Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([N:18]3[CH2:23][CH2:22][CH:21]([N:24]4[C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=5[CH2:27][O:26][C:25]4=[O:34])[CH2:20][CH2:19]3)=[O:17])=[C:11]([O:35][CH2:36][C:37]([F:40])([F:39])[F:38])[CH:10]=2)[CH2:4][CH2:3]1.[CH3:41][N:42]([CH3:46])[C:43](Cl)=[O:44].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:41][N:42]([CH3:46])[C:43]([N:2]1[CH2:3][CH2:4][CH:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([N:18]3[CH2:23][CH2:22][CH:21]([N:24]4[C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=5[CH2:27][O:26][C:25]4=[O:34])[CH2:20][CH2:19]3)=[O:17])=[C:11]([O:35][CH2:36][C:37]([F:40])([F:38])[F:39])[CH:10]=2)[CH2:6][CH2:7]1)=[O:44]
Reactant: CN(C)C(=O)Cl
Reactant: O=C(Cc1ccc(OC2CCNCC2)cc1OCC(F)(F)F)N1CCC(N2C(=O)OCc3ccccc32)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)N1CCC(Oc2ccc(CC(=O)N3CCC(N4C(=O)OCc5ccccc54)CC3)c(OCC(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 1-(1-(4-(4-piperidinyloxy)-2-(2,2,2-trifluoroethoxy)phenylacetyl)piperidin-4-yl)-4H-3,1-benzoxazin-2(1H)-one hydrochloride (0.20 g, 0.35 mmol) from Example 2 in CH2Cl2 (20 mL) was added dimethylcarbamoyl chloride (0.042 g, 0.39 mmol) and DIEA (0.14 mL, 0.80 mmol). The solution was stirred at ambient temperature for 6 h and the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with 0.25 M aqueous citric acid (25 mL), H2O (25 mL), and saturated aqueous NaHCO3 (25 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 97:3 CH2Cl2 :MeOH as eluant to give the title compound as an amorphous solid.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:24][N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:4][N:5]([S:14]([C:17]2[O:18][C:19]([CH2:22]O)=[CH:20][CH:21]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(N(S(F)(F)[F:40])CC)C.C(=O)([O-])O.[Na+]>ClCCl>[F:1][C:2]1[C:3]([CH2:24][N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:29])[CH3:30])=[CH:4][N:5]([S:14]([C:17]2[O:18][C:19]([CH2:22][F:40])=[CH:20][CH:21]=2)(=[O:15])=[O:16])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2ccc(CO)o2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN(Cc1cn(S(=O)(=O)c2ccc(CF)o2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.1 %

Procedure:
To a solution of tert-butyl [(4-fluoro-5-(2-fluoropyridin-3-yl)-1-{[5-(hydroxymethyl)-2-furyl]sulfonyl}-1H-pyrrol-3-yl)methyl]methylcarbamate (223 mg) in dichloromethane (5 mL) was added diethylaminosulfur trifluoride (78.7 mg) under ice-cooling, and the mixture was stirred at room temperature for 18 hr. Saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→2:1) to give the title compound as a pale-yellow oil (yield 166 mg, 57%).
Reaction SMILES: [F:1][C:2]([F:50])([F:49])[C:3]1[CH:4]=[C:5]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[N:26]([CH2:29][C@H:30]1[CH2:35][CH2:34][C@H:33]([CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:32][CH2:31]1)[CH2:27][CH3:28])[C:8]1[N:13]=[CH:12][C:11](Br)=[CH:10][N:9]=1.CS(C)=[O:53].C([O-])(=O)C.[K+].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1>[Cl-].[Na+].O.C(OCC)(=O)C>[F:1][C:2]([F:50])([F:49])[C:3]1[CH:4]=[C:5]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[N:26]([CH2:29][C@H:30]1[CH2:35][CH2:34][C@H:33]([CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:32][CH2:31]1)[CH2:27][CH3:28])[C:8]1[N:13]=[CH:12][C:11]([OH:53])=[CH:10][N:9]=1
Reactant: CCOC(=O)C[C@H]1CC[C@H](CN(CC)c2ccc(C(F)(F)F)cc2CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(Br)cn2)CC1
Reactant: CS(C)=O
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C[C@H]1CC[C@H](CN(CC)c2ccc(C(F)(F)F)cc2CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(O)cn2)CC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Ethyl trans-(4-{[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-amino]-methyl}-cyclohexyl)-acetate (which is prepared by treating the corresponding starting compound in a same manner as in Example 12 (1)-(3)) (2.6 g) is dissolved dimethylsulfoxide (15 ml), and thereto are added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (73 mg), potassium acetate (977 mg) and bis(pinacolato)diboron (1.26 g), and the mixture is heated to 80° C. under nitrogen atmosphere and stirred for 2 hours. The reaction solution is cooled to room temperature and thereto are added a saturated brine and ethyl acetate, and the mixture is separated and the organic layer is washed with a saturated brine again, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is dissolved in tetrahydrofuran (30 ml) and thereto is added dropwise a 30% aqueous hydrogen peroxide solution (30 ml) under ice-cooling. The mixture is stirred for 1 hour, and thereto is added a saturated aqueous sodium thiosulfate solution to consume the excess hydrogen peroxide and thereto are added water and ethyl acetate, and the mixture is separated. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=19:1 to 7:3) to give ethyl trans-(4-{[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-hydroxy-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethylamino]-methyl}-cyclohexyl)-acetate (1.29 g). MS (m/z): 721 [M+H]+
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.ClCCl.[F:21][C:22]([F:31])([F:30])[C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26]>O>[F:21][C:22]([F:30])([F:31])[C:23]1[CH:24]=[C:25]([NH:26][C:2](=[O:9])[C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1ccncc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 48.3 %

Procedure:
Isonicotinoyl chloride hydrochloride (670 mg, 3.76 mmol, commercially available product) and triethylamine (864 μl, 6.20 mmol) were sequentially added at 0° C. to a dichloromethane (5 ml) solution of 3-(trifluoromethyl)aniline (208 mg, 1.29 mmol, commercially available product). The resulting mixture was warmed to room temperature and stirred for 23 hours. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by recrystallization (ethyl acetate). Thus, N-[3-(trifluoromethyl)phenyl]isonicotinamide (GIF-0608) (166 mg, 48.3%) was yielded as a colorless solid.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[C:8]=2[C:26]([O:28]C(C)(C)C)=[O:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC(Cl)(Cl)C(O)=O.O>C(Cl)Cl>[C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([S:16]([C:19]3[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=3)(=[O:18])=[O:17])[C:8]=2[C:26]([OH:28])=[O:27])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(C(=O)OC(C)(C)C)c(-c3ccccc3)c3ccccc32)cc1
Agent: O=C(O)C(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2c(C(=O)O)c(-c3ccccc3)c3ccccc32)cc1
Reaction time: 16 h
Yield: 94.2 %

Procedure:
To a stirred solution of 2.55 g of compound J in 10 cc of methylene chloride was added 2.20 g of trichloroacetic acid under ice-cooling and the mixture was stirred for 16 hours. Water was added to the reaction mixture, the desired compound was extracted with ethyl acetate. The extract was dried over magnesium sulfate and distilled to remove the solvent. The crude product thus obtained was purified by a silica gel column chromatography (eluent: ethyl acetate/hexane=3/7) to obtain 2.10 g of 3-phenyl-1-(p-toluenesulfonyl)indole-2-carboxylic acid. Yield: 94.1%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[C:25]1([CH3:36])[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][S:32](Cl)(=[O:34])=[O:33]>>[O:16]=[C:12]1[NH:11][C:10]2[C:17]3[C:22]([CH:23]=[CH:24][C:9]=2[N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:32]([CH2:31][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[CH3:36])(=[O:34])=[O:33])=[CH:3][CH:4]=2)[C:14](=[O:15])[CH2:13]1)=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: Cc1ccccc1CS(=O)(=O)Cl
Product: Cc1ccccc1CS(=O)(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 37 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione obtained in Example 1, (3), and o-tolyl-methanesulfonyl chloride, the title compound (yield 37%) was obtained in the same manner as that of Example 145.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([CH2:9][N:10]2[CH2:13][CH:12]([C:14]([O:16]C)=[O:15])[CH2:11]2)[CH:6]=[CH:5][C:4]=1[C:18]1[N:22]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH:30]([CH3:32])[CH3:31])=[C:25]([F:33])[CH:24]=2)[O:20][N:19]=1)[CH3:2].[OH-].[Na+]>>[CH2:1]([C:3]1[N:8]=[C:7]([CH2:9][N:10]2[CH2:11][CH:12]([C:14]([OH:16])=[O:15])[CH2:13]2)[CH:6]=[CH:5][C:4]=1[C:18]1[N:22]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH:30]([CH3:32])[CH3:31])=[C:25]([F:33])[CH:24]=2)[O:20][N:19]=1)[CH3:2]
Reactant: CCc1nc(CN2CC(C(=O)OC)C2)ccc1-c1noc(-c2ccc(CC(C)C)c(F)c2)n1
Agent: [Na+]
Agent: [OH-]
Product: CCc1nc(CN2CC(C(=O)O)C2)ccc1-c1noc(-c2ccc(CC(C)C)c(F)c2)n1
Yield: 85.5 %

Procedure:
The title compound (90 mg) was synthesized in a yield of 87% as a white crystalline solid by conducting the reaction similar to that mentioned in Example 3 (3e) using methyl 1-({6-ethyl-5-[5-(3-fluoro-4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]pyridin-2-yl}methyl)azetidine-3-carboxylate (0.11 g, 0.24 mmol) that was obtained in Example 30 (30b) and a 1 N aqueous solution of sodium hydroxide (0.71 mL, 0.71 mmol).
Reaction SMILES: [CH3:1][N:2]([S:20]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)(=[O:22])=[O:21])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([C:17]([OH:19])=[O:18])[CH2:15][N:16]=1)=[CH:8]2.N1(O)C2C=CC=C[C:31]=2N=N1.Cl.CN(C)CCCN=C=NCC.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O.CN(C1C=CN=CC=1)C.CO>[CH3:1][N:2]([S:20]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)(=[O:22])=[O:21])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([C:17]([O:19][CH3:31])=[O:18])[CH2:15][N:16]=1)=[CH:8]2
Reactant: CN(c1cccc2cc(C3=NCC(C(=O)O)S3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)C1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)S1
Temperature: 25 °C
Reaction time: 72 h
Yield: 65.4 %

Procedure:
To a solution of 2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazole-5-carboxylic acid (1.48 g) in N,N-dimethylformamide (30 ml) were added 1H-1,2,3-benzotriazol-1-ol (0.716 g), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (1.02 g), N,N-dimethyl-4-aminopyridine (0.043 g) and methanol (0.215 ml), and the mixture was stirred at room temperature for 3 days. 10% Aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=50:50-100:0), and recrystallized from hexane-ethyl acetate to give the title compound (1.00 g, yield 65%) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>N1C=CC=CC=1>[F:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: Cc1ccc(N)cc1
Solvent: c1ccncc1
Product: Cc1ccc(NS(=O)(=O)c2ccc(F)cc2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
4-Toluidine (6.430 g, 60 mmol) was dissolved in pyridine (200 mL). The resulting mixture was cooled down to 0° C. 4-fluoro-benzenesulfonyl chloride (7.784 g, 40 mmol) was added in portions. The mixture was stirred between 0° C. and room temperature overnight. Solvents were evaporated to dryness. The crude oil was dissolved in ethyl acetate (150 mL) and washed with 10% HCl (2×75 mL) and brine (1×75 mL). Organic phase was dried over magnesium sulfate before filtering and removal of solvent. The resulting solid was recrystallized in cyclohexane/ethyl acetate 9:1. The desired product, e.g. 4-fluoro-N-(4-methylphenyl)benzenesulfonamide (9.4754 g, 89%), was obtained as a colorless solid, in 98% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].Cl.Cl.[NH2:34][CH2:35][C:36]1[C:37]([NH2:43])=[N:38][C:39]([CH3:42])=[N:40][CH:41]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:43][C:37]1[C:36]([CH2:35][NH:34][C:3](=[O:4])[CH:2]([OH:1])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]=[C:15]([C:17]4[O:21][N:20]=[C:19]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[C:18]=4[C:28]([F:29])([F:30])[F:31])[O:14][N:13]=3)=[CH:8][CH:7]=2)=[CH:41][N:40]=[C:39]([CH3:42])[N:38]=1
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: Cc1ncc(CN)c(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1ncc(CNC(=O)C(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)c(N)n1
Reaction time: 1 h
Yield: 45.7 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 30 mg, 0.070 mmol), 5-(aminomethyl)-2-methylpyrimidin-4-amine-2HCl (22.02 mg, 0.104 mmol), 4-methylmorpholine (28.1 mg, 0.278 mmol), and HATU (34.4 mg, 0.090 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified via preparative LCMS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 45-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R/S)-N-((4-amino-2-methylpyrimidin-5-yl)methyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (17.5 mg, 0.032 mmol, 45.6% yield): LCMS=552.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.14 (2 H, d, J=8.53 Hz), 7.93 (1 H, s), 7.50-7.70 (7 H, m), 5.15 (1 H, s), 4.25 (2 H, d, J=4.02 Hz), 2.40 (3 H, s); HPLC peak RT=2.4 min (Method E).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:38])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([OH:31])[N:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH:39]1(O)[CH2:42][CH2:41][CH2:40]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:38])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH:39]3[CH2:42][CH2:41][CH2:40]3)[N:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: OC1CCC1
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)n(-c3ccccc3)n2)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OC3CCC3)n(-c3ccccc3)n2)CC1
Reaction time: 16 h

Procedure:
To a solution of 50 mg of 4-{(S)-4-tert-Butoxycarbonyl-2-[(5-hydroxy-1-phenyl-1H-pyrazole-3-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester and 8 mg of Cyclobutanol in 2 ml of THF, 37 mg of polymerbound triphenyl phosphine (Fluka, 3 mmol triphenylphosphine/g resin) and 20 mg of Diethyl azodicarboxylate was added and stirred for 16 h. Then, the reaction mixture was filtered and the solvents were removed under reduced pressure. The residue was dissolved in 1 ml of DCM and 0.2 ml TFA. After 4 h 10 ml of toluene was added and the solvents were removed under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. Yield: 2 mg MS (ES+): m/e=528.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[N:10][C:11]2[CH:19]=[C:15]([C:16](Cl)=[O:17])[C:14]([OH:20])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[NH2:21][CH2:22][C:23]1[NH:27][N:26]=[N:25][N:24]=1>>[OH:20][C:14]1[CH:13]=[CH:12][C:11]([N:10]=[N:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:19][C:15]=1[C:16]([NH:21][CH2:22][C:23]1[NH:27][N:26]=[N:25][N:24]=1)=[O:17]
Reactant: NCc1nnn[nH]1
Reactant: COc1ccc(N=Nc2ccc(O)c(C(=O)Cl)c2)cc1
Product: COc1ccc(N=Nc2ccc(O)c(C(=O)NCc3nnn[nH]3)c2)cc1

Procedure:
5-(4-Methoxyphenylazo)salicoyl chloride and 5-aminomethyltetrazole were reacted together under the conditions described for the preparation of Dye 6 to form Dye 16, m.p. 220°-225° decomp., after crystallization from aqueous acetic acid, λmax (methanol)=350 nm.
Reaction SMILES: [CH3:1][C:2]([NH:4][CH2:5][CH2:6][C:7]1[C:11]2[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:10]=2[NH:9][CH:8]=1)=[O:3].[OH-].[Na+].[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:17][O:16][C:13]1[CH:12]=[C:11]2[C:10](=[CH:15][CH:14]=1)[N:9]([S:26]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:28])=[O:27])[CH:8]=[C:7]2[CH2:6][CH2:5][NH:4][C:2](=[O:3])[CH3:1]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1ccc2[nH]cc(CCNC(C)=O)c2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc2c(c1)c(CCNC(C)=O)cn2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5 g of melatonin are dissolved in 150 ml of dichloromethane, and then 3.41 g of sodium hydroxide and 0.35 g of tetrabutylammonium hydrogen sulphate are added. The reaction mixture is then cooled in an ice-bath, and 4.06 ml of benzenesulphonyl chloride are added dropwise. After stirring overnight at room temperature, the excess sodium hydroxide and the catalyst are filtered off, the solvent is removed by evaporation in vacuo, and the resulting solid is recrystallised to yield the title product in the form of white crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:15]2[CH2:19][C@H:18]([C:20](OCCCC)=[O:21])[O:17][C:16]2=[O:27])[CH:5]=[C:6]([F:14])[C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[CH3:28][NH2:29]>CO>[CH3:28][NH:29][C:20]([C@@H:18]1[O:17][C:16](=[O:27])[N:15]([C:4]2[CH:3]=[C:2]([F:1])[C:7]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)=[C:6]([F:14])[CH:5]=2)[CH2:19]1)=[O:21]
Reactant: CN
Reactant: CCCCOC(=O)[C@H]1CN(c2cc(F)c(N3CCOCC3)c(F)c2)C(=O)O1
Solvent: CO
Product: CNC(=O)[C@H]1CN(c2cc(F)c(N3CCOCC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The butyl (5R)-3-[3,5-difluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinecarboxylate (EXAMPLE 17, Step 1) is treated with 2M methylamine in MeOH (0.1 M in starting material), and the reaction mixture is stirred at ambient temperature for 30 mins and then concentrated under reduced pressure. The residue is purified by radial chromatography [4000 micron silica gel rotor; MeOH/CH2Cl2 (3/97) eluent] to give the title compound, mp 179-181° C.; MS (ESI+) for C15H17N3O4F2 m/z 342 (M+H)+; [α]25D−40 (c 0.95, DMSO).
Reaction SMILES: Cl[CH:2]([F:4])[F:3].[O:5]=[CH:6][C:7]1[CH:15]=[CH:14][C:12]([OH:13])=[C:9]([O:10][CH3:11])[CH:8]=1.[OH-].[Na+]>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.O1CCOCC1>[F:3][CH:2]([F:4])[O:13][C:12]1[CH:14]=[CH:15][C:7]([CH:6]=[O:5])=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: FC(F)Cl
Reactant: COc1cc(C=O)ccc1O
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1cc(C=O)ccc1OC(F)F
Reaction time: 2 h

Procedure:
Chlorodifluoromethane is introduced into a mixture of 200 g of vanillin, 6.7 g of benzyltrimethylammonium chloride, 314 g of 50% strength sodium hydroxide solution and 2 liters of dioxane with vigorous stirring for about 2 h. The mixture is then partitioned between ice water and ethyl acetate, the organic phase is separated off, the aqueous phase is extracted twice by stirring with ethyl acetate, and the combined organic phases are dried over magnesium sulphate and concentrated in vacuo. To remove unreacted vanillin, the oil is chromatographed on neutral silica gel using toluene. After evaporating the eluate, 249 g of 4-difluoromethoxy-3-methoxybenzaldehyde are obtained as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([S:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:17]O>>[OH:1][C:2]1[CH:10]=[C:9]([S:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: CSc1ccc(C(=O)O)c(O)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(SC)cc1O
Temperature: 65 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
The 2-hydroxy-4-(methylthio)benzoic acid (836 mg, 4.54 mmol) was dissolved in MeOH (45 mL). Thionyl chloride (0.35 mL, 4.80 mmol) was added and the solution was heated to 65° C. and left overnight. TLC indicated that there was still starting material present; so more thionyl chloride (1.0 mL, 13.7 mmol) was added. After about 1.5 hour, TLC indicated formation of baseline material; so the reaction was concentrated in vacuo. The crude residue was purified using flash column chromatography (100% CH2Cl2) to give the desired compound as an off-white solid (567 mg, 2.86 mmol, 63%).
Reaction SMILES: [CH:1]([N:4]1[C:8](=[O:9])[CH2:7][S:6][C:5]1=[N:10][OH:11])([CH3:3])[CH3:2].[CH3:12][N:13]=[C:14]=[O:15]>CC(C)=O.C(#N)C.C(N(CC)CC)C>[CH:1]([N:4]1[C:8](=[O:9])[CH2:7][S:6][C:5]1=[N:10][O:11][C:14](=[O:15])[NH:13][CH3:12])([CH3:3])[CH3:2]
Reactant: CC(C)N1C(=O)CSC1=NO
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CC(C)=O
Product: CNC(=O)ON=C1SCC(=O)N1C(C)C
Reaction time: 8 h

Procedure:
To a solution of 1.0 g of 3-isopropyl-2-oximino-4-thiazolidinone in 50 ml acetone-acetonitrile solution (1:1) was added 1 ml of methylisocyanate and 5 drops of triethylamine. The reaction mixture was placed in a pressure bottle and left overnight at ambient temperature. After concentrating under vacuo the residual oil was diluted with diethylether. On cooling the product crystallized. Recrystallized from ethyl ether. Weight 1.8 g. m.p. 94°-96°C.