Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][N:9]=1)[CH:5]=O.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[C:3]([F:10])=[C:4](/[CH:5]=[N:23]/[S@@:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22])[CH:7]=[CH:8][N:9]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: O=Cc1ccnc(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)[S@@](=O)/N=C/c1ccnc(Cl)c1F
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 91.5 %

Procedure:
To a stirred suspension of 2-chloro-3-fluoroisonicotinaldehyde (0.75 g, 4.70 mmol) and Cs2CO3 (2.297 g, 7.05 mmol) in DCM (20 mL) was added a solution of (R)-2-methylpropane-2-sulfinamide (0.570 g, 4.70 mmol) in DCM (20 mL) dropwise for 10 min. The solution was then stirred for 3.5 h at rt. The reaction mixture was diluted with EtOAc and washed with brine (3×20 mL). The organic solution was dried over MgSO4, filtered, and concentrated in vacuo to give (R,E)-N-((2-chloro-3-fluoropyridin-4-yl)methylene)-2-methylpropane-2-sulfinamide (1.13 g, 91%) as a yellow oil which solidified upon standing. MS (ESI) m/z: 263.0 (M+H)+.
Reaction SMILES: [O:1]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CN(C)[P:15](N(C)C)N(C)C>C1(C)C=CC=CC=1>[N:10]12[P:15]3[N:7]([CH2:6][CH2:5][N:4]3[CH2:3][CH2:2][O:1][CH2:12][CH2:11]1)[CH2:8][CH2:9]2
Reactant: CN(C)P(N(C)C)N(C)C
Reactant: C1CNCCOCCNCCN1
Solvent: Cc1ccccc1
Product: C1CN2CCN3CCN(CCO1)P23
Yield: 102.5 %

Procedure:
A solution of 2.50 g of 1-oxa-4,7,10-triazacyclododecane and 2.35 g of hexamethylphosphorous triamide in 25 ml of toluene is refluxed for forty hours. It is then concentrated to dryness in a rotary evaporator, to give 2.97 g (100%) of 10-oxa-1,4,7-triaza-13-phosphatricyclo[5.5.1.04,13 ]tridecane as a brittle, white solid. Sublimation at 80° C (0.007 mm) gives 2.08 g of white crystals having a melting point of 68°-70° C.
Reaction SMILES: Br[C:2]1[C:3]([O:15][CH3:16])=[C:4]([C:13]#[N:14])[C:5](=[O:12])[N:6]([CH:8]([CH2:10][CH3:11])[CH3:9])[CH:7]=1.[CH3:17][N:18]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[N:19]1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O.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>[CH:8]([N:6]1[CH:7]=[C:2]([C:20]2[CH:21]=[CH:22][N:18]([CH3:17])[N:19]=2)[C:3]([O:15][CH3:16])=[C:4]([C:13]#[N:14])[C:5]1=[O:12])([CH2:10][CH3:11])[CH3:9]
Reactant: CCC(C)n1cc(Br)c(OC)c(C#N)c1=O
Reactant: Cn1ccc(B2OC(C)(C)C(C)(C)O2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCC(C)n1cc(-c2ccn(C)n2)c(OC)c(C#N)c1=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 68.9 %

Procedure:
To a mixture of 5-bromo-1-(sec-butyl)-4-methoxy-2-oxo-1,2-dihydropyridine-3-carbonitrile obtained in Step B (130 mg), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (114 mg), 2M aqueous sodium carbonate solution (1.37 mL) and 1,2-dimethoxyethane (2.5 mL) was added tetrakis(triphenylphosphine)palladium(0) (52.7 mg), and the mixture was stirred with microwave irradiation at 100° C. for 1 hr. The reaction mixture was diluted with water, and the mixture was extracted twice with ethyl acetate. The extracts were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, ethyl acetate/hexane) to give the title compound (90 mg).
Reaction SMILES: C(C1C=CC([S:9]([Cl:12])(=[O:11])=[O:10])=CC=1OCC)#N.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][C:19]=1[N+]([O-])=O>>[C:22]([C:21]1[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[C:19]([S:9]([Cl:12])(=[O:11])=[O:10])[CH:20]=1)#[N:23]
Reactant: COc1ccc(C#N)cc1[N+](=O)[O-]
Reactant: CCOc1cc(S(=O)(=O)Cl)ccc1C#N
Product: COc1ccc(C#N)cc1S(=O)(=O)Cl

Procedure:
The titled compound was prepared analogously to 4-cyano-3-ethoxy-benzenesulfonyl chloride (Intermediate 127c) by replacing 2-ethoxy-4-nitro-benzonitrile with 4-methoxy-3-nitro-benzonitrile.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([OH:13])=O)=[CH:2]1.[CH:14]([N:17]=[C:18]=[N:19][CH:20]([CH3:22])[CH3:21])([CH3:16])[CH3:15].CN(C=[O:27])C>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([N:17]([CH:14]([CH3:16])[CH3:15])[C:18](=[O:27])[NH:19][CH:20]([CH3:22])[CH3:21])=[O:13])=[CH:2]1
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Reactant: CC(C)N=C=NC(C)C
Reactant: CN(C)C=O
Product: CC(C)NC(=O)N(C(=O)Cc1c[nH]c2ccccc12)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To 87.5 mg (0.5 mM) of 3-indolylacetic acid dissolved in dry DMF was added 79 ul (0.5 mM) N,N′-diisopropyl carbodiimide and the mixture was stirred overnight at RT. The solvent was evaporated, the residue was triturated with dry diethyl ether and the crystals formed from DIU were filtered. The flash chromatography from CHCl3 and CHCl3/MeOH 99/1 yielded 91 mg light yellow oil (60%) with Rf=0.82 (CHCl3/MeOH 9/1). The observed mass by LC/MS was 302 for [M+H]+, corresponding to the expected mass of 301.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[N:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.[OH:11][C:12]1C=NC=CC=1OC.NO>>[CH3:1][C:2]1[C:6]2[N:7]=[CH:8][CH:9]=[C:10]([O:11][CH3:12])[C:5]=2[O:4][N:3]=1
Reactant: COc1ccncc1O
Reactant: Cc1noc2cccnc12
Agent: NO
Product: COc1ccnc2c(C)noc12

Procedure:
Scheme I-16-2 depicts the preparation of a 3-methyl-4-azabenzisoxazole ti derivative which may be used as starting material for Scheme I-16. Steps a, b, AP and c of equation 1 may be carried out as previously described for Scheme I-14-2. The acetyl derivative may then be treated with hydroxylamine to provide the oxime as depicted in step d and then cyclized as depicted in step e (as described for steps f and g of Scheme I-14, respectively) to provide the 3-methyl-4-azabenzisoxazole shown. In equation 2 of Scheme I-16-2 the 3-hydroxy-4-methoxypyridine is first acetylated (step a) then is treated with hydroxylamine and cyclized as previously described to provide 3-methyl-7-methoxy-4-azabenzisoxazole.
Reaction SMILES: [C:1](=O)([O:32]C1C=CC([N+]([O-])=O)=CC=1)[O:2][C@@H:3]1[CH2:7][C@H:6]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17](S(C5C=CC(C)=CC=5)(=O)=O)[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[C@H:5]([CH2:30][CH3:31])[CH2:4]1.[CH:43]1([NH2:47])[CH2:46][CH2:45][CH2:44]1.[OH-].[Na+]>O1CCOCC1>[CH:43]1([NH:47][C:1](=[O:32])[O:2][C@@H:3]2[CH2:7][C@H:6]([C:8]3[N:12]4[C:13]5[CH:19]=[CH:18][NH:17][C:14]=5[N:15]=[CH:16][C:11]4=[N:10][N:9]=3)[C@H:5]([CH2:30][CH3:31])[CH2:4]2)[CH2:46][CH2:45][CH2:44]1
Reactant: NC1CCC1
Reactant: CC[C@@H]1C[C@H](OC(=O)Oc2ccc([N+](=O)[O-])cc2)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC[C@@H]1C[C@H](OC(=O)NC2CCC2)C[C@@H]1c1nnc2cnc3[nH]ccc3n12
Temperature: 60 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
A solution of a scalemic mixture enriched in (1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl 4-nitrophenyl carbonate (0.150 g, 0.254 mmol) in 1,4-dioxane (1 mL) was added to a solution of cyclobutanamine (0.090 g, 1.27 mmol) in 1,4-dioxane (0.2 mL). After about 1 h, aqueous NaOH (1 N, 1.5 mL, 1.50 mmol) was added and the reaction mixture was heated at about 60° C. for about 2 h before cooling to rt. The organic solvent was removed under reduced pressure. The resulting aqueous layer mixture was acidified with AcOH to pH about 5 and extracted with DCM (3×5 mL). The combined organic extracts were concentrated under reduced pressure. The residue was purified by preparative HPLC (Table 1 method d) to give (1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl cyclobutylcarbamate (0.0468 g, 50%): LC/MS (Table 1, Method c) Rt=1.17 min; MS m/z: 369 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].[C:10]([OH:14])(=O)[CH2:11][SH:12].C=O.[C:17](O)(=O)C>C(O)C.C1(C)C(C)=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[C:4]([N:5]2[C:10](=[O:14])[CH2:11][S:12][CH2:17]2)[CH:6]=[C:7]([Cl:9])[CH:8]=1
Reactant: O=C(O)CS
Reactant: CC(=O)O
Reactant: Nc1cc(Cl)cc(Cl)c1
Agent: C=O
Solvent: O
Solvent: Cc1ccccc1C
Solvent: CCO
Product: O=C1CSCN1c1cc(Cl)cc(Cl)c1

Procedure:
3,5-Dichloroaniline (40.25 g, 0.25 mol) and thioglycolic acid (23 g, 0.25 mol) in ethanol (75 ml) were mixed and stirred. Formaldehyde solution (21.3 ml, 37% by weight) was added to the solution. An exotherm developed and a solid precipitated out. After stirring for several hours, water was added. The solids that had precipitated were collected on a filter, washed with water and air-dried. The product, 2-[[(3,5-dichlorophenyl)amino]methyl]thio]acetic acid (38 g, 0.15 mol), was refluxed in xylene (275 ml). The water formed during refluxing was removed azeotropically. Removal of the solvent left a solid having a melting point of 87°-92° C.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C:9](=[O:10])[N:8]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][C:6]2[CH:19]=[C:20]([C:23]([O:25]C(C)(C)C)=O)[CH:21]=[CH:22][C:5]=2[NH:4]1.[CH3:30][N:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[C:32]1[CH2:40][NH:41][CH3:42].CCN(CC)CC.C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.Cl>>[OH:1][CH2:2][C@@H:3]1[C:9](=[O:10])[N:8]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][C:6]2[CH:19]=[C:20]([C:23]([N:41]([CH3:42])[CH2:40][C:32]3[N:31]([CH3:30])[C:39]4[C:34]([CH:33]=3)=[CH:35][CH:36]=[CH:37][CH:38]=4)=[O:25])[CH:21]=[CH:22][C:5]=2[NH:4]1
Reactant: CC(C)(C)OC(=O)c1ccc2c(c1)CN(CCc1ccccc1)C(=O)[C@@H](CO)N2
Reactant: CNCc1cc2ccccc2n1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Product: CN(Cc1cc2ccccc2n1C)C(=O)c1ccc2c(c1)CN(CCc1ccccc1)C(=O)[C@@H](CO)N2
Yield: 88.9 %

Procedure:
According to the procedure of Example 8, except using tert-butyl (2R)-2-hydroxymethyl-3-oxo-4-phenethyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxylate (0.49 g, 1.2 mmole), 1-methyl-2-(methylaminomethyl)indole (0.23 g, 1.4 mmole), Et3N (0.37 mL, 2.62 mmole), HOBt.H2O (0.19 g, 1.4 mmole), and EDC.HCl (0.27 g, 1.4 mmole), the title compound (0.53 g, 82%) was prepared as an off-white solid following flash chromatography on silica gel (gradient: 1-3% MeOH/CHCl3): MS (ES) m/e 497.1 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([OH:15])=O)=[CH:7]2)([O-:3])=[O:2].CN(C)CCCN=C=NCC.Cl.[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C)C1C=CN=CC=1.ClCCl.CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:15])=[CH:7]2)([O-:3])=[O:2]
Reactant: Nc1ccccc1
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Nc1ccccc1)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.44 g (26.39 mmol) of 5-nitro-1H-indole-2-carboxylic acid from Example XLVII, 7.59 g (39.58 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide×HCl and 1.61 g (13.19 mmol) of 4-dimethylaminopyridine are initially charged in 400 ml of a 10:1 dichloromethane:DMF mixture. 2.95 g (2.89 ml, 31.67 mmol) of aniline are added, and the mixture is stirred at RT overnight. For work-up, the mixture is diluted and extracted with aqueous hydrochloric acid and dichloromethane. The organic phase is washed with sat. sodium chloride solution, dried with sodium sulphate, filtered and dried under reduced pressure.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]([CH3:17])=[CH:7][C:8]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9]>C(Cl)Cl>[CH3:5][C:6]1([CH3:17])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[O:10][C:8](=[O:9])[CH2:7]1
Reactant: CC(C)=CC(=O)Oc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1(C)CC(=O)Oc2ccccc21
Reaction time: 42 h

Procedure:
To a stirred, ice-cooled suspension of 10.4 g (78 mmol) of aluminum chloride in 160 ml of methylene chloride was added slowly under argon a solution of 7 g (39.8 mmol) of phenyl 3,3-dimethylacrylate (Compound 37) in 40 ml of methylene chloride The cooling bath was removed and the mixture stirred for a further 42 h. The mixture was poured into a mixture of ice and brine and the organic layer separated. The aqueous layer was extracted with methylene chloride and the organic extracts were combined and washed with saturated NaCl solution and then dried (MgSO4). The solvent was removed in vacuo and the residue purified by flash chromatography (silica; 10% ether in hexane) to give the title compound as a colorless oil. PMR (CDCl3: & 1.30 (6H, s), 2.56 (2H, s), 7.06 (1H, dd, J~8.0 Hz, 1.4 Hz), 7.16 (1H, td, J~8.0 Hz, 1.4 Hz), 7.26 (1H, td, J~8.0 Hz, 1.7 Hz), 7.33 (1H, dd, J~8.0 Hz, 1.7 Hz). MS exact mass, m/e 176.0852 (calcd. for C11H12O2, 176.0837.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:30])[N:15]([CH2:17][CH2:18][N:19]4C(=O)C5C(=CC=CC=5)C4=O)[N:16]=[C:10]3[C:9]=2[C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)=[CH:4][CH:3]=1.O.NN>C(O)C.C(OCC)(=O)C>[NH2:19][CH2:18][CH2:17][N:15]1[C:14](=[O:30])[N:11]2[N:12]=[CH:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[C:9]([C:31]3[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=3)[C:10]2=[N:16]1
Reactant: O=C1c2ccccc2C(=O)N1CCn1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn2c1=O
Agent: NN
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: NCCn1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn2c1=O
Reaction time: 8 h
Yield: 16.2 %

Procedure:
2-(2-(7,8-Bis(4-chlorophenyl)-3-oxo-[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl)ethyl)isoindoline-1,3-dione (180 mg, 0.34 mmol) was reacted with hyrazine hydrate (0.9 ml, 18.5 mmol) in ethanol (10 ml) and stirred overnight. After this time, the reaction mixture was diluted with ethyl acetate and washed with saturated aqueous NaCl. The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by preparative HPLC to give the title compound, 2-(2-aminoethyl)-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (22 mg, 13%) as a yellow foam. MS M+H=400; 1H NMR (CDCl3) δ 8.12 (broad, 2H), 7.38-7.15 (6H), 7.05 (2H), 4.45 (2H), 3.59 (2H).
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[S:4]([C:7]1[S:11][C:10]([NH:12]C(=O)C)=[N:9][C:8]=1[CH3:16])(=[O:6])=[O:5])[CH3:2].C[O-].[Na+]>CO.O>[CH2:17]([N:3]([CH2:1][CH3:2])[S:4]([C:7]1[S:11][C:10]([NH2:12])=[N:9][C:8]=1[CH3:16])(=[O:6])=[O:5])[CH3:18]
Reactant: CCN(CC)S(=O)(=O)c1sc(NC(C)=O)nc1C
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCN(CC)S(=O)(=O)c1sc(N)nc1C
Temperature: 5 °C
Yield: 22.4 %

Procedure:
The product from Step 1 (2.5 g) was dissolved in methanol (25 cm3) and cooled to 5° C. with stirring under an atmosphere of nitrogen. Sodium methoxide in methanol (2 cm3 of 25% wt./vol. solution) was added dropwise and the mixture allowed to warm to the ambient temperature for 18 hours. The reaction was heated under reflux for 1 hour, cooled, diluted with water (250 cm3), extracted with diethyl ether (2×100 cm3), dried (MgSO4) and evaporated under reduced pressure to give N,N-diethyl 2-amino-4-methylthiazole-5-sulfonamide (0.48 g). M+ 249; 1H NMR: δ 1.20(6H,t); 2.48(3H,s); 3.28(4H,q); 5.25(2H,br s); (solid).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[C:17]3[CH:16]=[C:15]4[CH2:18][CH2:19][CH2:20][C:21](=[O:22])[C:14]4=[CH:13][C:12]=3[O:11][CH2:10][C:9]=2[CH:23]=1)=[O:4].[C:24]([O:28][C:29]([N:31]1[C@@H:35]([CH3:36])[CH2:34][CH2:33][C@H:32]1[C:37]([OH:39])=[O:38])=[O:30])([CH3:27])([CH3:26])[CH3:25].C(N(CC)CC)C>CC#N.CCOC(C)=O>[CH3:36][C@@H:35]1[N:31]([C:29]([O:28][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:30])[C@H:32]([C:37]([O:39][CH2:2][C:3](=[O:4])[C:5]2[CH:6]=[CH:7][C:8]3[C:17]4[CH:16]=[C:15]5[CH2:18][CH2:19][CH2:20][C:21](=[O:22])[C:14]5=[CH:13][C:12]=4[O:11][CH2:10][C:9]=3[CH:23]=2)=[O:38])[CH2:33][CH2:34]1
Reactant: C[C@H]1CC[C@@H](C(=O)O)N1C(=O)OC(C)(C)C
Reactant: O=C(CBr)c1ccc2c(c1)COc1cc3c(cc1-2)CCCC3=O
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[C@H]1CC[C@@H](C(=O)OCC(=O)c2ccc3c(c2)COc2cc4c(cc2-3)CCCC4=O)N1C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 15 h
Yield: 65 %

Procedure:
To a solution of 3-(2-bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one in MeCN (30 mL) was added (2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid (1.2 g, 3.23 mmol) and triethyl amine (0.48 mL, 3.55 mmol) and the solution was heated to 50° C. After stirring for 15 h, the solution was cooled to rt, and diluted with EtOAc and washed successively with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (20% to 50% EtOAc/hexanes) to afford (2S,5S)-1-tert-butyl 2-(2-oxo-2-(8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)ethyl) 5-methylpyrrolidine-1,2-dicarboxylate (1.09 g, 65%).
Reaction SMILES: S(=O)(=O)(O)[OH:2].ClC1C=CC(C[C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH2:14][CH2:15][CH:16]3[C:21]#N)=CC=1.[OH2:25]>>[CH:16]1([C:21]([OH:2])=[O:25])[C:17]2[C:13](=[CH:12][CH:20]=[CH:19][CH:18]=2)[CH2:14][CH2:15]1
Reactant: O=S(=O)(O)O
Reactant: O
Reactant: N#CC1CCc2c(Cc3ccc(Cl)cc3)cccc21
Product: O=C(O)C1CCc2ccccc21

Procedure:
To 60 % sulfuric acid is added 3.0 g. of 4-(p-chlorobenzyl)indan-1-carbonitrile and the mixture is refluxed in a current of nitrogen gas for 2 hours. After cooling, water is added and the mixture is extracted with ether. The ethereal solution is washed with water and extracted with a 5 % aqueous solution of potassium carbonate. The extract is rendered acidic with hydrochloric acid and the resultant precipitate is extracted with chloroform. The chloroform layer is washed with water and dried. The solvent is distilled off under reduced pressure and the residue is crystallized from cyclohexane. The described procedure gives 4-p-chlorobenzyl)indan-1-carboxylic acid as crystals melting at 127°-129° C.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:20][CH:21]([CH2:25][C:26]([F:29])([F:28])[F:27])[C:22]([NH2:24])=[O:23])=[N:7][C:8]=1[NH:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][CH:14]=[CH:13]2)#[N:2].[OH-].[Na+].OO.CC(O)=[O:36]>CCO.CS(C)=O>[NH2:24][C:22](=[O:23])[CH:21]([NH:20][C:6]1[N:7]=[C:8]([NH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[C:3]([C:1]([NH2:2])=[O:36])=[N:4][CH:5]=1)[CH2:25][C:26]([F:28])([F:29])[F:27]
Reactant: N#Cc1ncc(NC(CC(F)(F)F)C(N)=O)nc1Nc1ccc2ncccc2c1
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: NC(=O)c1ncc(NC(CC(F)(F)F)C(N)=O)nc1Nc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound 2-(5-cyano-6-(quinolin-6-ylamino)pyrazin-2-ylamino)-4,4,4-trifluorobutanamide (5 mg, 0.012 mmol) was dissolved in EtOH (1 mL) and DMSO (0.5 mL), aq. 1N NaOH (0.5 mL) and aq. H2O2 (50%, 0.5 mL) were added. The mixture was stirred at room temperature for 30 min. HOAc (0.5 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (4 mg). MS 420.3 (M+H); UV 204.7, 263.3, 297.7 nm; t 0.417 min.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[OH:34][C@H:35]([C:55]1[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[CH:57][CH:56]=1)[C@H:36]([NH:40][C:41](=[O:54])[C@@H:42]([NH:44][C:45](=[O:53])[CH2:46][N:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1)[CH3:43])[C:37](O)=[O:38].[NH2:63][C@@H:64]([CH2:71][CH:72]1[CH2:76][CH2:75][CH2:74][CH2:73]1)[C:65]([C@@:67]1([CH3:70])[CH2:69][O:68]1)=[O:66]>CN(C=O)C>[CH:72]1([CH2:71][C@H:64]([NH:63][C:37](=[O:38])[C@@H:36]([NH:40][C:41](=[O:54])[C@@H:42]([NH:44][C:45](=[O:53])[CH2:46][N:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)[CH3:43])[C@H:35]([OH:34])[C:55]2[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[CH:57][CH:56]=2)[C:65]([C@@:67]2([CH3:70])[CH2:69][O:68]2)=[O:66])[CH2:73][CH2:74][CH2:75][CH2:76]1
Reactant: COc1ccc([C@@H](O)[C@H](NC(=O)[C@H](C)NC(=O)CN2CCOCC2)C(=O)O)cc1
Reactant: C[C@]1(C(=O)[C@@H](N)CC2CCCC2)CO1
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([C@@H](O)[C@H](NC(=O)[C@H](C)NC(=O)CN2CCOCC2)C(=O)N[C@@H](CC2CCCC2)C(=O)[C@@]2(C)CO2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
Sequentially HATU (1.84 g, 4.80 mmol) and DIEA (0.63 mL, 20 mmol) were added to a 0° C. solution of (2S,3R)-3-hydroxy-3-(4-methoxyphenyl)-2-((S)-2-(2-morpholinoacetamido)propanamido)propanoic acid (1.65 g, 4.00 mmol) and (S)-2-amino-3-cyclopentyl-1-((R)-2-methyloxiran-2-yl)propan-1-one (1.2 g, 4.0 mmol) in DMF (30 mL). The reaction mixture was allowed to warm to ambient temperature and stirred for 30 min. The mixture was concentrated and the residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc=2:1 to EtOAc) to afford (2S,3R)-N-((S)-3-cyclopentyl-1-((R)-2-methyloxiran-2-yl)-1-oxopropan-2-yl)-3-hydroxy-3-(4-methoxyphenyl)-2-((S)-2-(2-morpholinoacetamido)propanamido)propanamide (1.45 g, 61% yield) as a colorless solid. 1H NMR (300 MHz, CDCl3): δ 7.40 (d, J=5.7 Hz, 1H), 7.32-7.22 (m, 2H), 7.06-6.99 (m, 2H), 6.82 (d, J=8.7 Hz, 2H), 5.26-5.21 (m, 1H), 4.68-4.60 (m, 2H), 4.58-4.39 (m, 2H), 4.01-3.85 (m, 1H), 3.81 (s, 3H), 3.74-3.72 (m, 4H), 3.25 (d, J=4.8 Hz, 1H), 2.99-2.85 (m, 2H), 2.53-2.39 (m, 4H), 1.74-1.61 (m, 8H), 1.53 (s, 3H), 1.33 (d, J=6.9 Hz, 3H), 1.28-1.20 (m, 3H). MS(EI) for C30H44N4O8, found 589.3 (MH)+.
Reaction SMILES: Br[CH2:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][F:6].[NH:10]1[CH:14]=[N:13][CH:12]=[N:11]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:7][C:4]([CH3:8])([CH2:5][F:6])[C:3](=[O:9])[CH2:2][N:10]1[CH:14]=[N:13][CH:12]=[N:11]1
Reactant: CC(C)(CF)C(=O)CBr
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(CF)C(=O)Cn1cncn1
Yield: 60.5 %

Procedure:
197 g (1 mole) of 1-bromo-3,3-dimethyl-4-fluoro-2-butanone were slowly added dropwise to a boiling solution of 77 g (1.1 mols) of 1,2,4-triazole and 210 g (1.5 moles) of potassium carbonate in 500 ml of acetone such that, after removing the heating bath, the exothermic reaction kept the solution simmering. The mixture was then kept under reflux for a further 3 hours, the inorganic salts were filtered off and the filtrate was concentrated in vacuo. The residue was taken up in chloroform/water and the organic phase was separated off and evaporated. The residue which remained was distilled in vacuo and the distillate was crystallized with cyclohexane. 112 g (55% of theory) of 3,3-dimethyl-4-fluoro-1-(1,2,4-triazol-1-yl)-butan-2-one of melting point 59° C. were obtained. ##STR15##
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10](O)(=O)[CH2:11][C:12]([OH:14])=[O:13].N1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.N1C=CC=CC=1.Cl>>[C:12]([O-:14])(=[O:13])[CH:11]=[CH:6][C:5]1[CH:8]=[CH:9][CH:2]=[CH:3][CH:4]=1.[CH3:10][C:11]12[CH2:12][CH:20]([CH2:21][CH2:22]1)[CH:19]=[CH:18]2
Reactant: C1CCNCC1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc(F)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CC12C=CC(CC1)C2
Product: O=C([O-])C=Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
17.1 g (0.138 mol) of 4-fluorobenzaldehyde, 28.7 g (0.276 mol) of malonic acid, and 0.1 equivalent of piperidine were dissolved in 3 equivalents of pyridine. The resulting mixture was stirred at room temperature for 30 min, and further stirred at 90° C. for 5 h. The temperature was lowered to room temperature, and the mixture was titrated to pH 1˜2 using a 3 M hydrochloric acid aqueous solution. The formed powder was filtered, and washed with a solvent mixture of ethanol/water (1/9 volume ratio), thus obtaining poly(cinnamate-methyl-2-norbornene) at a yield of 72% with a weight average molecular weight of 703,000 and PDI of 2.0.