Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH2:7][CH:6]1[CH2:5][C:4](=[O:10])[CH2:3][CH2:2]2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[N:1]12[CH2:9][CH2:8][CH2:7][CH:6]1[CH2:5][CH:4]([OH:10])[CH2:3][CH2:2]2
Reactant: O=C1CCN2CCCC2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC1CCN2CCCC2C1
Yield: 98.4 %

Procedure:
1-Azabicyclo[4,3,0]nonan-4-one (1.0 g, 0.0072 moles) (King, F. D., J. Chem. Soc. Perkin. Trans. 1, (1986) 447) in tetrahydrofuran (50 ml) was treated with lithium aluminium hydride (0.7 g. 0.0185 moles) at ambient temperature for 18 hours. Work up in the usual way gave the title compound 1.0 g (100%). M.S. (+ve ion electrospray) m/z 142 (MH30 , 95%).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(O)(=O)C.[NH2:16][C:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[C:22]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:37])([F:36])[F:35])[NH:23][C:24]2=[O:27])=[CH:19][CH:18]=1.B(C#N)([O-])[O-].[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.CO>[Si:1]([O:8][CH2:9][CH2:10][NH:16][C:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[C:22]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:37])([F:35])[F:36])[NH:23][C:24]2=[O:27])=[CH:19][CH:18]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: Nc1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Agent: N#CB([O-])[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)[Si](C)(C)OCCNc1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 92.1 %

Procedure:
(tert-Butyldimethylsilanyloxy)acetaldehyde (93.9 μL, 0.493 mmol) and acetic acid (169 μL, 2.96 mmol) were added to a methanol solution (30 ml) that contained the 7-amino-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (150 mg, 0.493 mmol) prepared in step C of Example 1-1. The obtained solution was cooled to 0° C., and sodium cyanoborate (1M THF solution, 1.48 mL, 1.48 mmol) was then added thereto. The obtained mixture was stirred at a room temperature for 18 hours. The reaction solution was poured into a mixed solution of ethyl acetate and a saturated sodium bicarbonate aqueous solution. An organic layer was dried over anhydrous sodium sulfate, and the solvent was then distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (methylene chloride:methanol=40:1), so as to obtain 7-[2-(tert-butyldimethylsilanyloxy)ethylamino]-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (210 mg, 92%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]2[NH:7][C:6]3[CH2:12][CH:13]4[NH:17][CH:16]([C:5]=3[C:4]=2[C:3]=1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15][CH2:14]4.[H-].[Na+].I[CH3:28]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]2[N:7]([CH3:28])[C:6]3[CH2:12][CH:13]4[NH:17][CH:16]([C:5]=3[C:4]=2[C:3]=1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15][CH2:14]4
Reactant: Cc1cc(Br)c(C(=O)OC(C)(C)C)c2c3c([nH]c12)CC1CCC3N1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(Br)c(C(=O)OC(C)(C)C)c2c3c(n(C)c12)CC1CCC3N1
Reaction time: 1.5 h
Yield: 79.9 %

Procedure:
To a solution of the product of step B (410 mg, 1.05 mmol) in DMF (3.5 ml) at 0° C., under nitrogen was added sodium hydride (60% dispersion in mineral oil, 51 mg, 2.09 mmol). The mixture was stirred for 45 min at 0-5° C. before iodomethane (0.13 mL, 2.09 mmol) was added. The mixture was stirred for a further 90 min then quenched with ice water. The mixture was diluted with ethyl acetate, washed with water, brine and dried over anhydrous sodium sulfate. Concentration in vacuo afforded a viscous oil which was dissolved in a minimal amount of ethyl acetate and precipitated by addition of hexanes. The separated solid was filtered and dried in vacuo to give tert-butyl 2-bromo-4,5-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (340 mg, 80%) as an off-white solid. 1H NMR (CDCl3, 300 MHz): δ 7.43 (d, J=1.2 Hz, 1H), 6.94 (d, J=1.2 Hz, 1H), 5.05-5.30 (m, 1H), 4.52-4.70 (m, 1H), 3.80 (s, 3H), 3.15-3.47 (m, 1H), 2.69 (s, 3H), 2.43 (dd, J=15.9, 0.9 Hz, 1H), 2.23-2.30 (m, 1H), 2.08-2.22 (m, 1H), 1.85-1.95 (m, 1H), 1.58-1.64 (m, 1H), 1.39 (br s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([Cl:9])[CH:3]=1.[Br:10]NC(=O)CCC(N)=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:10])=[C:4]([Cl:9])[CH:3]=1
Reactant: NC(=O)CCC(=O)NBr
Reactant: Cc1ccc(Br)cc1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cc(Br)ccc1CBr
Yield: 70.8 %

Procedure:
Dissolve 4-bromo-2-chloro-1-methyl-benzene (64.3 g, 312.9 mmol) in carbon tetrachloride (1 L). Add benzoyl peroxide (760 mg, 3.1 mmol) and N-bromosuccinamide (58.5 g, 329 mmol) and heat to 80° C. for 18 hours. Cool reaction to room temperature and filter. Concentrate the filtrate and purify by silica gel (hexanes) to yield 63 g (71%) of the title compound. NMR (CDCl3) δ 7.57 (d, 1H), 7.39 (dd, 1H), 7.31 (d, 1H), 4.53 (s, 2H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][CH2:17][C:18]([N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=O)=[CH:8]1.O>C1COCC1>[N:20]1([CH2:18][CH2:17][CH2:16][C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[NH:7][CH:8]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C(CCc1c[nH]c2ccccc12)N1CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc2c(CCCN3CCCC3)c[nH]c2c1
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere 3.40 mL (3.40 mmol) of a 1M lithium aluminium hydride solution in THF was slowly added dropwise to 670 mg (2.77 mmol) 3-(1H-indol-3-yl)-1-pyrrolidin-1-yl-propan-1-one in 30 mL THF. The reaction mixture was stirred for 1 h at 65 C and after cooling combined with 1 mL water. After 10 min stirring at RT the organic phase was dried on sodium sulphate and evaporated down i. vac. The product was reacted further without any further purification.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]([CH3:14])=[C:8]2[C:3]=1[C:4](=[O:38])[C:5]([C:33]([O:35]CC)=[O:34])=[CH:6][N:7]2[C:15]1[C:20]([F:21])=[CH:19][C:18]([F:22])=[C:17]([NH:23]CC2C=CC(OC)=CC=2)[N:16]=1>Cl>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]([CH3:14])=[C:8]2[C:3]=1[C:4](=[O:38])[C:5]([C:33]([OH:35])=[O:34])=[CH:6][N:7]2[C:15]1[C:20]([F:21])=[CH:19][C:18]([F:22])=[C:17]([NH2:23])[N:16]=1
Reactant: CCOC(=O)c1cn(-c2nc(NCc3ccc(OC)cc3)c(F)cc2F)c2c(C)c(F)c(F)c(N)c2c1=O
Agent: Cl
Product: Cc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn(-c3nc(N)c(F)cc3F)c12
Yield: 123.4 %

Procedure:
To 0.99 g of ethyl 5-amino-6,7-difluoro-1-(3,5-difluoro-6-p-methoxybenzylaminopyridine-2-yl)-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate was added 10 ml of 12N hydrochloric acid, and the mixture was heated under reflux for 10 hours. The reaction solution was allowed to cool, and the solid content was collected by filtration. The solid content was washed with ethanol, and then, with diethylether to obtain 880 mg of the title compound as a yellow powder.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:7]2[C:6]([C:4]3[N:3]=[CH:2][N:1]([C:23]4[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=4)[CH:5]=3)=[C:10]([CH3:11])[O:9][N:8]=2)=[CH:13][CH:14]=1
Reactant: Cc1onc(-c2ccc(F)cc2)c1-c1c[nH]cn1
Reactant: OB(O)c1ccc(F)cc1
Product: Cc1onc(-c2ccc(F)cc2)c1-c1cn(-c2ccc(F)cc2)cn1
Yield: 10 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-5-methyl-3-(4-fluorophenyl)-isoxazole (73 mg, 0.3 mmol) was converted, using 4-fluorophenylboronic acid instead of 4-fluorophenylboronic acid, to the title compound (10 mg, 10%) which was obtained as an off-white solid. MS: m/e=338.7[M+H]+.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:15]Br>C([O-])(O)=O.[Na+]>[CH2:1]([C:8]1[CH:9]=[C:10]([Br:15])[C:11]([NH2:14])=[N:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(Cc2ccccc2)cn1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Product: Nc1ncc(Cc2ccccc2)cc1Br
Reaction time: 0.5 h

Procedure:
To a stirred solution of 5-benzylpyridin-2-amine 2 (6.0 g, 32.3 mmol) in CH2C12 (100 mL) cooled to 0° C. was added bromine (5.1 g, 32.3 mmol) dropwise [Kelly, et al., J. Am. Chem. Soc. 112, 8024-8034 (1990)]. The bromine decolorized immediately and the mixture was left stirring for 30 min. The mixture was shaken with saturated NaHCO3 solution (100 mL), the organic layer was then dried over anhydrous Na2SO4, and distilled off to give a yellow residue which was purified by flash chromatography on silica gel (EtOAc:hexane, 3:7). Yield 7.3 g (86%), white solid, mp 110-111° C. 1H NMR (CDCl3, 500 MHz): δ 3.86 (s, 2H, CH2), 4.88 (bs, 2H, NH2), 7.19-7.35 (m, 5H, Ar—H), 7.50 (d, 1H, CH, J=1.5 Hz), 7.94 (d, 1H, CH, J=1.0 Hz). 13C NMR (CDCl3, 125 MHz): δ 37.7, 104.6, 126.4, 126.4, 128.1, 128.6, 128.6, 128.7, 140.2, 140.8, 146.7, 154.0; HRMS (M+H)+ calcd for C12H13BrN2 263.0184, found 263.0184.
Reaction SMILES: [N:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH:5]1[OH:17])=[N+]=[N-]>CO>[NH2:1][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[CH2:6][CH:5]1[OH:17]
Reactant: CC(C)(C)OC(=O)N1CCC(N=[N+]=[N-])C(O)C1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(N)C(O)C1
Reaction time: 48 h
Yield: 99.4 %

Procedure:
tert-Butyl 4-azido-3-hydroxypiperidine-1-carboxylate (62 g) obtained in Step 3 was dissolved in 300 ml of methanol. The mixture was hydrogenated with 10%-palladuim at room temperature under 35 psi for about 48 hours and filtered. The resulting filtrate was concentrated to give the titled compound (55 g) as a colorless and oily form.
Reaction SMILES: C([O:3][C:4]([C:6]12[CH2:23][CH:22]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]([CH3:24])[C:14](=[O:25])[CH:13]1[CH:9]([CH2:10][CH:11]([O:26][C:27]3[CH:32]=[C:31]([C:33]([CH3:36])([CH3:35])[CH3:34])[N:30]=[C:29]([O:37][CH3:38])[N:28]=3)[CH2:12]1)[C:8](=[O:39])[NH:7]2)=[O:5])C.CO.[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O>[C:33]([C:31]1[N:30]=[C:29]([O:37][CH3:38])[N:28]=[C:27]([O:26][CH:11]2[CH2:10][CH:9]3[CH:13]([C:14](=[O:25])[N:15]([CH3:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH:21][CH:22]4[C:6]([C:4]([OH:5])=[O:3])([NH:7][C:8]3=[O:39])[CH2:23]4)[CH2:12]2)[CH:32]=1)([CH3:36])([CH3:34])[CH3:35]
Reactant: CCOC(=O)C12CC1C=CCCCCN(C)C(=O)C1CC(Oc3cc(C(C)(C)C)nc(OC)n3)CC1C(=O)N2
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1nc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)cc(C(C)(C)C)n1
Temperature: 60 °C
Yield: 96.4 %

Procedure:
Compound 3i (350 mg, 0.645 mmol) was dissolved in a 2:1:1 mixture of THF:MeOH:H2O (100 ml). LiOH (1 M, 6.5 ml) was added and the reaction mixture was stirred at 60° C. over night. The mixture was acidified by adding citric acid and then extracted three times with EtOAc. The combined organic layers were dried (MgSO4), filtered and evaporated. The afforded residue was purified by column chromatography (DCM/MeOH 98/2→94/6) which gave the title compound (320 mg, 97%), MS (M+H)+515.
Reaction SMILES: Cl.Cl.[CH:3]1([NH:9][C:10]2[C:14]3([CH2:19][CH2:18][NH2+:17][CH2:16][CH2:15]3)[N:13]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)[C:12](=[O:27])[N:11]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH:28]([C:30]1[CH:31]=[C:32]([B:36]([OH:38])[OH:37])[CH:33]=[CH:34][CH:35]=1)=O.CCN(C(C)C)C(C)C.C([BH3-])#N>C1COCC1.CC(O)=O>[CH:3]1([NH:9][C:10]2[C:14]3([CH2:15][CH2:16][N:17]([CH2:28][C:30]4[CH:31]=[C:32]([B:36]([OH:38])[OH:37])[CH:33]=[CH:34][CH:35]=4)[CH2:18][CH2:19]3)[N:13]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)[C:12](=[O:27])[N:11]=2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: O=C1N=C(NC2CCCCC2)C2(CC[NH2+]CC2)N1c1cccc(F)c1
Agent: Cl
Agent: [BH3-]C#N
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C1N=C(NC2CCCCC2)C2(CCN(Cc3cccc(B(O)O)c3)CC2)N1c1cccc(F)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 3.0 g (7.188 mmol) 4-(cyclohexylamino)-1-(3-fluorophenyl)-2-oxo-1,3-diaza-8-azoniaspiro[4.5]dec-3-ene dihydrochloride in 30 mL THF:AcOH (9:1) was added 1.8 g (12.005 mmol) 3-formylphenylboronic acid and 5.53 g (21.567 mmol) PS-DIEA resin and 5.97 g (14.388 mmol) MP-cyanoborohydride resin. The heterogeneous reaction mixture was stirred at rt for 24 hrs, then filtered, washed with 100 mL methanol, and concentrated. Purification by automated flash chromatography (8-30% CH3CN/H2O over 41 min, 0.05% added TFA reverse phase YMC ODSA 120 Å, 15-30 μM particle size,) afforded 3-{[4-(cyclohexylamino)-1-(3-fluorophenyl)-2-oxo-1,3,8-triazaspiro[4.5]dec-3-en-8-yl]methyl}phenylboronic acid as a solid. 1H NMR (CD3OD, 400 MHz) δ 7.44 (m, 1H), 7.38 (d, J=7.32 Hz, 1H), 7.29 (s, 1H), 7.18 (m, 1H), 7.09 (m, 3H) 6.93 (m, 1H), 3.75 (m, 1H), 3.31 (s, 2H), 2.78 (m, 2H), 2.12 (m, 4H), 1.97 (m, 4H), 1.78 (m, 2H), 1.65 (m, 1H), 1.35 (m, 5H). High resolution mass spec (FT/ICR) calc M+H=478.2661 found 478.2709.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:20]=[CH:19][C:18]([C:21]([OH:23])=[O:22])=[C:17]3[C:12]=2[CH:13]=[CH:14][CH:15]=[N:16]3)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.OS(O)(=O)=O.[CH3:29][CH2:30]O>>[CH2:29]([O:22][C:21]([C:18]1[CH:19]=[CH:20][C:11]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=2)=[C:12]2[C:17]=1[N:16]=[CH:15][CH:14]=[CH:13]2)=[O:23])[CH3:30]
Reactant: COc1cc(OC)cc(-c2ccc(C(=O)O)c3ncccc23)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(-c2cc(OC)cc(OC)c2)c2cccnc12

Procedure:
A mixture of 5-(3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid (Step 159.2) (2 g), H2SO4 conc. (0.6 mL) and EtOH (100 mL) was stirred at reflux for 30 h, allowed to cool and concentrated. The residue was diluted in EtOAc and a saturated aqueous solution of NaHCO3. The aqueous phase was separated and extracted with EtOAc. The combined organic layers were washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography (Hex/EtOAc, 3:2) to provide 1.77 g of the title compound as a white solid. Title compound: ESI-MS: 338.2 [M+H]+; tR=3.81 min (System 1); TLC: Rf=0.29 (Hex/EtOAc, 3:2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[F:23].[CH3:24][N:25]([CH3:43])[CH2:26][CH2:27][C:28]1[C:29]([C:40](O)=[O:41])=[N:30][N:31]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[CH:32]=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>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:40]([C:29]2[C:28]([CH2:27][CH2:26][N:25]([CH3:43])[CH3:24])=[CH:32][N:31]([C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)[N:30]=2)=[O:41])=[CH:18][C:17]=1[F:23]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Reactant: CN(C)CCc1cn(-c2ccc(F)cc2)nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4nn(-c5ccc(F)cc5)cc4CCN(C)C)cc3F)c2cc1OC
Temperature: 60 °C
Reaction time: 12 h

Procedure:
To a solution of A2 (50 mg, 0.16 mmol, 1.0 eq), O2 (44 mg, 0.16 mmol, 1.0 eq.) and DIPEA (62 mg, 0.48 mmol, 3.0 eq.) in dry DMF (4 mL) was added HATU (121 mg, 0.32 mmol, 2.0 eq.). The mixture was stirred for 12 h at 60° C. Then the mixture was diluted with EtOAc and washed three times with aq. NaHCO3-solution. The organic phase was dried over MgSO4 and evaporated in vacuo. 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 desired compound O3 with impurities. A subsequent purification by chromatography on silica gel (DCM/MeOH=20:1) yielded the product O3 (15 mg, 0.026 mmol, 16%) as a white solid. 1H NMR (400 MHz, d6-DMSO, 300K) δ 2.34 (s, 6H), 2.72 (m, 2H), 2.98 (t, J=7.4 Hz, 2H), 3.94 (s, 6H), 6.47 (d, J=5.3 Hz, 1H), 7.40 (s, 1H), 7.44 (m, 3H), 7.53 (s, 1H), 7.77 (d, J=8.8 Hz, 1H), 8.03 (m, 3H), 8.48 (d, J=5.3 Hz, 1H), 8.51 (s, 1H), 10.44 (s, 1H). MS (ES) C31H29F2N5O4 requires: 573. Found: 574 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:3]=1.[Br:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>>[Br:22][C:23]1[CH:28]=[C:27]([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:5]=[C:4]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([F:19])([F:21])[F:20])=[CH:16][CH:17]=3)[N:3]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)cc(Br)n2)cc1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)cc(-c3cccc(Br)c3)n2)cc1

Procedure:
The title compound was prepared from 2-bromo-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridine (example A.19) (3.0 g, 8 mmol) and commercially available 3-bromo-benzene-boronic acid (1.954 g, 10 mmol) according to the general procedure IVb. Obtained as an orange oil (3.28 g, 91%). MS (ISP) 446.0 [(M+H)+] and 448.0 [(M+2+H)+].
Reaction SMILES: [Br:1][C:2]1[C:13](=[O:14])[N:12]([CH2:15][CH3:16])[C:5]2[N:6]=[C:7]([S:10][CH3:11])[N:8]=[CH:9][C:4]=2[CH:3]=1.ClC1C=CC=C(C(OO)=[O:25])C=1>ClCCl>[Br:1][C:2]1[C:13](=[O:14])[N:12]([CH2:15][CH3:16])[C:5]2[N:6]=[C:7]([S:10]([CH3:11])=[O:25])[N:8]=[CH:9][C:4]=2[CH:3]=1
Reactant: CCn1c(=O)c(Br)cc2cnc(SC)nc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCn1c(=O)c(Br)cc2cnc(S(C)=O)nc21
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
To a solution of 6-bromo-8-ethyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (3, 0.96 g, 3.19 mmol) in dichloromethane (40 mL) was added 3-chloroperbenzoic acid (77%, 0.68 g, 3.04 mmol) in dichloromethane (10 mL) at 0-5° C. and the mixture was stirred at 0-5° C. for 1 h. The reaction mixture was washed with 10% sodium bicarbonate solution (1×20 mL) and water (1×20 mL). The organic layer was dried over sodium sulfate, filtered and evaporated. The title compound was obtained as a pale yellow solid (0.98 g, 3.10 mmol, 97%). ESMS m/z 316 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)#[N:2].[Br:18]Br.C(OCC)(=O)C>CN(C=O)C.[Cl-].[Na+].O>[Br:18][C:12]1[C:11]2[C:15](=[CH:16][CH:17]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]#[N:2])[CH:10]=2)[NH:14][CH:13]=1
Reactant: N#Cc1ccccc1-c1ccc2[nH]ccc2c1
Reactant: BrBr
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccccc1-c1ccc2[nH]cc(Br)c2c1
Yield: 92.7 %

Procedure:
5-(2-Cyanophenyl)indole (1.38 mmoles, 300 mg) was dissolved in DMF (1 ml). A solution of bromine (1.4 moles, 0.074 ml) in 0.5 ml DMF was added. The reaction was poured into ethyl acetate and brine. The organic phase was washed with water, dried over sodium sulfate, and concentrated. The intermediate was chromatographed over silica gel eluted with 50 % ether in hexane to yield 380 mg of 3-bromo-5-(2-cyanophenyl)indole (MS)
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[C:11](Cl)([C:13](Cl)=[O:14])=[O:12].[CH3:17][CH2:18][OH:19].C([O-])(O)=O.[Na+]>C1COCC1>[CH2:18]([O:19][C:13](=[O:14])[C:11]([C:6]1[C:5]2[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)[NH:8][CH:7]=1)=[O:12])[CH3:17]
Reactant: Fc1ccc2cc[nH]c2c1
Reactant: CCO
Reactant: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1c[nH]c2cc(F)ccc12
Temperature: 0 °C
Reaction time: 15 h

Procedure:
To a solution of 6-fluoroindole (1.18 g, 8.56 mmol) in dry THF (65 mL) at 0° C. under argon was added (COCl)2 (0.93 mL, 10.7 mmol). The reaction mixture was stirred at 0° C. for 2 h and at rt for 15 h. The reaction mixture was cooled to 0° C. and EtOH (0.90 mL, 15.5 mmol) was added. The reaction mixture was stirred at rt for 24 h, then poured into cold satd NaHCO3. The mixture was extracted with EtOAc. The combined EtOAc extracts were washed with satd aq NaHCO3 and brine, dried, and evaporated to give the title compound: TLC Rf=0.48 (19:1 CH2Cl2/Me2CO); MS (ESI−) m/z 234.0; 1H NMR (CDCl3, 300 MHz) δ 10.95 (1H), 8.38 (1H), 8.31 (1H), 7.07 (1H), 4.37 (2H), 1.39 (3H).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH2:10]([N:17]([CH3:28])[C@H:18]([C:20]([C@:22]([CH3:27])([OH:26])[C:23]([OH:25])=O)=[O:21])[CH3:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>C(Cl)Cl>[CH2:10]([N:17]([CH3:28])[C@H:18]([C:20]([C@:22]([CH3:27])([OH:26])[C:23]([N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)=[O:25])=[O:21])[CH3:19])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C[C@@H](C(=O)[C@](C)(O)C(=O)O)N(C)Cc1ccccc1
Reactant: C1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](C(=O)[C@](C)(O)C(=O)N1CCCCC1)N(C)Cc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
5.4 g (41.4 mmol) of N,N-diisopropylethylamine (Hünig's base) and 5.3 g (20.7 mmol) of bis(2-oxo-3-oxazolidinyl)-phosphonium acid chloride (BOP-Cl) are added at 0° C. to a solution of 5.0 g (18.8 mmol) of N-benzyl-N-methyl-L-alanyl-D-lactic acid and 1.6 g (20.7 mmol) of piperidine in 150 ml of methylene chloride, and the mixture is stirred at 0° C. for two hours and then at room temperature for 18 hours. The residual crude product is chromatographed on a silica gel column (silica gel 60—Merck, particle size: 0.04 to 0.063 mm) using the eluent cyclohexane:ethyl acetate (3:1). 3.5 g (55.8% of theory) of N-benzyl-N-methyl-L-alanyl-D-lactic acid piperidide are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5](/[CH:9]=C/C(OC)=O)=[C:4]([Cl:15])[CH:3]=1.[O:16]=[O+][O-].CSC>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH:9]=[O:16])=[C:4]([Cl:15])[CH:3]=1
Reactant: O=[O+][O-]
Reactant: COC(=O)/C=C/c1c(Cl)cc(Br)cc1Cl
Solvent: ClCCl
Solvent: CSC
Product: O=Cc1c(Cl)cc(Br)cc1Cl

Procedure:
4-Bromo-2,6-dichloroaniline (5, 80 g) was dissolved in acetone (640 mL), and a 48% hydrogen bromide aqueous solution (120 mL) was added, followed by stirring at 0° C. A sodium nitrite (32 g) aqueous solution (160 ml,) was added dropwise thereto, the mixture was stirred for 30 minutes, and methyl acrylate (200 nit), and water (200 mL) were added, followed by stirring for 1 hour. At room temperature, cuprous oxide (2 g) was added, followed by stirring for 2 hours. The reaction solution was extracted with ethyl acetate, and purified by column chromatography to obtain methyl (E)-3-(4-bromo-2,6-dichlorophenyl)acrylate (48.5 g). Methyl (E)-3-(4-bromo-2,6-dichlorophenyl)acrylate (48.5 g) was dissolved in dichloromethane, an ozone gas was introduced at −70° C., and ozone oxidization was performed. To the reaction solution was added dimethyl sulfide (40 mL), and this was extracted with ethyl acetate to obtain 4-bromo-2,6-dichlorobenzaldehyde (6, 37.2 g).