Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]([CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])=[O:15])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[OH-].[Na+].O>C(O)C>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([NH:13][C:14]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[O:15])[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: CCOC(=O)CCCC(=O)Nc1cc(OC)c(OC)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(NC(=O)CCCC(=O)O)cc(OC)c1OC

Procedure:
A solution of 8 g of the compound obtained in Step A, 50 ml of 1M sodium hydroxide solution, 50 ml of water and 100 ml of ethanol is stirred for 6 hours at 50° C. The ethanol is then removed by distillation under a partial vacuum. The residual solution is rendered acidic by the addition of 1M hydrochloric acid and extracted with dichloromethane. The combined organic phases are dried with Na2SO4 and evaporated to dryness to yield a colourless oil (quantitative yield).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:20][CH2:19][N:18]([CH:21]2[CH2:26][CH2:25][CH2:24][N:23]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:22]2)[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[CH2:27]([N:23]1[CH2:24][CH2:25][CH2:26][CH:21]([N:18]2[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]2)[CH2:22]1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCCN(Cc3ccccc3)C2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(CN2CCCC(N3CCNCC3)C2)cc1
Reaction time: 5 h
Yield: 95.2 %

Procedure:
30 g of TFA are added to a solution of 9.2 g of the compound obtained in step 4.1, in 85 ml of DCM. The medium is stirred at AT for 5 h, and then concentrated. The crude obtained is taken up in DCM and then washed 4 times with a 2M sodium hydroxide solution. The organic phase is washed with a saturated NaCl solution. After drying over MgSO4, the organic phase is concentrated, to give 6.32 g of the expected product.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][CH:15]([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[CH:18]1([CH2:21][C:22]([NH2:30])([CH3:29])[C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)[CH2:20][CH2:19]1>>[CH:1]1([C:4]2[C:5]([O:13][CH2:14][CH:15]([F:17])[F:16])=[CH:6][C:7]([C:10]([NH:30][C:22]([C:23]3[N:27]=[C:26]([CH3:28])[O:25][N:24]=3)([CH3:29])[CH2:21][CH:18]3[CH2:19][CH2:20]3)=[O:12])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cc(OCC(F)F)c(C2CC2)cn1
Reactant: Cc1nc(C(C)(N)CC2CC2)no1
Product: Cc1nc(C(C)(CC2CC2)NC(=O)c2cc(OCC(F)F)c(C3CC3)cn2)no1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-cyclopropyl-4-(2,2-difluoroethoxy)pyridine-2-carboxylic acid (Example 145d) and 2-Cyclopropyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (example 66e) as starting materials and isolated (66 mg, 72%); MS (ESI, m/z): 407.6 (M+H+).
Reaction SMILES: [CH2:1]([OH:12])[C@H:2]([OH:11])[C@@H:3]([OH:10])[C@H:4]([OH:9])[C:5]([CH:7]=[O:8])=[O:6].P([O-])([O-])([O-])=[O:14].[K+].[K+].[K+]>O>[CH2:1]([OH:12])[C@H:2]([OH:11])[C@@H:3]([OH:10])[C@H:4]([OH:9])[C:5]([C:7]([OH:14])=[O:8])=[O:6]
Reactant: O=CC(=O)[C@@H](O)[C@H](O)[C@@H](O)CO
Reactant: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)C(=O)[C@@H](O)[C@H](O)[C@@H](O)CO

Procedure:
The reaction mixture containing 100 ml of cell free extract of UV-10, FERM BP-1267 (total enzyme activity, 115 units), as prepared by the manner as described in steps (1) to (2) of Example 1, 50 ml of 0.5M potassium phosphate buffer (pH 7.0), 50 ml of 10% L-sorbosone solution and 300 ml of water was incubated at 30° C. with gentle shaking. As a result, 2-keto-L-gulonic acid was formed with the rate of 700 mg/hr.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20]([O:22]N3C4C=CC=CC=4N=N3)=O)([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:43]([O:45][C:46]([CH:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)=[O:47])[CH3:44]>>[CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20]([N:51]3[CH2:52][CH2:53][CH:48]([C:46]([O:45][CH2:43][CH3:44])=[O:47])[CH2:49][CH2:50]3)=[O:22])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)On3nnc4ccccc43)(CC1)CC2
Reactant: CCOC(=O)C1CCNCC1
Product: CCOC(=O)C1CCN(C(=O)C23CCC(N(CC(=O)N4C[C@@H](F)C[C@H]4C#N)C(=O)OCc4ccccc4)(CC2)CC3)CC1

Procedure:
In a similar manner to Example 4, (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(benzotriazol-1-yl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-ethoxycarbonylpiperidine (20.1 μL) were used to obtain (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(4-ethoxycarbonylpiperidin-1-yl)carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (43.1 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH2:14]([CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][NH:18]1)[CH2:15][CH3:16]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:18]3[CH2:19][CH2:20][C:21]4[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:17]3[CH2:14][CH2:15][CH3:16])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CCCC1NCCc2ccccc21
Product: CCCC1c2ccccc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Propyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: F[C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:9][C:10]([F:13])([F:12])[F:11])=[O:7])=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].[CH:24]1([CH2:30][NH2:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.CCN(CC)CC>CCO>[CH:24]1([CH2:30][NH:31][C:2]2[CH:20]=[CH:19][C:5]([C:6]([N:8]([CH2:14][C:15]([F:17])([F:16])[F:18])[CH2:9][C:10]([F:12])([F:13])[F:11])=[O:7])=[CH:4][C:3]=2[N+:21]([O-:23])=[O:22])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(c1ccc(F)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F
Reactant: NCC1CCCCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(c1ccc(NCC2CCCCC2)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F

Procedure:
Following the general procedure for Intermediate 2 using 4-fluoro-3-nitro-N,N-bis(2,2,2-trifluoroethyl)benzamide (100 mg, 0.287 mmol) and cyclohexylmethyl amine (0.041 mL, 0.315 mmol) in 3 mL of EtOH containing Et3N (0.080 mL, 0.574 mmol). The product was purified by flash chromatography on silica gel using 4:1/hexanes:EtOAc as eluent. Yield: 107 mg (85%); 1H NMR (CDCl3) 1.05 (m, 2H), 1.24 (m, 4H), 1.69 (m, 2H), 1.75 (m, 2H), 1.83 (m, 1H), 3.17 (t, J=6.64 Hz, 2H), 4.23 (q, J=8.53 Hz, 4H), 6.91 (d, J=8.98 Hz, 1H), 7.51 (d, J=8.89 Hz, 1H), 8.28 (s, 1H), 8.39 (s, 1H); MS (ESI) 442.29 (MH+).
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[F:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[C:22]=1[CH2:23][NH2:24].CCN(C(C)C)C(C)C>>[F:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[C:22]=1[CH2:23][NH:24][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1
Reactant: COc1cccc(F)c1CN
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(F)c1CNC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, 2-fluoro-6-methoxy-benzylamine and DIEA to give 2-(2-fluoro-6-methoxy-benzylamino)-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 394 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[N+:12]([O-])([O-:14])=[O:13].[K+].C(=O)([O-])[O-].[K+].[K+]>S(=O)(=O)(O)O>[CH3:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:7][CH:6]=2
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1cc2ccccc2cn1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1cc2c([N+](=O)[O-])cccc2cn1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 3-methylisoquinoline (5.4 g, 0.04 mol) in concentrated sulfuric acid (30 ml) was cautiously added to a solution of potassium nitrate (4.25 g, 1.1 eq) in concentrated sulfuric acid (23 ml) whilst maintaining the temperature below 4° C. (ice bath). Stirring was continued for 2 h and then temperature raised to ambient. Reaction was further stirred for 3 h and then poured into ice-water slurry (500 mL. Neutralisation using solid potassium carbonate affored a yellow solid which was filtered and washed with water. This material was dissolved in ethanol (200 mL, filtered and concentrated under reduced pressure to afford the title compound as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].Br[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.CCOC(C)=O>[C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:11]=1)[CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: Brc1ccccn1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1cccc(O)c1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: C[C@H](NC(=O)OC(C)(C)C)c1cccc(Oc2ccccn2)c1
Temperature: 115 °C
Yield: 91.4 %

Procedure:
A mixture of (S)-[1-(3-hydroxy-phenyl)-ethyl]-carbamic acid tert-butyl ester (10 g, 42.1 mmol), 2-bromopyridine (8 g, 50.6 mmol), potassium carbonate (powder, 14 g, 101 mmol) and copper iodide (325 mesh powder, 6 g, 31.6 mmol) was heated at 115° C. for 12 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. CH2Cl2 (100 mL) was added, and the resulting reaction mixture was filtered. The filtrate was washed with H2O (3×50 mL) followed by brine (100 ml), dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with 2:1/Hexane:EtOAc to give the title product (12.1 g, 91% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:43])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]#[C:12][C:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]3[CH2:35][CH2:34][CH2:33][N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:31]3)=[CH:26][CH:25]=2)[N:14]=1.C(O)C.[H][H]>CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3](=[O:43])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][C:13]1[C:18]([C:19]([F:21])([F:22])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]3[CH2:35][CH2:34][CH2:33][N:32]([C:36]([O:38][C:39]([CH3:41])([CH3:42])[CH3:40])=[O:37])[CH2:31]3)=[CH:26][CH:25]=2)[N:14]=1
Reactant: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(C3CCCN(C(=O)OC(C)(C)C)C3)cc2)ncc1C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCCN(C(=O)OC(C)(C)C)C3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 82 %

Procedure:
tert-Butyl 3-(4-((4-((2-(2-methoxy-2-oxoethyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I25) (0.302 g, 0.508 mmol) was dissolved in EtOAc (12 mL) and absolute ethanol (8 mL) under an atmosphere of nitrogen. 10% Pd/C (0.250 g) in EtOAc (4 mL) was added to the solution and the atmosphere was changed to hydrogen gas (balloon). The reaction was sealed with a balloon and stirred at room temperature for 18 hours after which the catalyst was removed by filtration through Celite and the solvent was removed in vacuo. The resulting solid was again dissolved in EtOAc (12 mL) and absolute ethanol (8 mL) under an atmosphere of nitrogen and 10% Pd/C (0.250 g) in EtOAc (4 mL) was added to the solution and the atmosphere was changed to hydrogen gas (balloon). The reaction was sealed with a balloon and stirred at room temperature for 24 hours. The catalyst was removed by filtration through Celite, which was washed with EtOAc (7×10 mL) and the solvent was removed in vacuo to give a pale yellow viscous oil. The crude product was purified by silica gel chromatography (Biotage Isolera, 40 g Si Cartridge, 0-50% EtOAc in petroleum benzine 40-60° C.) to give the title compound (I26) (0.249 g, 82% yield) as a pale yellow viscous oil; 1H NMR (400 MHz, d5-DMSO) δ 10.18 (s, 1H), 8.67 (s, 1H), 7.72-7.64 (m, 2H), 7.26-7.16 (m, 6H), 4.02-3.89 (m, 2H), 3.76 (s, 2H), 3.57 (s, 3H), 3.10-2.95 (m, 4H), 2.91-2.66 (m, 2H), 2.61-2.51 (m, 1H), 1.88 (d, J=11.8 Hz, 1H), 1.75-1.54 (m, 2H), 1.43 (m, 10H). LCMS Method C: rt 7.11 min; m/z 599.3 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[NH2:13][C:14]1[CH:29]=[CH:28][C:17]2[N:18]=[C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[NH:20][C:16]=2[CH:15]=1>>[CH3:12][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:13][C:14]2[CH:29]=[CH:28][C:17]3[NH:18][C:19]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:20][C:16]=3[CH:15]=2)=[O:9])=[CH:10][CH:11]=1
Reactant: Nc1ccc2nc(Nc3ccccc3)[nH]c2c1
Reactant: CN(C)c1ccc(C(=O)O)cc1
Product: CN(C)c1ccc(C(=O)Nc2ccc3[nH]c(Nc4ccccc4)nc3c2)cc1

Procedure:
Compound 180 was prepared according to the procedure similar to that described in Scheme III from 4-dimethylaminobenzoic acid and 5-amino-2-phenylaminobenzimidazole. [M+H]+ calcd for C22H22N5O: 372.18; found: 371.95.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]([O:12][CH2:13][CH3:14])(=[O:11])[CH:9]=[CH2:10]>C(O)(=O)C>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH2:10][CH2:9][C:8]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: C=CC(=O)OCC
Reactant: Nc1ccccn1
Solvent: CC(=O)O
Product: CCOC(=O)CCNc1ccccn1
Temperature: 88 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
200 g (2.12 mol) of 2-aminopyridine and 346 mL (3.18 mol) of ethyl acrylate were dissolved in 53 mL of acetic acid. The mixture was heated to 88° C. and stirred overnight at the same temperature. Solvent was removed under vacuum, and the title compound was purified by column chromatography, eluting with ethyl acetate, to obtain 358 g of ethyl 3-(2-pyridylamino)propionate as a pale red solid. Yield: 86.7%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14](N(OC)C)=[O:15])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:20][CH3:21].[CH2:22]([Mg]Br)[CH3:23].Cl>CCOCC.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][CH:11]([C:14](=[O:15])[CH2:22][CH3:23])[CH2:12][CH2:13]2)=[CH:4][C:3]=1[O:20][CH3:21]
Reactant: CC[Mg]Br
Reactant: COc1cc(N2CCC(C(=O)N(C)OC)CC2)ccc1Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(=O)C1CCN(c2ccc(Cl)c(OC)c2)CC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 93 %

Procedure:
A solution of 1-(4-chloro-3-methoxyphenyl)-N-methoxy-N-methylpiperidine-4-carboxamide (450 mg, 1.439 mmol) in anhydrous Et2O (10 mL) and THF (5 mL) was placed under nitrogen and cooled to −78° C. The solution was treated with ethylmagnesium bromide (2.16 mL of a 2.0 M solution in Et2O, 4.32 mmol) within 2 minutes and the stirred at for 20 minutes before warming the reaction to 0° C. The reaction was continued at 0° C. for 30 min and then poured into 0.5 M HCl (15 mL) and stirred vigorously for 5 min. The mixture was adjusted to pH 6 and extracted with Et2O. The extract was washed with brine, dried (MgSO4) and concentrated on a rotary evaporator to give 1-(1-(4-chloro-3-methoxyphenyl)piperidin-4-yl)propan-1-one (375 mg, 1.331 mmol, 93% yield) as a white solid.
Reaction SMILES: [CH:1]([C@@H:4]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:10][CH:9]=1)[CH2:5]O)([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:37]N1C(=O)CCC1=O>ClCCl>[Br:37][CH2:5][C@@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:10][CH:9]=1
Reactant: CC(C)[C@H](CO)Cc1ccc(C(C)(C)C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)[C@H](CBr)Cc1ccc(C(C)(C)C)cc1
Temperature: 0 °C

Procedure:
To a solution of 2.3 g of 2(R)-isopropyl-3-(p-tert-butyl-phenyl)-propanol in 50 ml of dichloromethane there are added, with stirring at 0° C., 3.15 g of triphenylphosphine and then, in portions, 2.14 g of N-bromosuccinimide. The reaction mixture is subsequently stirred for 16 hours at room temperature and is then concentrated by evaporation. The residue is purified by FC (100 g of silica gel, eluant: dichloromethane/hexane=1:1). The title compound is obtained: Rf (hexane)=0.49.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([Cl:11])=[C:8]([CH:10]=1)[NH2:9].[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1>C1COCC1>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([Cl:11])=[C:8]([CH:10]=1)[N:9]([CH2:18][C:17]1[CH:20]=[CH:21][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1)[CH2:18][C:17]1[CH:20]=[CH:21][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Nc1cc(Br)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(Br)ccc2Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under argon, 5.07 g (126.93 mmol, 60%) of sodium hydride were suspended in 150 ml of THF, and the mixture was cooled to 0° C. 10.70 g (51.81 mmol) of 5-bromo-2-chloroaniline dissolved in 10 ml of THF were then slowly added dropwise, and the mixture was stirred at 0° C. for 30 min. 25 g (124.34 mmol) of 4-methoxybenzyl chloride were then added to the reaction mixture, and the mixture was subsequently warmed to room temperature. The mixture was stirred at RT for 2 h and then slowly poured onto 150 ml of ice-water. The organic phase was separated off, and the aqueous phase was extracted three more times with ethyl acetate. The combined organic phases were dried over sodium sulphate. After filtration, the solvent was removed under reduced pressure. The crude product was purified chromatographically [column: Kromasil Si 6012, 350 mm×30 mm; mobile phase A: isohexane, mobile phase B: ethyl acetate; gradient: 0 min 98% A→4.65 min 98% A→13 min 87% A→13.01 min 98% A→13.28 min 98% A; flow rate: 70 ml/min; temperature: 20° C.; UV detection: 265 nm]. This gave 12.37 g (27.69 mmol, 57% of theory) of the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=2[C:7]=1[CH3:8].[CH3:13][C:14]1([CH3:28])[C:18]([CH3:20])([CH3:19])[O:17][B:16]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)[O:15]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:8][C:7]1[C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[O:4][C:3]=1[CH2:2][O:27][C:24]1[CH:23]=[CH:22][C:21]([B:16]2[O:17][C:18]([CH3:20])([CH3:19])[C:14]([CH3:28])([CH3:13])[O:15]2)=[CH:26][CH:25]=1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: Cc1c(CCl)oc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1c(COc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)oc2ccccc12
Reaction time: 12 h
Yield: 44 %

Procedure:
A mixture of 2-Chloromethyl-3-methyl-benzofuran (675.9 mg, 3.75 mmol), 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (825 mg, 3.75 mmol, 1 eq), K2CO3 (2.1 g, 15.2 mmol, 4 eq) in 20 mL of CH3CN was heat to reflux under nitrogen atmosphere. Reaction was complete after 12 hrs. Regular work-upwork up and column purification (5% EtOAc/hexane) to give 3-Methyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxymethyl]-benzofuran in 44% yield (601 mg). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.3 (s, 12 H) 2.3 (s, 3 H) 5.2 (s, 2 H) 7.0 (d, J=8.6 Hz, 2 H) 7.3 (m, 2 H) 7.5 (dd, J=21.6, 7.7 Hz, 2 H) 7.8 (d, J=8.8 Hz, 2 H).
Reaction SMILES: [CH3:1][CH:2]([C@H:4]([NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C:5]([O:7]C1C=CC([N+]([O-])=O)=CC=1)=O)[CH3:3].[NH2:28][CH2:29][C:30]([NH:32][C@H:33]([C:35]([N:37]1[CH2:48][CH2:47][CH2:46][C@H:38]1[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[O:36])[CH3:34])=[O:31]>C(OCC)(=O)C>[NH:17]([C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])[C@H:4]([C:5]([NH:28][CH2:29][C:30]([NH:32][C@H:33]([C:35]([N:37]1[CH2:48][CH2:47][CH2:46][C@H:38]1[C:39]([O:41][C:42]([CH3:43])([CH3:44])[CH3:45])=[O:40])=[O:36])[CH3:34])=[O:31])=[O:7])[CH:2]([CH3:1])[CH3:3]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: C[C@H](NC(=O)CN)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NCC(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C

Procedure:
3.73 g of Z-Val-ONP and 2.99 g of H-Gly-Ala-Pro-OtBu in 12 ml of ethyl acetate are stirred for one hour at 0°C and 20 hours at room temperature. After dilution with ethyl acetate the mixture is washed with 50 % saturated potassium carbonate solution and water, dried over sodium sulphate and evaporated at 30°C in a waterpump vacuum. The oil is crystallised from methanol-water. Melting point 73°-75°C. In a thin layer chromatogram on silica gel Rf = 0.42 in the system tolueneacetone (1:1) and Rf = 0.46 in the system chloroform-methanol (9:1).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:50]([C:57]1[CH:62]=[CH:61][C:60]([C:63]2[CH:68]=[CH:67][CH:66]=[C:65]([NH2:69])[CH:64]=2)=[CH:59][CH:58]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>CN(C=O)C>[O:50]([C:57]1[CH:62]=[CH:61][C:60]([C:63]2[CH:68]=[CH:67][CH:66]=[C:65]([NH:69][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:64]=2)=[CH:59][CH:58]=1)[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: Nc1cccc(-c2ccc(Oc3ccccc3)cc2)c1
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: CN(C)C=O
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4ccc(Oc5ccccc5)cc4)c3)c(=O)oc12
Temperature: 25 °C
Yield: 83.3 %

Procedure:
DIEA (0.011 mL, 0.063 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.013 g, 0.057 mmol) and HATU (0.024 g, 0.063 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 4′-phenoxy-biphenyl-3-ylamine (0.015 g, 0.057 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.022 g of product in 83% yield: LCMS (ESI) m/z 464 (MH+).
Reaction SMILES: Cl[C:2]1[C:13]2=[C:14]3[N:9]([CH:10]([CH2:15][CH3:16])[CH:11]=[CH:12]2)[CH:8]=[C:7]([C:17]([OH:19])=[O:18])[C:6](=[O:20])[C:5]3=[CH:4][C:3]=1[F:21].[CH:22]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)([CH3:24])[CH3:23]>CS(C)=O>[F:21][C:3]1[CH:4]=[C:5]2[C:14]3[N:9]([CH:8]=[C:7]([C:17]([OH:19])=[O:18])[C:6]2=[O:20])[CH:10]([CH2:15][CH3:16])[CH:11]=[CH:12][C:13]=3[C:2]=1[N:28]1[CH2:29][CH2:30][N:25]([CH:22]([CH3:24])[CH3:23])[CH2:26][CH2:27]1
Reactant: CC(C)N1CCNCC1
Reactant: CCC1C=Cc2c(Cl)c(F)cc3c(=O)c(C(=O)O)cn1c23
Solvent: CS(C)=O
Product: CCC1C=Cc2c(N3CCN(C(C)C)CC3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reaction time: 8 h
Yield: 64.8 %

Procedure:
4.62 g (0.015 mole) of 8-chloro-9-fluoro-5-ethyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid was suspended in 45 ml of dimethyl sulfoxide, 7.69 g (0.06 mole) of N-isopropylpiperazine was added thereto, and this mixture was stirred at 100°-110° C. for 8 hours. The resulting reaction solution was evaporated to dryness under reduced pressure. 40 ml of methanol was added to the resulting residue and this mixture was stirred. The insoluble matter was collected by filtration and recrystallized from ethanol to obtain 3.88 g (64.7% yield) of 9-fluoro-5-ethyl-8-(4-isopropyl-1-piperazinyl)-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid in the form of pale-yellow crystals. These crystals had a melting point of 186°-195° C. (dec.).