Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]12[CH2:20][CH2:19][N:18]([C:21](=[O:23])[CH3:22])[CH:6]1[N:7]([C:15](=[O:17])[CH3:16])[C:8]1[C:13]2=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)(=[O:3])[CH3:2].CN1CCOCC1.Cl[C:32]([O:34][C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=1)=[O:33]>O1CCCC1>[C:1]([O:4][C:5]12[CH2:20][CH2:19][N:18]([C:21](=[O:23])[CH3:22])[CH:6]1[N:7]([C:15](=[O:17])[CH3:16])[C:8]1[C:13]2=[CH:12][C:11]([O:14][C:32]([O:34][C:35]2[CH:36]=[CH:37][C:38]([N+:41]([O-:43])=[O:42])=[CH:39][CH:40]=2)=[O:33])=[CH:10][CH:9]=1)(=[O:3])[CH3:2]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)OC12CCN(C(C)=O)C1N(C(C)=O)c1ccc(O)cc12
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(=O)OC12CCN(C(C)=O)C1N(C(C)=O)c1ccc(OC(=O)Oc3ccc([N+](=O)[O-])cc3)cc12
Reaction time: 72 h
Yield: 11.8 %

Procedure:
To the solution of 1,8-diacetyl-5-hydroxy-2,3,8,8a-tetrahydropyrrolo[2,3-b]indol-3a(1H)-yl acetate (88 mg; 0.28 mmol) in N-methylmorpholine (62 μl, 0.56 mmol) and small amount of tetrahydrofuran, the 4-nitrophenyl chloroformate (112.9 mg; 0.56 mmol) dissolved in tetrahydrofuran was added. Reaction was carried out for 3 days under an argon atmosphere. The solvent was evaporated. The residue was purified by column chromatography (SiO2, cyclohexane/methylene chloride/methanol) to give 16 mg of title compound with 12% of yield.
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([OH:19])=O)[CH:15]=2)[O:10][C:9]([C:20]2[N:25]=[CH:24][N:23]3[CH:26]=[CH:27][CH:28]=[C:22]3[CH:21]=2)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:59][CH2:60][CH2:61][N:62]1[CH2:67][CH2:66][O:65][CH2:64][CH2:63]1>CN(C)C=O>[N:62]1([CH2:61][CH2:60][NH:59][C:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[O:10][C:9]([C:20]2[N:25]=[CH:24][N:23]4[CH:26]=[CH:27][CH:28]=[C:22]4[CH:21]=2)=[CH:8][C:7]3=[N:6][O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:19])[CH2:67][CH2:66][O:65][CH2:64][CH2:63]1
Reactant: NCCN1CCOCC1
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(C(=O)O)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(C(=O)NCCN3CCOCC3)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 78 %

Procedure:
A suspension of 4-(tert-Butoxyimino)-2-pyrrolo[1,2-c]pyrimidin-3-yl-4H-chromene-6-carboxylic acid methyl ester (example 115B) (170 mg, 0.43 mmol) in a mixture of tetrahydrofuran/methanol/water (2.0 ml/0.5 ml/0.5 ml) was treated with lithium hydroxide monohydrate (55 mg, 1.29 mmol) and heated at 60° C. for 2 hours. The solvents were removed and the residue was diluted with water, neutralized to pH 5-6 with a 1N solution of hydrochloric acid and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated to dryness to give 4-(tert-Butoxyimino)-2-pyrrolo[1,2-c]pyrimidin-3-yl-4H-chromene-6-carboxylic acid (135 mg, 84%) as a green solid. A solution of the previous carboxylic acid, (3-Dimethylamino-propyl)-ethyl-carbodiimide, hydrochloride (90 mg, 0.47 mmol), 1-Hydroxybenzotriazole hydrate (68 mg, 0.50 mmol) and triethylamine (250 μl, 1.80 mmol) in dimethylformamide (6.0 ml) was stirred at 0° C. for 1 hour then 4-(2-aminoethyl)-morpholine (52 μl, 0.40 mmol) was added. The mixture was stirred at room temperature for 18 hours. The volatiles were removed under vacuum and the residue taken into ethyl acetate, washed several times with a saturated solution of sodium hydrogenocarbonate, brine, dried over sodium sulfate and concentrated to dryness. The residue was purified by silica gel flash chromatography (gradient ethyl acetate/methanol 0-8%) to yield the title compound as a yellow solid (137 mg, 78%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:7]([O:9][CH3:10])=[O:8])([O-])=O>CO.[C].[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1ccc(N2CCCCC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(N2CCCCC2)c(N)c1
Yield: 85.2 %

Procedure:
Using 10% palladium carbon cartridge, a solution of methyl 3-nitro-4-(piperidin-1-yl)benzoate (3.07 g) in methanol (50 ml) was pumped through the H-Cube™ reactor (ThalesNano Inc.). After all the reaction mixture had passed through the H-Cube™ reactor, the reaction mixture was concentrated under reduced pressure. The residue was purified by NH-silica gel column chromatography to obtain a title compound (2.32 g).
Reaction SMILES: [C:1](Cl)(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].N1C=CC=CC=1.ON1C(=O)CCC1=O.[NH2:31][CH2:32][CH2:33][SH:34]>O>[C:1]([NH:31][CH2:32][CH2:33][SH:34])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: NCCS
Reactant: CCCCCCCCCCCCCC(=O)Cl
Agent: O=C1CCC(=O)N1O
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCC(=O)NCCS
Temperature: 23 °C
Reaction time: 4 h

Procedure:
Myristoyl chloride (1.0 mmol) was added with vigorous string to ice-cooled dry pyridine (1.0 ml), and followed immediately by N-hydroxysuccinimide (1.5 mmol). The mixture was stirred for 4 h at ambient temperature (˜23° C.). 2-aminoethanethiol free base (1.1 mmol) was added as solid to the mixture and allowed to react for 6 h at ambient temperature, followed by 3 days at 4° C. The product was treated with water (5 ml), stirred for 1 h at ambient and filtered, washing with cold water. The white solid was dissolved in dimethylsulphoxide and reprecipitated with water and then vacuum dried over phosphorous pentoxide. The final yield was 0.21 g (˜70%). Thiol titration using Ellman's reagent indicated that the product contained ˜45% free thiol.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:16])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[N:6][CH:7]=1.C(N(CC)CC)C.[C:24]([Si:26]([CH3:29])([CH3:28])[CH3:27])#[CH:25]>O1CCCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[O:16]=[C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([C:25]#[C:24][Si:26]([CH3:29])([CH3:28])[CH3:27])=[CH:7][N:6]=1)[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)CCC(=O)Nc1ccc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CCC(=O)Nc1ccc(C#C[Si](C)(C)C)cn1
Temperature: 65 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
To a solution of methyl 4-[(5-bromo-2-pyridyl)amino]-4-oxo-butanoate (commercially available: 0.25 g, 0.871 mmol) in tetrahydrofuran was added bis(triphenylphosphine) palladium(II) dichloride (61.7536 mg, 0.087 mmol), copper(I) iodide (16.6 mg, 0.087 mmol), triethylamine (889 mg, 1.23 mL, 8.70 mmol) and ethynyltrimethylsilane (130 mg, 0.19 mL, 1.30 mmol). The reaction mixture was stirred at 65° C. overnight. The reaction was stopped and the solution was partitioned between ethyl acetate and water. The aqueous layer was separated and extracted with ethyl acetate (2×). The combined organic layer was dried on magnesium sulfate and concentrated under vacuum. The residue was purified by flash chromatography eluting with cyclohexane-ethyl acetate (3/1) to give methyl 4-oxo-4-[[5-(2-trimethylsilylethynyl)-2-pyridyl]amino]butanoate (26 mg, 10% yield). 1H NMR (400 MHz, CDCl3) 8.39 (s, 1H), 8.14 (m, 2H), 7.74 (d, 1H), 3.72 (s, 3H), 2.74 (m, 4H), 0.24 (s, 9H) ppm.
Reaction SMILES: [C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]1[CH:36]=[CH:35][C:24]([C:25]([O:27][CH:28]=[CH:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:26])=[CH:23][CH:22]=1)([O:3][CH3:4])=[O:2].[H][H]>[Pd].O1CCCC1>[C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([O:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:26])=[CH:35][CH:36]=1)([O:3][CH3:4])=[O:2]
Reactant: [H][H]
Reactant: CCOC(=O)C=COC(=O)c1ccc(NCCCCCCCCCCCCCCCC(=O)OC)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)CCOC(=O)c1ccc(NCCCCCCCCCCCCCCCC(=O)OC)cc1

Procedure:
A solution of 4 g. 2-(ethoxycarbonyl)vinyl 4-(15-carbomethoxypentadecylamino)benzoate and 400 mg. 10% palladium-on-carbon in 100 ml. tetrahydrofuran is hydrogenated at 50 psi until hydrogen uptake stops. The catalyst is filtered, the solution is evaporated, and the residue is crystallized from acetonitrile to yield 2-(ethoxycarbonyl)ethyl 4-(15-carbomethoxypentadecylamino)benzoate.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[CH:4][C:3]=1[CH3:11].[ClH:12].Cl[O-].[Na+]>O1CCCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[C:4]([Cl:12])[C:3]=1[CH3:11]
Reactant: Cc1cc(C=NO)ccc1Br
Reactant: Cl
Agent: [Na+]
Agent: [O-]Cl
Solvent: C1CCOC1
Product: Cc1c(Br)ccc(C=NO)c1Cl
Reaction time: 0.75 h
Yield: 98.2 %

Procedure:
In a solution of 82.0 g of 4-bromo-3-methylbenzaldoxime in 450 ml of tetrahydrofuran, 120.0 g of concentrated hydrochloric acid was added a dropwise with stirring under ice cooling over 45 minutes. Then, 220 ml of 8% sodium hypochlorite aqueous solution was carefully added dropwise over 75 minutes so that the temperature of the reaction mixture would not exceed 5° C., after the completion of the addition, continued to stir at 10° C. or less further for 90 minutes. After the completion of the reaction, nitrogen gas was blown through the reaction mixture for 45 minutes and precipitated insoluble material was filtered off, and tetrahydrofuran was distilled off under reduced pressure. The remaining aqueous solution was extracted with 240.0 g of ethyl acetate. The organic phase was washed with water (240 ml×2) and then insoluble material was filtered off, the solvent was distilled off under reduced pressure to obtain 93.5 g of the aimed product as pale yellow crystal.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][OH:29])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])C.Br[CH2:31][CH:32]1[CH2:34][CH2:33]1.[H-].[Na+]>CN(C=O)C>[CH:32]1([CH2:31][O:29][CH2:28][CH2:27][C:22]2[C:23]([CH3:26])=[N:24][O:25][C:21]=2[C:18]2[CH:19]=[CH:20][C:15]([C:12]3[CH:13]=[CH:14][C:9]([C:6]4([C:4]([OH:3])=[O:5])[CH2:7][CH2:8]4)=[CH:10][CH:11]=3)=[CH:16][CH:17]=2)[CH2:34][CH2:33]1
Reactant: BrCC1CC1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCO)cc3)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1CCOCC1CC1
Temperature: 25 °C

Procedure:
To a solution of 1-{4′-[4-(2-hydroxy-ethyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester (0.144 g, 0.37 mmol) and (bromomethyl)cyclopropane (0.04 mL, 0.44 mmol) in DMF (1.4 mL) as added sodium hydride (60% in mineral oil, 0.022 g, 0.55 mmol) and the reaction was stirred at room temperature. Analytical LCMS indicated that there was a mixture of products, including the hydrolyzed acid, so the mixture was submitted to aqueous workup procedure and purified by silica gel chromatography (0-100% EtOAc in hexanes). Fractions containing the desired product were purified by preparative HPLC to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2Br)[CH:9]=[CH:8][CH:7]=1)=[O:5])[CH3:2].[CH:17]([Sn](CCCC)(CCCC)CCCC)=[CH2:18].[F-].[K+]>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[CH:17]=[CH2:18])[CH:9]=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CCOC(=O)c1cccc2cccc(Br)c12
Agent: [Pd]
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C=Cc1cccc2cccc(C(=O)OCC)c12
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
A stream of argon was passed through a solution of 8-bromo-naphthalene-1-carboxylic acid ethyl ester (1.44 g) in toluene (15 ml) for 15 min. Then tetrakis (triphenylphosphine) palladium (179 mg) and vinyltributylstannane (1.65 ml) were added. The reaction mixture was heated under an Argon atmosphere to 100° C. overnight, then cooled to r.t. and treated with 4M potassium fluoride solution. The suspension was stirred for 10 min and then filtered. The solids were washed with toluene. The filtrate was washed with 4M K solution, then dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel; gradient: cyclohexane→cyclohexane/EtOAc 3:2) to give 8-vinyl-naphthalene-1-carboxylic acid ethyl ester (1.11 g) as light yellow liquid. MS (ISP): 227.1 ((M+H)+.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[NH:9]N.O=[C:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH2:14][CH2:13]1>>[Br:8][C:6]1[CH:5]=[C:4]2[C:3](=[C:2]([F:1])[CH:7]=1)[NH:9][C:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19](=[O:23])[CH:20]([CH3:21])[CH3:22])[CH2:14][C:13]2=1
Reactant: NNc1ccc(Br)cc1F
Reactant: CC(C)C(=O)NC1CCC(=O)CC1
Product: CC(C)C(=O)NC1CCc2[nH]c3c(F)cc(Br)cc3c2C1
Yield: 32 %

Procedure:
Prepare the tide compound by essentially following the procedure as described in Preparation 4 (Method 2) with 2-fluoro-4-bromophenylhydrazine (Preparation 14) and N-(4-oxo-cyclohexyl)-isobutyramide, to obtain the title compound as a tan foam in 32% yield. MS (ES): m/z 353, 355 (M+H), 351, 353(M−H); HPLC (Method A): Rt=2.34, (89%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH:9]([CH3:11])[OH:10])=[CH:4][CH:3]=1.[C:20]([Si:24]([CH3:27])([CH3:26])Cl)([CH3:23])([CH3:22])[CH3:21].N1C=CN=C1.C(=O)([O-])O.[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[CH:9]([O:10][Si:24]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:27])[CH3:26])[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(O)C(Cc1ccc(Cl)cc1)c1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(O[Si](C)(C)C(C)(C)C)C(Cc1ccc(Cl)cc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
0.70 g of (1RS, 2SR)-2-(4-bromophenyl)-3-(4-chlorophenyl)-1-methylpropanol was dissolved in 7 ml of dimethylformamide, and 0.34 g of tert-butyldimethylchlorosilane and 0.18 g of imidazole were added thereto. The mixture was stirred at room temperature overnight. The reaction solution was poured into a saturated sodium hydrogencarbonate aqueous solution and extracted by an addition of ethyl ether. Then, the organic layer was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The drying agent was separated by filtration, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (hexane) to obtain 0.70 g (yield: 75%) of [(2RS, 3SR)-3-(4-bromophenyl)-2-(tert-butyldimethylsilyloxy)-4-(4-chlorophenyl)butane as colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH2:30][CH2:31][OH:32])(=[NH:29])=[O:28])=[CH:23][CH:22]=2)=[O:20])=[O:10])=[N:6][CH:7]=1.N1C=CC=CC=1.[C:39](Cl)(=[O:41])[CH3:40]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH2:30][CH2:31][OH:32])(=[N:29][C:39](=[O:41])[CH3:40])=[O:28])=[CH:23][CH:22]=2)=[O:20])=[O:10])=[N:6][CH:7]=1
Reactant: CC(=O)Cl
Reactant: N=S(=O)(CCO)c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N=S(=O)(CCO)c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Temperature: 27.5 °C
Reaction time: 3 h
Yield: 16.8 %

Procedure:
To a stirring solution of S-[4-(N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]-4-chlorophenyl}carbamoyl)phenyl]-S-(2-hydroxy ethyl)-sulfoximide (0.550 g, 0.00111 mol) in DCM(10 mL) was added pyridine (0.131 g, 0.001665 mol) at 5-10° C. under nitrogen atmosphere followed acetyl chloride (0.105 g, 0.00134 mol). Reaction mixture was stirred for 3 hr at 25-30° C. Subsequent work up and column purification (55% ethyl acetate in hexane and 100-200 mesh silica gel) gave 100 mg of desired product in 17% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([P:8]([O:13][CH2:14][CH3:15])(=[O:12])[O:9][CH2:10][CH3:11])=[CH:4][CH:3]=1.C1N2CN3CN(C2)CN1C3.C(O)(=[O:28])C>>[CH:1]([C:2]1[CH:3]=[CH:4][C:5]([P:8]([O:13][CH2:14][CH3:15])(=[O:12])[O:9][CH2:10][CH3:11])=[CH:6][CH:7]=1)=[O:28]
Reactant: CCOP(=O)(OCC)c1ccc(C)cc1
Reactant: CC(=O)O
Agent: C1N2CN3CN1CN(C2)C3
Product: CCOP(=O)(OCC)c1ccc(C=O)cc1

Procedure:
Diethyl 4-formyl-benzenephosphonate was prepared in a known manner by bromination of diethyl 4-methyl-benzenephosphonate and subsequent reaction of the product with hexamethylenetetramine in acetic acid.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:25]([OH:27])=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([NH:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]([C:25]([OH:27])=[O:26])[NH:18][C:16]([O:15][CH2:14][CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[O:17])(=[O:37])=[O:36])=[CH:31][CH:30]=1
Reactant: NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: O=C(N[C@@H](CCCCNS(=O)(=O)c1ccc(Cl)cc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Yield: 37 %

Procedure:
Nα-(9-fluorenylmethoxycarbonyl)-L-lysine was reacted with 4-chlorobenzenesulfonyl chloride under the conditions used in example 2 giving 37% of the title compound.
Reaction SMILES: [C:1]1(C)C=CC=CC=1.C(O)C.C(OB(C=C)OCCCC)CCC.[F:24][C:25]1([F:54])[CH2:53][CH:28]2[CH:29]([C:43]3[CH:48]=[CH:47][C:46]([O:49][CH2:50][O:51][CH3:52])=[CH:45][CH:44]=3)[O:30][C:31]3[C:36]([CH:27]2[CH2:26]1)=[CH:35][C:34]([O:37][CH2:38][O:39][CH3:40])=[CH:33][C:32]=3[C:41]#N>CCOC(C)=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>[F:24][C:25]1([F:54])[CH2:53][CH:28]2[CH:29]([C:43]3[CH:48]=[CH:47][C:46]([O:49][CH2:50][O:51][CH3:52])=[CH:45][CH:44]=3)[O:30][C:31]3[C:32]([CH:41]=[CH2:1])=[CH:33][C:34]([O:37][CH2:38][O:39][CH3:40])=[CH:35][C:36]=3[CH:27]2[CH2:26]1
Reactant: Cc1ccccc1
Reactant: COCOc1ccc(C2Oc3c(C#N)cc(OCOC)cc3C3CC(F)(F)CC32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C=CB(OCCCC)OCCCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: C=Cc1cc(OCOC)cc2c1OC(c1ccc(OCOC)cc1)C1CC(F)(F)CC21
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
Add 0.45 mL of toluene, 0.1 mL of absolute ethanol, and vinylboronic acid dibutyl ester (0.030 mL, 0.136 mmol) to a 4 mL vial containing preparation 16 (30 mg, 0.062 mmol) and Pd(PPh3)4 (7 mg, 0.0061 mmol). Bubble nitrogen through the solution for 5 min, seal tightly, and warm to 80° C. with stirring overnight. Dilute the solution with EtOAc and wash with brine. Back extract the aqueous solution with EtOAc. Wash the combined organic solutions with brine, dry over Na2SO4, filter, and concentrate. Adsorb the material to 500 mg of silica gel and purify by silica gel flash chromatography (4 g, 0-20% A/B, A=EtOAc, B=10% CH2Cl2 in hexanes) to afford 12 mg (0.028 mmol, 45%) of preparation 18. 1H NMR (400 MHz, CDCl3) δ 7.38-7.33 (m, 2H), 7.14-7.05 (m, 4H), 6.74 (d, 1H, J=2.6 Hz), 5.77 (dd, 1H, J=1.3, 18.1 Hz), 5.28 (dd, 1H, J=1.3, 12.3 Hz), 5.20 (s, 2H), 5.15 (d, 1H, J=10.1 Hz), 5.13 (d, 1H, J=9.7 Hz), 5.02 (bs, 1H), 3.67 (dt, 1H, J=3.1, 11.0 Hz), 3.50 (s, 1H), 2.89 (m, 1H), 2.74 (m, 1H), 2.30 (m, 1H), 2.17 (m, 1H), 1.86 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:10]([F:13])([F:12])[F:11])=[N:5][N:6]([CH3:9])[C:7]=1[CH3:8])#[CH:2].C(P(C(C)(C)C)C1C=CC=CC=1)(C)(C)C.[F:29][C:30]([F:43])([F:42])[C:31]1[CH:32]=[C:33](Br)[CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1.C1(N(C)C)CCCCC1.Cl>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Cu]I.CC(N(C)C)=O>[C:1]([C:3]1[CH:4]([C:10]([F:12])([F:13])[F:11])[N:5]([C:33]2[CH:34]=[C:35]([C:37]([F:40])([F:38])[F:39])[CH:36]=[C:31]([C:30]([F:29])([F:43])[F:42])[CH:32]=2)[N:6]([CH3:9])[C:7]=1[CH3:8])#[CH:2]
Reactant: C#Cc1c(C(F)(F)F)nn(C)c1C
Reactant: FC(F)(F)c1cc(Br)cc(C(F)(F)F)c1
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C1CCCCC1
Solvent: CC(=O)N(C)C
Product: C#CC1=C(C)N(C)N(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1C(F)(F)F
Temperature: 110 °C
Yield: 85 %

Procedure:
183 mg (0.983 mmol) of 4-ethinyl-1,5-dimethyl-3-(trifluoromethyl)-1H-pyrazole, 2.3 mg (0.01 mmol) of palladium acetate and 3.9 mg (0.02 mmol) of copper(I) iodide are weighed into a round-bottom flask and placed under protective gas. Subsequently, 9.1 mg (0.04 mmol) of di(tertbutyl)phenylphosphine, 300 mg (1.03 mmol) of 3,5-bis(trifluoromethyl)bromobenzene, 137 mg (1.08 mmol) of cyclohexyldimethylamine and dimethylacetamide (5 ml) are added and the mixture is heated to 110° C. for 12 h. After the end of the reaction, the mixture is cooled, poured onto cold, dilute hydrochloric acid and extracted with ether. The combined ether phases which have been dried over MgSO4 are concentrated. The product is obtained as a solid in an 85% yield.
Reaction SMILES: [CH:1]1([N:4]2[C:8]([C:9]3[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=3)=[N:7][N:6]=[C:5]2[CH2:15]O)[CH2:3][CH2:2]1.[CH2:17]([O:19][C:20](=[O:31])[CH:21](P(OCC)(OCC)=O)[CH3:22])[CH3:18].C1CCN2C(=NCCC2)CC1>C(#N)C.O=[Mn]=O>[CH2:17]([O:19][C:20](=[O:31])[C:21]([CH3:22])=[CH:15][C:5]1[N:4]([CH:1]2[CH2:2][CH2:3]2)[C:8]([C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)=[N:7][N:6]=1)[CH3:18]
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Reactant: OCc1nnc(-c2ccncc2)n1C1CC1
Agent: O=[Mn]=O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C(C)=Cc1nnc(-c2ccncc2)n1C1CC1
Temperature: 80 °C

Procedure:
(4-cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-methanol (6.8 g, 31.4 mmol) was mixed with MnO2 (40 g, 0.46 mol) in acetonitrile at r.t. for 2 hours and then heated at 80° C. for another 30 min. The reaction mixture was filtered through celite. The filtrate was mixed with 2-(diethoxy-phosphoryl)-propionic acid ethyl ester (12.35 g, 51.8 mmol) and DBU (7.17 g, 47 mmol) at 80 to 90° C. for 4 h. The reaction mixture was concentrated, dissolved in EA and washed with water and brine. The organic layer was dried, concentrated and triturated with hex. to give the title compound in 5.76 g (61%) yield. 1H-NMR: 8.78(d, 2H), 7.78 (d, 2H), 7.67 (s, 1H), 4.32 (q, 2H), 3.43 (m, 1H), 2.53 (s, 3H), 1.38 (t, 3H), 1.24 (m, 2H) and 0.73 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6](C)=[CH:5][C:4]([C:10]2[CH:15]=[CH:14][C:13]([C@@H:16]([N:18]3[CH2:23][CH2:22][C@:21]([CH2:30][C:31]([OH:34])([CH3:33])[CH3:32])([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:20][C:19]3=[O:35])[CH3:17])=[CH:12][CH:11]=2)=[N:3]1.Cl[C:37]1C(C)=CC(=O)N(C)N=1>>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([CH3:37])[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C@@H:16]([N:18]3[CH2:23][CH2:22][C@:21]([CH2:30][C:31]([OH:34])([CH3:33])[CH3:32])([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[O:20][C:19]3=[O:35])[CH3:17])=[CH:12][CH:11]=2)=[N:3]1
Reactant: Cc1cc(=O)n(C)nc1Cl
Reactant: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)nn(C)c1=O
Product: Cc1cc(=O)n(C)nc1-c1ccc([C@H](C)N2CC[C@](CC(C)(C)O)(c3ccccc3)OC2=O)cc1

Procedure:
The title compound was prepared from 3-{(S)-1-[4-(1,5-dimethyl-6-oxo-1,6-dihydro-pyridazin-3-yl)-phenyl]-ethyl}-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one and 6-chloro-2,5-dimethylpyridazin-3(2H)-one following a procedure analogous to that described in Example 17. Mass spectrum (ESI+): m/z=476 [M+H]+