Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.Cl[C:7](OC1C=CC([N+]([O-])=O)=CC=1)=[O:8].C(N(C(C)C)CC)(C)C.[Cl:28][C:29]1[CH:38]=[C:37]2[C:32]([C:33]([N:39]3[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]3)=[CH:34][CH:35]=[N:36]2)=[CH:31][CH:30]=1>C(Cl)Cl.CO>[Cl:28][C:29]1[CH:38]=[C:37]2[C:32]([C:33]([N:39]3[CH2:44][CH2:43][N:42]([C:7]([NH:5][CH:1]4[CH2:4][CH2:3][CH2:2]4)=[O:8])[CH2:41][CH2:40]3)=[CH:34][CH:35]=[N:36]2)=[CH:31][CH:30]=1
Reactant: NC1CCC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NC1CCC1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1

Procedure:
As described for example 78, cyclobutylamine (87 mg, 1.21 mmol), 4-nitrophenyl chloroformate (244 mg, 1.21 mmol), diisopropyl(ethyl)amine (2×261 mg, 2×2.02 mmol), and 7-chloro-4-(piperazin-1-yl)quinoline (250 mg, 1.01 mmol) are reacted affording the title product after flash chromatography with CH2Cl2-MeOH.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](O)=[O:5].CN(C)C=O.C(Cl)(=O)C([Cl:21])=O>C(#N)C>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([Cl:21])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(F)c(F)cc1Cl
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(F)c(F)cc1Cl

Procedure:
In accordance with the above reaction scheme, a solution of 2-chloro-4,5-difluorobenzoic acid (V) in acetonitrile containing a catalytic amount of dimethylformamide is reacted under an inert atmosphere with the dropwise addition of oxalyl chloride, giving 2-chloro-4,5-difluorobenzoic acid chloride (VI) which is dissolved in diethyl ether and slowly added to a cold solution of magnesium diethylmalonate, followed by the addition to ice water and acidification to pH 2.5, giving (2-chloro-4,5-difluorobenzoyl)propanedioic acid diethyl ester (VII). A solution of compound (VII) in p-dioxane and water is heated at reflux, then evaporated and distilled, giving 2-chloro-4,5-difluoro-β-oxobenzenepropanoic acid ethyl ester (VIII). A solution of compound (VIII) and triethyl orthoformate in acetic anhydride is heated at 150° C. for 2 hours, giving 2-chloro-α-(ethoxymethylene)-4,5-difluoro-β-oxobenzenepropanoic acid, ethyl ester (IX). Cyclopropylamine is added to a solution of compound (IX) in ethanol, giving 2-chloro-α-[(cyclopropylamino)methylene]-4,5-difluoro-β-oxobenzenepropanoic acid, ethyl ester (X). Compound (X) is reacted with sodium hydride in dry dimethylformamide under an inert atmosphere with heat, giving 1-cyclopropyl-6,7-difluoro- 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, ethyl ester (XI). Ester (XI) is then refluxed with acid, giving the desired 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (XII).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N:11]([CH3:18])[C:12]1[CH:13]=[N:14][CH:15]=[N:16][CH:17]=1.[CH3:19][C:20]1[N:25]=[C:24]([NH2:26])[CH:23]=[CH:22][CH:21]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:26][C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:19])[N:25]=2)=[O:8])=[CH:4][C:3]=1[N:11]([CH3:18])[C:12]1[CH:13]=[N:14][CH:15]=[N:16][CH:17]=1
Reactant: CN(c1cncnc1)c1cc(C(=O)O)ccc1F
Reactant: Cc1cccc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(NC(=O)c2ccc(F)c(N(C)c3cncnc3)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.1 %

Procedure:
Compound 20 (300 mg, 1.15 mmol, 1.00 eq) was dissolved in Dioxane (5.0 mL), and 1N LiOH (5.0 mL) was added. The reaction was stirred at rt for 45 minutes. The reaction was quenched with 1N HCl (5.0 mL) and extracted (3×) with ether. The combined organics were dried (MgSO4), filtered, and concentrated in vacuo to afford 200 mg (70%) of crude 4-fluoro-3-(methyl(pyrimidin-5-yl)amino)benzoic acid as a yellow solid. The product was confirmed by LCMS (>90% @ 220 nm and 254 nm) and carried forward without purification. 4-fluoro-3-(methyl(pyrimidin-5-yl)amino)benzoic acid (30 mg, 0.12 mmol, 1.0 eq), 6-methylpyridin-2-amine (15 mg, 0.14 mmol, 1.2 eq), O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (91 mg, 0.24 mmol, 2.0 eq), and N,N-Diisopropylethylamine (85 mg, 0.66 mmol, 5.5 eq) were dissolved in DMF (0.98 mL) and stirred at rt overnight. The reaction was quenched with water, and the layers were separated via phase separation. The organic layer was dried on air concentrator and purified by mass directed preparatory HPLC to afford 15 mg (36%) of the title compound as a mono-TFA salt: 1H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 8.65 (s, 1H), 8.28 (s, 2H), 8.14 (dd, J=7.7, 2.2 Hz, 1H), 8.00-7.94 (m, 2H), 7.75 (t, J=7.9 Hz, 1H), 7.48 (dd, J=10.7, 8.7 Hz, 1H), 7.05 (dd, J=7.4, 1H), 3.39 (s, 3H), 2.45 (s, 3H); ES-MS [M+1]+:338.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>>[F:20][C:21]([F:31])([F:32])[C:22]1[CH:23]=[CH:24][C:25]([NH:28][C:29](=[O:30])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:16]4[C:11](=[CH:12][N:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=2)=[CH:26][CH:27]=1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: NC(=O)c1[nH]c2cnccc2c1-c1ccc(N)cc1
Product: NC(=O)c1[nH]c2cnccc2c1-c1ccc(NC(=O)Nc2ccc(C(F)(F)F)cc2)cc1

Procedure:
91 mg of solid yellow 3-{4-[3-(4-trifluoromethylphenyl)ureido]phenyl}-1H-pyrrolo[2,3-c]pyridine-2-carboxamide are prepared as described in Example 1 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide and 4-trifluoromethylphenyl isocyanate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH2:11][C:12]([CH2:15]Cl)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>CN(C)C=O>[CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH2:11][C:12]([CH:15]=[CH2:18])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1CC(CCl)=NC=C1OCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CC1=NC=C(OCc2ccccc2)C(=O)C1
Reaction time: 3 h
Yield: 66.2 %

Procedure:
A solution of 5-benzyloxy-2-chloromethyl-4-pyridone (10.0 g) and triphenylphosphine (10.5 g) in N,N-dimethylformamide (50 ml) was stirred for 5 hours at 90°-100° C. The resulting mixture was poured into ethyl acetate (800 ml). The precipitate was collected by filtration, washed with ethyl acetate and dissolved in dichloromethane (500 ml). To the solution were added water (300 ml) and 38% aqueous formaldehyde (100 ml). The mixture was adjusted to pH 10-10.5 with potassium carbonate. After being stirred for 3 hours at 35°-40° C., the organic layer was separated, washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The product was isolated by column chromatography on silica gel with ethyl acetate as an eluent to give 5-benzyloxy-2-vinyl-4-pyridone (6.02 g) .
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[N:8]=[CH:7][N:6]=[C:5]([C:9]([O:11]CC)=O)[CH:4]=1.[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:16][CH3:17].[H-].[Na+]>COCCOC>[CH3:14][N:2]([CH3:1])[C:3]1[N:8]=[CH:7][N:6]=[C:5]([C:9](=[O:11])[CH:16]([CH3:17])[C:15]([O:19][CH2:20][CH3:21])=[O:18])[CH:4]=1
Reactant: CCOC(=O)c1cc(N(C)C)ncn1
Reactant: CCOC(=O)CC
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C(C)C(=O)c1cc(N(C)C)ncn1
Yield: 60.6 %

Procedure:
A solution of 6-dimethylamino-4-ethoxycarbonyl-pyrimidine (19.5 g) and ethyl propionate (11.2 g) in 1,2-dimethoxyethane (75 cc) is added to a suspension of sodium hydride (9.6 g) (50% in mineral oil) in 1,2-dimethoxyethane (25 cc), and the reaction mixture is refluxed. Refluxing is maintained for a further 30 minutes. The solvent is evaporated, and then the residue is taken up in diethyl ether (350 cc) and 4N hydrochloric acid (70 cc). After decanting, the aqueous phase is again extracted with diethyl ether (450 cc). The combined organic phases are washed with an 8% (w/v) sodium bicarbonate solution (120 cc). They are dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure to give ethyl 3-(6-dimethylaminopyrimidin-4-yl)-2-methyl-3-oxopropionate (15.2 g).
Reaction SMILES: C1([C@H]([N:9]2[C@H:17]3[C@@H:13]([CH2:14][O:15][CH2:16]3)[O:12][CH2:11][CH2:10]2)C)C=CC=CC=1.[Cl:18]C(OC(Cl)C)=O>ClCCCl>[ClH:18].[CH2:16]1[C@@H:17]2[C@H:13]([O:12][CH2:11][CH2:10][NH:9]2)[CH2:14][O:15]1
Reactant: C[C@H](c1ccccc1)N1CCO[C@@H]2COC[C@H]21
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: C1CO[C@@H]2COC[C@H]2N1
Product: Cl
Temperature: 25 °C

Procedure:
A solution of (3aS,7aR)-7-((1R)-1-phenyl-ethyl)-hexahydro-2,4-dioxa-7-aza-indene (1.0 g, 4.9 mmol) and 1-chloroethyl chloroformate (2.7 ml, 25 mmol) in 1,2-dichloroethane (15 mL) was refluxed for 15 hours and cooled to room temperature. After the reaction mixture was concentrated under reduced pressure, the resulting residue was dissolved into methanol and the mixture was refluxed for 2 hours. The reaction mixture was cooled to room temperature and concentrated. Ethyl acetate was added to the residue and the precipitated white solid of (3aS,7aR)-hexahydro-2,4-dioxa-7-aza-indene hydrochloride was triturated and collected by filtration (0.74 g, 4.5 mmol, 91%).
Reaction SMILES: [CH3:1][C:2](C)([O-:4])[CH3:3].[K+].[C:7]([C:9]1[CH:10]=C2[C:15](=[CH:16][CH:17]=1)[NH:14]C(=S)C2C)#[N:8].[O:20]1CCCC1>>[C:7]([C:9]1[CH:10]=[C:1]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:3](=[O:20])[C:2]2=[O:4])#[N:8]
Reactant: CC1C(=S)Nc2ccc(C#N)cc21
Reactant: C1CCOC1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Product: N#Cc1ccc2c(c1)C(=O)C(=O)N2
Reaction time: 15 h
Yield: 35 %

Procedure:
According to the general procedure, using an equimolar amount of potassium t-butoxide, 0.62 g of 5-cyano-3-methylthiooxindole in 200 ml of dry tetrahydrofuran was stirred and aerated for 9 h at 0° C. and 15 h at 25° C. Acidification with 0.25 ml of conc. hydrochloric acid in 25 ml of water, followed by extraction with ether and standard workup (vide supra), gave an orange solid. Recrystallization from 95% ethanol gave 0.18 g (35% yield) of 5-cyanoisatin, mp 273°-274° C. (dec.).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH:13][CH:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]2[NH:19][N:18]=[N:17][N:16]=2)=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:26]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]([NH:13][CH:14]([C:15]2[N:19]([CH3:26])[N:18]=[N:17][N:16]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:12])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)c1ccc(CC(=O)NC(c2ccccc2)c2nnn[nH]2)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CC(C)c1ccc(CC(=O)NC(c2ccccc2)c2nnnn2C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 22.7 %

Procedure:
To a solution 2-(4-isopropylphenyl)-N-[phenyl(1H-tetrazol-5-yl)methyl]acetamide (34.0 mg, 0.101 mmol) in 0.5 ml of anhydrous DMF was added K2CO3 (14.0 mg, 0.101 mmol) and MeI (0.006 ml, 0.101 mmol). The resulting solution was stirred at RT for 3 hour. Filtered and the residue was purified by preparative HPLC (5-90% CH3CN/H2O over 30 min, 0.05% added TFA, C18 column) to afford 8.0 mg (23%) of the title compound. 1H NMR (CDCl3, 400 MHz) δ 7.342 (m, 3H); 7.226 (m, 2H), 7.172 (ABq, J=8.2 Hz, 4H), 6.894 (br d, J=7.6 Hz, 1H), 6.424 (d, J=7.9 Hz, 1H), 3.910 (s, 3H), 3.587 (s, 2H), 2.888 (sept, J=7.0 Hz, 1H), 1.234 (d, J=7.0 Hz, 6H). ES-MS [M+1]+: 350.2.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18](=[O:32])[N:19]([CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[CH:20]=[N:21]2)=[CH:16][C:15]=1[O:33][CH3:34].[N:35]1([CH2:40][CH2:41]O)[CH:39]=[N:38][CH:37]=[N:36]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH3:34][O:33][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:14]=1[O:13][CH2:41][CH2:40][N:35]1[CH:39]=[N:38][CH:37]=[N:36]1)[N:21]=[CH:20][N:19]([CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:28])([CH3:29])[CH3:30])[C:18]2=[O:32]
Reactant: OCCn1cncn1
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCn1cncn1
Temperature: 5 °C
Reaction time: 1 h
Yield: 73.6 %

Procedure:
Diethyl azodicarboxylate (1.1 ml, 7 mmol) was added dropwise to a solution of 7-hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (1.7 g, 5.55 mmol), 2-(1,2,4-triazol-1-yl)ethanol (791 mg, 7 mmol), (Ann. Pharm. Fr. 1977,35,503-508) and triphenylphosphine (1.8 g, 7 mmol) cooled at 5° C. The mixture was allowed to warm to ambient temperature and stirred for 1 hour. The mixture was poured directly on to a column of silica and eluted with methylene chloride/methanol (95/5) to give 6-methoxy-3-((pivaloyloxy)methyl)-7-(2-(1,2,4-triazol-1-yl)ethoxy)-3,4-dihydroquinazolin-4-one (1.64 g, 74%.).
Reaction SMILES: [CH3:1][C:2]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([N+:15]([O-])=O)=[CH:10][CH:9]=2)([CH3:5])[CH2:3][OH:4].O.O.[Sn](Cl)(Cl)(Cl)Cl>C(O)C.C(OCC)(=O)C.O>[NH2:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:2]([CH3:5])([CH3:1])[CH2:3][OH:4])=[CH:14]2
Reactant: CC(C)(CO)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(CO)c1cc2cc(N)ccc2[nH]1
Temperature: 120 °C
Yield: 97.9 %

Procedure:
To a solution of 2-methyl-2-(5-nitro-1H-indol-2-yl)propan-1-ol (0.094 g, 0.40 mmol) in ethanol (4 mL) was added tin chloride dihydrate (0.451 g, 2.0 mmol). The mixture was heated in the microwave at 120° C. for 1 h. The mixture was diluted with ethyl acetate and water before being quenched with saturated aqueous NaHCO3. The reaction mixture was filtered through a plug of celite using ethyl acetate. The organic layer was separated from the aqueous layer, dried over Na2SO4, filtered and evaporated under reduced pressure to give 2-(5-amino-1H-indol-2-yl)-2-methylpropan-1-ol (0.080 g, 98%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]([C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH:22]2[S:26][C:25](=[O:27])[NH:24][C:23]2=[O:28])=[CH:19][CH:18]=1)=O.Cl.[NH2:32][OH:33].N1C=CC=CC=1>C(O)C.C(OCC)(=O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]([C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH:22]2[S:26][C:25](=[O:27])[NH:24][C:23]2=[O:28])=[CH:19][CH:18]=1)=[N:32][OH:33]
Reactant: Cc1oc(-c2ccccc2)nc1CCC(=O)c1ccc(CC2SC(=O)NC2=O)cc1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1oc(-c2ccccc2)nc1CCC(=NO)c1ccc(CC2SC(=O)NC2=O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83 %

Procedure:
Title product of Example 9 (0.10 g, 0.238 mmol), hydroxylamine hydrochloride (0.041 g, 0.595 mmol) and 2 mL of pyridine were combined in 3 mL of ethanol and the mixture stirred 18 hours at room temperature, then stripped of solvent and the residue taken up in 7.5 mL ethyl acetate, washed with 5 mL of cold 18% HCl and then 5 mL brine, dried (MgSO4) and stripped to yield 0.086 g of present title product as a white solid; mp 202°-205° C.; tlc Rf 0.53 (1:1 hexane:ethyl acetate).
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][C@:6]([CH3:12])([CH2:10][CH3:11])[C:7]([OH:9])=[O:8].[CH3:13]O>>[ClH:3].[CH3:13][O:8][C:7](=[O:9])[C@@:6]([NH2:5])([CH3:12])[CH2:10][CH3:11]
Reactant: O=S(Cl)Cl
Reactant: CC[C@@](C)(N)C(=O)O
Reactant: CO
Product: CC[C@@](C)(N)C(=O)OC
Product: Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Thionyl chloride (0.50 mL) was added dropwise to dry MeOH (2 mL) at −10° C. After stirring at −10° C. for 1 h, a 0° C. solution of (R)-2-amino-2-methyl-butyric acid (0.068 g) in MeOH (1 mL) was added, and the mixture was allowed to warm to room temperature, and was stirred for an additional 24 h. The reaction mixture was concentrated in vacuo, repeatedly diluted with toluene (50 mL) and reconcentrated in vacuo to give 0.076 g (quant. yield) of (R)-2-amino-2-methyl-butyric acid methyl ester hydrochloride as a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:4]=2[CH:3]=1.C1CCCCC1.CO[CH:22](OC)[N:23]([CH3:25])[CH3:24]>>[Br:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][CH2:7][CH2:8]/[C:9](=[CH:22]\[N:23]([CH3:25])[CH3:24])/[C:10](=[O:11])[C:4]=2[CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: O=C1CCCOc2ccc(Br)cc21
Solvent: C1CCCCC1
Product: CN(C)/C=C1\CCOc2ccc(Br)cc2C1=O
Temperature: 25 °C
Yield: 67 %

Procedure:
7-Bromo-3,4-dihydro-2H-benzo[b]oxepin-5-one (10.0 g, 41.5 mmol) in dimethylformamide dimethylacetal (100 mL) was heated at 110° C. for 18 h. The reaction was allowed to cool to room temperature and cyclohexane (100 mL) was added. The resulting solid precipitate was collected by filtration, washed with cyclohexane and then dried under vacuum at 40° C. to yield 7-Bromo-4-[1-dimethylamino-meth-(E)-ylidene]-3,4-dihydro-2H-benzo[b]-oxepin-5-one as yellow crystals (8.19 g, 67%). 1H NMR δ (ppm) (CDCl3): 7.83 (1H, d, J=2.59 Hz), 7.74 (1H, s), 7.46 (1H, dd, J=8.51, 2.58 Hz), 6.88 (1H, d, J=8.52 Hz), 4.27-4.19 (2H, m), 3.14 (6H, s), 2.76-2.69 (2H, m).
Reaction SMILES: [H-].[Na+].C([C:7]1[CH:12]=[CH:11][N:10]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[N:8]=1)CCC.[H][H].FC(F)(F)S(O[CH2:28][C:29]([F:43])([F:42])[C:30]([F:41])([F:40])[C:31]([F:39])([F:38])[CH2:32][O:33][CH2:34][CH2:35][CH2:36][CH3:37])(=O)=O>O.CN(C)C=O.C1(C)C=CC=CC=1>[CH2:9]([C:12]1[CH:11]=[N:10][C:9]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:28][C:29]([F:42])([F:43])[C:30]([F:40])([F:41])[C:31]([F:38])([F:39])[CH2:32][O:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:17][CH:18]=2)=[N:8][CH:7]=1)[CH2:13][CH2:14][CH3:15]
Reactant: [H][H]
Reactant: CCCCc1ccnc(-c2ccc(O)cc2)n1
Reactant: CCCCOCC(F)(F)C(F)(F)C(F)(F)COS(=O)(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCCCOCC(F)(F)C(F)(F)C(F)(F)COc1ccc(-c2ncc(CCCC)cn2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 108.3 %

Procedure:
Dry sodium hydride (0.5 g, 0.0206 moles) was weighed into a 100 ml flask in a glove bag under dry nitrogen. The flask was then fitted with a magnetic stir bar and a water-cooled condenser with a nitrogen inlet. 15 ml of toluene and 15 ml of anhydrous N,N-dimethylformamide were added, and then 2.5 g (0.0110 moles) of 4-butyl-2-(4-hydroxyphenyl)pyrimidine was added slowly to control the rate of hydrogen evolution. After stirring at room temperature for 20 minutes, 4.4 g (0.0110 moles) of 2,2,3,3,4,4-hexafluoro-5-butoxypentyl trifluoromethanesulfonate (prepared essentially as described in Example 2) was added, and the contents were heated to reflux for 1 hour. Upon cooling to room temperature, the contents of the flask were poured into a separatory funnel containing 50 ml of water. The funnel was shaken and the two layers formed were allowed to separate. The aqueous layer was extracted twice with 20 ml aliquots of toluene. The three organic layers were combined, then washed four times with 25 ml aliquots of deionized water, dried with anhydrous sodium sulfate, and stripped of solvent on a rotary evaporator. The resulting oil was chromatographed on silica gel, eluting with chloroform, to yield 2.85 g of pale yellow liquid, 5-butyl-2-(4-(2,2,3,3,4,4-hexafluoro-5-butoxypentoxy)phenyl)pyrimidine.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][CH2:6][C:7]1[C:8](=[O:17])[NH:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.[H][H].[CH2:20](Br)[CH:21]=[C:22]([CH3:24])[CH3:23]>CN(C=O)C>[CH2:20]([N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:16]=[C:7]([CH2:6][CH2:5][CH2:4][OH:3])[C:8]1=[O:17])[CH:21]=[C:22]([CH3:24])[CH3:23]
Reactant: O=c1[nH]c2ccccc2nc1CCCO
Reactant: [H][H]
Reactant: CC(C)=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)=CCn1c(=O)c(CCCO)nc2ccccc21
Yield: 56.5 %

Procedure:
To a suspension of 9.68 g of 60% sodium hydride in 50 ml of anhydrous DMF, there is slowly added a solution of 44.9 g of 3-(3-hydroxy propyl) 1,2-dihydro 2-oxo quinoxaline (obtained in accordance with 1.1) in 450 ml of DMF. The solution is agitated until completion of the liberation of hydrogen, whereupon 36 g of prenyl bromide are added. The resultant solution is agitated overnight at room temperature and then evaporated to dryness under reduced pressure. The brown residue is treated with 150 ml of water and 400 ml of methylene chloride. After evaporation under vacuum, a beige solid is obtained which is recrystallized from 200 ml of toluene. In this way there are isolated 33.8 g of compound 1 in the form of pale yellow crystals.
Reaction SMILES: C1(C)C(S(O)(=O)=O)=CC=CC=1.[NH2:12][N:13]1[CH2:17][CH:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[N:15]([CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[C:14]1=[O:36].Cl.[N:38]1[CH:43]=[CH:42][CH:41]=[C:40]([S:44](Cl)(=[O:46])=[O:45])[CH:39]=1.CN1CCOCC1>ClCCl>[N:38]1[CH:43]=[CH:42][CH:41]=[C:40]([S:44]([NH:12][N:13]2[CH2:17][CH:16]([C:18]3[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)[N:15]([CH2:26][CH2:27][C:28]3[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=3)[C:14]2=[O:36])(=[O:46])=[O:45])[CH:39]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: COc1ccc(CCN2C(=O)N(N)CC2c2ccc(OC)cc2)cc1
Agent: Cc1ccccc1S(=O)(=O)O
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccc(CCN2C(=O)N(NS(=O)(=O)c3cccnc3)CC2c2ccc(OC)cc2)cc1
Temperature: 80 °C
Yield: 42.9 %

Procedure:
1-Amino-3-[2-(4-methoxyphenyl)ethyl]-4-(4-methoxyphenyl)-2-imidazolidinone toluenesulfonic acid (0.3 g, 0.58 mmol) is stirred in dichloromethane (6 mL) and 3-pyridylsulfonylchloride HCl (135 mg, 0.63 mmol) is added followed by 4-methylmorpholine (0.2 mL). The mixture is heated in a microwave oven at 80° C. for 25 minutes. The mixture is evaporated and purified over silica (hexane/ethylacetate) to give the afford 0.12 g (41% yield) of the desired product as a white solid. 1H NMR (DMSO-d6) δ 10.3 (s, 1H), 9.0 (s, 1H), 8.9 (d, J=6 Hz, 1H), 8.2 (d, J=7.8 Hz, 1H), 7.65 (m, 1H), 7.2 (d, J=7.8 Hz, 2H), 7.05, (d, J=7.8 Hz, 2H), 6.95 (d, J=7.8 Hz, 2H), 6.8 (d, J=7.8 Hz, 2H), 4.5 (t, J=7 Hz, 1H), 3.8 (s, 3H), 3.75 (s, 3H), 3.3 (m, 1H), 3.2 (m, 1H), 2.75 (m, 2H), 2.4 (m, 2H). Anal. calcd. for C24H26N4O5S: C, 59.74; H, 5.43; N, 11.61. found C, 59.60; H, 5.47; N, 11.37. FAB-HRMS calcd. 483.1702. found 483.1720 (MH+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([OH:13])=O)[CH2:3][CH2:2]1.[NH2:17][CH2:18][CH:19]([OH:31])[CH2:20][N:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22]1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>CC#N>[CH2:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:29][CH2:30][N:21]1[CH2:20][CH:19]([OH:31])[CH2:18][NH:17][C:11](=[O:13])[C:10]1[CH:14]=[CH:15][CH:16]=[C:8]([CH2:7][N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)[CH:9]=1
Reactant: NCC(O)CN1CCc2ccccc2C1
Reactant: O=C(O)c1cccc(CN2CCOCC2)c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CC#N
Product: O=C(NCC(O)CN1CCc2ccccc2C1)c1cccc(CN2CCOCC2)c1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 3.6 %

Procedure:
To a solution of 3-(morpholinomethyl)benzoic acid (60 mg, 0.27 mmol) in MeCN (3 mL) were added 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (60 mg, 0.29 mmol), TEA (70 mg, 0.69 mmol) and the resulting mixture was stirred at 20° C. for 10 min. BOPCl (70 mg, 0.28 mmol) was added and the reaction mixture was stirred at 20° C. for 16 h. The reaction solution was concentrated and the residue was purified by prep-HPLC to give the title compound (4 mg, Yield 3.6%). 1H NMR (CD3OD, 400 MHz): δ 7.77 (s, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.50 (d, J=7.7 Hz, 1H), 7.35 (t, J=7.7 Hz, 1H), 7.07-7.14 (m, 3H), 7.00-7.06 (m, 1H), 4.11 (quin, J=6.0 Hz, 1H), 3.75 (s, 2H), 3.64-3.72 (m, 4H), 3.43-3.59 (m, 4H), 2.83-2.93 (m, 4H), 2.61-2.74 (m, 2H), 2.44 (brs, 4H). LCMS (m/z): 410.1 (M+1).