Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][C@@H:5]([CH:8]=[O:9])[CH2:4][CH:3]=1.[CH2:10]([Mg]Br)[CH3:11].C[N+]1([O-])CCOCC1>[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH3:1][C:2]1[CH2:7][CH2:6][C@@H:5]([C:8](=[O:9])[CH2:10][CH3:11])[CH2:4][CH:3]=1
Reactant: CC1=CC[C@H](C=O)CC1
Reactant: CC[Mg]Br
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Product: CCC(=O)[C@H]1CC=C(C)CC1

Procedure:
(1R)-4-Methyl-3-cyclohexene-1-carboxaldehyde was treated with ethylmagnesium bromide followed by tetrapropylammonium perruthenate and 4-methylmorpholine N-oxide to afford 1-[(1R)-4-methylcyclohex-3-en-1-yl]-propan-1-one; [α]D=+41.3 (c=1.0, CHCl3). The product was identical in all respects to the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:19])[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])=[CH:10][O:11][C:6]=2[CH:5]=[C:4]([O:20][CH2:21][C:22]([O:24]CC)=[O:23])[CH:3]=1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[C:7]2[C:8](=[O:19])[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])=[CH:10][O:11][C:6]=2[CH:5]=[C:4]([O:20][CH2:21][C:22]([OH:24])=[O:23])[CH:3]=1
Reactant: CCOC(=O)COc1cc(Cl)c2c(=O)c(-c3ccccc3C)coc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccccc1-c1coc2cc(OCC(=O)O)cc(Cl)c2c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
In 1.2 l of ethanol was suspended 132 g of ethyl {[5-chloro-3-(2-methylphenyl)-4-oxo-4H-1-benzopyran-7-yl]oxy}acetate, and 0.53 l of a 1N sodium hydroxide aqueous solution was slowly added dropwise to the suspension at room temperature, followed by stirring at room temperature for 3 hours. The insoluble material was removed by filtration, and the filtrate was acidified with hydrochloric acid while ice-cooling and stirring. The stirring was continued at room temperature overnight. The precipitated crystals were collected by filtration, washed with water, and dried to obtain 105 g of the entitled compound having a melting point of 191° to 192° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17](=[O:24])(=[O:23])[NH:18][CH2:19][CH2:20][O:21][CH3:22])=[CH:13][C:12]=2[CH3:25])=[O:9])[CH:3]=1.C(NC(C)C)(C)C.[CH:33]1([CH2:36][NH:37][CH2:38][CH2:39][CH3:40])[CH2:35][CH2:34]1>C(O)C>[CH:33]1([CH2:36][N:37]([CH2:38][CH2:39][CH3:40])[C:2]2[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([S:17]([NH:18][CH2:19][CH2:20][O:21][CH3:22])(=[O:24])=[O:23])=[CH:13][C:12]=3[CH3:25])=[O:9])[CH:3]=2)[CH2:35][CH2:34]1
Reactant: COCCNS(=O)(=O)c1ccc(NC(=O)c2cc(Cl)ncn2)c(C)c1
Reactant: CCCNCC1CC1
Solvent: CC(C)NC(C)C
Solvent: CCO
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(S(=O)(=O)NCCOC)cc2C)ncn1
Temperature: 160 °C

Procedure:
A solution of 6-chloro-N-(4-(N-(2-methoxyethyl)sulfamoyl)-2-methylphenyl)pyrimidine-4-carboxamide (Intermediate 38, 100 mg; 0.26 mmol) and diisopropylamine (91 mL; 0.52 mmol) in ethanol (2.5 ml) was treated with N-(cyclopropylmethyl)propan-1-amine (0.7 ml, 0.33 mmol). The mixture was heated to 160° C. in a microwave for 1 hour and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4](=[O:20])[C:5]2[N:6]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[CH:7]=[N:8][C:9]=2[N:10]=1.[H-].[Na+].Cl[CH2:24][C:25]#[N:26]>CN(C=O)C>[Cl:1][C:2]1[N:3]([CH2:24][C:25]#[N:26])[C:4](=[O:20])[C:5]2[N:6]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[CH:7]=[N:8][C:9]=2[N:10]=1
Reactant: COc1ccc(Cn2cnc3nc(Cl)[nH]c(=O)c32)cc1
Reactant: N#CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cnc3nc(Cl)n(CC#N)c(=O)c32)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To 2-chloro-7-(4-methoxybenzyl)-1H-purin-6(7H)-one 7 (5.98 g, 20.62 mmol) in DMF (90 ml) at 0° C. was added NaH (1.072 g, 26.81 mmol). The mixture was stirred at room temperature for 10 minutes, and then stirred at 55° C. for 3 hours. Chloroacetonitrile (1.57 ml, 24.74 mmol) was added to the reaction flask at 0° C. The reaction mixture was stirred over night. Another 0.65 ml (10.31 mmol) of chloroacetonitrile was added into the reaction flask. The mixture was stirred over night. The reaction was quenched with water at 0° C. The mixture was extracted with DCM (3×), washed with water and brine, dried (MgSO4) and concentrated. The crude product was purified by flash chromatography (EtOAc/Hexane) to afford pure product 2-(2-chloro-7-(4-methoxybenzyl)-6-oxo-6,7-dihydro-1H-purin-1-yl)acetonitrile 8. 1H NMR δ 7.878 (s, 1H), 7.269 (d, J=8.8 Hz, 2H), 6.880, (d, J=8.8 Hz, 2H), 5.465 (s, 2H), 5.189 (s, 2H), 3.789 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:33])[CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([CH:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)[CH:19]=3)[N:14]=2)=[CH:8][C:7]=1[CH2:31][CH3:32].[C:34](O)(=[O:37])[CH2:35][OH:36].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.CC(=O)OCC>[CH:26]1([C:20]2[CH:19]=[C:18]([C:15]3[N:14]=[C:13]([C:9]4[CH:10]=[C:11]([CH3:12])[C:6]([O:5][CH2:4][C@@H:3]([OH:33])[CH2:2][NH:1][C:35](=[O:36])[CH2:34][OH:37])=[C:7]([CH2:31][CH3:32])[CH:8]=4)[O:17][N:16]=3)[CH:23]=[C:22]([O:24][CH3:25])[N:21]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=C(O)CO
Reactant: CCc1cc(-c2nc(-c3cc(OC)nc(C4CCCC4)c3)no2)cc(C)c1OC[C@@H](O)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(-c2nc(-c3cc(OC)nc(C4CCCC4)c3)no2)cc(C)c1OC[C@@H](O)CNC(=O)CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.9 %

Procedure:
To a solution of (2S)-1-amino-3-{4-[3-(2-cyclopentyl-6-methoxy-pyridin-4-yl)-[1,2,4]oxadiazol-5-yl]-2-ethyl-6-methyl-phenoxy}-propan-2-ol (100 mg, 220 μmol), glycolic acid (22 mg, 289 μmol) and DIPEA (86 mg, 666 μmol) in DMF (3 mL), TBTU (93 mg, 289 μmol) is added. The mixture is stirred at rt for 1 h before it is diluted with EA (50 mL) and washed with sat. aq. NaHCO3 solution (20 mL) followed by brine (20 mL). The org. extract is dried over MgSO4, filtered and concentrated. The crude product is purified by prep. HPLC to give the title compound (65 mg) as an almost colourless oil; LC-MS**: tR=0.84 min, [M+H]+=511.03; 1H NMR (CDCL3): δ1.33 (t, J=7.5 Hz, 3H), 1.68-1.79 (m, 2H), 1.82-1.95 (m, 4H), 2.05-2.15 (m, 2H), 2.41 (s, 3H), 2.76 (q, J=7.5 Hz, 2H), 3.18-3.28 (m, 1H), 3.49-3.59 (m, 1H), 3.75-3.95 (m, 3H), 4.01 (s, 3H), 4.18-4.26 (m, 3H), 7.08 (t, J=4.3 Hz, 1H), 7.49 (s, 1H), 7.91 (s, 1H), 7.93 (s, 1H).
Reaction SMILES: Br[C:2]1[N:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.CC(C)([O-])C.[Na+].C1COCC1.Cl.Cl.[NH2:22][CH2:23][CH2:24][NH:25][C@:26]12[CH2:61][CH2:60][C@@H:59]([C:62]([CH3:64])=[CH2:63])[C@@H:27]1[C@@H:28]1[C@@:41]([CH3:44])([CH2:42][CH2:43]2)[C@@:40]2([CH3:45])[C@@H:31]([C@:32]3([CH3:58])[C@@H:37]([CH2:38][CH2:39]2)[C:36]([CH3:47])([CH3:46])[C:35]([C:48]2[CH:57]=[CH:56][C:51]([C:52]([O:54]C)=[O:53])=[CH:50][CH:49]=2)=[CH:34][CH2:33]3)[CH2:30][CH2:29]1.C(O)(C(F)(F)F)=O>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:44][C@:41]12[C@@:40]3([CH3:45])[C@@H:31]([C@:32]4([CH3:58])[C@@H:37]([CH2:38][CH2:39]3)[C:36]([CH3:46])([CH3:47])[C:35]([C:48]3[CH:57]=[CH:56][C:51]([C:52]([OH:54])=[O:53])=[CH:50][CH:49]=3)=[CH:34][CH2:33]4)[CH2:30][CH2:29][C@@H:28]1[C@H:27]1[C@H:59]([C:62]([CH3:64])=[CH2:63])[CH2:60][CH2:61][C@:26]1([NH:25][CH2:24][CH2:23][NH:22][C:2]1[N:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1)[CH2:43][CH2:42]2
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: Cc1ccc(Br)nn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: COCCOC
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: C=C(C)[C@@H]1CC[C@]2(NCCNc3ccc(C)nn3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 110 °C
Reaction time: 0.17 h
Yield: 11.6 %

Procedure:
In a 1 dram vial under nitrogen were combined (2R)-1-[(1R)-1-[bis(1,1-dimethylethyl)phosphino]ethyl]-2-(dicyclohexylphosphino)ferrocene (CAS#158923-11-6) (2.52 mg, 4.55 mmol), palladium(II) acetate (1.02 mg, 4.55 mmol) and dry DME (0.5 ml). The contents of the vial were stirred for 10 min, and were then added all at once to a separate mixture of 3-bromo-6-methylpyridazine (0.017 g, 0.100 mmol) and sodium tert-butoxide, 2.0M solution in THF (0.200 mL, 0.400 mmol) in dry DME (0.500 mL) contained in a separate 1 dram vial. The resulting mixture was allowed to stir very briefly (1 min) before solid methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-aminoethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate bis HCl salt (0.060 g, 0.091 mmol) was added in one portion. The mixture was heated to 110° C. overnight. Iterative purification of the crude mixture by reverse phase preparative HPLC first using Prep HPLC Method 9 and then repurification by Prep HPLC Method 10 gave the title compound (0.0070 g, 8.3% yield) as a white glassy solid bis TFA salt. LCMS: m/e 665.5 (M+H)+, 2.22 min (method 11). 1H NMR (500 MHz, 1:1 mixture of CDCl3 and MeOD, MeOD lock) δ ppm 7.90 (d, J=8.5 Hz, 2H), 7.49-7.42 (m, 1H), 7.32-7.23 (m, 1H), 7.18 (d, J=8.2 Hz, 2H), 5.27 (dd, J=6.0, 1.4 Hz, 1H), 4.88 (br. s., 1H), 4.72 (br. s., 1H), 3.94-3.84 (m, 1H), 3.84-3.73 (m, 1H), 3.26-3.13 (m, 1H), 2.84 (d, J=12.5 Hz, 1H), 2.57 (s, 3H), 2.12 (dd, J=16.9, 6.3 Hz, 1H), 2.05 (d, J=15.6 Hz, 1H), 2.01-1.91 (m, 2H), 1.91-1.74 (m, 2H), 1.70 (s, 3H), 1.69-1.59 (m, 2H), 1.59-1.43 (m, 4H), 1.43-1.28 (m, 4H), 1.28-1.18 (m, 4H), 1.18-1.06 (m, 2H), 1.05 (s, 3H), 0.99 (s, 3H), 0.97 (s, 3H), 0.92 (s, 3H), 0.92-0.89 (m, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@@H:8]([NH2:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[NH:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.[Cu]I>[N:11]1([C:2]2[CH:3]=[C:4]([C@@H:8]([NH2:10])[CH3:9])[CH:5]=[CH:6][CH:7]=2)[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: C[C@H](N)c1cccc(Br)c1
Reactant: c1nc[nH]n1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: C[C@H](N)c1cccc(-n2cncn2)c1
Temperature: 195 °C
Yield: 35.7 %

Procedure:
To a solution of (S)-1-(3-bromo-phenyl)-ethylamine (1.5 g, 7.5 mmol) and 1,2,4-triazole (1.04 g, 15 mmol) in N-methylpyrrolidinone (10 mL) in a quartz tube were added potassium carbonate (2.1 g, 15 mmol) and copper (1) iodide (143 mg, 0.75 mmol). The reaction mixture was heated at 195° C. for 5 h in a Mars 5 microwave oven (600 W), cooled down to room temperature and filtered. The crude product was purified by flash chromatography (10% MeOH/89% EtOAC/1% triethylamine) to provide the title compound (504 mg, 36% yield) as a brown oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[CH:2]=1.CN1CCOCC1.[Si](I)(C)(C)C>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(c2cccnc2)c2cccnc2)CC1
Agent: C[Si](C)(C)I
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: c1cncc(C(c2cccnc2)N2CCNCC2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 65.4 %

Procedure:
A round bottom flask was charged with tert-butyl 4-(di(pyridin-3-yl)methyl)piperazine-1-carboxylate (220 mg, 0.621 mmol), CH2Cl2 (20 mL), and NMM (136 μL, 1.23 mmol). The reaction was cooled to 0° C. and TMSI (106 μL, 0.745 mmol) was added dropwise. After 10 min at 0° C., additional TMSI (100 μL, 0.700 mmol) was added. After stirring 10 min at 0° C. the reaction was allowed to warm to room temperature. After 15 min at room temperature the reaction was diluted in CH2Cl2 and washed (1×) sat Na2CO3. The organics were dried (Na2SO4), filtered, and concentrated and yielded 103 mg crude product (0.406 mmol, 65%) as a yellow oil, which was used without further purification in the next step. 1H NMR 400 MHz (CDCl3) δ 8.64 (d, J=2.4 Hz, 2H), 8.47 (dd, J=4.8, 1.6 Hz, 2H), 7.70 (dt, J=8.0, 2.0 Hz, 2H), 7.23 (dd, J=7.9, 4.8 Hz, 2H), 4.36 (s, 1H), 2.91 (t, J=4.9 Hz, 4H), 2.38 (t, J=5.0 Hz, 5H). LCMS (ESI, m/z): 255 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=1)[C:7]([CH:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH2:10]1)=[O:8].[F:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26]Br>CN(C)C=O>[F:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18](=[O:19])[C:9]([C:7](=[O:8])[C:6]2[CH:20]=[CH:21][CH:22]=[C:4]([CH3:3])[CH:5]=2)=[CH:10]1
Reactant: Fc1ccccc1CBr
Reactant: Cc1cccc(C(=O)C2CNc3ccccc3C2=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(C(=O)c2cn(Cc3ccccc3F)c3ccccc3c2=O)c1
Yield: 45.8 %

Procedure:
Compound 4x was prepared following the procedure outlined in Step 3 of Example 1 using 26 mg (0.65 mmol) of sodium hydride (60%), 132 mg (0.50 mmol) of 3-(3-methyl-benzoyl)-2,3-dihydro-1H-quinolin-4-one, 3 mL of anhydrous dimethylformamide, and 123 mg (0.65 mmol) of 2-fluorobenzylbromide. The crude product was purified by flash chromatography to yield 85 mg of a colorless solid 4x: LC-MSD, m/z for C24H18FNO2, [M+H]+=372.4, [M+2H]+=373.4; Reverse phase HPLC (gradient acetonitrile 0.1% TFA 20-95% in 4 min) retention time=2.687 min; 1H NMR (400 MHz, CDCl3/HCl): δ 2.40 (s, 3H), 5.42 (s, 2H), 7.02-7.18 (m, 3H), 7.28-7.36 (m, 3H), 7.36-7.42 (m, 2H), 7.58-7.66 (m, 3H), 8.31 (s, 1H), 8.43-8.47 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:18][C:11]3=[N:12][CH:13]=[C:14]([Cl:17])[C:15]([CH3:16])=[C:10]3[N:9]=2)=[CH:4][C:3]=1[OH:19].[CH:20]([C@H:22]1[CH2:26][CH2:25][CH2:24][N:23]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=O.C[Si](Cl)(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CN1C(=O)CCC1.C(O)(=O)C>[Cl:17][C:14]1[C:15]([CH3:16])=[C:10]2[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][CH2:20][C@H:22]4[CH2:26][CH2:25][CH2:24][N:23]4[C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])=[C:3]([OH:19])[CH:4]=3)[NH:18][C:11]2=[N:12][CH:13]=1
Reactant: Cc1c(Cl)cnc2[nH]c(-c3ccc(N)c(O)c3)nc12
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[Si](C)(C)Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Product: Cc1c(Cl)cnc2[nH]c(-c3ccc(NC[C@H]4CCCN4C(=O)OC(C)(C)C)c(O)c3)nc12
Reaction time: 8 h

Procedure:
2-Amino-5-(6-chloro-7-methyl-3H-imidazo[4,5-b]pyridin-2-yl)phenol (Example 249) (0.050 g, 0.18 mmol) and tert-butyl (2R)-2-formylpyrrolidine-1-carboxylate (0.036 g, 0.18 mmol) were dissolved in NMP (1.0 ml) and acetic acid (0.10 ml). TMSCl (0.046 ml, 0.36 mmol) and NaBH(OAc)3 (0.072 g, 0.36 mmol) were added and the mixture stirred overnight. The crude mixture was purified by HPLC-C18 giving the title compound (0.017 g, 21%).
Reaction SMILES: Cl.[O:2]1[CH2:6][CH2:5][CH2:4][NH:3]1.C(Cl)(Cl)Cl.[F:11][C:12]([F:33])([F:32])[C:13]1[CH:31]=[CH:30][C:16]([O:17][C:18]2[CH:29]=[CH:28][C:21]([O:22][CH:23]([CH3:27])[C:24](Cl)=[O:25])=[CH:20][CH:19]=2)=[CH:15][CH:14]=1.C(N(CC)CC)C>O>[F:11][C:12]([F:32])([F:33])[C:13]1[CH:31]=[CH:30][C:16]([O:17][C:18]2[CH:29]=[CH:28][C:21]([O:22][CH:23]([CH3:27])[C:24]([N:3]3[CH2:4][CH2:5][CH2:6][O:2]3)=[O:25])=[CH:20][CH:19]=2)=[CH:15][CH:14]=1
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)Cl
Reactant: C1CNOC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)N1CCCO1
Yield: 97.7 %

Procedure:
To a mixture of isoxazolidine hydrochloride (11.0 g) and chloroform (200 ml), under stirring and ice-cooling, was added (±)-2-[4-(4-trifluoromethylphenoxy)phenoxy]propionyl chloride (34.5 g) and then added dropwise triethylamine (22.2 g). After the completion of addition, the reaction mixture was stirred for further 30 minutes at room temperature, to which water was added to form two layers. The organic layer so separated was washed with 1 N hydrochloric acid and then with 1 N aqueous sodium hydroxide and dried over anhydrous sodium sulfate. Removal of the solvent by a distillation in vacuo gave N-[(±)-2-[4-(4-trifluoromethylphenoxy)phenoxy]propionyl]isoxazolidine (37.3 g) as a white crystalline solid. After recrystallization from a mixture of n-hexane/acetone, the resulting white crystalline solid showed the melting point of 105°-107° C.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)=[CH:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)(=O)=O)C=CC=CC=1.[OH-].[Na+]>C(O)C.O1CCCC1.ClCCl>[CH3:36][S:33]([C:30]1[CH:29]=[CH:28][C:27]([C:19]([C:11]2[NH:10][C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=2)=[CH:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)=[CH:32][CH:31]=1)(=[O:34])=[O:35]
Reactant: CS(=O)(=O)c1ccc(C(=CC2CCCCO2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(C(=CC2CCCCO2)c2cc3cccnc3[nH]2)cc1
Yield: 8.3 %

Procedure:
A mixture of 1-benzenesulfonyl-2-[1-(4-methanesulfonyl-phenyl)-2-(tetrahydro-pyran-2-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (0.36 g, 6.9 mmol) in ethanol (3 mL), tetrahydrofuran (3 mL) and an aqueous sodium hydroxide solution (10%, 1 mL) was heated at 50° C. for 2 h. The mixture was diluted with dichloromethane (50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[1-(4-methanesulfonyl-phenyl)-2-(tetrahydro-pyran-2-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (220 mg, 84%): LC/MS m/e calcd for C21H22N2O3S [M+H]+ 383.49, observed 383.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:24]2[CH:38]=[CH:37][C:27]([O:28][CH2:29][C:30]([NH:32][CH2:33][C:34](O)=[O:35])=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[C:68]([CH2:72][C@H:73]([C:75]([OH:77])=[O:76])[NH2:74])([CH3:71])([CH3:70])[CH3:69].[BH4-].[Na+]>CN(C=O)C.CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[OH:16])[C@H:9]2[C:24]2[CH:25]=[CH:26][C:27]([O:28][CH2:29][C:30]([NH:32][CH2:33][C:34]([NH:74][C@@H:73]([C:75]([OH:77])=[O:76])[CH2:72][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:35])=[O:31])=[CH:37][CH:38]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)C[C@@H](N)C(=O)O
Reactant: O=C(O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [BH4-]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)C[C@@H](NC(=O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)C(=O)O
Reaction time: 1 h
Yield: 70.6 %

Procedure:
N-{[4-((2R,3R)-1-(4-Fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycine (20 mg, 0.037 mmol) was dissolved in 1.5 ml DMF. N-Methylmorpholine (13 μl, 118 mmol) and TBTU (15 mg, 0.047 mmol) were added and the mixture was stirred for 1 h., β-tert-Butyl-D-alanine (11 mg, 0.076 mmol) was added and the mixture was stirred for 3 h. Water (0.2 ml) was added and the mixture was stirred for 15 min. MeOH (2 ml) and NaBH4 (15 mg) were added. NH4Ac (ca 20 mg) was added after 15 min. Purification was performed using preparative HPLC on a C8 column. A gradient from 20-50% MeCN in 0.1M NH4Ac was used as mobile phase. Lyophilization yielded 17.5 mg (70%) of the title compound. M/z: 668 (M−1). NMR (400 MHz, DMSO): 8.24 (t, 1H), 7.77-7.87 (m, 1H), 7.32-7.40 (m, 4H), 7.22-7.27 (m, 2H), 7.07-7.19 (m, 4H), 6.99 (d, 2H), 5.06 (dd, 1H), 4.70-4.78 (m, 1H), 4.53 (s, 2H), 4.31 (dd, 1H), 4.09-4.17 (m, 1H), 3.65-3.81 (m, 2H), 2.84-3.00 (m, 2H), 1.65 (dd, 1H), 1.42 (dd, 1H), 0.86 (s, 9H).
Reaction SMILES: C([N:8]1[CH2:25][CH2:24][C:11]2([O:19][C:18]3[CH:17]=[N:16][N:15]([CH:20]([CH3:22])[CH3:21])[C:14]=3[C:13](=[O:23])[CH2:12]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>ClCCCl>[CH:20]([N:15]1[C:14]2[C:13](=[O:23])[CH2:12][C:11]3([CH2:10][CH2:9][NH:8][CH2:25][CH2:24]3)[O:19][C:18]=2[CH:17]=[N:16]1)([CH3:22])[CH3:21]
Reactant: CC(C)n1ncc2c1C(=O)CC1(CCN(Cc3ccccc3)CC1)O2
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: CC(C)n1ncc2c1C(=O)CC1(CCNCC1)O2
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
1-Benzyl-1′-isopropyl-1′H-spiro[piperidine-4,5′-pyrano[3,2-c]pyrazol]-7′(6′H)-one (81 mg, 0.22 mmol) was dissolved in 10 mL 1,2-dichloroethane. Added 1-chloroethyl chloroformate (60 mL, 0.54 mmol) was added and the mixture was stirred 1 h at reflux then cooled to room temperature. The volatiles were removed under reduced pressure and the residue taken up in 10 mL methanol and heated at reflux for 1 h. The mixture was cooled to ambient temperature and the volatiles were removed under reduced pressure. The residue was taken up in 50 mL saturated aqueous sodium bicarbonate and extracted 2×30 mL ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and concentrated to yield 46 mg (86%) of 1′-isopropyl-1′H-spiro[piperidine-4,5′-pyrano[3,2-c]pyrazol]-7′(6′H)-one as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm 7.20 (s, 1H), 5.13 (spt, 1H), 2.93 (m, 2H), 2.80 (dt, J=12.8, 4.0 Hz, 2H), 2.64 (s, 2H), 2.02 (m, 2H), 1.63 (m, 2H), 1.40 (m, 6H); m/z (M+1)=250.2
Reaction SMILES: C([NH:4][C:5]1[C:6]([Cl:15])=[C:7]([CH:11]=[CH:12][C:13]=1[Cl:14])[C:8]([OH:10])=[O:9])(=O)C.C(O)(=O)C>Cl>[NH2:4][C:5]1[C:6]([Cl:15])=[C:7]([CH:11]=[CH:12][C:13]=1[Cl:14])[C:8]([OH:10])=[O:9]
Reactant: CC(=O)Nc1c(Cl)ccc(C(=O)O)c1Cl
Agent: Cl
Solvent: CC(=O)O
Product: Nc1c(Cl)ccc(C(=O)O)c1Cl

Procedure:
3-Acetylamino-2,4-dichloro-benzoic acid (21.0 g, 84.6 mmol) is stirred in 6 M aq HCl-solution (120 mL) and acetic acid (250 mL) at reflux for 24 h. The reaction mixture is cooled, concentrated, diluted with water and concentrated again. The residue is diluted with water, stirred under cooling and filtered. The filtercake is washed and dried to give the sub-title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]([S:18]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25]4[C:30]=3[N:29]=[CH:28][CH:27]=[CH:26]4)(=[O:20])=[O:19])[CH2:12][C:13]([O:15]CC)=[O:14])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:31][CH2:32][C:33]1[S:37][C:36]([C:38](=[NH:40])[NH2:39])=[CH:35][CH:34]=1.[OH-].[Na+]>>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]([S:18]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25]4[C:30]=3[N:29]=[CH:28][CH:27]=[CH:26]4)(=[O:20])=[O:19])[CH2:12][C:13]([OH:15])=[O:14])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:31][CH2:32][C:33]1[S:37][C:36]([C:38](=[NH:39])[NH2:40])=[CH:35][CH:34]=1
Reactant: CCOC(=O)CN(c1ccc2c(c1)nc(CCc1ccc(C(=N)N)s1)n2C)S(=O)(=O)c1cccc2cccnc12
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(CCc2ccc(C(=N)N)s2)nc2cc(N(CC(=O)O)S(=O)(=O)c3cccc4cccnc34)ccc21

Procedure:
Prepared analogously to Example 3 from 1-methyl-2-[2-(2-amidinothiophen-5-yl)-ethyl]-5-[N-(ethoxycarbonylmethyl)-quinoline-8-sulphonylamino]-benzimidazole and sodium hydroxide solution.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6](CC1C=CC(OC)=CC=1)[C:5]2([CH3:22])[CH3:21]>C(#N)C.O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][C:5]2([CH3:22])[CH3:21]
Reactant: COc1ccc(CN2C(=O)c3ccc(Br)cc3C2(C)C)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC1(C)NC(=O)c2ccc(Br)cc21
Yield: 86 %

Procedure:
A solution of 5-bromo-2-(4-methoxybenzyl)-3,3-dimethyl-2,3-dihydroisoindol-1-one (640 mg, 1.78 mmol) and ceric ammonium nitrate (2.91 g, 5.33 mmol) in acetonitrile (11 mL) and water (5 mL) is stirred at 0° C. for 45 min. The solution is diluted with ethyl acetate (100 mL) and washed with brine (40 mL). The organic solvents are dried over MgSO4 and evaporated under reduced pressure. The residue is purified by silica chromatography, eluting with 10% to 50% ethyl acetate in petroleum ether to afford the title compound (367 mg, 1.53 mmol).