Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21]5[CH:22]=[C:23]([NH:27]C(=O)C)[CH:24]=[CH:25][CH:26]=5)=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.C(=O)(O)[O-].[Na+]>C(O)C>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21]5[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=5)[NH2:27])=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)Nc1cccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1cccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)c1
Yield: 52.3 %

Procedure:
To a solution of example 69 (0.045 g, 0.152 mmol) in ethanol (1 ml), con. HCl (0.5 ml) was added and refluxed for 2 h. The reaction mixture was cooled, basified with sodium bicarbonate solution, extracted with ethyl acetate, dried over sodium sulphate and concentrated under reduced pressure to afford the title compound as brown solid (0.028 g, 70%). M.P.: 187-189° C. MS (m/z): 352.90 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27]([OH:29])=O)[CH:5]=[CH:6][CH:7]=1.[N:30]1([CH2:36][C:37]([N:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)=[O:38])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH:9]([C:27]([N:33]3[CH2:32][CH2:31][N:30]([CH2:36][C:37](=[O:38])[N:39]4[CH2:40][CH2:41][CH2:42][CH2:43]4)[CH2:35][CH2:34]3)=[O:29])[NH:10][CH:11]([CH2:22][C:23]([CH3:24])([CH3:26])[CH3:25])[C:12]2([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:13]#[N:14])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Reactant: O=C(CN1CCNCC1)N1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)N2CCN(CC(=O)N3CCCC3)CC2)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Yield: 70.8 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (61.0 mg, 0.14 mmol) prepared in Example 1d was reacted with 2-piperazin-1-yl-1-pyrrolidin-1-yl-ethanone (65.0 mg, 0.33 mmol), HATU (106.0 mg, 0.28 mmol) and iPr2NEt (38.8 mg, 0.30 mmol) in CH2Cl2 (2 mL) at rt overnight to give rac-(2S,3R,4R,5R)-4-(3-Chloro-phenyl)-3-(4-chloro-phenyl)-2-(2,2-dimethyl-propyl)-5-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazine-1-carbonyl]-pyrrolidine-3-carbonitrile (60.5 mg, 70.8%).
Reaction SMILES: Cl[O-:2].[Na+].Br[O-].I[O-].[N+:8]([C:11]1[S:15][C:14]([CH:16]=[O:17])=[CH:13][CH:12]=1)([O-:10])=[O:9]>C(O)(=O)C>[N+:8]([C:11]1[S:15][C:14]([C:16]([OH:2])=[O:17])=[CH:13][CH:12]=1)([O-:10])=[O:9]
Reactant: [O-]Cl
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Agent: [Na+]
Agent: [O-]Br
Agent: [O-]I
Solvent: CC(=O)O
Product: O=C(O)c1ccc([N+](=O)[O-])s1
Yield: 75 %

Procedure:
It has also been observed, in accordance with another aspect of the present invention, that a mixture of halogen and alkali metal hydroxide i.e. an alkali metal hypohalide such as sodium hypochlorite, hypobromite or hypoiodite when it is added to an aqueous suspension of 5-nitro-2-formyl-thiophene maintained at a pH between 4.5 and 6.5 by means of acetic acid or an acetic acid/alkali metal acetate mixture, provides pure 5-nitro-2-thenoic acid in a yield of at least 75%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])[C:7](=O)[CH2:6][CH2:5]2.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+].[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH3:15][N:14]([CH3:16])[CH2:13][CH2:12][N:8]1[C:9]2[C:4](=[CH:3][C:2]([NH2:1])=[CH:11][CH:10]=2)[CH2:5][CH2:6][CH2:7]1
Reactant: CN(C)CCN1C(=O)CCc2cc(N)ccc21
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CN(C)CCN1CCCc2cc(N)ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 76.1 %

Procedure:
A solution of 6-amino-1-(2-(dimethylamino)ethyl)-3,4-dihydroquinolin-2(1H)-one (1.3 g, 5.57 mmol) in 10 mL anhydrous THF was added dropwise to a cooled suspension of 1M LiAlH4 in THF (22.3 mL, 22.3 mmol). The suspension was stirred at room temperature for 1 day. After this time, the mixture was cooled to 0° C. and treated with 5 mL 1N NaOH dropwise with rapid stirring. After stirring for 30 minutes, the suspension was treated with Na2SO4 and filtered. The filter cake was rinsed with 10% 2M NH3 in MeOH/CH2Cl2 (100 mL total). The filtrate was concentrated and the dark residue was subjected to flash chromatography on silica gel using 5-10% 2M NH3 in MeOH/CH2Cl2 to give a dark viscous oil (930 mg, 76.2%). 1H-NMR (CDCl3) δ: 6.49 (brs, 2H), 6.40 (s, 1H), 3.34-3.30 (m, 2H), 3.30 (br s, 2H), 3.21 (t, J=5.7 Hz, 2H), 2.68 (t, J=5.7 Hz, 2H), 2.49-2.44 (m, 2H), 2.28 (s, 6H), 1.95-1.87 (m, 2H).
Reaction SMILES: [OH:1][CH:2]([CH2:20][CH3:21])[C:3]([N:5]1[CH2:10][CH2:9][C:8]2[N:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:13][C:7]=2[CH2:6]1)=S.[CH2:22]([O:24][C:25]([NH:27][NH2:28])=[O:26])[CH3:23]>C1COCC1.C([O-])(=O)C.[Hg+]>[OH:1][CH:2]([CH2:20][CH3:21])[C:3](=[N:28][NH:27][C:25]([O:24][CH2:22][CH3:23])=[O:26])[N:5]1[CH2:10][CH2:9][C:8]2[N:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:13][C:7]=2[CH2:6]1
Reactant: CCC(O)C(=S)N1CCc2nc(-c3ccccc3)oc2C1
Reactant: CCOC(=O)NN
Agent: CC(=O)[O-]
Agent: [Hg+]
Solvent: C1CCOC1
Product: CCOC(=O)NN=C(C(O)CC)N1CCc2nc(-c3ccccc3)oc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
185.00 mg (612 μmol) 2-hydroxy-1-(2-phenyl-6,7-dihydro-4H-oxazolo[5,4-c]pyridin-5-yl)-butan-1-thione, 70.00 mg (672 μmol) ethylhydrazinecarboxylate and 200.00 mg (628 μmol) mercury acetate are placed in 10 mL THF and the mixture is stirred for 2 h at RT. The reaction mixture is filtered through silica gel suction and the solvent is eliminated in vacuo.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:15][C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[CH:22]=[C:21]([C@:26]2([CH3:32])[CH2:30][O:29]C(=O)[NH:27]2)[CH:20]=[CH:19]3)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.O.[OH-].[Li+]>>[NH2:27][C@@:26]([C:21]1[CH:20]=[CH:19][C:18]2[C:23](=[CH:24][CH:25]=[C:16]([S:15][C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:10]=3)[CH:17]=2)[CH:22]=1)([CH3:32])[CH2:30][OH:29]
Reactant: C[C@@]1(c2ccc3cc(Sc4cccc(OCc5ccccc5)c4)ccc3c2)COC(=O)N1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C[C@](N)(CO)c1ccc2cc(Sc3cccc(OCc4ccccc4)c3)ccc2c1
Yield: 92.1 %

Procedure:
(R)-4-(6-(3-(benzyloxy)phenylthio)naphthalen-2-yl)-4-methyloxazolidin-2-one (30.0 mg, 0.0000679 mol) was dissolved in ethanol (2 mL, 0.03 mol) and water (0.8 mL, 0.05 mol) then lithium hydroxide (17 mg, 0.00072 mol) was added and was heated to reflux overnight. LCMS shows no SM and a new peak at 1.51 399.17 ([M-NH2]+, 100). After concentration, the residue was taken up into methylene chloride and water. The aqueous layer was extracted with methylene chloride and concentrated. Column chromatography with MeOH/methylene chloride gave (R)-2-amino-2-(6-(3-(benzyloxy)phenylthio)naphthalen-2-yl)propan-1-ol as a white solid (26.0 mg, 92%). LCMS 1.51 399.17 ([M-NH2]+, 100%). 1H NMR (400 MHz, MeOD) δ=7.95 (br. s., 1 H), 7.89-7.76 (m, 3 H), 7.64 (d, J=8.6 Hz, 1 H), 7.43-7.20 (m, 7 H), 6.98-6.87 (m, 3 H), 5.00 (br. s., 2 H), 3.84-3.77 (m, 1 H), 3.77-3.69 (m, 1 H), 1.60 (s., 3 H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[O:7]=[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:17])[N:9]1[CH2:18][CH2:19][C@@H:20]([C@H:24]([O:41]C=O)[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:34]=[N:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=2)=[CH:29][CH:28]=1)[C:21]([OH:23])=[O:22]>CO>[O:17]=[C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](=[O:7])[N:9]1[CH2:18][CH2:19][C@@H:20]([C@H:24]([OH:41])[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:34]=[N:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=2)=[CH:29][CH:28]=1)[C:21]([OH:23])=[O:22]
Reactant: COc1ccc(-c2ccc(CC[C@@H](OC=O)[C@H](CCN3C(=O)c4ccccc4C3=O)C(=O)O)cc2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1ccc(-c2ccc(CC[C@@H](O)[C@H](CCN3C(=O)c4ccccc4C3=O)C(=O)O)cc2)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Potassium carbonate (0.165 g) was added to a solution of the compound obtained from step i above (0.4 g) in methanol (6 mL) at 0° C. The reaction mixture was stirred at room temperature for 3 hours. The solvents were evaporated, and the residue was taken into water and ethyl acetate. The organic layer was washed with water and brine solution, and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure to obtain a residue which was purified with preparatory TLC using 7% methanol in ethyl acetate as eluent to get the title compound (0.13 gm).
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:14][C:15]1[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=1[C:17]([O:19]C)=[O:18])[CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>CO>[CH2:3]([O:14][C:15]1[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=1[C:17]([OH:19])=[O:18])[CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCC/C=C\CCCOc1ccccc1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCC/C=C\CCCOc1ccccc1C(=O)O
Yield: 99.5 %

Procedure:
500 μl of 1 N sodium hydroxide solution (500 μmol) are added portionwise to 80 mg of 29 (263 μmol) in methanol (3 mL). The solution is refluxed for 24 hours. After evaporating off the solvent, the reaction medium is acidified with 0.5 N HCl and extracted with DCM. 76 mg of a yellow oil are obtained, i.e. a yield of 99%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([CH:11]([OH:13])[CH3:12])=[CH:9][CH:10]=1)=[O:5])[CH3:2].[CH3:14][C:15]1[CH:20]=[C:19](O)[CH:18]=[C:17]([CH3:22])[C:16]=1[C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CO>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([CH:11]([O:13][C:19]2[CH:20]=[C:15]([CH3:14])[C:16]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:32])[F:31])=[CH:25][CH:24]=3)=[C:17]([CH3:22])[CH:18]=2)[CH3:12])=[CH:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(C(C)O)s1
Reactant: Cc1cc(O)cc(C)c1-c1ccc(C(F)(F)F)cc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(C(C)Oc2cc(C)c(-c3ccc(C(F)(F)F)cc3)c(C)c2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.8 %

Procedure:
A mixture of (±)-5-(1-hydroxy-ethyl)-thiophene-2-carboxylic acid ethyl ester (0.402 g, 2.01 mmol), 2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-ol (0.593 g, 2.23 mmol), and PPh3 (0.798 g, 3.04 mmol) is dissolved in toluene (20 mL) and treated with 1,1′-(azodicarbonyl)dipiperidine (ADDP, 0.763 g, 3.02 mmol) and stirred overnight at rt. The mixture is diluted with MeOH until homogeneous and concentrated. The residue is loaded onto silica gel and eluted using hexanes with an ethyl acetate gradient from 0% to 40% giving (±)-5-[1-(2,6-Dimethyl-4′-trifluoromethyl-biphenyl-4-yloxy)-ethyl]-thiophene-2-carboxylic acid ethyl ester (0.638 g, 71%) as a clear syrup. MS (ES): 447.3 [M−H]−.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:22][CH:23]4[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[C:36]1([C:42]2[N:43]=[C:44]([C:47](O)=[O:48])[S:45][CH:46]=2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH3:20][O:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:21][CH2:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[N:12]=[CH:11][CH:10]=[C:9]2[O:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:47]([C:44]2[S:45][CH:46]=[C:42]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:43]=2)=[O:48])=[N:7][CH:6]=1
Reactant: COc1cc2c(Oc3ccc(N)nc3)ccnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(O)c1nc(-c2ccccc2)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(NC(=O)c4nc(-c5ccccc5)cs4)nc3)ccnc2cc1OCC1CCNCC1
Temperature: 55 °C
Reaction time: 72 h

Procedure:
A mixture of tert-butyl 4-(((4-((6-aminopyridin-3-yl)oxy)-6-methoxyquinolin-7-yl)oxy)methyl)piperidine-1-carboxylate (70 mg, 0.14 mmol), 4-phenylthiazole-2-carboxylic acid (46 mg, 0.21 mmol), DIPEA (56 mg, 0.43 mmol) and HATU (110 mg, 0.29 mmol) in dry DMF (5 mL) was stirred for 72 h at 55° C. The solution was diluted with EtOAc (150 mL) and washed twice with aq.NaHCO3-solution and once with brine. The residue was dissolved in 50% TFA in DCM (5 mL) and stirred for 2 h at RT. The mixture was concentrated under reduced pressure. The residue was purified by reverse phase RP-HPLC (column: C18), using H2O and ACN as eluents. The desired fractions were lyophilized to yield the title compound X14 (25 mg, 30%) as a white powder. 1H NMR (400 MHz, d6-DMSO, 300K) δ 1.25 (m, 2H), 1.76 (d, J=12.0 Hz, 2H), 1.95 (m, 1H), 2.55 (t, J=11.0 Hz, 2H), 3.00 (d, J=12.0 Hz, 2H), 3.94 (s, 3H), 3.99 (d, J=6.3 Hz, 2H), 6.58 (d, J=5.2 Hz, 1H), 7.41 (m, 2H), 7.51 (m, 3H), 7.90 (dd, J=2.9 Hz, J=9.0 Hz, 1H), 8.17 (d, J=7.4 Hz, 2H), 8.29 (d, J=9.0 Hz, 1H), 8.48 (d, J=2.9 Hz, 1H), 8.50 (d, J=5.2 Hz, 1H), 8.55 (s, 1H). MS (ES) C3H29N5O4S requires: 567. Found: 568 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([NH:7][C:8]2[C:9]([C:20](O)=[O:21])=[N:10][C:11]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[N:12][CH:13]=2)[CH:4]=[N:3][CH:2]=1.[CH3:23][NH:24][C:25]([C:27]1[N:28]([CH3:33])[N:29]=[CH:30][C:31]=1[NH2:32])=[O:26]>>[CH3:33][N:28]1[C:27]([C:25](=[O:26])[NH:24][CH3:23])=[C:31]([NH:32][C:20]([C:9]2[C:8]([NH:7][C:5]3[CH:4]=[N:3][CH:2]=[N:1][CH:6]=3)=[CH:13][N:12]=[C:11]([O:14][CH2:15][C:16]([F:19])([F:17])[F:18])[N:10]=2)=[O:21])[CH:30]=[N:29]1
Reactant: O=C(O)c1nc(OCC(F)(F)F)ncc1Nc1cncnc1
Reactant: CNC(=O)c1c(N)cnn1C
Product: CNC(=O)c1c(NC(=O)c2nc(OCC(F)(F)F)ncc2Nc2cncnc2)cnn1C

Procedure:
The product was obtained starting from 5-(pyrimidin-5-ylamino)-2-(2,2,2-trifluoro-ethoxy)-pyrimidine-4-carboxylic acid (50 mg, 0.16 mmol) and 4-amino-2-methyl-2H-pyrazole-3-carboxylic acid methylamide (32 mg, 0.21 mmol) according to the method described in example 64, step 6 as yellow solid (50 mg, 69%).
Reaction SMILES: P(Br)(Br)([Br:3])=O.[Cl:6][C:7]1[CH:8]=[C:9]([C:17]2[O:21][N:20]=[C:19]([C:22]3[CH:31]=[CH:30][CH:29]=[C:28]4[C:23]=3[CH:24]=[CH:25][NH:26][C:27]4=O)[N:18]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH:14]([CH3:16])[CH3:15].C([O-])(O)=O.[Na+]>ClCCCl>[Br:3][C:27]1[C:28]2[C:23](=[C:22]([C:19]3[N:18]=[C:17]([C:9]4[CH:10]=[CH:11][C:12]([O:13][CH:14]([CH3:16])[CH3:15])=[C:7]([Cl:6])[CH:8]=4)[O:21][N:20]=3)[CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:25][N:26]=1
Reactant: O=P(Br)(Br)Br
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(=O)[nH]ccc34)no2)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(Br)nccc34)no2)cc1Cl
Reaction time: 8 h
Yield: 33 %

Procedure:
Phosphorus oxybromide (3.9 g) was added to a suspension of 5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1(2H)-isoquinolinone (D39; 2.6 g) in 1,2-dichloroethane (300 ml) at room temperature. The resulting suspension was heated under reflux and stirred overnight. The reaction mixture was poured into cold sat. aq. NaHCO3 and the organic layer was separated. The aqueous layer was extracted with DCM (100 ml). The organic fractions were combined and dried over anhydrous sodium sulphate. The dried solution was filtered and the filtrate was concentrated to give the title compound (1 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=2)[CH:5]=[C:4]([N:21]([CH2:23][CH2:24][OH:25])[CH3:22])[N:3]=1.[CH3:26][C:27]1[CH:32]=[CH:31][N:30]=[C:29]([NH2:33])[CH:28]=1.CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1>O1CCOCC1>[OH:25][CH2:24][CH2:23][N:21]([CH3:22])[C:4]1[CH:5]=[C:6]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:10][CH:9]=2)[CH:7]=[C:2]([NH:33][C:29]2[CH:28]=[C:27]([CH3:26])[CH:32]=[CH:31][N:30]=2)[N:3]=1
Reactant: Cc1ccnc(N)c1
Reactant: CN(CCO)c1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)cc(Cl)n1
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1ccnc(Nc2cc(C3=CCN(C(=O)OC(C)(C)C)CC3)cc(N(C)CCO)n2)c1
Temperature: 120 °C
Yield: 51.2 %

Procedure:
To a mixture of tert-butyl 4-(2-chloro-6-(2-hydroxyethyl(methyl)amino)-4-pyridyl)-5,6-dihydro-2H-pyridine-1-carboxylate (220 mg, 0.60 mmol), 4-methylpyridin-2-amine (71.13 mg, 0.66 mmol), sodium tert-butoxide (86.2 mg, 0.90 mmol), 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (34.9 mg, 0.075 mmol), and RuPhos palladium(II) phenethylamine chloride (43.6 mg, 0.06 mmol) in 1,4-dioxane (3.0 mL) was capped in a small CEM microwave vial, de-gassed with N2, and heated in microwave at 120° C. for 15 min. It was concentrated onto Celite, purified by column chromatography (ISCO), 12 g column, eluded with 0-5% MeOH/DCM to give 135 mg (51%) of the title compound as a yellow gum. LC-MS: m/z=440 (M+H+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([CH3:19])=[C:8]([CH:12]=[CH:13][C:14]=1[S:15]([CH3:18])(=[O:17])=[O:16])[C:9](O)=[O:10].S(Cl)([Cl:22])=O.CN(C=O)C>C1(C)C=CC=CC=1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([CH3:19])=[C:8]([CH:12]=[CH:13][C:14]=1[S:15]([CH3:18])(=[O:17])=[O:16])[C:9]([Cl:22])=[O:10]
Reactant: O=S(Cl)Cl
Reactant: COCCOc1c(S(C)(=O)=O)ccc(C(=O)O)c1C
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COCCOc1c(S(C)(=O)=O)ccc(C(=O)Cl)c1C
Temperature: 100 °C
Reaction time: 2 h

Procedure:
3-(2-Methoxyethoxy)-2-methyl-4-(methylsulfonyl)benzoic acid (100 g) and toluene (300 mL) were mixed, and thionyl chloride (47.5 g) and DMF (2.5 g) were added, followed by heating and stirring at 100° C. for 2 hours. After completion of the reaction, 180 mL of toluene was distilled off under reduced pressure to obtain a solution of 3-(2-methoxyethoxy)-2-methyl-4-(methylsulfonyl)benzoyl chloride.
Reaction SMILES: CS(O[C@H:6]1[CH2:10][C@@H:9]([CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C@@H:8]([O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:7]1)(=O)=O.CN(C)C=O.[N-:33]=[N+:34]=[N-:35].[Na+]>>[N:33]([C@@H:6]1[CH2:10][C@@H:9]([CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C@@H:8]([O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:7]1)=[N+:34]=[N-:35]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@H](OS(C)(=O)=O)C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](N=[N+]=[N-])C[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 55 °C

Procedure:
To a solution of (1S,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl methanesulfonate (2.66 g, 0.00606 mol) in N,N-Dimethylformamide (20 mL, 0.2 mol) was added sodium azide (1.21 g, 0.0186 mol), and the mixture was heated at 55° C. for 3 hours. The reaction was cooled to 23° C., quenched by addition of water and extracted with Et2O (3×), washed with water, brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (0 to 15% ethyl acetate/hexane) to obtain 2.13 g (91.1%).
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].[C:8](Cl)([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:9]>>[NH:1]([C:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:9])[C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4]
Reactant: N[C@@H](CS)C(=O)O
Reactant: CCCCCCCCCC(=O)Cl
Product: CCCCCCCCCC(=O)N[C@@H](CS)C(=O)O

Procedure:
20 g of L-cysteine (0.1652 mol) are reacted with 28.2 g (0.1487 mol) of capric acid chloride analogously to Stage 6.1 to form decanoyl-Cys; m.p. 57°-58°, Rf =0.21 (CHCl3 :methanol=85:15), [α]D20 =-15° (c=0.814, CHCl3 :MeOH=1:1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]([C:12]4[C:17]=2[C:16]=1[CH:15]=[CH:14][CH:13]=4)=[CH:10][CH:9]=[CH:8][CH:7]=3.[Cl:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.CC(C)([O-])C.[Na+]>[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C1(C)C=CC=CC=1>[Cl:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH:21][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]([C:12]4[C:17]=2[C:16]=1[CH:15]=[CH:14][CH:13]=4)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: Brc1ccc2c3c(cccc13)-c1ccccc1-2
Reactant: Nc1ccccc1Cl
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: Clc1ccccc1Nc1ccc2c3c(cccc13)-c1ccccc1-2
Temperature: 80 °C
Yield: 75.2 %

Procedure:
Under an argon atmosphere, 7.0 g of 3-bromofluoranthene, 4.76 g of 2-chloroaniline, 0.46 g of tris(dibenzylideneacetone) dipalladium(0), 0.58 g of tri-t-butylphosphine tetrafluorohydroborate, 3.4 g of sodium t-butoxide, and 200 mL of dry toluene were charged in a flask, and the resultant mixture was stirred under heating at 80° C. for 8 h. After cooling to room temperature, the reaction solution was extracted with toluene and the extract was filtered through celite. The filtrate was concentrated and the residue was purified by silica gel column chromatography to obtain 6.14 g of 3-(2-chloroanilino)fluoranthene (yield: 75%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[O:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH2:19])[N:12]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:30])[CH3:29]>C1COCC1>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[O:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH:19][C:28](=[O:30])[CH3:29])[N:12]=1
Reactant: CC(=O)Cl
Reactant: COC(=O)CCCCc1nc(-c2ccccc2N)co1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CCCCc1nc(-c2ccccc2NC(C)=O)co1
Temperature: 25 °C

Procedure:
Dissolve 5-[4-(2-amino-phenyl)-oxazol-2-yl]-pentanoic acid methyl ester (4.05 g, 14.8 mmol) and triethylamine (2.26 mL, 16.2 mmol) in THF (40 mL) and stir at room temperature. Add acetyl chloride (1.16 mL, 16.2 mmol) and allow the mixture to stir overnight at room temperature. Concentrate the mixture and partition the residue between aq NaHCO3 and EtOAc. Dry the combined extracts over Na2SO4 before concentrating. Chromatograph the residue over silica gel (MeOH/CH2Cl2) which allows for the isolation of 5-[4-(2-acetylamino-phenyl)-oxazol-2-yl]-pentanoic acid methyl ester (3.51 g, 75%). MS (ES): (M+1)+ 317.2 m/z.
Reaction SMILES: C[O:2][C:3]1(OC)[C:9]([NH:10][C:11]([C:13]2[C:14]([OH:23])=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:12])=[CH:8][C:7](=[O:24])[CH:6]2[CH:4]1[O:5]2.FC(F)(F)C(O)=O>>[O:2]=[C:3]1[C:9]([NH:10][C:11]([C:13]2[C:14]([OH:23])=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:12])=[CH:8][C:7](=[O:24])[CH:6]2[CH:4]1[O:5]2
Reactant: COC1(OC)C(NC(=O)c2cc3ccccc3nc2O)=CC(=O)C2OC21
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC1=CC(=O)C2OC2C1=O)c1cc2ccccc2nc1O
Reaction time: 3 h
Yield: 102.1 %

Procedure:
To a flask containing N-(2,2-dimethoxy-5-oxo-7-oxabicyclo[4.1.0]hept-3-en-3-yl)-2-hydroxyquinoline-3-carboxamide (65 mg, 0.18 mmol) was added trifluoroacetic acid (15 mL) in one portion. The solution was stirred 3 hours, after which the reaction was judged complete by LC-MS. The trifluoroacetic acid was removed in vacuo and the product dried with a stream of nitrogen to afford 57 mg (100%) of the title product that contained ca. 15% of a byproduct that was suggested to be the hydrolyzed product (at both amide and epoxide positions; M+ 204). The solid was used in the next step without additional characterization or purification.