Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O)(=O)=O.[NH2:6][C:7]1[C:15](=[O:16])[N:10]2[CH2:11][CH2:12][CH2:13][CH2:14][N:9]2[C:8]=1[NH2:17].[NH2:18][C:19]1[C:20]([Cl:27])=[C:21]([OH:26])[C:22]([CH3:25])=[CH:23][CH:24]=1.N.OO>O.C(O)C>[NH2:17][C:8]1[N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][N:10]2[C:15](=[O:16])[C:7]=1[N:6]=[C:24]1[CH:23]=[C:22]([CH3:25])[C:21](=[O:26])[C:20]([Cl:27])=[C:19]1[NH2:18]
Reactant: Nc1c(N)n2n(c1=O)CCCC2
Reactant: Cc1ccc(N)c(Cl)c1O
Agent: CS(=O)(=O)O
Agent: N
Agent: OO
Solvent: CCO
Solvent: O
Product: CC1=CC(=Nc2c(N)n3n(c2=O)CCCC3)C(N)=C(Cl)C1=O

Procedure:
0.68 mmol of 2,3-diamino-5,6,7,8-tetrahydro-1H-pyrazolo[1,2-a]pyridazin-1-one methanesulfonate was dissolved in a mixture of water and ethanol (7.5 ml/1.5 ml). This solution was admixed with 0.68 mmol of 3-amino-2-chloro-6-methylphenol, then with 1.8 ml of concentrated aqueous ammonia, then with 9 ml of hydrogen peroxide.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9][C@H:8]2[CH2:21][S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])[C:3]1=[O:27].[F:28][C:29]([F:40])([F:39])[C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](O)=[O:34].C(N(C(C)C)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:25]([S:22]([CH2:21][C@H:8]1[C@@H:7]([N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:33](=[O:34])[C:32]3[CH:36]=[CH:37][CH:38]=[C:30]([C:29]([F:28])([F:39])[F:40])[CH:31]=3)[C:3]2=[O:27])[CH2:12][CH2:11][C@@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9]1)(=[O:24])=[O:23])[CH3:26]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: CCS(=O)(=O)C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Agent: CCN(CC)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCS(=O)(=O)C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)c2cccc(C(F)(F)F)c2)C1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A sample of tert-butyl (1R,3R,4S)-4-((S)-3-amino-2-oxopyrrolidin-1-yl)-3-(ethylsulfonylmethyl)cyclohexylcarbamate (100 mg, 0.25 mmol) in DMF (10 mL) was charged with 3-(trifluoromethyl)benzoic acid (57 mg, 0.29 mmol), N,N-diethylisopropylamine (0.05 mL, 0.29 mmol), and HATU (114 mg, 0.29 mmol). The reaction was stirred for 48 h at RT and then partitioned between EtOAc and sat. NaHCO3; the aqueous phase was back extracted with EtOAc (1×). The organic phases were combined, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to afford tert-butyl (1R,3R,4S)-3-(ethylsulfonylmethyl)-4-((S)-2-oxo-3-(3-(trifluoromethyl)benzamido)pyrrolidin-1-yl)cyclohexylcarbamate. MS found: (M+H)+=578.
Reaction SMILES: [O:1]([C:8]1[C:9]2[NH:16][C:15]([C:17]([NH2:19])=O)=[CH:14][C:10]=2[N:11]=[CH:12][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>P(Cl)(Cl)(Cl)=O>[O:1]([C:8]1[C:9]2[NH:16][C:15]([C:17]#[N:19])=[CH:14][C:10]=2[N:11]=[CH:12][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1cc2ncnc(Oc3ccccc3)c2[nH]1
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cc2ncnc(Oc3ccccc3)c2[nH]1
Temperature: 70 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
4-Phenoxy-5H-pyrrolo[3,2-d]pyrimidine-6-carboxamide (1.67 g) was suspended in phosphorus oxychloride (20 mL), and the suspension was stirred at 70° C. for 3 hrs. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (25 mL). Water and aqueous ammonia were added to the solution, and the mixture was extracted with a mixed solvent of ethyl acetate/tetrahydrofuran=1/1. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=90:10→67:33) to give the title compound (1.07 g) as a pale-yellow powder.
Reaction SMILES: C([O:5][C:6](=[O:49])[CH2:7][N:8]([C:18](=[O:48])[C@H:19]([CH3:47])[NH:20][C@@H:21]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:22][CH2:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][N:29](C(OCC2C=CC=CC=2)=O)[CH2:28][CH2:27]1)[CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)(C)(C)C.[BrH:50].C(O)(=O)C.C(OCC)C>C(O)(=O)C>[BrH:50].[BrH:50].[CH2:45]([O:44][C:42]([C@H:21]([NH:20][C@H:19]([C:18]([N:8]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)[CH2:7][C:6]([OH:49])=[O:5])=[O:48])[CH3:47])[CH2:22][CH2:23][CH2:24][CH2:25][CH:26]1[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]1)=[O:43])[CH3:46]
Reactant: CCOC(=O)[C@@H](CCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@@H](C)C(=O)N(CC(=O)OC(C)(C)C)C1Cc2ccccc2C1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOC(=O)[C@@H](CCCCC1CCNCC1)N[C@@H](C)C(=O)N(CC(=O)O)C1Cc2ccccc2C1
Reaction time: 1 h

Procedure:
In 2 ml of acetic acid is dissolved 0.35 g of N-[N-[(R)-5-(1-benzyloxycarbonyl-4-piperidyl)-1-ethoxycarbonylpentyl]-L-alanyl]-N-(indan-2-yl)glycine tert-butyl ester, and 2 ml of 30% hydrogen bromide-acetic acid solution is added to the solution, followed by standing at room temperature for 1 hour. 50 ml of ethyl ether is added to the reaction mixture, followed by shaking, and the supernatant layer is removed by decantation. The colorless precipitate is rinsed with ethyl ether and dried under reduced pressure to give 0.3 g of N-[N-[(R)-1-ethoxycarbonyl-5-(4-piperidyl)pentyl]-L-alanyl]-N-(indan-2-yl)glycine.dihydrobromide as a colorless powder.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:3][CH2:4]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:31]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:3][CH2:4][Br:31]
Reactant: CC(C)CCCC(C)CCO
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)CCCC(C)CCBr
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 3,7-dimethyl-1-octanol (50.0 ml, 0.264 mol) and triphenylphosphine (86.9 g, 0.331 mol) in 300 ml of CH2Cl2 were added N-bromosuccinimide (56.6 g, 0.318 mol) in portions at 0° C. After stirring at 0° C. for 2 h, the solvent was evaporated. The residue was treated with hexane and filtered. The solids were washed thoroughly with hexane and the combined hexane extracts evaporated. The residue was chromatographed on silica gel with hexane. Yield=54.13 g (93% based on 50.0 ml of 3,7-dimethyl-1-octanol). 1H NMR (360 MHz, CDCl3): δ 3.37-3.50 (m, 2H, —CH2Br), 1.07-1.94 (m, 10H, (CH3)2CHCH2CH2CH2CH(CH3)CH2CH2Br), 0.89 (d, 3H, J=6.5 Hz, —CH3), 0.87 (d, 6H, J=6.8 Hz, —CH3). CI MS m/z: 220.048 (M+) (calcd 220.083).
Reaction SMILES: Br[C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].[CH3:22][O:23][CH2:24][CH2:25][NH2:26].O>O1CCOCC1>[Cl:18][C:8]1[CH:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:12]([Cl:13])[C:7]=1[N:6]1[C:2]([NH:26][CH2:25][CH2:24][O:23][CH3:22])=[C:3]([N+:19]([O-:21])=[O:20])[CH:4]=[N:5]1
Reactant: O=[N+]([O-])c1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1Br
Reactant: COCCN
Solvent: C1COCCO1
Solvent: O
Product: COCCNc1c([N+](=O)[O-])cnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Yield: 55.1 %

Procedure:
12.0 g (0.03 mole) of 5-bromo-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-nitro-pyrazole and 10 g (0.13 mole) of 2-methoxyethylamine are stirred in 50 ml of dioxane at 50° C. to 60° C. for 12 hours. For working up, the cooled reaction mixture is poured into water and extracted several times with chloroform. The combined organic phases are washed with water, dried over sodium sulphate and concentrated in vacuo and the residue is crystallized with ligroin. 6.6 g (55% of theory) of 1-(2,6-dichloro-4-trifluoromethyl-phenyl)-5-(2-methoxyethylamino)-4-nitro-pyrazole of melting point 85° C.-90° C. are obtained.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH2:9]([O:16][C:17]1[C:18]([NH:24][C:25]2[S:26][CH:27]=[C:28]([CH2:30][CH3:31])[N:29]=2)=[N:19][CH:20]=[C:21]([Br:23])[CH:22]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(OCC)(=O)C>C(#N)C>[CH2:9]([O:16][C:17]1[C:18]([NH:24][C:25]2[S:26][C:27]([Cl:1])=[C:28]([CH2:30][CH3:31])[N:29]=2)=[N:19][CH:20]=[C:21]([Br:23])[CH:22]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCc1csc(Nc2ncc(Br)cc2OCc2ccccc2)n1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCc1nc(Nc2ncc(Br)cc2OCc2ccccc2)sc1Cl
Reaction time: 1 h
Yield: 56.6 %

Procedure:
1-Chloropyrrolidine-2,5-dione (0.103 g, 0.769 mmol) was added to a solution of 3-(benzyloxy)-5-bromo-N-(4-ethylthiazol-2-yl)pyridin-2-amine (0.25 g, 0.641 mmol) in acetonitrile (6 mL). The reaction mixture was stirred for 1 hour and then partitioned between ether and water. The organic layer was washed with brine, dried, and concentrated. The residue was purified by MPLC (Biotage) eluting with 6:1 hexane:ethyl acetate to afford 3-(benzyloxy)-5-bromo-N-(5-chloro-4-ethylthiazol-2-yl)pyridin-2-amine (0.154 g, 56.6% yield) as a light yellow powder. 1H NMR (DMSO-d6) δ 1.17 (t, 3H), 2.58 (q, 2H), 5.28 (s, 2H), 7.30-7.43 (m, 3H), 7.59 (d, 2H), 7.66 (s, 1H), 7.98 (s, 1H), 10.79 (bs, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:30])[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[C@H:25]([CH2:26][OH:27])[CH2:24][O:23][C:22]3=[O:28])=[CH:17][C:16]=2[F:29])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:31]I>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:30])[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[C@H:25]([CH2:26][O:27][CH3:31])[CH2:24][O:23][C:22]3=[O:28])=[CH:17][C:16]=2[F:29])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3CO)cc2F)CC1
Product: COC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c(F)c1
Yield: 69.1 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 93 and using (R)-4-[2-fluoro-4-(4-hydroxymethyl-2-oxooxazolidin-3-yl)benzoyl]piperazine-1-carboxylic acid tert-butyl ester (1.64 g) described in Preparation Example 156 and methyl iodide (658 mg), the title compound (1.17 g) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[C:8]2[CH:14]=[CH:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].C1C(=O)N([Cl:36])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(OOC(C1C=CC=CC=1)=O)(C1C=CC=CC=1)=O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[C:8]2[C:14]([Cl:36])=[CH:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2c(ccn2Cc2ccccc2)c1OC(=O)C(C)(C)C
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ncc2c(c(Cl)cn2Cc2ccccc2)c1OC(=O)C(C)(C)C
Yield: 91.8 %

Procedure:
A mixture of 1-benzyl-4-(2,2-dimethyl-propionyloxy)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester (67 mg, 0.176 mmol), NCS (28 mg), BzOOBz (2.3 mg) in carbon tetrachloride (2 mL) was refluxed for 1 h; then cooled, solvent was removed and the residue was purified with column to give the desired product (67 mg). 1H NMR (200 MHz, CDCl3): δ (ppm)=8.63 (s, 1H), 7.4-7.2 (m, 6H), 5.35 (s, 2H), 4.41 (q, J=7.1 Hz), 1.46 (s, 9H), 1.41 (t, 3H, J=7.1 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:9]([OH:11])=[S:10])=[C:5]([CH3:8])[S:6][CH:7]=1.[Cl:12]N1C(=O)CCC1=O.O>C(Cl)(Cl)Cl.C(O)(=O)C>[Cl:12][C:7]1[S:6][C:5]([CH3:8])=[C:4]([C:9]([OH:11])=[S:10])[C:3]=1[O:2][CH3:1]
Reactant: COc1csc(C)c1C(O)=S
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: COc1c(Cl)sc(C)c1C(O)=S
Reaction time: 2 h

Procedure:
Equimolecular amounts of the thiophene (d) above and N-chlorosuccinimide were dissolved in 1/1 chloroform/acetic acid mixture. The mixture was stirred for two hours and then poured into water. The organic layer was washed with 10% aqueous sodium hydroxide, dried over sodium sulphate and the solvent evaporated. The carboxylic acid was purified by recrystallisation from ethanol, m.p. 193°-194° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:13]2[C:12]3[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH2:4][CH2:3]1.Br[CH:18]=[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[F:27])[CH3:20].N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.[Cu]I>[F:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1/[C:19](/[CH3:20])=[CH:18]/[N:6]1[C:7]2[CH:8]=[CH:9][C:10]([CH3:16])=[CH:11][C:12]=2[C:13]2[CH2:14][CH2:15][N:2]([CH3:1])[CH2:3][CH2:4][C:5]1=2
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)CC3
Reactant: CC(=CBr)c1ccccc1F
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(C)ccc31)CCN(C)CC2)c1ccccc1F
Temperature: 85 °C

Procedure:
3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (214 mg, 1 mmol), 1-(1-bromoprop-1-en-2-yl)-2-fluorobenzene (260 mg, 1.2 mmol), L-proline (0.2 mmol), CuI (19 mg, 0.1 mmol) and potassium phosphate tribasic (424 mg, 2 mmol) in DMF was stirred at RT and purged with nitrogen. The reaction mixture was heated at 85° C. overnight. An additional 1 eq. of reagents was added and the mixture heated for an additional 24 h. The DMF was evaporated and the residue was poured into water. The precipitate obtained was filtered and purified by silica gel chromatography (100-200-mesh) using 0-5% MeOH:DCM as eluant followed by reverse phase HPLC to separate the isomers. 1HNMR (CDCl3, TFA salt) δ (ppm): 7.42 (m, 1H), 7.33 (m, 1H), 7.28 (s, 1H), 7.24 (d, 1H), 7.18 (dd, 1H), 7.11 (d, 1H), 7.09 (d, 1H), 6.72 (s, 1H), 3.82 (m, 2H), 3.40 (m, 1H), 3.30 (m, 5H), 3.0 (s, 3H), 2.45 (s, 3H), 1.90 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:12](=[O:14])[CH3:13])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nc(N)ccc1[N+](=O)[O-]
Product: CC(=O)Nc1ccc([N+](=O)[O-])c(C)n1

Procedure:
6-Methyl-5-nitro-pyridin-2-ylamine (1.0 g) was treated with acetic anhydride according to General Procedure Y to give N-(6-Methyl-5-nitro-pyridin-2-yl)-acetamide (1.2 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([C:8]([NH2:10])=O)=[N:3]1>P(Cl)(Cl)(Cl)=O>[CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([C:8]#[N:10])=[N:3]1
Reactant: Cc1cc(C(N)=O)nn1C
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(C#N)nn1C
Yield: 89.4 %

Procedure:
The method described in Part E of Examples 1 through 4 was used to treat 1,5-dimethyl-1H-pyrazole-3-carboxamide (5.0 g, 36 mmol) with phosphorous oxychloride (20 mL) to afford 3.9 g of 1,5-dimethyl-1H-pyrazole-3-carbonitrile. A small portion was recrystallized from hexane to provide the following data.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([F:18])[C:15]([C:19]2[C:24]([F:25])=[CH:23][C:22]([C:26]([F:29])([F:28])[F:27])=[CH:21][N:20]=2)=[CH:14][C:3]=1[O:4][C@H:5]([CH3:13])[C:6]([O:8]CC(C)C)=[O:7]>C(O)(=O)C.Cl>[Cl:1][C:2]1[CH:17]=[C:16]([F:18])[C:15]([C:19]2[C:24]([F:25])=[CH:23][C:22]([C:26]([F:29])([F:27])[F:28])=[CH:21][N:20]=2)=[CH:14][C:3]=1[O:4][C@H:5]([CH3:13])[C:6]([OH:8])=[O:7]
Reactant: CC(C)COC(=O)[C@@H](C)Oc1cc(-c2ncc(C(F)(F)F)cc2F)c(F)cc1Cl
Agent: Cl
Solvent: CC(=O)O
Product: C[C@@H](Oc1cc(-c2ncc(C(F)(F)F)cc2F)c(F)cc1Cl)C(=O)O

Procedure:
2.0 g (0.0046 mol) of the compound of Example 9 were stirred at 80° C. in a mixture of 35 ml of glacial acetic acid and 15 ml of 2 N hydrochloric acid for 3 h. After cooling, the mixture was partitioned between methylene chloride and water and the organic phase was dried and concentrated. 1.6 g (91.7% of theory) of the title compound of mp. 48-50° C. were obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:10][C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28]O)=[CH:22][N:21]=1)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:44]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.F.F.F.C(N(CC)CC)C>O1CCCC1.O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:10][C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][F:44])=[CH:22][N:21]=1)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(CCCO)cn1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(CCCF)cn1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 24 h

Procedure:
Di-tert-butyl (4R)—N-(tert-butoxycarbonyl)-4-{[5-(3-hydroxypropyl)pyridin-2-yl]methyl}-L-glutamate (68 mg, 0.13 mmol) was dissolved in 2 ml tetrahydrofuran, and cooled to 0° C. Triethylamine (280 μl, 2.01 mmol), 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride (162 mg, 0.53 mmol), and triethylamine trihydrofluoride (86 mg, 0.53 mmol) were added, and the reaction was stirred at room temperature for 24 h. The same amounts of triethylamine, 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride and triethylamine trihydrofluoride were added again and the reaction was continued for 1 h. Water (10 ml) was added, and the mixture was extracted with dichloromethane (3×10 ml). The organic phases were dried over magnesium sulfate and concentrated. The so derived material was used without further purification.
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([Br:11])=[CH:6][C:5]=1[CH2:12]Br.[O:15]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[Br:11][C:7]1[CH:6]=[C:5]2[C:4](=[C:9]([Cl:10])[CH:8]=1)[C:3](=[O:14])[N:27]([CH2:26][C:25]1[CH:28]=[CH:29][C:22]([O:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:23][CH:24]=1)[CH2:12]2
Reactant: COC(=O)c1c(Cl)cc(Br)cc1CBr
Reactant: NCc1ccc(Oc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1c2c(Cl)cc(Br)cc2CN1Cc1ccc(Oc2ccccc2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 29.2 %

Procedure:
A mixture of 4-bromo-2-bromomethyl-6-chloro-benzoic acid methyl ester (0.492 g, 1.6 mmol), 4-phenoxy-benzylamine (0.256 mL, 2.0 mmol), and K2CO3 (0.414 g, 3 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 5-bromo-7-chloro-2-(4-phenoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.200 g, 32%). GC-MS: m/z 429 (M)+, 336 (M−93)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]([C:14]1[N:15]=[C:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[S:17][CH:18]=1)[C:9]([O:11]CC)=[O:10].[OH-].[Na+].O.Cl>C(OCC)(=O)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]([C:14]1[N:15]=[C:16]([NH:19][S:20]([CH3:23])(=[O:21])=[O:22])[S:17][CH:18]=1)[C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)C(OC1CCCCO1)c1csc(NS(C)(=O)=O)n1
Agent: CCOC(=O)C(OC1CCCCO1)c1csc(=NS(C)(=O)=O)[nH]1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1nc(C(OC2CCCCO2)C(=O)O)cs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To ethyl 2-(2-tetrahydropyranyl)oxy-2-(2-mesylamino-1,3-thiazol-4-yl)acetate, which can be represented as ethyl 2-(2-tetrahydropyranyl)oxy-2-(2-mesylimino-2,3-dihydro-1,3-thiazol-4-yl)acetate, (0.85 g.) was added 1H sodium hydroxide aqueous solution prepared by sodium hydroxide (0.28 g.) and water (7 ml.), and then the mixture was stirred for 1 hour at room temperature. After the reaction, to the reaction mixture was added ethyl acetate. The mixture was adjusted to pH 1 to 2 with 2 N hydrochloric acid, and the aqueous layer was separated. The aqueous layer was subjected to salting-out and then extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then the solvent was distilled off to give a foamy substance of 2-(2-tetrahydropyranyl)oxy-2-(2-mesylamino-1,3-thiazol-4-yl)acetic acid, which can be represented as 2-(2-tetrahydropyranyl)oxy-2-(2-mesylimino-2,3-dihydro-1,3-thiazol-4-yl)acetic acid, (0.52 g.).
Reaction SMILES: Cl[C:2]1[C:3]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])(=[O:11])=[O:10])=[N:4][CH:5]=[CH:6][N:7]=1.[C:22]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)([OH:24])=[O:23]>>[F:19][C:18]([F:21])([F:20])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[S:9]([NH:8][C:3]1[C:2]([C:28]2[CH:29]=[CH:30][C:25]([C:22]([OH:24])=[O:23])=[CH:26][CH:27]=2)=[N:7][CH:6]=[CH:5][N:4]=1)(=[O:11])=[O:10]
Reactant: O=S(=O)(Nc1nccnc1Cl)c1ccccc1C(F)(F)F
Reactant: O=C(O)c1ccc(B(O)O)cc1
Product: O=C(O)c1ccc(-c2nccnc2NS(=O)(=O)c2ccccc2C(F)(F)F)cc1
Yield: 80 %

Procedure:
Following the general method as outlined for Intermediate 4, starting from N-(3-chloropyrazin-2-yl)-2-(trifluoromethyl)benzenesulfonamide and 4-carboxybenzene boronic acid, the title compound was isolated, after evaporation and recrystallization, as a yellowish solid in 80% yield (98% purity by HPLC).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[N:6](C)[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([F:14])=[CH:9][CH:8]=2)=O.CNC(C1N(C)C2C(C=1)=CC=CC=2)=O>>[F:14][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[NH:6][C:5]([CH2:3][NH:2][CH3:1])=[CH:13]2
Reactant: CNC(=O)c1cc2cc(F)ccc2n1C
Agent: CNC(=O)c1cc2ccccc2n1C
Product: CNCc1cc2cc(F)ccc2[nH]1
Yield: 78 %

Procedure:
According to the procedure of Preparation 1(c), except substituting N,1-dimethyl-5-fluoro-1H-indole-2-carboxamide for the N,1-dimethyl-1H-indole-2-carboxamide, the title compound (1.5 g, 78%) was prepared as a white solid: MS (ES) m/e 193 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5](Cl)=[N:4][CH:3]=1.[CH2:12]([NH2:14])[CH3:13]>>[CH2:12]([NH:14][C:5]1[C:6]2[N:7]([CH:8]=[CH:9][N:10]=2)[C:2]([Cl:1])=[CH:3][N:4]=1)[CH3:13]
Reactant: Clc1ncc(Cl)n2ccnc12
Reactant: CCN
Product: CCNc1ncc(Cl)n2ccnc12
Reaction time: 12 h

Procedure:
A solution of 1.5 g (9.8 mmol) of 5,8-dichloroimidazo[ 1,2-a]pyrazine in 25 ml of a 40% strength aqueous ethylamine solution is maintained with stirring for 12 hours. After concentration under reduced pressure and chromatography on a silica column (eluant=ether), 5-chloro-8-ethylaminoimidazo[1,2-a]pyrazine (m.p. 94° C.), is obtained.
Reaction SMILES: C([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)=[CH:7][CH:6]=1)C.O.[OH-].[Li+]>C1COCC1>[F:19][C:16]([F:17])([F:18])[C:14]1[O:13][N:12]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:4]([OH:20])=[O:3])=[CH:6][CH:7]=2)[CH:15]=1
Reactant: CCOC(=O)c1ccc(-c2cc(C(F)(F)F)on2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2cc(C(F)(F)F)on2)cc1
Reaction time: 16 h
Yield: 73.2 %

Procedure:
A solution of 4-(5-Trifluoromethyl-isoxazol-3-yl)-benzoic acid ethyl ester (Preparative Example 9, 2.25 g, 7.86 mmol) in THF (20 mL) was treated with an aqueous solution (5 mL) of lithium hydroxide monohydrate (660 mg, 15.72 mmol) and allowed to stir for 16 hr. The reaction was then evaporated to a small volume and treated with a 1 N aqueous hydrochloric acid solution (25 mL) and the resulting solids filtered, washed with water and air dried to afford product as a colorless solid (1.48 g, 73%). 1H NMR (DMSO-d6) 8.06 (s, 4H), 8.13 (s, 1H). 13C NMR 106.5, 118.0 (q, J=270), 127.9, 130.8, 131.2, 132.4, ˜150 quartet not resolved from baseline noise, 133.8, 162.8, 167.3. 19F NMR −63.6. LC/MS 6.04 min, [M+1]+ 258.