Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12](/[C:15](/[CH3:19])=[CH:16]/[CH2:17][OH:18])=[CH:11][CH:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:20]([O:22][C@@H:23]([CH2:29][C:30]1[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:21]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12](/[C:15](/[CH3:19])=[CH:16]/[CH2:17][O:18][C:33]3[CH:32]=[CH:31][C:30]([CH2:29][C@H:23]([O:22][CH2:20][CH3:21])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:35][CH:34]=3)=[CH:13][CH:14]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: C/C(=C\CO)c1ccc(-c2cc(Cl)cc(Cl)c2)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3cc(Cl)cc(Cl)c3)cc2)cc1)OCC
Yield: 77.3 %

Procedure:
The title compound (794 mg, 77%) was prepared as a colourless gum from (E)-3-(3′,5′-dichloro-biphenyl-4-yl)-but-2-en-1-ol (586 mg, 2.0 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (500 mg, 2.10 mmol) by a procedure analogous to that described in example 52c.
Reaction SMILES: [CH2:1]([S:8][CH2:9][C@H:10]([NH:14][C:15]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:16])[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]([F:38])([F:37])[O:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][CH2:33][C@@H:34]([NH2:36])[CH3:35])=[CH:28][CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:1]([S:8][CH2:9][C@H:10]([NH:14][C:15]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:16])[C:11](=[O:13])[NH:36][C@@H:34]([CH3:35])[CH2:33][NH:32][C:29]1[CH:28]=[CH:27][C:26]([O:25][C:24]([F:23])([F:37])[F:38])=[CH:31][CH:30]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@H](CSCc1ccccc1)NC(=O)N1CCOCC1
Reactant: C[C@H](N)CNc1ccc(OC(F)(F)F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](CNc1ccc(OC(F)(F)F)cc1)NC(=O)[C@H](CSCc1ccccc1)NC(=O)N1CCOCC1
Yield: 6.4 %

Procedure:
3-Benzylsulfanyl-2-(R)-[(morpholine-4-carbonyl)-amino]-propionic acid (182 mg, 0.56 mmol, 1.2 eq.), N1-(4-Trifluoromethoxy-phenyl)-(S)-propane-1,2-diamine from Scheme 1a (110 mg, 0.47 mmol, 1.0 eq.), and HATU (185 mg, 0.56 mmol, 1.2 eq.) were dissolved in CH2Cl2 (2 mL) at room temperature. DIPEA (245 μL, 1.41 mmol, 3.0 eq.) was added via syringe and the resulting mixture was monitored by LC/MS to completion. After the reaction was complete, the solvent was evaporated and directly purified by mass-directed HPLC and provided 22 mg (0.03 mmol, 5%) of a off-white solid (mono-TFA salt): HPLC-MS calcd. for C25H31F3N4O4S (M+H+) 541.2, found 541.3.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][CH:9]1[CH2:26][CH2:25][C:12]2([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[CH2:11][CH2:10]1)(=O)=O.[H-].[Na+].[NH:29]1[CH:33]=[CH:32][N:31]=[CH:30]1>CN(C=O)C.C(OCC)(=O)C>[N:29]1([CH2:6][CH2:7][O:8][CH:9]2[CH2:10][CH2:11][C:12]3([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[CH2:25][CH2:26]2)[CH:33]=[CH:32][N:31]=[CH:30]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(OCCOS(C)(=O)=O)CC2)CC1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2(CCC(OCCn3ccnc3)CC2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
A solution of tert-butyl 9-(2-(methylsulfonyloxy)ethoxy)-3-azaspiro[5.5]undecane-3-carboxylate (2.68 mmol, 1.0 eq.) in DMF (10 ml) was added dropwise to a stirred mixture of NaH (8.04 mmol, 3.0 eq.) and imidazole (5.36 mmol, 2.0 eq.) in DMF (15 ml) at 0° C. and the resulting mixture was stirred at 25° C. for 16 h. The reaction mixture was diluted with ethyl acetate (300 ml) and washed with water (200 ml) and brine (200 ml). The organic layer was dried over sodium sulfate and concentrated under reduce pressure to give the crude product which was purified by silica gel column chromatography eluting with 2% MeOH in MC to afford the desired product as a yellow oil. Yield: 84%
Reaction SMILES: [SH:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][N:7]=1.[Br:10]Br>C(OCC)(=O)C>[Br:10][C:8]1[C:3]2[C:2](=[N:7][CH:6]=[CH:5][N:4]=2)[S:1][N:9]=1
Reactant: BrBr
Reactant: N#Cc1nccnc1S
Solvent: CCOC(C)=O
Product: Brc1nsc2nccnc12
Temperature: 25 °C

Procedure:
Crude 3-mercaptopyrazine-2-carbonitrile (1.1 g, 8.0 mmol) was dissolved in ethyl acetate (30 mL) and treated with bromine (0.46 mL, 8.8 mmol). The reaction mixture was heated to reflux. As soon as the bromine was added, the mixture became homogeneous but after several minutes a precipitate began to form. After 90 min the reaction mixture was cooled to room temperature and then partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to yield 3-bromoisothiazolo[5,4-b]pyrazine as a pale orange solid. MW=215 confirmed by LC-MS, tr=10.34 min (Method Y) MH+=214-216.
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])[CH3:3].[Br:9][C:10]1[CH:11]=[CH:12][C:13]([Cl:18])=[C:14]([CH2:16][OH:17])[CH:15]=1.N1C=CN=C1.[NH4+].[Cl-]>CN(C=O)C>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([Cl:18])=[C:14]([CH:15]=1)[CH2:16][O:17][Si:5]([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:7])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cc(Br)ccc1Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cc(Br)ccc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
TBDMS-Cl (10.6 g, 66.7 mmol) was added to a sol. of (5-bromo-2-chloro-phenyl)-methanol (12.8 g, 55.6 mmol) and imidazole (9.42 g, 138 mmol) in DMF (190 mL) at 0° C. The mixture was stirred for 2 h at 0° C., and aq. sat. NH4Cl was added. The mixture was extracted with heptane (2×). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (heptane→EtOAc/heptane 1:49) yielded the title compound (18.0 g, 96%). LC-MS: tR=1.22 min.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:25]([CH:29]=1)[C:26](Cl)=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:38]([CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41]>>[CH2:43]([O:42][C:40](=[O:41])[CH2:39][N:38]([CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])[C:26](=[O:27])[C:25]1[CH:29]=[C:21]([O:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:22]=[CH:23][C:24]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:44]
Reactant: CCOC(=O)CNCC(=O)OCC
Reactant: O=C(Cl)c1cc(OCCCCCCCCCCCCOc2ccccc2)ccc1OCc1ccccc1
Product: CCOC(=O)CN(CC(=O)OCC)C(=O)c1cc(OCCCCCCCCCCCCOc2ccccc2)ccc1OCc1ccccc1
Yield: 56 %

Procedure:
The reaction of 5-[(12-phenoxydodecyl)oxy]-2-(phenylmethoxy) benzoic acid chloride with diethyl iminodiacetate under conditions described in Example 80 gave N-(2-ethoxy-2-oxoethyl)-N-[5-[(12-phenoxydodecyl)oxy]-2-(phenylmethoxy)benzoyl]glycine ethyl ester (56% yield, mp 49°-50° ). The structure was confirmed by nmr and mass spectra.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:18]1[C:19]([CH3:35])=[C:20]([NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:21]=[CH:22][CH:23]=1)[C:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:10][CH:11]=2)[NH:6][CH:5]=1.O=[CH:37][C:38]([O:40][CH2:41][CH3:42])=[O:39].C1(C)C=CC=CC=1.Cl.O1CCOCC1>C(OCC)(=O)C.C(Cl)Cl>[CH2:27]([O:26][C:25]([NH:24][C:20]1[C:19]([CH3:35])=[C:18]([C:3]2[C:4]3[C:12]4[C:7](=[CH:8][C:9]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:10][CH:11]=4)[NH:6][C:5]=3[C:37]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[N:1][CH:2]=2)[CH:23]=[CH:22][CH:21]=1)=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)C=O
Reactant: COCCOc1ccc2c(C(CN)c3cccc(NC(=O)OCc4ccccc4)c3C)c[nH]c2c1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ncc(-c2cccc(NC(=O)OCc3ccccc3)c2C)c2c1[nH]c1cc(OCCOC)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.8 %

Procedure:
To a solution of benzyl 3-(2-amino-1-(6-(2-methoxyethoxy)-1H-indol-3-yl)ethyl)-2-methylphenylcarbamate (0.780 g, 1.647 mmol) and ethyl 2-oxoacetate in toluene (50%) (0.653 mL, 3.29 mmol) at room temperature was added hydrogen chloride in 1,4-dioxane (4.0 M) (0.494 mL, 1.977 mmol). The mixture was stirred room temperature for 16 hr. The volatiles were removed under vacuum. The residue was diluted with water (50 mL), basified with NaHCO3 solution to pH 10, and extracted with ethyl acetate (4×50 mL). The combined extract was washed with brine (40 ml), dried over anhydrous MgSO4, and concentrated to dryness under vacuum. To the residue were added p-xylene (60 mL) and 10% Pd/C (0.46 g), and the mixture was heated at 125° C. under an ambient atmosphere for 4.5 hr. The solid phase was removed by suction filtration. The filtrate was diluted with ethyl acetate (120 ml), washed with brine (40 ml), and dried over anhydrous MgSO4. The desired product (0.399 g, 0.721 mmol, 43.8% yield) was isolated by ISCO (40 g silica gel, solid loading, 15-35% ethyl acetate/CH2Cl2).
Reaction SMILES: CC([O-])(C)C.[K+].Cl.[NH2:8][C@@H:9]([CH2:14][CH2:15][CH2:16]C)[C:10]([O:12][CH3:13])=[O:11].C(N(CC)CC)C.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32]Br)=[CH:28][N:27]=1>COCCOC.CN(C=O)C>[Br:25][C:26]1[N:27]=[CH:28][C:29]([CH2:32][NH:8][C@H:9]([C:10]([O:12][CH3:13])=[O:11])[CH2:14][CH2:15][CH3:16])=[CH:30][CH:31]=1
Reactant: BrCc1ccc(Br)nc1
Reactant: CCCC[C@H](N)C(=O)OC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: COCCOC
Product: CCC[C@H](NCc1ccc(Br)nc1)C(=O)OC
Temperature: 20 °C
Reaction time: 1 h

Procedure:
1.48 g (13.2 mmol) of potassium tert-butylate are added to a solution of 2.18 g (12 mmol) of methyl (S)-2-aminohexanoate hydrochloride and 1.66 ml of triethylamine in 20 ml of DME and 15 ml of DMF under argon. After stirring at 20° C. for 1 h, a solution of 3.01 g (12 mmol) of 2-bromo-5-bromomethylpyridine in 15 ml of DMF is injected and the mixture is stirred for 16 h. Subsequently, the solvent is distilled off in vacuo and the residue is taken up in dichloromethane/water; the organic phase is then dried over sodium sulphate and, after concentrating, purified on silica gel using petroleum ether/ethyl acetate (4:1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][C:10]1[C:15]([NH2:16])=[CH:14][CH:13]=[C:12]([C:17]([F:20])([F:19])[F:18])[N:11]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:16][C:15]2[C:10]([CH3:9])=[N:11][C:12]([C:17]([F:20])([F:18])[F:19])=[CH:13][CH:14]=2)=[N:3][CH:4]=1
Reactant: Cc1nc(C(F)(F)F)ccc1N
Reactant: Brc1ccc(Br)nc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1nc(C(F)(F)F)ccc1Nc1ccc(Br)cn1
Temperature: 100 °C

Procedure:
2,5-dibromopyridine (474 mg, 2 mmol) and 2-Methyl-6-trifluoromethyl-pyridin-3-ylamine (352 g, 2 mmol) were dissolved in 1,4-dioxane (4 mL) in a pressure vessel. Pd2dba3 (55 mg, 0.06 mmol) and XANTPHOS (46 mg, 0.08 mmol) were added, followed by cesium carbonate (1.3 g, 4 mmol). The mixture was sparged with nitrogen for 10 minutes, then the vessel was sealed and heated at 100° C. for 18 hours. The mixture was partitioned between EtOAc and saturated aqueous NH4Cl, then the organic layer was washed with brine, dried with magnesium sulfate, filtered, and concentrated via rotary evaporation. The crude material was purified via column chromatography on silica gel, eluting with a gradient of EtOAc/hexanes (7-60%) to obtain the target compound as a solid: 1H NMR (400 MHz, CDCl3) δ ppm 2.62 (s, 3 H) 6.36 (br. s., 1 H) 6.75 (d, J=8.59 Hz, 1 H) 7.53 (d, J=8.34 Hz, 1 H) 7.69 (dd, J=8.84, 2.53 Hz, 1 H) 8.32-8.37 (m, 2 H); MS (M+H)+ 334.7.
Reaction SMILES: [C:1]([N:11]1[CH2:13][CH:12]1[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH3:15][C:16]1([CH3:24])[CH2:20][CH2:19][C:18]([CH3:22])([CH3:21])[CH:17]1[OH:23].B(F)(F)F.CCOCC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([NH:11][CH:12]([CH3:14])[CH2:13][O:23][CH:17]1[C:18]([CH3:22])([CH3:21])[CH2:19][CH2:20][C:16]1([CH3:24])[CH3:15])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CC1(C)CCC(C)(C)C1O
Reactant: CC1CN1C(=O)OCc1ccccc1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CC(COC1C(C)(C)CCC1(C)C)NC(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
N-Cbz-2-Methyl aziridine and 2,2,5,5-tetramethyl-1-cyclopentanol are dissolved in CH2Cl2 at 0° C. under argon. Boron trifluoride etherate is added and the flask is stirred overnight. The contents are poured into saturated NaHCO3 and are extracted with ethyl acetate. The organic layer is dried over MgSO4 and evaporated to yield N-Cbz-1-(2-aminopropoxy)-2,2,5,5-tetramethylcyclopentane.
Reaction SMILES: C(N(CC)CC)C.[CH:8]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[N:21]=[N:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)=[N:18]2)=[CH:13][CH:12]=1)([CH3:10])[CH3:9].[C:29](Cl)(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31]>CN(C)C1C=CN=CC=1.ClCCl>[C:29]([O:28][C:25]1[CH:24]=[CH:23][C:22]([C:19]2[N:20]=[N:21][N:17]([C:14]3[CH:13]=[CH:12][C:11]([CH:8]([CH3:10])[CH3:9])=[CH:16][CH:15]=3)[N:18]=2)=[CH:27][CH:26]=1)(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(C)c1ccc(-n2nnc(-c3ccc(O)cc3)n2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1ccc(-n2nnc(-c3ccc(OC(=O)C(C)(C)C)cc3)n2)cc1
Reaction time: 1 h
Yield: 54.9 %

Procedure:
Triethylamine (0.167 g) and 4-dimethylaminopyridine (0.02 g) were added to a solution of 4-[2-(4-isopropylphenyl)tetrazol-5-yl]phenol (0.42 g), obtained in the reference example 2, in dichloromethane (5 ml), and pivaloyl chloride (0.199 g) was added to the solution under ice cooling. Stirring was continued for 1 h at the same temperature. The mixture was washed with water, dried and evaporated to dryness. The residue was recrystallized from ethyl acetate-hexane to give 0.3 g (55%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH:12]2[C:17](=[O:18])[NH:16][C:15](=[O:19])[NH:14][C:13]2=[O:20])=[CH:5][CH:4]=1.[Br:21]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:21][C:12]1([CH2:11][CH2:10][CH2:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:13](=[O:20])[NH:14][C:15](=[O:19])[NH:16][C:17]1=[O:18]
Reactant: COc1ccc(CCCC2C(=O)NC(=O)NC2=O)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(CCCC2(Br)C(=O)NC(=O)NC2=O)cc1
Yield: 87.1 %

Procedure:
A mixture of 5-[3-(4-Methoxyphenyl)propyl]barbituric Acid (2.5 g), N-bromosuccinimide (2 g) and dibenzoyl peroxide (catalytic amount) in 110 ml of carbon tetrachloride is refluxed for about 1 hour, then the solid which separated is filtered. The solid is redissolved in ethyl acetate and filtered through a silica gel cake in order to eliminate the succinimide residue. The organic phase is then concentrated to dryness and the residue is crystallized from diethylether/carbon tetrachloride mixture. A pale yellow solid separates which is filtered and dried under vacuum at 60° C. to give 2.8 g of the product, m.p. 113-114° C.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:15]=[C:16]([C:24]4([OH:30])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]1=[O:31].[CH3:32]I>>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:15]=[C:16]([C:24]4([O:30][CH3:32])[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)[CH:17]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:19]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]1=[O:31]
Reactant: CI
Reactant: Cn1c(=O)ccc2cc(COc3cc(C(F)(F)F)cc(C4(O)CCOCC4)c3)ccc21
Product: COC1(c2cc(OCc3ccc4c(ccc(=O)n4C)c3)cc(C(F)(F)F)c2)CCOCC1
Yield: 95 %

Procedure:
Using the procedure described in Example 11, 4-[3-(1,2-dihydro-1-methyl-2-oxoquinolin-6-ylmethoxy)-5-trifluoromethylphenyl]-4-hydroxytetrahydropyran was reacted with methyl iodide to give 4-[3-(1,2-dihydro-1-methyl-2-oxoquinolin-6-ylmethoxy)-5trifluoromethylphenyl]-4-methoxytetrahydropyran in 95% yield, m.p. 103° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([O:19][C:20]([F:23])([F:22])[F:21])[CH:18]=1)[C:5]([NH:7][CH2:8][C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1)=[O:6].[CH3:24][C:25]1[CH:26]=[CH:27][C:28]([Sn](CCCC)(CCCC)CCCC)=[N:29][CH:30]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH3:24][C:25]1[CH:26]=[CH:27][C:28]([C:2]2[CH:3]=[C:4]([CH:16]=[C:17]([O:19][C:20]([F:23])([F:22])[F:21])[CH:18]=2)[C:5]([NH:7][CH2:8][C:9]2[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=2)=[O:6])=[N:29][CH:30]=1
Reactant: Cc1ccc(CNC(=O)c2cc(Br)cc(OC(F)(F)F)c2)cn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2cc(OC(F)(F)F)cc(C(=O)NCc3ccc(C)nc3)c2)nc1
Temperature: 25 °C

Procedure:
A mixture of 3-bromo-N-((6-methylpyridin-3-yl)methyl)-5-(trifluoromethoxy)benzamide (60 mg, 0.15 mmol), 5-methyl-2-(tributylstannyl)pyridine (0.1 mL, 0.3 mmol), tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.02 mmol) and toluene (4 mL) under argon was subjected to microwave irradiation at 120° C. for 2 hours. LC-MS indicated strong peak of starting material. The mixture was degassed with nitrogen and re-applied to microwave irradiation at 120° C. for 2 hours. The mixture was cooled to room temperature and concentrated in vacuo. The residue was purified via preparative HPLC (100×21.2 mm C18 column, CH3CN/water[10 mM Et2NH]) to afford the desired product as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:20])[C:5]1[CH:17]=[C:16]([CH2:18][F:19])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)C.[OH-].[Li+]>C1COCC1>[F:19][CH2:18][C:16]1[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=[C:5]([CH:17]=1)[C:4]([OH:20])=[O:3]
Reactant: CCCN(C)C(=O)c1cc(CF)cc(C(=O)OCC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCN(C)C(=O)c1cc(CF)cc(C(=O)O)c1
Yield: 85 %

Procedure:
Stir a solution of 5-fluoromethyl-N-methyl-N-propyl-isophthalamic acid ethyl ester (73 mg, 0.26 mmol), 1 N lithium hydroxide (1.3 mL, 1.3 mmol) and THF (1.3 mL) at room temperature overnight. Add water (10 mL) and extract with dichloromethane (3×10 mL). Acidify the aqueous with 5 N HCl (260 μL), extract with dichloromethane (3×10 mL), dry (magnesium sulfate) and concentrate to give the title compound (56 mg, 85%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:20]([OH:23])(=[O:22])=[O:21])[CH:5]=[C:6]2[C:11]=1[C:10]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:9][C:8]([S:16]([OH:19])(=[O:18])=[O:17])=[CH:7]2.C1C(N=NC2C(=O)N(C3C=CC(S([O-])(=O)=O)=CC=3)N=C2C([O-])=O)=CC=C(S([O-])(=O)=O)C=1.[Na+].[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+].[N+:64]([C:67]1[CH:68]=[C:69]([S:73](Cl)(=[O:75])=[O:74])[CH:70]=[CH:71][CH:72]=1)([O-:66])=[O:65]>O>[N+:64]([C:67]1[CH:68]=[C:69]([S:73]([NH:1][C:2]2[CH:3]=[C:4]([S:20]([OH:23])(=[O:22])=[O:21])[CH:5]=[C:6]3[C:11]=2[C:10]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:9][C:8]([S:16]([OH:19])(=[O:17])=[O:18])=[CH:7]3)(=[O:75])=[O:74])[CH:70]=[CH:71][CH:72]=1)([O-:66])=[O:65]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: Nc1cc(S(=O)(=O)O)cc2cc(S(=O)(=O)O)cc(S(=O)(=O)O)c12
Agent: O=C([O-])C1=NN(c2ccc(S(=O)(=O)[O-])cc2)C(=O)C1N=Nc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1cccc(S(=O)(=O)Nc2cc(S(=O)(=O)O)cc3cc(S(=O)(=O)O)cc(S(=O)(=O)O)c23)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.4 %

Procedure:
To a stirred solution of 21.9 g of 8-amino-1,3,6-naphthalenetrisulfonic acid, trisodium salt and 11.4 g of anhydrous sodium carbonate in 280 ml of water is added 24.0 g of m-nitrobenzenesulfonyl chloride. The mixture is stirred at room temperature for 16 hours, then an additional 1.0 g of sodium carbonate and 2.0 g of m-nitrobenzenesulfonyl chloride are added and stirring is continued for 3 hours longer. The mixture is evaporated and the residue is dissolved in 200 ml of water. A copious amount of absolute ethanol is added and the solid formed is collected and washed with ethanol and ether, then is dried to yield 26.1 g of 8-m-nitrobenzenesulfonamido-1,3,6-naphthalenetrisulfonic acid, trisodium salt.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][N:7]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[C:8]=1[CH3:9])(=O)[CH3:2].Cl.[Cl:18][C:19]1[CH:20]=[C:21]([N:25]2[CH:29]=[CH:28]C=N2)[CH:22]=[CH:23][CH:24]=1>>[ClH:16].[Cl:18][C:19]1[CH:20]=[C:21]([N:25]2[CH2:29][CH2:28][N:7]([CH2:10][CH:2]=[CH:1][C:4]3[CH:5]=[N:6][N:7]([C:10]4[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=4)[C:8]=3[CH3:9])[CH2:8][CH2:4]2)[CH:22]=[CH:23][CH:24]=1
Reactant: Clc1cccc(-n2cccn2)c1
Reactant: CC(=O)c1cnn(-c2ncccc2Cl)c1C
Agent: Cl
Product: Cc1c(C=CCN2CCN(c3cccc(Cl)c3)CC2)cnn1-c1ncccc1Cl
Yield: 68.7 %

Procedure:
4-Acetyl-1-(3-chloro-2-pyridyl)-5-methylpyrazole (648 mg), 1-(3-chlorophenyl)pyrazole hydrochloride (641 mg), and p-formaldehyde (1.65 g) were reacted, and the product was worked up in the same manner as in Example 5-(4) to yield 439 mg of the title compound.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:14]([OH:16])=O)=[N:5][O:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH3:2].[Na].C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.C(Cl)CCl.O[N:42]=[C:43]([C:45]1[CH:62]=[CH:61][C:48]([CH2:49][N:50]2[CH2:53][CH:52]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:51]2)=[CH:47][CH:46]=1)[NH2:44].N1C=CC=CC=1C1C(C(F)(F)F)=C(C2ON=C(C3C=CC(CN4CC(C(O)=O)C4)=CC=3)N=2)ON=1>C(#N)C>[CH2:1]([C:3]1[C:4]([C:14]2[O:16][N:44]=[C:43]([C:45]3[CH:46]=[CH:47][C:48]([CH2:49][N:50]4[CH2:51][CH:52]([C:54]([O:56][C:57]([CH3:58])([CH3:60])[CH3:59])=[O:55])[CH2:53]4)=[CH:61][CH:62]=3)[N:42]=2)=[N:5][O:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH3:2]
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(C(N)=NO)cc2)C1
Reactant: CCc1c(C(=O)O)noc1-c1ccccn1
Agent: O=C(O)C1CN(Cc2ccc(-c3noc(-c4onc(-c5ccccn5)c4C(F)(F)F)n3)cc2)C1
Agent: On1nnc2ccccc21
Agent: [Na]
Solvent: CC#N
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1c(-c2nc(-c3ccc(CN4CC(C(=O)OC(C)(C)C)C4)cc3)no2)noc1-c1ccccn1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of 4-ethyl-5-(pyridin-2-yl)isoxazole-3-carboxylic acid, sodium salt (22 mg), HOBt (27.8 mg, 0.181 mmol), and diisopropylethylamine (0.070 mL, 0.403 mmol) in acetonitrile (1 mL) was added EDC (45.4 mg, 0.237 mmol) and tert-butyl 1-(4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate, Int. 1 (30.8 mg, 0.101 mmol). The reaction mixture was stirred at 80° C. for 4 h. and then concentrated under reduced pressure. The residue was diluted with ethyl acetate (3 mL), washed with a saturated aqueous solution of sodium bicarbonate, washed with water (1 mL), washed with brine (1 mL), and dried over anhydrous sodium sulfate. Concentration followed by purification by preparative HPLC [Prep HPLC: Column: PHENOMENEX® S10 30×100 mm; Gradient time: 10 min; Flow rate=40 ml/min; Solvent A=10% MeOH—90% Water—0.1% TFA; Solvent B=90% MeOH—10% water—0.1% TFA; Start % B=20; Final % B=100.] afforded tert-butyl 1-(4-(5-(4-ethyl-5-(pyridin-2-yl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate.