Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[C:10]([CH2:14]O)[CH:11]=[CH:12][CH:13]=1.S(Cl)([Cl:25])=O>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[C:10]([CH2:14][Cl:25])[CH:11]=[CH:12][CH:13]=1
Reactant: OCc1cccc(-c2ccccc2F)c1-c1cccc(F)c1
Reactant: O=S(Cl)Cl
Product: Fc1cccc(-c2c(CCl)cccc2-c2ccccc2F)c1
Temperature: 0 °C

Procedure:
To a cooled (0° C.) flask containing [(2-fluorophenyl)(3-fluorophenyl)phenyl]carbinol (20 g, 67.5 mmol) (obtained in example 1) was slowly added thionyl chloride (12.82 g, 108 mmol) with vigorous stirring. Once the reaction had been initiated (gas evolution), the rest of the thionyl chloride was added at once and the reaction mixture heated to reflux for 4 h. Volatiles were removed in vacuo and the remaining traces of thionyl chloride were removed by azeotropic evaporation with toluene (2×). The resulting residue was dissolved in petroleum ether and precipitated by cooling to -20° C. The solid was filtered and dried to afford the title compound as a slightly cream-colored solid (18.1 g, 85%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10](Cl)=[O:11])[CH:6]=[CH:7][CH:8]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1ccccc1
Reactant: COc1cccc(CC(=O)Cl)c1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cccc(CC(=O)Nc2ccccc2)c1
Reaction time: 3 h
Yield: 88.5 %

Procedure:
To a solution of 3-methoxyphenylacetyl chloride (2.3 g, 12.5 mmol) in ethyl acetate (30 mL) was added a solution of aniline (1.16 g, 12.5 mmol) in ethyl acetate (30 mL). After 3 hours, the reaction was poured into water (50 mL). The organic layer was separated, dried over MgSO4, filtered and concentrated to provide the title compound (2.67 g, 89% yield): EI-MS (m/z) 241.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].O(C(C)(C)C)[K].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([NH:27][C:2]2[CH:3]=[N:4][C:5]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)=[N:6][CH:7]=2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Brc1cnc(N2CCOCC2)nc1
Agent: [Pd]
Agent: CC(C)(C)O[K]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(Nc2cnc(N3CCOCC3)nc2)CC1
Temperature: 100 °C
Reaction time: 16 h
Yield: 2 %

Procedure:
To a degassed solution of 4-(5-bromo-pyrimidin-2-yl)-morpholine (4.70 g, 19.26 mmol, 1.0 equiv; commercially available) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (4.63 g, 23.11 mmol, 1.2 equiv; commercially available) in toluene (40 mL) was added KOtert-Bu (5.40 g, 48.15 mmol, 2.5 equiv), dicyclohexyl-(2′,4′,6′-triisopropyl-biphenyl-2-yl)-phosphane (0.18 g, 0.39 mmol, 0.02 equiv; X-Phos ligand [CAS RN 564483-18-7]; commercially available from Strem Chemicals, USA) and tris(dibenzylideneacetone)dipalladium(0) (1.60 g, 1.54 mmol, 0.08 equiv). The reaction mixture was stirred under nitrogen at 100° C. for 16 h, cooled to rt, filtered and the filtrate concentrated by evaporation under reduced pressure. The crude material was purified with silica column chromatography eluting with a gradient of heptane/ethyl acetate (3:2→2:3) to provide 0.14 g (2%) of the title compound in 90% purity according to 1H NMR. 1H NMR (360 MHz, DMSO): δ 1.11-1.25 (m, 2H), 1.39 (s, 9H), 1.84 (d, J=14.1 Hz, 2H), 2.88 (br s, 2H), 3.30 (br s, 1H), 3.46 (t, J=5.0 Hz, 4H), 3.64 (t, J=4.1 Hz, 4H), 3.84 (d, J=12.7 Hz, 2H), 5.03 (d, J=8.6 Hz, 1H), 7.96 (s, 2H). MS (ESI): 364.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15](Cl)[N:14]=1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O.C(COC)OC>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:14]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: Clc1cccc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: O
Product: COc1cccc(-c2cccc(Cl)n2)c1
Temperature: 25 °C

Procedure:
A mixture of m-methoxy-phenylboronic acid (10 g, 65.8 mmol), 2,6-dichloropyridine (9.7 g, 65.8 mmol), potassium carbonate (27.3 g, 197.4 mmol), triphenylphosphine (2.07 g, 7.9 mmol), dimethoxyethane 250 mL and water 80 mL was prepared. Nitrogen was bubbled directly in the mixture for 20 minutes. Then palladium acetate was added (0.44 g, 2.0 mmol). Nitrogen was bubbled again in the mixture for another 10 minutes. The mixture was heated to reflux under nitrogen overnight. The reaction mixture was cooled to room temperature. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and evaporated. The mixture was purified by silica column with up to 10% ethyl acetate in hexanes to gain 6.5 g colorless oil (45%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:20]([O:21][CH2:22][C:23]([O:25]CC)=O)=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O.CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:23](=[O:25])[CH2:22][O:21][C:20]3[CH:19]=[CH:18][CH:17]=[N:16][C:15]2=3)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)COc1cccnc1NC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(N2C(=O)COc3cccnc32)CC1
Reaction time: 6 h
Yield: 48.3 %

Procedure:
To a stirring solution of 0.9 g (0.0023 mol) of 4-(3-ethoxycarbonylmethoxy-pyridin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester in H2O/MeOH (1 mL/11 mL) was added 0.05 g (0.0023 mol) of LiOH. After 6 h, the solvent was removed under reduced pressure. The residue was dissolved in DMF (12 mL) and to the stirring solution was added 1.82 g (0.0048 mol) of HATU. After 3 h, the reaction was partitioned between EtOAc (250 mL) and saturated NaHCO3 (100 mL), and washed with water (3×100 mL). The combined aqueous layers were extracted with EtOAc (100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, and concentrated to afford 0.37 g (46%) of a white solid. MS (electrospray): exact mass calculated for C17H23N3O4, 333.17. m/z found, 356.1 [M+Na]+. 1H NMR (400 MHz, CDCl3): 7.97 (dd, J=4.8 Hz, 1.5 Hz, 1H), 7.25 (dd, J=8.1 Hz, 1.5 Hz, 1H), 6.96 (dd, J=8.1 Hz, 4.8 Hz, 1H), 5.03 (tt, J=11.9 Hz, 4.0 Hz, 1H), 4.55 (s, 2H), 4.13 (d, J=10.9 Hz, 2H), 2.82-2.69 (m, 2H), 2.68 (qd, J=12.4 Hz, 4.0 Hz, 2H), 1.65 (d, J=12.1 Hz, 2H), 1.46 (s, 9H).
Reaction SMILES: [C:1](Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:13]=[C:14]([CH:19]([CH2:33][CH2:34][OH:35])[CH2:20][C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=2)=[O:22])[CH:15]=[CH:16][C:17]=1[Cl:18].CCN(CC)CC>C(Cl)Cl>[Cl:11][C:12]1[CH:13]=[C:14]([CH:19]([CH2:33][CH:34]=[O:35])[CH2:20][C:21]([N:23]([CH3:1])[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=2)=[O:22])[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cccc(CNC(=O)CC(CCO)c2ccc(Cl)c(Cl)c2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1cccc(CN(C)C(=O)CC(CC=O)c2ccc(Cl)c(Cl)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 127 %

Procedure:
Oxalyl chloride (3.23 g) in CH2Cl2 (100 mL) was added to a -78° C. solution of DMSO (4.14 g) in CH2Cl2 (20 mL) over 15 mins. This mixture was stirred for 15 minutes whereupon a CH2Cl2 (30 mL) solution of 3,4-Dichloro-beta-(2-hydroxyethyl)-N-[(3-methoxyphenyl)methyl]benzenepropanamide (8.4 g) was added dropwise. The mixture was stirred for 30 minutes and then treated with a solution of Et3N (6.43 g) in CH2Cl2 (30 mL) and stirred for an additional 30 minutes at -78° C., then allowed to warm to ambient temperature. The reaction mixture was washed with water (100 mL), the organic fraction separated, dried over MgSO4, filtered and concentrated under reduced pressure to yield an oil (11 g). Silica gel chromatography eluting with 10% EtOAc/CH2Cl2 gave the title compound (7.75 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4](I)[CH:3]=1.[CH2:10]([OH:14])[CH2:11][C:12]#[CH:13].C(NC(C)C)(C)C>C(OC(C)C)(=O)C.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][C:12]([CH2:11][CH2:10][OH:14])=[CH:13][C:4]=2[CH:3]=1
Reactant: C#CCCO
Reactant: Oc1ccc(Br)cc1I
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: CC(=O)OC(C)C
Product: OCCc1cc2cc(Br)ccc2o1
Temperature: 60 °C
Yield: 72.2 %

Procedure:
The product from Example 3A (14.95 g, 50 mmol), palladium(ll) acetate (0.11 g, 0.5 mmol), triphenylphosphine (0.26 g, 1.0 mmol), and copper(I) iodide (0.19 g, 1.0 mmol) were combined in isopropyl acetate (100 mL). Nitrogen gas was bubbled through the reaction mixture for about 15 minutes. The mixture was treated with 3-butyn-1-ol (5.6 mL, 75.0 mmol) stirred briefly and then treated with diisopropylamine (42 mL, 300 mmol) slowly over about 10 minutes. After stirring for 2 hours at about 22° C., the mixture was heated at about 60° C. for about 6 hours and then cooled to about 22° C. The reaction mixture was filtered through a pad of Celite® (˜5 g) and the Celite® was washed with isopropyl acetate (˜30 mL). The filtrate was washed with saturated NaHCO3 solution (100 mL, 2×), 10% Na2S2O3 solution (100 mL, 2×), brine (50 mL), dried over Na2SO4, and distilled to dryness. The residue was purified by silica gel column chromatography to provide the title compound (8.7 g, 72% yield). MS DCl (M+NH4)+ m/z at 258,260; 1H NMR(CDCl3at 400 MHz) δ 3.03 (m, 2H), 3.98 (m, 2H), 6.45 (m, 1H), 7.25-7.32 (m, 2H), 7.60 (d, 1H); 13C NMR (CDCl3 at 100 MHz) δ 32.2, 60.6, 103.0, 112.1, 115.4, 122.8, 126.1, 130.4, 153.1, 157.0.
Reaction SMILES: [C:1](Cl)(=[O:10])[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.[CH2:13]([NH2:17])/[CH:14]=[CH:15]/[CH3:16].CCN(C(C)C)C(C)C>C(#N)C.[Cl-].[Na+].O>[CH2:13]([NH:17][C:1](=[O:10])[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)/[CH:14]=[CH:15]/[CH3:16]
Reactant: C/C=C/CN
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: O
Product: C/C=C/CNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Benzyl carbonochloridate (22.8 mL, 167 mmol) was added to a solution of (2E)-but-2-en-1-amine hydrochloride (12.0 g, 112 mmol) and Hunig's base (43.2 g, 330 mmol) in acetonitrile (120 mL) under a nitrogen atmosphere at 0° C. The reaction mixture was stirred under nitrogen at 0° C. for 1 hour and then allowed to warm to ambient temperature. After 3 hours, the reaction mixture was diluted with brine (50 mL) and was extracted with ethyl acetate (3×50 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude product residue. The crude product residue was purified by silica gel chromatography (ethyl acetate/petroleum ether) to give benzyl (2E)-but-2-en-1-ylcarbamate. MS ESI calc'd. for C12H16NO2 [M+H]+ 206. found 206.
Reaction SMILES: O(C)[Na].[C:4]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])#[N:5].Cl.Cl.[NH2:17][C:18]1[CH:19]=[C:20]([CH3:26])[C:21]([CH3:25])=[CH:22][C:23]=1N.O>CO>[CH3:26][C:20]1[C:21]([CH3:25])=[CH:22][C:23]2[NH:5][C:4]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[N:17][C:18]=2[CH:19]=1
Reactant: Cc1cc(N)c(N)cc1C
Reactant: CC(C)(C)OC(=O)NCC#N
Agent: CO[Na]
Agent: Cl
Solvent: CO
Solvent: O
Product: Cc1cc2nc(CNC(=O)OC(C)(C)C)[nH]c2cc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.3 g of a 30% NaOCH3 solution were added to tert-butyl cyanomethylcarbamate (0.4 g; 25.6 mmol) in 10 ml of CH3OH, and the mixture was stirred at room temperature for 1 h. After addition of 5.15 g of 4,5-diamino-ortho-xylene bishydrochloride, the reaction mixture was stirred overnight and then added to 100 ml of H2O, and the solid obtained by filtration was dried at 30° C. in vacuo. 0.5 g; ESI-MS [M+H+]=276
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N:25]=[CH:24][C:23](Cl)=[N:22]3)=[CH:4][N:3]=1.[N:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C([O-])(=O)C.[K+].O>CC(P(C(C)(C)C)C1C=CC=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC=CC=1)(C)C.Cl[Pd]Cl>[Cl:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N:25]=[CH:24][C:23]([C:33]2[CH:34]=[CH:35][N:30]=[CH:31][CH:32]=2)=[N:22]3)=[CH:4][N:3]=1
Reactant: OB(O)c1ccncc1
Reactant: O=S(=O)(Nc1cc(-c2ccc3ncc(Cl)nc3c2)cnc1Cl)c1ccc(F)cc1
Agent: Cl[Pd]Cl
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1)C(C)(C)C
Solvent: O
Product: O=S(=O)(Nc1cc(-c2ccc3ncc(-c4ccncc4)nc3c2)cnc1Cl)c1ccc(F)cc1
Temperature: 90 °C
Reaction time: 6 h
Yield: 57 %

Procedure:
To a 5 mL microwave vial, N-(2-chloro-5-(3-chloroquinoxalin-6-yl)pyridin-3-yl)-4-fluorobenzenesulfonamide (0.106 g, 0.236 mmol), pyridine-4-ylboronic acid (0.0430 g, 0.350 mmol), dichlorobis(di-tert-butylphenylphosphine)palladium(II) (0.0111 g, 0.0178 mmol), potassium acetate (0.0581 g, 0.592 mmol) and water (0.300 ml, 16.7 mmol) were mixed into (4 mL). The mixture was degassed by bubbling nitrogen through for 5 min. The reaction mixture was stirred at 90° C. for 6 h, then at 110° C. for 1.5 h. The reaction mixture was partitioned between Tris-1M HCl pH 7 buffer (20 mL) and EtOAc (20 mL). The aqueous phase was extracted with EtOAc (20 mL). The combined organic phases were washed with saturated aqueous NaCl (40 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (eluent: acetone in DCM 0%-50%) to afford a light yellow solid (0.0662 g) as the desired product. MS (ESI pos. ion) m/z calcd for C24H15ClFN5O2S: 491.1; found 491.9 [M+1]. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 7.06-7.23 (m, 3 H) 7.82-7.92 (m, 2 H) 8.01 (dd, J=8.77, 2.05 Hz, 1 H) 8.14 (dd, J=4.53, 1.61 Hz, 2 H) 8.31 (d, J=8.77 Hz, 1 H) 8.40 (t, J=1.83 Hz, 2 H) 8.57 (d, J=2.34 Hz, 1 H) 8.89 (dd, J=4.68, 1.46 Hz, 2 H) 9.42 (s, 1 H).
Reaction SMILES: [CH3:1][CH2:2][Mg+].[Br-].[CH3:5][C@:6]12[CH2:22][CH2:21][C@H:20]3[C@@H:11]([CH:12]=[CH:13][C:14]4[C@@H:19]3[CH2:18][CH2:17][C:16](=[O:23])[CH:15]=4)[C@@H:10]1[CH2:9][CH2:8][C:7]2=[O:24].[NH4+].[Cl-].CCOC(C)=O.CCCCCC>C1COCC1>[CH2:1]([C@H:12]1[CH2:13][C:14]2[C@H:19]([CH2:18][CH2:17][C:16](=[O:23])[CH:15]=2)[C@@H:20]2[C@@H:11]1[C@H:10]1[C@@:6]([CH2:22][CH2:21]2)([CH3:5])[C:7](=[O:24])[CH2:8][CH2:9]1)[CH3:2]
Reactant: C[C@]12CC[C@H]3[C@@H](C=CC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Reactant: CC[Mg+]
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC[C@H]1CC2=CC(=O)CC[C@@H]2[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Temperature: -78 °C
Yield: 39 %

Procedure:
To a mixture of CuI(Bu3P)4 (15.7 g, 40 mmol) in THF (50 mL) was added a 1.0 M solution of EtMgBr in THF (40 mL, 40 mmol) at −30° C., and stirred for 20 mm. The reaction mixture was cooled to −78° C. and dione 54 (3.5 g, 12.94 mmol) was added. The reaction mixture was warmed to −30° C. for 0.5 h, and poured into saturated aqueous NH4Cl. The mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous MgSO4, filtered, and then concentrated to afford a solid. Chromatography (20% EtOAc/hexane) yielded dione 55 as a yellow solid (1.5 g, 39%). The major 7α-ethyl isomer of 55: 1H NMR (300 MHz, CDCl3) δ0.89 (t, J=7.0 Hz, 3, CH2CH3), 0.93 (s, 3, CH3), 2.60 (dd, J=2.4, 14.3 Hz, 1), 5.85 (s, 1).
Reaction SMILES: [C:1]([CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:4][C:5]([OH:7])=O)#[N:2].[OH-].[K+].C(Cl)(=O)C(Cl)=O.[CH:22]([NH:25][CH:26]([CH3:28])[CH3:27])([CH3:24])[CH3:23]>C1C=CC=CC=1.C(OCC)C>[CH:22]([N:25]([CH:26]([CH3:28])[CH3:27])[C:5](=[O:7])[CH2:4][CH:3]([C:1]#[N:2])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:24])[CH3:23]
Reactant: CC(C)NC(C)C
Reactant: N#CC(CC(=O)O)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: CCOCC
Product: CC(C)N(C(=O)CC(C#N)c1ccccc1)C(C)C
Temperature: 80 °C
Reaction time: 2 h

Procedure:
3-Cyano-3-phenylpropanoic acid (67.7 g, 0.389 mol) was dissolved in 2-PrOH. To the filtered acid solution was carefully added KOH (18.4 g, 0.33 mol) dissolved in 2-PrOH (200 mL), diethyl ether (100 mL) was added and the precipitate was filtered off. The dried acid salt (51.9 g, 0.24 mol) was suspended in benzene (400 mL) and oxalyl chloride was carefully added. The reaction mixture was stirred at 80° C. for 2 hours. The solvent was evaporated and the residue was co-evaporated twice with benzene. The brown oil was dissolved in benzene (200 mL) and cooled in an ice-bath. A solution of diisopropylamine (82 g, 0.81 mol) in benzene (200 mL) was added to the stirred reaction mixture during 45 min. The mixture was left to slowly warm up to room temperature overnight. The solvent was evaporated and the residue was taken up in diethyl ether and 1 M HCl. The organic phase was washed once with water, once with 1 M NaOH, again with water, dried (Na2SO4) and the solvent evaporated to afford the title compound as a dark brown oil, 41.7 g (41%): 1H NMR (CDCl3) δ1.07 (d, 3H), 1.17 (d, 3H), 1.36 (m, 6H), 2.77 (m, 1H), 2.97 (m, 1H), 3,51 (br, 1H), 3.81 (m, 1H), 4.50 (dd, 1H), 7.39 (m, 5H).
Reaction SMILES: Cl[O-].[Na+].[NH2:4][C:5]([CH3:9])([CH3:8])[C:6]#[N:7].Cl.N([O-])=O.[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(#N)C>[N:4]([C:5]([CH3:9])([CH3:8])[C:6]#[N:7])=[N:4][C:5]([CH3:9])([CH3:8])[C:6]#[N:7]
Reactant: CC(C)(N)C#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=N[O-]
Solvent: O
Solvent: CC#N
Product: CC(C)(C#N)N=NC(C)(C)C#N

Procedure:
Next, 266 g (0.286 mole) of a 8% aqueous sodium hypochlorite solution (pH 12) was cooled to 5° C., and to the aqueous solution was added 150 ml of an acetonitrile solution containing 17.7 g (0.2 mole) of the resulting 95%-pure 2-amino-2-methylpropionitrile and 0.6 g of tetrabutylammonium bromide over 30 minutes with stirring. The resulting reaction mixture was stirred at 7° to 10° C. for 30 minutes to complete the reaction. By iodometry, it was found that the total oxidative compounds in both the water and acetonitrile phases after reaction was 0.08 equivalent. This reaction mixture was adjusted to a pH of 6 with a dilute hydrochloric acid and 4.2 g (0.12 equivalent) of sodium nitrite was added thereto, followed by stirring at 15° C. for 20 minutes. Thereafter, the reaction mixture was diluted with 1050 g of water, and the thus precipitated white crystals were filtered, washed with water and dried to obtain 16 g of 2,2'-azobis(isobutyronitrile). The resulting white crystals had a melting point of 104°-105.5° C. and a purity of 99% or more.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([O:11][C:12]([N:14]([C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)[CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([Cl:27])[CH:26]=1)[C:21]([OH:23])=O)=[O:13])([CH3:10])([CH3:9])[CH3:8].CCN(C(C)C)C(C)C.[F:43][C:44]1[CH:45]=[C:46]([NH:50][CH2:51][CH2:52][CH2:53][N:54]2[N:58]=[N:57][CH:56]=[N:55]2)[CH:47]=[CH:48][CH:49]=1>ClCCl.CN(C=O)C.CN(C1C=CN=CC=1)C>[C:7]([O:11][C:12](=[O:13])[N:14]([CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([C:21](=[O:23])[N:50]([C:46]2[CH:47]=[CH:48][CH:49]=[C:44]([F:43])[CH:45]=2)[CH2:51][CH2:52][CH2:53][N:54]2[N:58]=[N:57][CH:56]=[N:55]2)[CH:24]=[C:25]([Cl:27])[CH:26]=1)[C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)([CH3:9])([CH3:8])[CH3:10]
Reactant: Fc1cccc(NCCCn2ncnn2)c1
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCCn2ncnn2)c2cccc(F)c2)c1)c1ccncc1
Reaction time: 0.08 h
Yield: 86.8 %

Procedure:
2M Oxalyl chloride solution in dichloromethane (0.11 ml) and dry DMF (0.002 ml) were added to a stirred suspension of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid (0.060 g) in dry dichloromethane (1 ml) under nitrogen. After 5 min, DIPEA (0.090 ml) was added followed after a further 40 min by 3-fluorophenyl-(3-tetrazol-2-yl-propyl)-amine (0.066 g) and DMAP (0.002 g). After 3 days the solvent was evaporated and the residue was purified by flash chromatography eluting with dichloromethane:methanol (98:2 v/v) to give the title compound as a green foam (0.079 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C@@H:19]([C:21]([O:23][CH3:24])=[O:22])[CH3:20])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.Cl.Cl[CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N:29]1([CH2:28][CH2:27][N:18]([S:15]([C:12]2[CH:13]=[CH:14][C:9]([S:8][C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)=[CH:10][CH:11]=2)(=[O:17])=[O:16])[C@@H:19]([C:21]([O:23][CH3:24])=[O:22])[CH3:20])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1
Reactant: ClCCN1CCOCC1
Reactant: COC(=O)[C@@H](C)NS(=O)(=O)c1ccc(Sc2ccc(C)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@@H](C)N(CCN1CCOCC1)S(=O)(=O)c1ccc(Sc2ccc(C)cc2)cc1
Temperature: 70 °C
Yield: 81.9 %

Procedure:
A mixture of N-[[4-[(4-methylphenyl)thio]phenyl]sulfonyl]-D-alanine, methyl ester from Example 4b (6.4 g, 17.5 mmol), 4-(2-chloroethyl)morpholine hydrochloride (9.77 g, 52.5 mmol), and potassium carbonate (10 g, 72.4 mmol) in dry DMF (60 mL) was heated to 70° C. for 16 hours. After cooling to room temperature, mixture was poured into water and extracted with ethyl acetate. The combined ethyl acetate layers were washed with water and brine, dried over MgSO4, and concentrated to afford an oil which was purified by chromatography (40/100 acetone/hexane) to give N-[2-(4-morpholinyl)ethyl]-N-[[4-[(4-methylphenyl)thio]phenyl]sulfonyl]-D-alanine, methyl ester, (6.86 g, 81.86%) as an oil. The proton NMR was consistent with N-[2-(4-morpholinyl)ethyl]-N-[[4-[(4-methylphenyl)thio]phenyl]sulfonyl]-D-alanine, methyl ester. HR mass calculated for C23H30N2O5S2 : 478.1597.Found: 478.1596.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]([CH3:26])[CH2:21][C:22](=[O:25])[NH:23][N:24]=2)=[CH:15][C:14]=1[OH:27].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]([CH3:26])[CH2:21][C:22](=[O:25])[NH:23][N:24]=2)=[CH:15][C:14]=1[OH:27])=[O:5]
Reactant: O=C(Cl)c1ccc(Cl)nc1Cl
Reactant: CC1CC(=O)NN=C1c1ccc(N)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1CC(=O)NN=C1c1ccc(NC(=O)c2ccc(Cl)nc2Cl)c(O)c1
Reaction time: 8 h

Procedure:
A solution of 8.5 g (0.0405 mol) 2,6-dichloronicotinoyl chloride in 20 ml DMF is slowly added dropwise to a suspension of 8.8 g (0.04 mol) 6-(4-amino-3-hydroxy-phenyl)-5-methyl-4,5-dihydro-2H-pyridazin-3-one, 6.9 g (0.05 mol) potassium carbonate and 50 ml DMF and it is then stirred overnight. The reaction mixture is mixed with water, then the aqueous supernatant is decanted off, the residue is washed with water again, filtered off and then purified through silica gel (eluant: ethylene chloride/ethanol).