Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:22][CH3:23])[CH2:4][CH2:5][N:6]1[C:16]2[C:11](=[C:12]([C:18]([F:21])([F:20])[F:19])[CH:13]=[C:14]([I:17])[CH:15]=2)[C:9](=[O:10])[C:7]1=[O:8])[CH3:2].C(OCC)C.[Cl:29][C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=1[Mg]I>C1(C)C=CC=CC=1>[CH2:22]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]1[C:16]2[C:11](=[C:12]([C:18]([F:20])([F:21])[F:19])[CH:13]=[C:14]([I:17])[CH:15]=2)[C:9]([OH:10])([C:33]2[CH:32]=[CH:31][C:30]([Cl:29])=[CH:35][C:34]=2[Cl:36])[C:7]1=[O:8])[CH3:23]
Reactant: CCN(CC)CCN1C(=O)C(=O)c2c1cc(I)cc2C(F)(F)F
Reactant: Clc1ccc([Mg]I)c(Cl)c1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCN(CC)CCN1C(=O)C(O)(c2ccc(Cl)cc2Cl)c2c1cc(I)cc2C(F)(F)F
Reaction time: 1 h
Yield: 55 %

Procedure:
To a solution of 1-(2-diethylaminoethyl)-4-trifluoromethyl-6-iodoisatin (150 mg, 0.341 mmol) in a mixed solvent of diethyl ether (2 mL) and toluene (1 mL) was added dropwise a freshly prepared 0.794 N 2,4-dichlorophenyl magnesium iodide in ether (0.45 mL, 0.387 mmol) at room temperature. The mixture was stirred for 1 h at the same temperature and the reaction was quenched with aqueous NaHCO3. The mixture was extracted with ethyl acetate and the extracts were dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography with 80:1 to 50:1 chloroform/methanol to give the title compound (111 mg, 55%).
Reaction SMILES: C([O:5][C:6](=[O:17])[C@H:7]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[I:16])[NH2:8])(C)(C)C.C(=N)(C1C=CC=CC=1)C1C=CC=CC=1.[ClH:32].C(C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[ClH:32].[I:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][C@@H:7]([C:6]([OH:17])=[O:5])[NH2:8]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1I
Agent: Cl
Agent: N=C(c1ccccc1)c1ccccc1
Agent: O=C(c1ccccc1)c1ccccc1
Product: N[C@@H](Cc1ccccc1I)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 94 %

Procedure:
A 500 mL round bottomed flask equipped with a reflux condenser and a magnetic stirrer was charged with 15.72 g of 2-iodo-L-phenylalanine tert-butyl ester-benzophenone imine (86% ee) and 165 mL of 6 N aqueous HCl. The mixture was heated at reflux with stirring for 4 h and cooled to RT to afford a mixture of white crystalline solid and an immicible organic phase (benzophenone). The mixture was partitioned between water (100 mL) and ethyl ether (70 mL). The aqueous phase was separated, washed with four additional 70 mL portions of ether and concentrated in vacuo to dryness to give 9.5 g (94%) of 2-iodo-L-phenylalanine HCl as a fluffy white solid, m.p. 240° C. (dec).
Reaction SMILES: [O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:33])[N:13]2[C:16](=[C:30]([OH:32])[CH3:31])[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36].C(N(CC)CC)C>O1CCCC1.C(Cl)Cl>[O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:33])[N:13]2[C:16](=[C:30]([O:32][S:35]([CH3:34])(=[O:37])=[O:36])[CH3:31])[C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)=[O:18])[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(OS(C)(=O)=O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21
Reaction time: 3 h

Procedure:
To a solution of p-nitrobenzyl α-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-hydroxyethylidene)acetate (504 mg) in tetrahydrofuran (8 ml) are added dropwise methanesulfonyl chloride (0.13 ml) and triethylamine (0.23 ml) under ice cooling. After 3 hours, the mixture is evaporated to leave residue, which is dissolved in methylene chloride, washed with water, dried over magnesium sulfate, and evaporated. Purification of the residue by chromatography over silica gel containing 10% water (15 g) using a mixture of benzene and ethyl acetate (5:1) gives p-nitrobenzyl α-[3-phenoxymethyl- 7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-methanesulfonyloxyethylidene)acetate (353 mg). Colorless foam.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH3:12][N:13]1[CH:17]=[CH:16][N:15]=[C:14]1[CH:18]=[O:19].[N:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21]>ClCCl>[OH:21][N:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:18]([C:14]1[N:13]([CH3:12])[CH:17]=[CH:16][N:15]=1)=[O:19]
Reactant: Cn1ccnc1C=O
Reactant: O=Nc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: Cn1ccnc1C(=O)N(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
DBU (3.8 mg, 0.025 mmol) was added under argon to a solution of 1-methyl-1H-imidazole-2-carbaldehyde (110 mg, 1 mmol), nitrosobenzene (107 mg, 1 mmol) and catalyst (1.82 mg, 0.005 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 10 min. The solvent was removed under vacuum, and the residue was purified by flash silica gel column chromatography using hexane and ethyl acetate as the eluents.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=O.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>C(#N)C>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:14]=[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]3[CH:2]=2)=[CH:6][CH:7]=1)([O-:13])=[O:12]
Reactant: Nc1ccccn1
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(-c2cn3ccccc3n2)cc1
Temperature: 25 °C

Procedure:
5.00 g (20.49 mmol) 2-Bromo-1-(4-nitrophenyl)-ethanone and 3.86 g (40.98 mmol) 2-aminopyridine are heated to reflux in 50 mL acetonitrile for 3 hours. The mixture is allowed to cool to RT. The solvent is evaporated. The residue is suspended in ethanol and alkalinized with ammonia solution. The precipitate is filtered off, washed with diethyl ether and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.Cl.[C:33]([O:37][C:38](=[O:46])[NH:39][CH:40]1[CH2:44][CH2:43][CH:42]([NH2:45])[CH2:41]1)([CH3:36])([CH3:35])[CH3:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>O.CN(C=O)C>[C:33]([O:37][C:38](=[O:46])[NH:39][CH:40]1[CH2:44][CH2:43][CH:42]([NH:45][C:21]([C:20]2[C:14]3[C:15](=[N:16][CH:17]=[C:12]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=5)[N:8]([CH3:11])[N:7]=4)[N:13]=3)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[CH:19]=2)=[O:22])[CH2:41]1)([CH3:36])([CH3:34])[CH3:35]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Reactant: CC(C)(C)OC(=O)NC1CCC(N)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)NC2CCC(NC(=O)OC(C)(C)C)C2)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.7 %

Procedure:
A round-bottomed flask was charged with 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (300 mg, 0.66 mmol) and (3-aminocyclopentyl)-carbamic acid tert-butylester hydrochloride (233 mg, 0.98 mmol). DMF (3 ml) was added followed by HATU (274 mg, 0.72 mmol) and N,N-diisopropylethylamine (0.30 ml, 1.72 mmol). The reaction mixture was stirred at room temperature for 30 min. Additional DMF (2 ml) was added and the light yellow suspension was stirred at room temperature overnight. Water was added and the resulting suspension was filtered, washed with water and petroleum ether and dried under high vacuum to afford 413 mg (99%) of (3-{[2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-amino}-cyclopentyl)-carbamic acid tert-butyl ester as an off-white powder. The isolated product was determined to be a single diastereomer of unknown relative stereochemistry by NMR analysis.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[Br:7][C:8]1[CH:13]=[CH:12][C:11](CC(O)=O)=[CH:10][CH:9]=1.C(Cl)Cl>CN(C)C=O>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:1][C:2]([Cl:4])=[O:3])=[CH:10][CH:9]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)Cc1ccc(Br)cc1
Reaction time: 0.5 h

Procedure:
Initially, oxalyl chloride is added to an equimolar amount of p-bromophenylacetic acid (13) in an inert solvent, preferably methylene chloride, at about room temperature, with a catalytic amount of dimethylformamide. The mixture is stirred for about 30 minutes, after which the product, p-bromophenylacetyl chloride (14), is isolated by conventional means.
Reaction SMILES: Cl.[CH:2]([N:5]1[C:9]([C:10]2[N:19]=[C:18]3[N:12]([CH2:13][CH2:14][O:15][C:16]4[CH:23]=[C:22]([CH:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[CH:21]=[CH:20][C:17]=43)[CH:11]=2)=[N:8][C:7]([CH3:30])=[N:6]1)([CH3:4])[CH3:3].[CH2:31]([O:33][C:34](=[O:39])[C:35](Br)([CH3:37])[CH3:36])[CH3:32].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:31]([O:33][C:34](=[O:39])[C:35]([N:27]1[CH2:28][CH2:29][CH:24]([C:22]2[CH:21]=[CH:20][C:17]3[C:18]4[N:12]([CH2:13][CH2:14][O:15][C:16]=3[CH:23]=2)[CH:11]=[C:10]([C:9]2[N:5]([CH:2]([CH3:4])[CH3:3])[N:6]=[C:7]([CH3:30])[N:8]=2)[N:19]=4)[CH2:25][CH2:26]1)([CH3:37])[CH3:36])[CH3:32]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(C4CCNCC4)cc2OCC3)n(C(C)C)n1
Reactant: CCOC(=O)C(C)(C)Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)N1CCC(c2ccc3c(c2)OCCn2cc(-c4nc(C)nn4C(C)C)nc2-3)CC1
Temperature: 70 °C
Reaction time: 18 h
Yield: 36.4 %

Procedure:
A mixture of 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene hydrochloride (100 mg, 0.255 mmol), 2-bromo-2-methyl-propionic acid ethyl ester (45 uL, 0.31 mmol), cesium carbonate (187 mg, 0.57 mmol) and DMF (0.5 mL) was heated at 70° C. for 3 h the then stirred at RT for 18 h then heated again at 70° C. for 4 h before concentrating in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 5% methanol in DCM) to give 2-{4-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidin-1-yl}-2-methyl-propionic acid ethyl ester (47 mg, 36%). LCMS RT=2.24, [M+H]+=507.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:7][C:6]2[CH:8]=[CH:9][C:10]([CH2:12][CH:13]([N:15]([CH2:22][CH3:23])[C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH3:14])=[CH:11][C:5]=2[O:4]1.[C:24]1(=[O:30])[O:29][C:27](=[O:28])[CH2:26][CH2:25]1.C(N(CC)CC)C>ClCCCl.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[CH2:22]([N:15]([C:16](=[O:21])[C:17]([F:18])([F:20])[F:19])[CH:13]([CH3:14])[CH2:12][C:10]1[CH:9]=[CH:8][C:6]2[O:7][CH:3]([CH2:2][NH:1][C:24](=[O:30])[CH2:25][CH2:26][C:27]([OH:29])=[O:28])[O:4][C:5]=2[CH:11]=1)[CH3:23]
Reactant: CCN(C(=O)C(F)(F)F)C(C)Cc1ccc2c(c1)OC(CN)O2
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCN(C(=O)C(F)(F)F)C(C)Cc1ccc2c(c1)OC(CNC(=O)CCC(=O)O)O2
Temperature: 40 °C
Reaction time: 2.5 h
Yield: 86.8 %

Procedure:
To a solution of 558 mg (1.67 mmol) of 2J in 25 mL of 1,2 dichloroethane was added 435 mg (4.34 mmol) of succinic anhydride, 280 μL (2 mmol) of triethylamine and 112 mg (0.91 mmol) of 4-DMAP. The reaction mixture was allowed to stir at 40° C. under argon atmosphere for 2.5 hours. It was then diluted with 50 mL of ethyl acetate and washed with 3×30 mL of 5% ammonium chloride solution. The organic layer was dried (anhydrous Na2SO4) and concentrated under reduced pressure to dryness. The residue was purified by silica gel column chromatography to give 629 mg (1.45 mmol, 86%) of 2K as a colorless gum (M+H, 433).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:5][N:6]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][C:8]2[O:15][C:16]([CH:18]=O)=[CH:17][C:7]1=2.[Cl-].O[NH3+:26].C(OC(=O)C)(=O)C>N1C=CC=CC=1>[C:18]([C:16]1[O:15][C:8]2[CH:9]=[C:10]([C:11]([O:13][CH3:14])=[O:12])[N:6]([CH2:5][C:4]3[CH:20]=[CH:21][C:22]([Cl:23])=[C:2]([Cl:1])[CH:3]=3)[C:7]=2[CH:17]=1)#[N:26]
Reactant: [NH3+]O
Reactant: COC(=O)c1cc2oc(C=O)cc2n1Cc1ccc(Cl)c(Cl)c1
Agent: [Cl-]
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COC(=O)c1cc2oc(C#N)cc2n1Cc1ccc(Cl)c(Cl)c1
Temperature: 90 °C
Yield: 99.4 %

Procedure:
Methyl 4-(3,4-dichlorobenzyl)-2-formylfuro[3,2-b]pyrrole-5-carboxylate (0.7 g) was dissolved in pyridine (7 mL). To this was added hydroxyammonium chloride (0.23 g) and reaction heated at 90° C. for 30 min. Acetic anhydride (2.5 mL) was added dropwise and reaction heated at 90° C. for a further 2 hours. The reaction was quenched by pouring onto ice/water, and the resulting precipitate was filtered off and dried in vacuo to give a pale brown solid (0.69 g, 100%), NMR d(CDCl3) 3.85 (3H, s), 5.6 (2H, s), 6.85 (2H, d), 6.95 (1H, dd), 7.2 (1H, d), 7.4 (1H, d); M/z (−) 349 (M-H+), 347, 189.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]([NH2:15])=[NH:14])=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.[C:16]([N:19]1[CH2:24][CH2:23][C:22](=O)[CH:21]([C:26](OC)=[O:27])[CH2:20]1)(=[O:18])[CH3:17].[O-]CC.[Na+].O>C(O)C>[OH:27][C:26]1[C:21]2[CH2:20][N:19]([C:16](=[O:18])[CH3:17])[CH2:24][CH2:23][C:22]=2[N:14]=[C:13]([NH:12][C:9]2[CH:8]=[CH:7][C:6]([C:5]3[O:1][CH:2]=[N:3][CH:4]=3)=[CH:11][CH:10]=2)[N:15]=1
Reactant: COC(=O)C1CN(C(C)=O)CCC1=O
Reactant: N=C(N)Nc1ccc(-c2cnco2)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(O)c2C1
Temperature: 100 °C
Yield: 40.3 %

Procedure:
1-(4-(Oxazol-5-yl)phenyl)guanidine (2 g, 9.89 mmol, example 1e), methyl 1-acetyl-4-oxopiperidine-3-carboxylate (1.970 g, 9.89 mmol) and sodium ethoxide (0.673 g, 9.89 mmol) in ethanol were charged in a thick wall glass which was sealed and heated at 100° C. under microwave irradiation. The reaction mixture was allowed to reach room temperature and water was added until a solid was obtained. The solid was filtered and dried in a vacuum oven at 40° C. overnight yielding 1-(4-hydroxy-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanone (1.400 g, 40.3%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:12][C@@H:13]1[NH:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1.C(N(C(C)C)CC)(C)C.BrC1C=CC=CC=1S(Cl)(=O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([N:18]2[CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][C@@H:13]2[CH3:12])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Agent: O=C([O-])O
Agent: O=S(=O)(Cl)c1ccccc1Br
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1S(=O)(=O)c1cccc(Br)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 55 %

Procedure:
3-bromobenzene-1-sulfonyl chloride and (S)-tert-butyl 3-methylpiperazine-1-carboxylate was coupled following as follows: Dissolve 1 g (5 mmol) of the amine in 10 mL of methylene chloride. Add 2.0 eq. of diisopropyl ethylamine. Cool to 0° C. and add 1.5 equivalents of bromobenzene sulfonyl chloride dropwise (ca. 1 min) and stir for 5 min. Warm to rt and stir for an additional 16 h. Work up by adding a saturated solution of NaHCO3 and extracting with EtOAc. Wash the organic layer with HCl (1 N) followed by NaHCO3 and brine. Remove the solvent to afford crude, yellow oil. Purification of the sulfonamide derivative by Biotage on silica gel (99% MeOH/DCM) affords the desired product as a yellow oil. The yield was 55%. LC-MS showed the product was >95% pure and had the expected M+H+ of 420. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 7.9 (d, 1H) 7.72-7.65 (m, 2H) 7.4 (t, 1H), 3.7 (m, 2H) 3.6 (m, 1H), 3.13-3.0 (m, 2H) 2.92-2.77 (m, 2H), 1.4 (s, 12H) 1.0 (d, 3H).
Reaction SMILES: [OH:1][CH:2]([CH:8]([NH:16][C:17](=[O:35])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][C:19]=1[C:24]1[N:25]=[C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[S:27][CH:28]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]([O:5]CC)=[O:4].C1COCC1>O>[OH:1][CH:2]([CH:8]([NH:16][C:17](=[O:35])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][C:19]=1[C:24]1[N:25]=[C:26]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[S:27][CH:28]=1)[CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-c1csc(-c2ccccc2)n1
Solvent: O
Solvent: C1CCOC1
Product: O=C(NC(Cc1ccccc1)C(O)C(=O)O)c1cccnc1-c1csc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
To a solution of ethyl 2-hydroxy-4-phenyl-3-(2-(2-phenylthiazol-4-yl)nicotinamido)-butanoate (1.31 g, 2.69 mmol) in THF (40 ml) LiOH (0.14 g, 5.85 mmol) in water (10 ml) was added at 10° C., the mixture stirred for 1 hour at room temperature and then for 2 hours at 60° C. The mixture then was concentrated under reduced pressure, water and 3 ml of 2n HCl added, poured into 300 ml of a mixture of dichloromethane and 5% acetone. The organic layer was dried, filtered and concentrated under reduced pressure to give 1.19 g of the title acid;
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[CH2:13]([Sn](CCCC)(CCCC)C=C)[CH2:14]CC>C1(C)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([CH:13]=[CH2:14])[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COc1cc(Br)ccc1[N+](=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc([N+](=O)[O-])c(OC)c1
Reaction time: 5 h
Yield: 355.5 %

Procedure:
4-Bromo-2-methoxy-1-nitro-benzene (691 mg, 3.14 mmol), tributyl-vinyl-stannane (1.2 g, 3.77 mmol), triphenylphospine (49 mg, 0.19 mmol) and tetrakistriphenylphosphinpalladium(0) (73 mg, 0.06 mmol) were dissolved in toluene (25 ml) and stirred for 5 hours at reflux. The reaction mixture was concentrated in vacuo. The residue was partitioned between water (25 ml) and diethyl ether (50 ml). The organic phase was separated, dried over MgSO4, filtered and concentrated in vacuo to yield an oil (2.0 g). The residue was purified via silica gel chromatography with cyclohexane/ethyl acetate (gradient 0-25%). Fractions containing the product were combined, the solvent evaporated to give an oil (435 mg, 72%).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[C:6]1[C:7](=[O:21])[C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][C:11]([CH2:17][CH3:18])=[C:10]([CH2:19][CH3:20])[CH:9]=2>C(O)C>[N:1]([C:15]1[C:14](=[O:16])[C:13]2[C:8]([C:7](=[O:21])[CH:6]=1)=[CH:9][C:10]([CH2:19][CH3:20])=[C:11]([CH2:17][CH3:18])[CH:12]=2)=[N+:2]=[N-:3]
Reactant: CCc1cc2c(cc1CC)C(=O)C(Cl)=CC2=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCO
Product: CCc1cc2c(cc1CC)C(=O)C(N=[N+]=[N-])=CC2=O

Procedure:
An aqueous solution of sodium azide (6.15 g; 0.095 mole) was added in one portion to a stirred, refluxing solution of 2-chloro-6,7-diethyl-1,4-naphthoquinone (18.0 g; 0.073 mole) in ethanol (180 ml) and the mixture refluxed for a further 2 mins. The red solution was cooled and the orange solid filtered off and washed with cold ethanol then water. After drying the product weighed 13.87 g (75%) and had m.p. 73°-76° C. (d). Recrystallisation from ethanol gave long orange needles of m.p. 74°-76° C. (d). (Found; C, 65.64; H, 5.27; N, 16.66; C14H13N3O2 requires; C, 65.87; H, 5.13; N, 16.46%).
Reaction SMILES: C1COCC1.[Br-].[F:7][CH2:8][CH2:9][CH2:10]P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[F:36][C:37]1[CH:38]=[C:39]([CH:47]2[CH2:52][CH2:51][C:50](=O)[CH2:49][CH2:48]2)[CH:40]=[C:41]([F:46])[C:42]=1[O:43][CH2:44][CH3:45]>O>[F:36][C:37]1[CH:38]=[C:39]([CH:47]2[CH2:52][CH2:51][CH:50]([CH2:10][CH2:9][CH2:8][F:7])[CH2:49][CH2:48]2)[CH:40]=[C:41]([F:46])[C:42]=1[O:43][CH2:44][CH3:45]
Reactant: FCCC[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOc1c(F)cc(C2CCC(=O)CC2)cc1F
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1c(F)cc(C2CCC(CCCF)CC2)cc1F
Temperature: -50 °C
Yield: 21 %

Procedure:
THF (100 ml) was added to the above 3-fluoropropyltriphenylphosphine bromide (22.0 g, 54.6 mmol), followed by cooling the mixture down to -50° C. in a nitrogen atmosphere, adding to the mixture, a 70 ml THF solution of potassium-t-butoxide (6.10 g, 54.5 mmol), stirring the mixture for 3 hours, dropwise adding to the reaction solution, a 80 ml THF solution of 4-(3,5-difluorophenetyl)-1-cyclohexanone (10.0 g, 42.0 mmol), stirring the mixture for one hour at the same temperature, and heating it up to room temperature for 4 hours, adding water (200 ml) to the resulting reaction solution, extracting the resulting product with ethyl acetate, washing the extraction solution successively with a saturated aqueous solution of sodium bicarbonate and water, drying the organic layer over magnesium sulfate, distilling off the solvent under reduced pressure, purifying the residue according to column chromatography treatment using toluene as a developing solvent, hydrogenating the resulting purified substance in the presence of 5% Pd/C catalyst, in ethanol, and thereafter filtering off the catalyst to obtain 4-(3,5-difluorophenetyl)-1-(3-fluoropropyl)cyclohexane (2.51 g, 8.83 mmol). Yield: 21.0%.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1)C=C.C[N+]1([O-])[CH2:17][CH2:16][O:15]CC1.[OH2:19]>CC(C)=O.C(Cl)Cl.O=[Os](=O)(=O)=O>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:1][CH:16]([OH:15])[CH2:17][OH:19])=[CH:5][CH:6]=1
Reactant: C=CCc1ccc(Br)cc1
Reactant: O
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: OCC(O)Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1-allyl-4-bromo-benzene (2.0 g, 10.2 mmol) in acetone (60 mL) is treated with OsO4 (52 mg, 0.20 mmol), NMO (1.44 g, 12.2 mmol) and water (approx. 0.3 mL). The clear solution is stirred at rt for 2 h, diluted with DCM (150 mL) and washed twice with 10% aq. citric acid (2×75 mL). The aqueous phase is extracted twice with DCM. The organic extracts are combined, dried over MgSO4 and evaporated. The crude product is purified by CC on silica gel eluting with EA to give 3-(4-bromo-phenyl)-propane-1,2-diol (1.41 g) as an almost colourless oil; LC-MS: tR=0.72 min; 1H NMR (CDCl3): δ 7.46-7.40 (m, 2H), 7.14-7.08 (m, 2H), 3.96-3.87 (m, 1H), 3.73-3.67 (m, 1H), 3.55-3.47 (m, 1H), 2.81-2.67 (m, 2H), 1.90 (s br, 2H).