Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].C([O-])([O-])=O.[K+].[K+].[C:18]([O:22][C:23]([N:25]1[CH2:28][CH:27]([CH2:29]OS(C)(=O)=O)[CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C.CCOC(C)=O>[C:18]([O:22][C:23]([N:25]1[CH2:28][CH:27]([CH2:29][O:11][C:3]2[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=2[Cl:1])[CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CC(COS(C)(=O)=O)C1
Reactant: O=[N+]([O-])c1ccc(Cl)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(COc2cc([N+](=O)[O-])ccc2Cl)C1
Temperature: 50 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To the mixture of 2-chloro-5-nitro-phenol (1.31 g, 7.54 mmol) and K2CO3 (1.57 g, 11.31 mmol) in 20 mL of DMF was added 3-methanesulfonyloxymethyl-azetidine-1-carboxylic acid tert-butyl ester (2.0 g, 7.54 mol). The reaction mixture was stirred at 50° C. for 1 h. After cooling to RT, the reaction mixture was diluted in 100 mL of EtOAc and quenched with 50 mL of water. The organic layer was separated and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuum. The title compound was obtained via column chromatography (silica gel, 1;1 hexane/EtOAc) as yellow oil with 93% yield.
Reaction SMILES: [C:1]1([C:7]([NH:20][CH:21]2[CH:24]([S:25][CH2:26][C:27]#[C:28][CH2:29][O:30][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][O:32]3)[NH:23][C:22]2=[O:37])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([C:42](=[O:46])[C:43]([O-:45])=[O:44])(C)(C)C.O>C1C=CC=CC=1>[OH:46][CH:42]([N:23]1[CH:24]([S:25][CH2:26][C:27]#[C:28][CH2:29][O:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[CH:21]([NH:20][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:22]1=[O:37])[C:43]([O:45][C:1]([CH3:7])([CH3:6])[CH3:2])=[O:44]
Reactant: CC(C)(C)C(=O)C(=O)[O-]
Reactant: O=C1NC(SCC#CCOC2CCCCO2)C1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)C(O)N1C(=O)C(NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1SCC#CCOC1CCCCO1

Procedure:
3-(Triphenylmethylamino)-4-(4-tetrahydropyranyloxybut-2-ynylthio)azetidin-2-one (934 mg) and t-butylglyoxylate (2.5 g) were refluxed in benzene (20 ml) with provision for the removal of water. After 1 hour the cooled solution was washed with water (6 × 5 ml), dried and evaporated. Chromatography on silica gave 1-(1-hydroxy-1-t-butoxycarbonylmethyl)-3-(triphenylmethylamino)-4-(4-tetrahydropyranyloxybut-2-ynylthio)azetidine-2-one which still contained some t-butylglyoxylate. Re-chromatography on silica affored the pure material as an amorphous solid (519 mg) νmax (CHCl3) 3500, 3350, 1770, 1738 cm-1.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:18][CH:17]=[CH:16][CH2:15][N:14]([S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:13]1[C:30](O)=[O:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si]([NH:40][OH:41])(C(C)(C)C)(C)C.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH:12]1[CH2:18][CH:17]=[CH:16][CH2:15][N:14]([S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:13]1[C:30](=[O:31])[NH:40][OH:41])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(S(=O)(=O)N2CC=CCC(NC(=O)OCc3ccccc3)C2C(=O)O)cc1
Reactant: CC(C)(C)[Si](C)(C)NO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N2CC=CCC(NC(=O)OCc3ccccc3)C2C(=O)NO)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Benzyloxycarbonylamino-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid (21 mg, 0.043 mmol) is dissolved in dry Dimethylformamide (DMF) and cooled to -20° C. tert-Butyldimethylsilylhydroxyl amine (7 mg, 0.05 mmol), Hunigs Base (9.8 μl, 0.05 mmol) and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate (HATU) (18 mg, 0.05 mmol) are added. The reaction solution is stirred for 1 h and then allowed to warm to room temp. The solvent is evaporated. The residue is purified by flash-chromatography, Dichloromethane/Methanol (9:1), to afford the desired hydroxamide: Cal. 476.5, Found (MH)+ 476.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([OH:8])[CH:7]=1.Br[CH:12]([C:14](=[O:17])[CH2:15][CH3:16])[CH3:13].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([O:8][CH:12]([C:14](=[O:17])[CH2:15][CH3:16])[CH3:13])[CH:7]=1
Reactant: COc1ccc(Br)cc1O
Reactant: CCC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(=O)C(C)Oc1cc(Br)ccc1OC
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A mixture of 5-bromo-2-methoxyphenol (50.0 g), 2-bromo-3-pentanone (68.1 g), potassium carbonate (52.8 g), and DMF (500 ml) was stirred at 70° C. for 2 hours. After being allowed to stand for cooling, water was added to the mixture followed by extraction with ether. The organic layer was washed with a saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane:chloroform=1:1) to give Compound IIb-a (86.8 g, 94.0%) as a pale-yellow oily substance.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([NH2:18])=[O:17].[NH2:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([NH2:24])=[O:23].C(O)(=O)C>CN(C=O)C>[NH2:24][C:22]([C:21]1[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=1[NH:19][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([NH2:18])=[O:17])=[O:23]
Reactant: NC(=O)c1ccccc1N
Reactant: COc1cc2ncc(C(N)=O)c(Cl)c2cc1OC
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COc1cc2ncc(C(N)=O)c(Nc3ccccc3C(N)=O)c2cc1OC
Temperature: 100 °C
Yield: 41.7 %

Procedure:
A mixture of 4-chloro-6,7-dimethoxy-3-quinolinecarboxamide (0.046 g, 0.17 mmol), 2-aminobenzamide (0.029 g, 0.21 mmol) and acetic acid (40 μl) in DMF (0.8 ml) was heated at 100° C. for 6 h. After cooling the reaction mixture was evaporated. The residue was dissolved in a mixture of MeCN and water (1:3) containing 0.1% trifluoroacetic acid and the turbid solution was filtered through a plug of glass wool. Preparative HPLC using a gradient (containing 0.1% trifluoroacetic acid) of 10→40% MeCN in water as eluent gave, after evaporation, the title compound as the trifluoroacetic acid salt. The product was suspended in saturated aqueous NaHCO3 an absorbed on a short SPE column [ISOLUTE™ C18 (EC)] pre-conditioned subsequently with methanol and then water. The column was washed extensively with water until the pH of the eluent was neutral. The product was then eluted with methanol. After evaporation, the residue was crystallized from ethanol to give the title compound (26 mg, 41%).
Reaction SMILES: [O:1]=[C:2]([N:6]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[C:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH3:35])=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4]>CCOC(C)=O>[O:1]=[C:2]([N:6]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH3:35])=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:12][CH:13]=1)[C:3]([OH:5])=[O:4]
Reactant: CCCc1ccc(C#Cc2ccc(CN(Cc3ccc(C(F)(F)F)cc3)C(=O)C(=O)O)cc2)cc1
Solvent: CCOC(C)=O
Product: CCCc1ccc(CCc2ccc(CN(Cc3ccc(C(F)(F)F)cc3)C(=O)C(=O)O)cc2)cc1
Yield: 51 %

Procedure:
The same procedure as employed in the preparation of Example 1 (step c) but using oxo{{4-[(4-propylphenyl)ethynyl]benzyl}[4-(trifluoromethyl)benzyl]amino}acetic acid in EtOAc gave the title compound as a colorless oil (51%). M−(LC/MS(ESI)): 482. HPLC (Condition A), Rt: 5.43 min (HPLC purity: 89.2%).
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[N:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([O:13]C)=[O:12])[C:3]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[F:23].[Li+].[OH-].Cl>C1COCC1.CO>[F:1][C:2]1[C:7]2[N:8]=[N:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([OH:13])=[O:12])[C:3]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[F:23]
Reactant: COC(=O)c1cc2snnc2c(F)c1Nc1ccc(I)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc2snnc2c(F)c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
To a solution of methyl 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylate (1.90 g, 4.25 mmol) in THF and MeOH (20 mL, 4:1, v/v) was added 5.0 M LiOH (aq., 2 mL, 10 mmol). After stirring at ambient temperature for 2 h, the reaction was treated with 1.0 M HCl (aq.) till the solution was acidic. The aqueous layer was extracted with ethyl acetate (30 mL×3). The combined organic phase was washed with water (30 mL) and brine (30 mL) sequentially, dried over Na2SO4, filtered and concentrated to give the desired product (brown solid, 1.73 g, 94.0% yield). 1H NMR (400 MHz, CDCl3): δ 8.87 (s, 1H), 8.84 (s, 1H), 7.62 (d, 1H), 7.40 (d, 1H), 6.78 (m, 1H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:12]=[N:13][CH:14]=[C:15]([O:17][C:18]3[CH:19]=[N:20][CH:21]=[N:22][CH:23]=3)[CH:16]=2)=[O:9])[CH:3]=1.[CH3:24][OH:25]>Cl>[CH3:24][O:25][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:12]=[N:13][CH:14]=[C:15]([O:17][C:18]3[CH:19]=[N:20][CH:21]=[N:22][CH:23]=3)[CH:16]=2)=[O:9])[CH:3]=1
Reactant: CO
Reactant: O=C(Nc1cncc(Oc2cncnc2)c1)c1cc(F)ccn1
Agent: Cl
Product: COc1ccnc(C(=O)Nc2cncc(Oc3cncnc3)c2)c1
Yield: 19 %

Procedure:
Compound 8 (30 mg, 0.096 mmol, 1.0 eq) stirred in 1N HCl in MeOH (0.75 mL) at rt overnight. The reaction was concentrated in vacuo and purified by reverse-phase preparatory HPLC to afford 6 mg (19%) of the title compound as a mono-TFA salt: 1H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.09 (s, 1H), 9.03 (d, J=2.0 Hz, 1H), 8.79 (s, 2H), 8.55 (d, J=5.7 Hz, 1H), 8.29 (d, J=2.5 Hz, 1H), 8.14 (t, J=2.3 Hz, 1H), 7.66 (d, J=2.5 Hz, 1H), 7.25 (dd, J=5.7, 2.6 Hz, 1H), 3.93 (s, 3H); ES-MS [M+1]+: 324.1.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:24]([OH:26])=O)[CH2:9]2)=[O:7])[CH2:3]1.[F:27][C:28]1[C:29]([C:35](=[N:37]O)[NH2:36])=[N:30][CH:31]=[C:32]([F:34])[CH:33]=1>>[F:27][C:28]1[C:29]([C:35]2[N:36]=[C:24]([CH:10]3[CH2:11][CH:12]([C:14]4[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:23])[F:22])=[CH:18][CH:19]=4)[CH2:13][N:8]([C:6]([N:4]4[CH2:3][CH:2]([OH:1])[CH2:5]4)=[O:7])[CH2:9]3)[O:26][N:37]=2)=[N:30][CH:31]=[C:32]([F:34])[CH:33]=1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CC(O)C2)C1
Reactant: NC(=NO)c1ncc(F)cc1F
Product: O=C(N1CC(O)C1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3ncc(F)cc3F)no2)C1

Procedure:
90.0 mg (0.242 mmol) of 1-[(3-hydroxyazetidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 101A) and 61.0 mg (0.266 mmol) of 3,5-difluoro-N′-hydroxypyridine-2-carboximidamide were reacted according to the General Method 1. Yield: 24 mg (19% of theory).
Reaction SMILES: C(O)(=O)C.[F:5][C:6]([F:21])([F:20])[C:7]1[CH:8]=[C:9]([CH:17]=[CH:18][CH:19]=1)[NH:10][C:11](=[O:16])[CH2:12][C:13]([CH3:15])=[O:14].[Br:22]Br.II>O>[Br:22][CH2:15][C:13](=[O:14])[CH2:12][C:11]([NH:10][C:9]1[CH:17]=[CH:18][CH:19]=[C:7]([C:6]([F:20])([F:21])[F:5])[CH:8]=1)=[O:16]
Reactant: CC(=O)CC(=O)Nc1cccc(C(F)(F)F)c1
Reactant: BrBr
Agent: II
Solvent: CC(=O)O
Solvent: O
Product: O=C(CBr)CC(=O)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.3 %

Procedure:
A one-liter reaction flask equipped with a mechanical stirrer, air-cooled condenser, thermometer and dropping funnel was charged with 290 ml of acetic acid and 167.3 g (0.68 mole) of 3'-trifluoromethylacetoacetanilide. Only a portion of the latter dissolved. The dropping funnel contained 108.8 g (0.68 mole) of bromine, a crystal of iodine and 65 ml of acetic acid. The pot mixture was stirred as the bromine solution was added dropwise while maintaining the reaction temperature at 20°-25°. The reaction solids appeared to dissolve and reprecipitate as the bromine addition was continued. When about 65% of the bromine solution had been added, a clear reaction solution was obtained. All material remained in solution when the remaining quantity of bromine solution was added. The reaction solution was allowed to stir overnight at ambient temperature. On the following morning, the solidified mass was added to 2.8 liters of cold water and stirred. The white solid was collected on a vacuum filter and the filter cake was washed with an additional one liter of water. After drying, there was obtained 210 g (95%) of 4-bromo-3'-trifluoromethylacetoacetanilide, m.p. 66°-8°. N.M.R. (CDCl3) ##STR3## 5.3 (CH, enol), 7.2-7.8 (aromatic), 9.0 (HNC=O).
Reaction SMILES: [CH3:1][O:2][C:3](C1C=CC=C2C=1NC=C2)=[O:4].[C:14]([C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23](OC(F)(F)F)[CH:24]=2)[N:19]([CH2:31][C:32]([OH:34])=[O:33])[CH:18]=1)(=[O:16])[CH3:15]>>[CH3:1][O:2][C:3]([C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:20]=1[N:19]([CH2:31][C:32]([OH:34])=[O:33])[CH:18]=[C:17]2[C:14](=[O:16])[CH3:15])=[O:4]
Reactant: CC(=O)c1cn(CC(=O)O)c2ccc(OC(F)(F)F)cc12
Reactant: COC(=O)c1cccc2cc[nH]c12
Product: COC(=O)c1cccc2c(C(C)=O)cn(CC(=O)O)c12

Procedure:
was prepared from 1H-indole-7-carboxylic acid methyl ester in a similar manner as described in Scheme A13 for the preparation of (3-acetyl-5-trifluoromethoxy-indol-1-yl)-acetic acid. MS: 276 [M+H]+; tR (HPLC conditions k): 2.89 min.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][NH:7][C:6](=[O:9])[CH2:5][O:4]1.C(N(CC)CC)C.[S:17](Cl)([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18]>ClCCl>[CH3:24][C:23]1[CH:25]=[CH:26][C:20]([S:17]([O:1][CH2:2][CH:3]2[O:4][CH2:5][C:6](=[O:9])[NH:7][CH2:8]2)(=[O:19])=[O:18])=[CH:21][CH:22]=1
Reactant: O=C1COC(CO)CN1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2CNC(=O)CO2)cc1
Reaction time: 8 h
Yield: 42.6 %

Procedure:
To a stirred solution of 6-(hydroxymethyl)morpholin-3-one (Step-2 of Intermediate-9) (4.1 g, 31.29 mmole) in dichloromethane (25 mL), triethylamine (8.31 mL, 62.59 mmole) and TsCl (tosyl chloride) (6.56 g, 34.42 mmole) were added at 0° C. The reaction mixture was allowed to RT and further stirred overnight. Reaction mixture was diluted with dichloromethane (30 mL), and washed with brine solution (2×30 mL) and DM water, separated the organic layer, dried over Na2SO4, concentrated and further purified by flash chromatography (n-hexane:ethyl acetate, 1:4) to get the title compound as a white solid (3.8 gm). m/z 286.1
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6](Cl)=[O:7].[Cl:14][C:15]1[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:33][C:16]=1[O:17][C:18]1[CH:19]=[CH:20][C:21]([N+:30]([O-:32])=[O:31])=[C:22]([CH:29]=1)[C:23]([O:25][CH2:26][CH2:27][OH:28])=[O:24].N1C=CC=CC=1>C(Cl)Cl>[Cl:14][C:15]1[CH:36]=[C:35]([C:37]([F:39])([F:38])[F:40])[CH:34]=[CH:33][C:16]=1[O:17][C:18]1[CH:19]=[CH:20][C:21]([N+:30]([O-:32])=[O:31])=[C:22]([CH:29]=1)[C:23]([O:25][CH2:26][CH2:27][O:28][C:6](=[O:7])[CH2:5][O:4][C:3]1[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:2]=1[Cl:1])=[O:24]
Reactant: O=C(OCCO)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: O=C(Cl)COc1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(COc1ccc(Cl)cc1Cl)OCCOC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 1.5 %

Procedure:
2,4-Dichlorophenoxyacetyl chloride (5.3 g, 0.25 mole), was added portionwise to a solution of 2-hydroxyethyl 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzoate (10 g, 0.25 mole) and pyridine (70 ml). The resulting mixture was heated to 60° C. for 1 hr., cooled and taken into 500 ml CH2Cl2. The methylene chloride solution was washed two times with water, dried and concentrated to 12.5 g of gummy material. The crude gum was chromatographed through silica gel (3:10, ethyl acetate:hexane) to give 2.3 g of pure 2-(2,4-dichlorophenoxyacetoxy)ethyl 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzoate; nmr (DMSO) 4.20-4.76 (m, 4H), 5.04 (S, 2H), 6.96-8.42 (m, 9H); ir (CHCl3) 1755, 1770 Cm-1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH2:5][CH:6]2[C:11]([CH3:13])([CH3:12])[O:10][C:9](=[O:14])[NH:8][C:7]=12.[Br:15]Br>C(O)(=O)C>[Br:15][C:4]1[CH2:5][CH:6]2[C:11]([CH3:12])([CH3:13])[O:10][C:9](=[O:14])[NH:8][C:7]2=[C:2]([F:1])[CH:3]=1
Reactant: BrBr
Reactant: CC1(C)OC(=O)NC2=C(F)C=CCC21
Solvent: CC(=O)O
Product: CC1(C)OC(=O)NC2=C(F)C=C(Br)CC21
Reaction time: 0.17 h
Yield: 82.8 %

Procedure:
To a solution of 8-fluoro-4,4-dimethyl-dihydro-benzo[d][1,3]oxazin-2-one (0. 15 g, 0.77 mmol) in acetic acid (5 mL) was added dropwise a solution of bromine (0.37 g, 2.31 mmol) in acetic acid (5 mL) under nitrogen at rt. After stirred for 10 minutes, the mixture was concentrated and the residue obtained was purified by a silica gel column (hexane:ethyl acetate/4:1) to afford 6-bromo-8-fluoro-4,4-dimethyl-dihydro-benzo[d][1,3]oxazin-2-one as an off-white solid (0.176 g, 84%) which was used in next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][CH:9]([C:12]#[N:13])[C:10]#[N:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:19][CH2:20][C:21]([F:24])([F:23])[F:22]>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]([CH2:19][CH2:20][C:21]([F:24])([F:23])[F:22])([C:10]#[N:11])[C:12]#[N:13])=[CH:14][CH:15]=1)([O-:3])=[O:2]
Reactant: N#CC(C#N)Cc1ccc([N+](=O)[O-])cc1
Reactant: FC(F)(F)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1ccc([N+](=O)[O-])cc1
Yield: 10.8 %

Procedure:
Using 5.00 g of (4-nitrobenzyl)malononitrile, 60 ml of N,N-di-methylformamide, 1.10 g of sodium hydride (60% in oil), and 4.85 g of 1-bromo-3,3,3-trifluoropropane, and according to the process described in the Production Example 1, there was obtained 0.80 g of 2-(4-nitrobenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (18)).
Reaction SMILES: Br[C:2]1[C:3]([C:11]([N:13]([O:15][CH3:16])[CH3:14])=[O:12])=[N:4][C:5]([Cl:10])=[N:6][C:7]=1[NH:8][CH3:9].[CH2:17]([Sn](CCCC)(CCCC)C=C)[CH2:18]CC>C1(C)C=CC=CC=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>[Cl:10][C:5]1[N:4]=[C:3]([C:11]([N:13]([O:15][CH3:16])[CH3:14])=[O:12])[C:2]([CH:17]=[CH2:18])=[C:7]([NH:8][CH3:9])[N:6]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CNc1nc(Cl)nc(C(=O)N(C)OC)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1c(NC)nc(Cl)nc1C(=O)N(C)OC
Yield: 27.7 %

Procedure:
A solution of 5-bromo-2-chloro-N-methoxy-N-methyl-6-(methylamino)pyrimidine-4-carboxamide (100 mg), tributyl(vinyl)stannane (113 mg), tetrakis (23 mg) in toluene (1.6 mL) was heated at 95° C. for 12 h, and the solvent was removed. The residue was purified by preparative TLC eluting with 50% EtOAc/Hexanes to give the title compound as a colorless oil (23 mg). LC-MS (M+H)+=257.06.
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][N:3]([C:12]([NH:14][C@@H:15]([CH2:19][C:20]([F:23])([F:22])[CH3:21])[C:16](O)=[O:17])=[O:13])[CH2:2]1.ON1[C:29]2[N:30]=C[CH:32]=[CH:33][C:28]=2[N:27]=N1.CCN=C=NCCCN(C)C.Cl.C(N1CCOCC1)C>C1COCC1.CN(C=O)C>[C:29]([C:28]1([NH:27][C:16]([C@@H:15]([NH:14][C:12]([N:3]2[CH2:2][CH2:1][C:6]3([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]3)[CH2:5][CH2:4]2)=[O:13])[CH2:19][C:20]([F:22])([F:23])[CH3:21])=[O:17])[CH2:32][CH2:33]1)#[N:30]
Reactant: On1nnc2cccnc21
Reactant: CC(F)(F)C[C@H](NC(=O)N1CCC2(CCCCC2)CC1)C(=O)O
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(F)(F)C[C@H](NC(=O)N1CCC2(CCCCC2)CC1)C(=O)NC1(C#N)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The crude product from example 8, (S)-2-[(3-azaspiro[5.5]undecane-3-carbonyl)amino]-4,4-difluoropentanoic acid, was dissolved in 6 ml of 2:1 THF/DMF and admixed with 161.8 mg (1.365 mmol, 1.05 eq.) of 1-amino-1-cyclopropylnitrile hydrochloride and 176.9 mg (1.3 mmol, 1 eq.) of 1-hydroxy-7-azabenzotriazole, cooled to 0° C. and admixed with 250 mg (1.3 mmol, 1 eq.) of EDCl and with 0.496 ml (3.9 mmol, 3 eq.) of N-ethylmorpholine. Subsequently, the mixture was stirred at 0° C. to RT for 2 h, THF was distilled off under reduced pressure, ethyl acetate was added and the mixture was extracted by shaking with highly dilute HCl, sat. NaHCO3 solution and sat. NaCl solution. After concentration of the organic phase, a preparative HPLC separation (Merck Hibar Purospher RP18, 250×25, Standard-Gradient of acetonitrile-water-TFA) was performed directly. Product fractions were combined and freeze-dried.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:14]([OH:18])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:12]([NH:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:9])=[O:10])=[O:13])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)O
Reactant: O=C=NS(=O)(=O)c1ccc(Cl)cc1
Product: CC(C)(C)OC(=O)NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
The commercially available p-chlorophenylsulfonyl isocyanate (15.0 g, 58.6 mmol) is added dropwise to t-butanol (90 ml) and the mixture is allowed to stir at room temperature for 60 hours. The solvent is evaporated and the white solid is recrystallized from hexane and ethylacetate to obtain N-t-butoxycarbonyl-p-chlorophenylsulfonamide, m.p. 98°-99° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Cl.C(N(CC)CC)C.[N-:18]=[N+:19]=[N-:20].[Na+].Cl>C1(C)C=CC=CC=1>[NH:18]1[C:6]([C:5]2[CH:8]=[CH:9][C:2]([NH2:1])=[CH:3][CH:4]=2)=[N:7][N:20]=[N:19]1
Reactant: N#Cc1ccc(N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Nc1ccc(-c2nnn[nH]2)cc1
Yield: 44.1 %

Procedure:
A mixture of p-amino benzonitrile (2 g, 16.9 mmol), triethylamine hydrochloride (3.49 g, 25.38 mmol) and sodium azide (1.65 g, 25.38 mmol) were taken in anhydrous toluene (20 ml) and heated to reflux for 24 hr. The reaction mixture was cooled to room temperature and neutralized with dilute hydrochloric acid. The resultant precipitate was filtered, washed with water then dried to give 4-(1H-tetrazol-5-yl)-phenylamine (1.2 g, 44%).
Reaction SMILES: [H-].[Li+].[CH2:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH3:4].[CH2:12]1[CH2:16]O[CH2:14][CH2:13]1>>[CH2:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:14][CH2:13][CH2:12][C:16]2[CH:7]=[CH:6][CH:5]=[CH:3][CH:4]=2)=[CH:7][CH:6]=1)[CH3:4]
Reactant: C1CCOC1
Reactant: CCc1ccc(O)cc1
Agent: [H-]
Agent: [Li+]
Product: CCc1ccc(OCCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
To a suspension of LiH (0.005 g, 0.6 mmol) in THF was added p-ethyl phenol (0.08 g, 0.68 mmol) very slowly at 0° C. After 30 min of stirring at room temperature, the sulfonate ester, 2a (0.075 g, 0.17 mmol) was added to it and the reaction mixture was heated at 65° C. for 8 h. The reaction mixture was washed very carefully with cold water and extracted in EtOAc and dried over sodium sulfate. The organic layer was evaporated and the crude gummy material was purified by flash chromatography giving 0.038 g (93%) of an oil. 1H NMR (400 MHz, CDCl3) δ 7.31-7.18 (m, 5H), 7.13-7.09 (m, 2H), 6.85-6.81 (m, 2H), 3.94 (t, J=6.2 Hz, 2H), 2.84 (t, J=7.6 Hz, 2H), 2.58 (q, J=7.5, 2H), 2.13-2.03 (m, 2H), 1.21 (t, J=7.5 Hz, 3H); 13CNMR (100.75 MHz, CDCl3) 141.8, 130.6, 128.9, 128.7, 128.6, 126.1, 114.6, 67.1, 32.4, 31.1, 28.2, 16.1; HRMS (EI) [M]+: calcd for C17H20O 240.1514, found 240.1510.