Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([CH:14]=1)[C:12]#[N:13].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:3][CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([CH:14]=1)[C:12]#[N:13]
Reactant: N#Cc1cncc(CO)c1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1cncc(CCl)c1
Reaction time: 0.33 h
Yield: 9.6 %

Procedure:
Add thionyl chloride (1 mL) to a solution of 5-hydroxymethyl-nicotinonitrile (45 mg, 0.34 mmol, 1 equiv) in anhydr CH2Cl2 (1 mL). After 20 min, basify the reaction with satd aq NaHCO3 (12 mL). Extract this mixture with Et2O (2×5 mL). Dry the combined organic layers (anhydr MgSO4) and rotary evaporate (40° C.) to yield 4.9 mg (9.6%) of 5-chloromethyl-nicotinonitrile as a yellow film. MS (m/z): 152.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:14]2[CH2:15][CH2:16][CH:6]1[C:7]1[CH:8]=[C:9]([NH2:17])[CH:10]=[CH:11][C:12]=1[CH2:13]2.Cl[C:19]1[N:24]=[C:23]([NH:25][C@@H:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]2[NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[C:22]([Cl:37])=[CH:21][N:20]=1>>[Cl:37][C:22]1[C:23]([NH:25][C@@H:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]2[NH:32][S:33]([CH3:36])(=[O:35])=[O:34])=[N:24][C:19]([NH:17][C:9]2[CH:10]=[CH:11][C:12]3[CH2:13][CH:14]4[N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH:6]([CH2:16][CH2:15]4)[C:7]=3[CH:8]=2)=[N:20][CH:21]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: COCCN1C2CCC1c1cc(N)ccc1C2
Product: COCCN1C2CCC1c1cc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)ccc1C2
Yield: 46.5 %

Procedure:
Following procedures analogous to 61e, 12-(2-Methoxy-ethyl)-12-aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-trien-4-ylamine (95 mg, 0.41 mmol) and N-[(1R,2R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (139 mg, 0.41 mmol) were converted to the title compound as a white solid (102 mg, 47%) %) isolated as a mixture of diastereomers. 1HNMR (400 MHz, CDCl3) δ 7.9 (s, 1H), 7.3-7.2 (m, 2H), 7.0 (d, 1H, J=7.8 Hz), 6.8 (s, 1H), 5.4 (m, 1H), 5.3 (m, 1H), 4.0 (m, 1H), 3.9 (m, 1H), 3.7-3.5 (m, 3H), 3.3 (appt d, 3H), 3.2-3.1 (m, 2H), 2.9-2.7 (m, 5H), 2.4-2.2 (m, 4H), 1.9-1.8 (m, 3H), 1.7-1.5 (m, 3H), 1.4-1.3 (m, 3H); MS (m/e) 535 (M+1); mp 130-134° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][C:15]([CH2:19][N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)=[CH:14][N:13]=2)([O-])=O.C(O)(=O)C.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.[Fe]>[N:20]1([CH2:19][C:15]2[CH:16]=[C:17]3[N:18]=[C:10]([C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[NH2:1])[S:11][C:12]3=[N:13][CH:14]=2)[CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: O=[N+]([O-])c1ccccc1-c1nc2cc(CN3CCCC3)cnc2s1
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Nc1ccccc1-c1nc2cc(CN3CCCC3)cnc2s1
Temperature: 25 °C
Yield: 98.7 %

Procedure:
Iron powder (55 mmol, 3.1 g) was added to a solution of 2-(2-nitrophenyl)-6-(pyrrolidin-1-ylmethyl)thiazolo[5,4-b]pyridine (11.1 mmol, 3.8 g) in CH2Cl2 (100 mL) followed by acetic acid (10 mL). The reaction mixture was heated at reflux for 3 hours then cooled to room temperature. Na2CO3 (14 g) was added in portions. The mixture was passed through a pad of celite and rinsed with CH2Cl2. The combined filtrates were washed with Na2CO3 (3×20 mL), dried (MgSO4) and concentrated under reduced pressure to give 2-(6-(pyrrolidin-1-ylmethyl)thiazolo[5,4-b]pyridin-2-yl)aniline (3.4 g, 98% yield) as a yellow solid.
Reaction SMILES: [CH2:1]([NH:11][C:12](=[O:16])[CH2:13][C:14]#[N:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:17][C:18](=O)[CH2:19][C:20](=O)[CH3:21].N1CCCCC1>>[CH2:1]([N:11]1[C:18]([CH3:17])=[CH:19][C:20]([CH3:21])=[C:13]([C:14]#[N:15])[C:12]1=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CC(=O)CC(C)=O
Reactant: CCCCCCCCCCNC(=O)CC#N
Solvent: C1CCNCC1
Product: CCCCCCCCCCn1c(C)cc(C)c(C#N)c1=O

Procedure:
A mixture of N-(n-decyl)cyanoacetamide (93.4 g., 0.417 mole), 2.4-pentanedione (41.7 g., 0.417 mole), piperidine (8 ml.) and 2 B-ethanol (500 ml.) is stirred and refluxed for 17 hours. The mixture is cooled in an ice bath and the solid which crystallizes out is collected by filtration to give 1-(n-decyl)-3-cyano-4,6-dimethylpyrid-2-one, 95.2 g. mp. 82°-83° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5](Br)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C1(N(C)C)CCCCC1.[CH3:25][C:26]([N:28]([CH3:30])C)=O.CN1[C:36]([CH3:37])=[CH:35][C:34]([C:38]([F:41])([F:40])[F:39])=[N:33]1>C1(C)C=CC=CC=1.O>[CH:36]([C:35]1[CH:34]([C:38]([F:41])([F:40])[F:39])[N:33]([C:5]2[CH:4]=[C:3]([C:2]([F:15])([F:14])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=2)[N:28]([CH3:30])[C:26]=1[CH3:25])=[CH2:37]
Reactant: Cc1cc(C(F)(F)F)nn1C
Reactant: FC(F)(F)c1cc(Br)cc(C(F)(F)F)c1
Reactant: CC(=O)N(C)C
Solvent: Cc1ccccc1
Solvent: CN(C)C1CCCCC1
Solvent: O
Product: C=CC1=C(C)N(C)N(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1C(F)(F)F
Temperature: 110 °C
Reaction time: 3 h

Procedure:
10 g of 3,5-bis(trifluoromethyl)bromobenzene are mixed with 11 ml of cyclohexyldimethylamine and 30 ml of dimethylacetamide and degassed. 38 mg of palladium acetate and 152 mg of di(tert-butyl)phenylphosphine are dissolved in 5 ml of dimethylacetamide and added to the mixture. The mixture is transferred to an autoclave and 30 bar of ethylene are injected. The mixture is then heated to 110° C. and stirred at this temperature for 3 hours. At the end of the reaction, the mixture is cooled and the pressure released. Subsequently, 8.3 g of 1,5-dimethyl-3-trifluoromethyl-1H-pyrazole are added to the reaction mixture and the mixture is heated to 130° C. for 12 h. Afterwards, the mixture is cooled, added to water and worked up with toluene. Yield over the two steps: 10.5 g (76%) of slightly brownish solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10](=O)[C:11]([O:13][CH3:14])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[NH2:17][OH:18]>N1C=CC=CC=1.O>[N+:1]([C:4]1[CH:5]=[C:6](/[C:10](=[N:17]\[OH:18])/[C:11]([O:13][CH3:14])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[N+:1]([C:4]1[CH:5]=[C:6](/[C:10](=[N:17]/[OH:18])/[C:11]([O:13][CH3:14])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: NO
Reactant: COC(=O)C(=O)c1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)/C(=N/O)c1cccc([N+](=O)[O-])c1
Product: COC(=O)/C(=N\O)c1cccc([N+](=O)[O-])c1

Procedure:
Methyl (E)-3-nitro-alpha-hydroxyiminophenylacetate can be obtained as in Example 9 for the preparation of ethyl (E)-3-nitro-alpha-hydroxyiminophenylacetate, but starting from 15 g of methyl 3-nitrophenylglyoxylate and 10 g of hydroxylamine hydrochloride in a mixture of 250 cm3 of pyridine and 30 cm3 of water, for 30 minutes at 70° C. After treatment, 3.4 g of methyl (E)-3-nitro-alpha-hydroxyiminophenylacetate melting at 140° C. and 6.1 g of methyl (Z)-3-nitro-alpha-hydroxyiminophenylacetate melting at 190° C. are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:6][N:7]=[CH:8][C:9]1[S:17][C:12]2[N:13]=[CH:14][N:15]=[CH:16][C:11]=2[CH:10]=1.N1[CH2:28][CH2:27][NH:26][CH2:25]C1>C1COCC1.CCOC(C)=O.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:6][N:7]1[C:8]([C:9]2[S:17][C:12]3[N:13]=[CH:14][N:15]=[CH:16][C:11]=3[CH:10]=2)=[C:27]([C:28]2[CH:5]=[CH:4][CH:3]=[CH:20][CH:19]=2)[N:26]=[CH:25]1
Reactant: COc1ccc(CN=Cc2cc3cncnc3s2)cc1OC
Reactant: C1CNCCN1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Cn2cnc(-c3ccccc3)c2-c2cc3cncnc3s2)cc1OC
Yield: 96.2 %

Procedure:
N-(3,4Dimethoxybenzyl)-N-[thieno[2,3-d]pyrimidin-6-ylmethylidene]amine (intermediate 14) (76 mg), PhTosMIC (99 mg) and piperazine (31 mg) in THF (5 mL) were stirred under an inert atmosphere for 6 days. The reaction mixture was diluted with EtOAc and water. The organic layer was separated and the aqueous layer extracted with EtOAc (2×15 mL). The combined organics were dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica eluting with hexane:EtOAc (1:4) afforded the title compound as a pale yellow solid (50 mg, 48%);
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[F:7][C:8]([F:12])([F:11])[CH:9]=[CH2:10]>C1(C)C=CC=CC=1>[F:7][C:8]([F:12])([F:11])[CH2:9][CH2:10][S:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5]
Reactant: O=C(O)CCS
Reactant: C=CC(F)(F)F
Solvent: Cc1ccccc1
Product: O=C(O)CCSCCC(F)(F)F
Temperature: 20 °C
Reaction time: 24 h
Yield: 101 %

Procedure:
A 100 mL stainless steel Parr reactor was charged with 3-mercaptopropionic acid (3.67 g, 34.6 mmol), toluene (30.26 g), and 2,2′-azobis(4-methoxy-2,4-dimethyl) valeronitrile (V-70, 0.543 g, 1.76 mmol) and the reactor was cooled with a dry ice/acetone bath, purged with nitrogen, and pressure checked. 3,3,3-Trifluoropropene (3.20 g, 33.3 mmol) was added via transfer cylinder and the reaction was allowed to warm to 20° C. After 24 hours, the reaction was heated to 50° C. for 1 hour to decompose any remaining V-70 initiator. The reaction was allowed to cool to room temperature. The solution was concentrated by rotary evaporation to provide the title compound (6.80 g, 77.5 wt % linear isomer by GC internal standard assay, 5.27 g active, 76%, 200:1 linear:branched by GC, 40:1 linear:branched by fluorine NMR).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH:4]=O.[CH3:11][C:12]([CH3:14])=[O:13].[OH-].[Ca+2].[OH-]>O>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH:4]=[CH:11][C:12](=[O:13])[CH3:14]
Reactant: CC(C)=O
Reactant: Cc1cccc(C)c1C=O
Agent: [Ca+2]
Agent: [OH-]
Solvent: O
Product: CC(=O)C=Cc1c(C)cccc1C
Yield: 90 %

Procedure:
13.4 g (0.1 mol) of 2,6-dimethylbenzaldehyde, 100 ml of acetone, 100 ml of water and 2 g of calcium hydroxide are mixed together and refluxed for about 20-25 h with agitation. The precipitate is filtered off from the cold reaction mixture. 1 l of ice water is added to the filtrate with agitation. The product is crystallized at a yield of about 90%. M.p. of the recrystallized product: 34°-35° C.
Reaction SMILES: [CH2:1]=[CH:2][N:3]1[C:7](=[O:8])[CH2:6][CH2:5][CH2:4]1.N(C(C)(C)C#N)=N[C:11](C)(C)C#N.[C:21]([O:25][CH2:26][CH2:27][CH2:28]C)(=[O:24])[CH:22]=[CH2:23].CCCCCC>CN(C)C=O>[CH:2]([N:3]1[CH2:4][CH2:5][CH2:6][C:7]1=[O:8])=[CH2:1].[C:21]([O:25][CH:26]([CH2:27][CH3:28])[CH3:11])(=[O:24])[CH:22]=[CH2:23]
Reactant: C=CC(=O)OCCCC
Reactant: CC(C)(C#N)N=NC(C)(C)C#N
Agent: C=CN1CCCC1=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: C=CC(=O)OC(C)CC
Temperature: 60 °C
Reaction time: 6 h
Yield: 94 %

Procedure:
Along with 228 mg (0.08 mmol) of poly(1-vinyl-2-pyrrolidone) macroinitiator prepared in Example 67, 3.3 mg (0.02 mmol) of 2,2′-azobis(isobutyronitrile) and 1.04 g (8.1 mmole) of n-butyl acrylate (same as above) were placed into a glove box with the inside air replaced by nitrogen, followed by stirring at 60° C. for 6 hours. After the completion of the reaction, the reaction mixture was dissolved in 5 ml of N,N-dimethylformamide (DMF), and the solution was then poured into 300 ml of hexane which was being stirred. The resulting polymer precipitate was collected by suction filtration and dried to obtain block copolymer of poly(1-vinyl-2-pyrrolidone-b-n-butyl acrylate) (yield 94%).
Reaction SMILES: [NH2:1]CCN1CCNCC1.[Cl:10][CH2:11][CH2:12][C:13]([N:15]=[C:16]=[O:17])=[O:14]>>[Cl:10][CH2:11][CH2:12][C:13]([NH:15][C:16]([NH2:1])=[O:17])=[O:14]
Reactant: O=C=NC(=O)CCCl
Reactant: NCCN1CCNCC1
Product: NC(=O)NC(=O)CCCl
Yield: 263 %

Procedure:
In the same way, reaction of 6.5 g (50 mmols) of N-(2-aminoethyl)piperazine with 14.3 g (106 mmols) of 3-chloropropionyl isocyanate gives a quantitative yield of 19.8 g of the 3-chloropropionyl urea of the formula ##STR10## Melting point: 125°-130° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1>>[F:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)=[CH:25][CH:26]=1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: Fc1ccc(CBr)cc1
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(Cc3ccc(F)cc3)CC1)O2

Procedure:
Compound 125 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 1-(bromomethyl)-4-fluorobenzene and conditions outlined in procedure V. M.p.=104-106° C.; 400 MHz 1H NMR (CDCl3) δ 8.05 (d, 1H), 7.75 (d, 1H), 7.65 (t, 1H), 7.5 (t, 1H), 7.3 (m, 2H), 7.0 (t, 2H), 3.55 (s, 2H), 2.9 (s, 2H), 2.75 (d, 2H), 2.45 (t, 2H), 2.1 (d, 2H), 1.85 (t, 2H); LCMS: 410 [M+H].
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]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([CH2:40][OH:41])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:42][CH3:43])=[O:5])[CH3:2].[H-].[Na+].CI.[C:48](=O)([O-])O.[Na+]>O1CCCC1>[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:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:27]=[C:28]([C:36]([F:37])([F:38])[F:39])[CH:29]=[C:30]([C:32]([F:35])([F:33])[F:34])[CH:31]=3)[C:22]([CH2:40][O:41][CH3:48])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:42][CH3:43])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(CO)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(COC)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(2R*,4S*)-4-{[3,5-Bis(trifluoromethyl)benzyl]-(5-hydroxymethylpyrimidin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (150 mg) is dissolved in tetrahydrofuran (4 ml), then thereto are added sodium hydride (12 mg) and methyl iodide (0.02 ml) under ice-cooling, and the mixture is stirred at room temperature for 3 hours and 30 minutes. A saturated aqueous sodium hydrogen carbonate solution is added to the reaction solution and the mixture is extracted with 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=4:1→3:2) to give (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-methoxymethylpyrimidin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (92 mg). MS (m/z): 628 [M+H]+
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([CH2:15][C:16](O)=[O:17])[CH:11]=[CH:12][CH:13]=2)[C:8]([N+:19]([O-])=O)=[CH:7]1)[CH3:2]>CC(O)=O.O.[Fe]>[O:17]=[C:16]1[CH2:15][C:10]2[C:9]3=[C:14]([N:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:22])[CH:7]=[C:8]3[NH:19]1)[CH:13]=[CH:12][CH:11]=2
Reactant: CCOC(=O)Cn1cc([N+](=O)[O-])c2c(CC(=O)O)cccc21
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)Cn1cc2c3c(cccc31)CC(=O)N2
Temperature: 80 °C

Procedure:
To a solution of [1-(2-ethoxy-2-oxoethyl)-3-nitro-1H-indol-4-yl]acetic acid from Step F (250 mg, 0.816 mmol) in AcOH (18 mL) and H2O (2 mL) was added iron powder (456 mg, 8.16 mmol) and the reaction mixture was heated at 80° C. for 18 h. The mixture was concentrated in vacuo to remove most of the solvent and the residue was partitioned between saturated aqueous NaHCO3 (5 mL) and EtOAc (25 mL). The organic layer was washed with brine, then dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound, which was of sufficient purity for use in the next step. MS: m/z=259 (M+1).
Reaction SMILES: Cl.[C:2]1([S:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:17][C:18]1[CH:19]=[N:20][C:21](Cl)=[N:22][CH:23]=1.O1CCOCC1.C(N(CC)CC)C>O>[Br:17][C:18]1[CH:19]=[N:20][C:21]([N:14]2[CH2:15][CH2:16][N:11]([S:8]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)(=[O:10])=[O:9])[CH2:12][CH2:13]2)=[N:22][CH:23]=1
Reactant: O=S(=O)(c1ccccc1)N1CCNCC1
Reactant: Clc1ncc(Br)cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: O=S(=O)(c1ccccc1)N1CCN(c2ncc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.5 %

Procedure:
A 250 mL round-bottomed flask was charged with 1-(phenylsulfonyl)piperazine hydrochloride (4.08 g, 15.51 mmol, Example 15, step 1), 5-bromo-2-chloropyrimidine (2.50 g, 12.92 mmol, Sigma-Aldrich, St. Louis, Mo.), and 20 mL of dioxane. To this was added triethylamine (4.50 mL, 32.3 mmol). After stirring at room temperature for 3 h, the mixture was diluted with water (50 mL) and the resulting precipitate was collected by filtration to give 5-bromo-2-(4-(phenylsulfonyl)-1-piperazinyl)pyrimidine (2.50 g) as a white solid.
Reaction SMILES: C(Cl)(=O)[C:2](Cl)=[O:3].[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[O:18][N:17]=[C:16]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=2)[C:22]([NH2:24])=[O:23])[N:15]=1>ClCCl>[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[O:18][N:17]=[C:16]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=2)[C:22]([N:24]=[C:2]=[O:3])=[O:23])[N:15]=1
Reactant: NC(=O)c1cccc(-c2noc(-c3ccccc3F)n2)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: O=C=NC(=O)c1cccc(-c2noc(-c3ccccc3F)n2)c1
Temperature: 0 °C
Reaction time: 6 h
Yield: 94.5 %

Procedure:
Oxalyl chloride (2.5 ml, 28.2 mmol, 2.0 eq.) is then added dropwise under N2 to a suspension of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]benzamide (Compound A3, 4.0 g, 14.1 mmol) in anhydrous dichloromethane (20 mL) cooled to 0° C. The mixture is slowly heated to reflux and stirred for an additional 6 h. The solvent is removed on a rotary evaporator. The residue is azeotroped with anhydrous dichloromethane (20 mL) and dried under high vacuum for two hours to give 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]benzoyl isocyanate (Compound A4) as a tan solid 4.12 g (95%) which may be used immediately without further purification.
Reaction SMILES: [C:1]([C@H:5]([NH:9][NH:10][C:11](=[O:21])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:13]=1[CH3:20])[CH2:6][CH:7]=[CH2:8])([CH3:4])([CH3:3])[CH3:2].C[C@@:23]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:27]([F:30])([F:29])[F:28])[C:24](Cl)=[O:25].[C:37]([O-])([O-])=[O:38].[K+].[K+]>C(Cl)Cl.O>[C:1]([C@H:5]([N:9]([C:24](=[O:25])[C@@:23]([O:38][CH3:37])([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:27]([F:30])([F:29])[F:28])[NH:10][C:11](=[O:21])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:13]=1[CH3:20])[CH2:6][CH:7]=[CH2:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CC[C@@H](NNC(=O)c1cccc(OC)c1C)C(C)(C)C
Reactant: O=C([O-])[O-]
Reactant: C[C@@](C(=O)Cl)(c1ccccc1)C(F)(F)F
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: C=CC[C@@H](N(NC(=O)c1cccc(OC)c1C)C(=O)[C@@](OC)(c1ccccc1)C(F)(F)F)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.6 %

Procedure:
(R)-3-methoxy-2-methyl-benzoic acid N′-(1-tert-butyl-but-3-enyl)-hydrazide (100 mg, 0.344 mmoles) and (R)-(+)-alpha-methyl-alpha-(trifluoromethyl)-phenylacetyl chloride (104 mg, 0.413 mmoles) were dissolved in 1.5 mL methylene chloride in a vial. A solution of K2CO3 (95 mg, 0.69 mmoles) in ca. 0.5 mL water was added, and the reaction mixture was stirred at room temperature overnight, and monitored by TLC. The phases were separated, adding additional methylene chloride and/or water as needed to aid manipulation. The methylene chloride layer was dried over MgSO4 or Na2SO4, and solvent was removed in vacuo to provide crude product as an oily solid. This residue was triturated with hexanes/ether, whereupon crystallization commenced. Crystallization was allowed to proceed without further disturbance. Isolation from the mother liquor provided 83 mg (16.4%) crystalline (R)-3-methoxy-2-methyl-benzoic acid N′-(1-tert-butyl-but-3-enyl)-N′-((S)-3,3,3-trifluoro-2-methoxy-2-phenyl-propionyl)-hydrazide from which was obtained an X-ray crystal structure. Mp=128-129° C.; [α]25589+66.4° (c 2.00, CH3OH); 1H NMR (400 MHz, CDCl3) δ 7.5 (d, 2H), 7.2-7.3 (m, 4H), 7.07 (m, 1H), 6.9 (d, 1H), 6.6+6.2 (br, 1H), 5.2 (d, 1H), 5.1 (d, 1H), 4.8 (1H, br), 3.85 (s, 3H), 3.8 (s, 3H), 2.55 (br, 1H), 2.35 (br, 2H), 1.5 (3H), 1.05 (br s, 9H); 13C NMR (100 MHz, CDCl3) δ 168.1, 158.3, 138.7, 134.0, 129.4, 128.0, 126.5, 126.4, 126.3, 124.9, 122.1, 118.0, 117.0, 112.2, 57.3, 55.7, 35.8, 32.0, 28.1, 12.3; HRMS (ESI) m/z calcd for C27H34F3N2O4 [M+H]+ 507.2471. found 507.2463, m/z calcd for C27H33F3N2NaO4 [M+Na]+ 529.2290. found 529.2284. Anal. Cald for C27H33F3N2O4: C, 64.02; H, 6.57; F, 11.25; N, 5.53; 0, 12.63. Found: C, 63.87; H, 6.71; N, 5.52.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[N:23]1([CH:28]2[CH2:32][CH2:31][NH:30][CH2:29]2)[CH:27]=[N:26][CH:25]=[N:24]1.C1CCN2C(=NCCC2)CC1>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:17])[C:10]([F:16])=[C:11]([N:30]4[CH2:31][CH2:32][CH:28]([N:23]5[CH:27]=[N:26][CH:25]=[N:24]5)[CH2:29]4)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: c1ncn(C2CCNC2)n1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1c(F)c(N2CCC(n3cncn3)C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 28.9 %

Procedure:
1-Cyclopropyl-5-methyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (30 mg, 0.1 mmol) was reacted with 40 mg (0.2 mmol) of 3-(1,2,4-triazol-1-yl)pyrrolidine hydrochloride in 2 ml of pyridine in the presence of 70 mg (0.45 mmol) of DBU at 95° C. overnight. The orange solution was evaporated to dryness and to the residue water was added. The orange solid was collected and washed with methanol to yield 19 mg of the crude product, which upon further purification from methanol yielded 12 mg of the desired product. m.p. 207°-210° C. 1H NMR (TFA) δ: 9.81 (s, 1H), 9.27 (s, 1H), 8.78 (s, 1H), 5.75-5.55 (m, 1H), 4.83-4.12 (m, 5H), 3.0-2.7 (m, 5H), 1.7-1.2 (m, 4H). Anal. calcd. for C20H19F2N5O3H2O: C, 55.43; H, 4.88; N, 16.16. Found: C, 55.72; H, 4.73; N, 15.65.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=1)[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:15][C:16]([F:21])([F:20])[CH:17]1[O:19][CH2:18]1>>[O:1]([C:8]1[CH:9]=[C:10]([NH:11][CH2:18][CH:17]([OH:19])[C:16]([F:21])([F:20])[F:15])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)C1CO1
Reactant: Nc1cccc(Oc2ccccc2)c1
Product: OC(CNc1cccc(Oc2ccccc2)c1)C(F)(F)F
Temperature: 100 °C
Yield: 70.6 %

Procedure:
EX-588B)A mixture of solid 3-phenoxyaniline (2.96 g, 16 mmol) and 1,1,1-trifluoro-2,3-epoxypropane (1.30 mL, 15.0 mmol) was placed in a sealed tube and heated to 100° C. giving a dark solution. The stirred solution was heated 18 h and cooled to give a dark oil. Purification by flash chromatography on silica gel eluting with dichloromethane gave 3.15 g (71%) of the desired 3-[(N-3-phenoxy-phenyl)amino]-1,1,1-trifluoro-2-propanol product as a colorless oil. Anal. calcd. for C15H14NO2F3-0.05 CH2Cl2: C, 59.92; H, 4.71; N, 4.64. Found: C, 59.92; H, 4.53; N, 4.73. HRMS calcd. 298.1055 [M+H]+, found: 298.1056.