15 g, 0.36 mmol) in EtOAc (1.8 mL) was added 1N aqueous NaOH solution (0.6 mL, 0.60 mmol) followed by 2,2,2-trichloroethylchloroformate (54.0 μL, 0.40 mmol). The reaction was stirred at RT overnight then treated with another portion of 1N aqueous NaOH solution (0.3 mL, 0.30 mmol) followed by 2,2,2-trichloroethylchloroformate (27.0 μL, 0.20 mmol). After stirring for another 4 h, the mixture was diluted with EtOAc and water. The aqueous layer was then extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-25% EtOAc in cyclohexane, to give the title compound (176 mg, 84%). LCMS (Method 3): Rt 5.35 min, m/z 592, 594 [MH+].
Reaction SMILES: [C:1]1([N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH2:10])=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:18][C:19](=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(O)C>[C:1]1([N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]2[S:9][CH:18]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(=S)N(c1ccccc1)c1ccccc1
Solvent: CCO
Product: CCOC(=O)c1csc(N(c2ccccc2)c2ccccc2)n1

Procedure:
The reaction described in Preparation 42 was repeated, but using 20 g of 1,1-diphenylthiourea, 19 g of ethyl bromopyruvate and 200 ml of ethanol, giving the title compound as an orange oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH2:12][O:13][CH3:14])=[C:10]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].CO.[OH-].[Na+]>O>[Cl:1][C:2]1[C:11]([CH2:12][O:13][CH3:14])=[C:10]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COCc1c(S(C)(=O)=O)ccc(C(=O)OC)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COCc1c(S(C)(=O)=O)ccc(C(=O)O)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a solution comprising 3.0 g of methyl 2-chloro-4-methanesulfonyl-3-methoxymethylbenzoate and 20 ml of methanol, a solution comprising 0.57 g of sodium hydroxide (93%) and 2 ml of water was added, and the mixture was stirred at room temperature for 30 minutes. After an addition of 10 ml of water, the mixture was concentrated under reduced pressure. Then, dilute hydrochloric acid was added thereto, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate. Then, the solvent was distilled off to obtain 2.6 g of the desired product. Melting point: 137°-141° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH2:18])[CH2:8][C@H:7]1[CH3:19])=[O:5])[CH3:2].[Br:20][C:21]1[CH:22]=[N:23][C:24](Cl)=[N:25][CH:26]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:24]2[N:25]=[CH:26][C:21]([Br:20])=[CH:22][N:23]=2)[CH2:8][C@H:7]1[CH3:19])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](N)C[C@H]1C
Reactant: Clc1ncc(Br)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(Br)cn2)C[C@H]1C
Temperature: 25 °C
Yield: 97.9 %

Procedure:
(2R*,4S*)-4-Amino-6-methoxy-2-methyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (3.80 g), 5-bromo-2-chloropyrimidin (6.92 g) and N,N-diisopropylethylamine (6.23 ml) are dissolved in 1,4-dioxane (50 ml) and the mixture is heated under reflux for 4 hours. After cooling to room temperature, the reaction solution is partitioned by adding a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane: ethyl acetate=9:1→6:4) to give (2R*,4S*)-4-(5-bromopyrimidin-2-yl)amino-6-methoxy-2-methyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (5.92 g). MS (m/z): 422/424 [M+H]+
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[CH2:6][CH2:7][CH2:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1)=[O:10].[I-].[Na+].O>CN(C)C=O>[N:1]([CH2:6][CH2:7][CH2:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1)=[O:10])=[N+:2]=[N-:3]
Reactant: O=C(CCCCl)N1CCCc2ccccc21
Reactant: [N-]=[N+]=[N-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCCCC(=O)N1CCCc2ccccc21

Procedure:
Sodium azide (2.2 g), 1-(4-chlorobutanoyl)-1,2,3,4-tetrahydroquinoline, prepared in a manner analogous to that set forth in Preparation 1, (4.2 g) and sodium iodide (1.5 g) were heated in dimethylformamide (25 ml) at 90° for 2 hours. The solution was poured into water and extracted with ethyl acetate. The organic solution was washed, dried and evaporated to give 1-(4-azidobutanoyl)-1,2,3,4-tetrahydroquinoline as an oil.
Reaction SMILES: [F:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[CH:4][C:5]2[NH:10][C:9](=S)[CH2:8][O:7][C:6]=2[CH:12]=1.[NH2:16][NH2:17]>CO>[F:1][C:2]1[CH:12]=[C:6]2[C:5]([N:10]3[C:9]([CH2:8][O:7]2)=[N:17][NH:16][C:6](=[O:7])[CH:5]3[CH3:4])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: NN
Reactant: O=[N+]([O-])c1cc2c(cc1F)OCC(=S)N2
Solvent: CO
Product: CC1C(=O)NN=C2COc3cc(F)c([N+](=O)[O-])cc3N21
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
To a solution of 7-fluoro-6-nitro-2H-benzo[b][1,4]oxazine-3(4H)-thione (Example #56, Step D, 1.0 g, 3.05 mmol) in MeOH (10 mL) was added hydrazine (55% wt, 0.2 mL, 3.4 mmol) at ambient temperature and the reaction mixture was stirred at ambient temperature overnight. The precipitate was collected by filtration to give 7-fluoro-4-methyl-6-nitro-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.63 g, 74%) as an orange solid. LC/MS (Table 1, Method 2) Rt=0.884 min; MS m/z: 281 [M+H]+