Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)=O>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][N:12]1[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Cc2ccc(F)cc2F)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(CCc2ccc(F)cc2F)CC1
Temperature: 66 °C
Yield: 100.3 %

Procedure:
tert-Butyl 4-(2-(2,4-difluorophenyl)acetyl)piperazine-1-carboxylate (1.12 g, 3.30 mmol) was dissolved in THF (8.5 mL) and borane-tetrahydrofuran complex (1.0 M, 15.8 mL, 15.8 mmol) was added. The reaction was refluxed at 66° C. The reaction was quenched slowly with methanol (0.4 mL) dropwise. Then, 0.5 M HCl (10.0 mL) was added, and the mixture was extracted with EtOAc (2×100 mL). The organic extracts were dried over Na2SO4, filtered, and concentrated to give a residue that was purified by RP-HPLC. The best fractions were added to NaHCO3 (20 mL) and extracted with EtOAc (2×100 mL). The organic extracts were dried over Na2SO4, filtered, and concentrated to yield the title compound (1.08 g) as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 1.41 (s 9H), 2.80-2.96 (m, 6H), 3.10-3.03 (m, 2H), 3.50-3.60 (m, 4H), 7.06 (dt, J=2.6, 8.5 Hz, 1H), 7.22 (dt, J=2.6, 9.6 Hz, 1H), 7.38-7.46 (m, 1H). Exact mass calculated for C17H24F2N2O2: 326.2. Found: LCMS m/z=327.1 (M+H+).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)=[CH2:2].[CH2:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10]1.CC(C)([O-])C.[K+].C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH2:2][CH2:1][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)=[CH:10]1
Reactant: C=Cc1ccccn1
Reactant: C1=Cc2ccccc2C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: C1=C(CCc2ccccn2)c2ccccc2C1
Temperature: 115 °C
Reaction time: 2 h

Procedure:
43 g (0.47 mol) of 2-vinylpyridine were added to a mixture of 56 ml (0.48 mol) of indene in 40 ml of toluene and 4 g (0.036 mol) of solid potassium tert-butoxide at 60-90° C. over a period of 40 minutes. The mixture was then stirred for another 2 hours at 115° C., cooled to room temperature and subsequently neutralized by means of 2 ml of glacial acetic acid. Insoluble constituents were filtered off and the filtrate was distilled under reduced-pressure. This gave 42 g of 2-[2-(1H-inden-3-yl)ethyl]pyridine (40%, b.p. 161-163° C. at 2 mm).
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]([CH2:16][O:17][CH2:18][CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])=[C:14]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:13][N:12]=2)=[C:7]([Cl:35])[CH:6]=1.[Li+].[OH-].Cl.C(Cl)Cl>C1COCC1.O>[Cl:35][C:7]1[CH:6]=[C:5]([CH2:4][C:3]([OH:36])=[O:2])[CH:10]=[CH:9][C:8]=1[C:11]1[C:15]([CH2:16][O:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])=[C:14]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[O:13][N:12]=1
Reactant: COC(=O)Cc1ccc(-c2noc(-c3ccccc3)c2COCCOc2ccc(Cl)cc2Cl)c(Cl)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: O=C(O)Cc1ccc(-c2noc(-c3ccccc3)c2COCCOc2ccc(Cl)cc2Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
(3-Chloro-4-{4-[2-(2,4-dichloro-phenoxy)-ethoxymethyl]-5-phenyl-isoxazol-3-yl}-phenyl)-acetic acid methyl ester 41 (0.75 mmol) is dissolved in THF (5 mL). A solution of 1 M LiOH in H2O (3.5 mL) is added and the mixture is stirred for 6 hours at room temperature. The mixture is acidified with 1 M HCl (3 mL), DCM (50 mL) is added and the organic layer washed with H2O (2×30 mL). The organic layer is dried (MgSO4), filtered, concentrated and purified on reverse phase HPLC (H2O/MeCN gradient) to afford the title compound H2 as a white solid: 1H-NMR (400 MHz, CDCl3) δ=7.84 (m, 2H), 7.44-7.19 (m, 7H), 7.06 (dd, J=8.8 Hz, J=2.5 Hz, 1H), 6.70 (d, J=8.8 Hz, 1H), 4.45 (s, 2H), 4.00 (t, J=4.5 Hz, 2H), 3.71 (t, J=4.5 Hz, 2H), 3.62 (s, 2H). MS calculated for C26H21Cl3NO5 (M+H+) 532.0, found 532.1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][N:8]=[C:7]([N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]=2[CH:25]=1.[CH3:26][O:27][C:28]1[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[CH:49][C:29]=1[CH2:30][N:31]([C:44]1[S:48][N:47]=[CH:46][N:45]=1)[S:32]([C:35]1[CH:40]=[C:39]([F:41])[C:38](F)=[CH:37][C:36]=1[F:43])(=[O:34])=[O:33].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[CH3:26][O:27][C:28]1[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[CH:49][C:29]=1[CH2:30][N:31]([C:44]1[S:48][N:47]=[CH:46][N:45]=1)[S:32]([C:35]1[C:36]([F:43])=[CH:37][C:38]([O:1][C:2]2[CH:3]=[CH:4][C:5]3[O:9][N:8]=[C:7]([N:10]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:6]=3[CH:25]=2)=[C:39]([F:41])[CH:40]=1)(=[O:34])=[O:33]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1noc2ccc(O)cc12
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(F)cc2F)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(Oc3ccc4onc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c4c3)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87 %

Procedure:
To a solution of di-tert-butyl (5-hydroxy-1,2-benzoxazol-3-yl)imidodicarbonate (0.40 g, 1.1 mmol) in dimethyl sulfoxide (5 mL) was added N-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (0.50 g, 1.1 mmol) and potassium carbonate (0.19 g, 1.4 mmol). The reaction was stirred at ambient temperature for 18 h, diluted with ethyl acetate (10 mL), washed with water (3×10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford di-tert-butyl (5-{4-[(2,4-dimethoxybenzyl)(1,2,4-thiadiazol-5-yl)sulfamoyl]-2,5-difluorophenoxy}-1,2-benzoxazol-3-yl)imidodicarbonate as a colorless solid in 87% yield (1.09 g): 1H NMR (300 MHz, CDCl3) δ8.17 (s, 1H), 7.66-7.59 (m, 2H), 7.30-7.26 (m, 2H), 7.18-7.16 (m, 1H), 6.45-6.40 (m, 1H), 6.35 (d, J=8.1 Hz, 1H), 6.37 (s, 1H), 2.60 (s, 2H), 3.75 (s, 3H), 3.70 (s, 3H), 1.56 (s, 9H), 1.40 (s, 9H); MS (ES+) m/z 775.8 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:3]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21].C(O)C>N1C=CC=CC=1>[C:20]([NH:1][C:2]1[N:6]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:5]=[C:4]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)[CH:3]=1)(=[O:22])[CH3:21]
Reactant: CCOC(=O)Cn1nc(-c2ccc(F)cc2)cc1N
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)Cn1nc(-c2ccc(F)cc2)cc1NC(C)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.7 %

Procedure:
To a solution of ethyl 2-(5-amino-3-(4-fluorophenyl)-1H-pyrazol-1-yl)acetate (6.91 g, 26.3 mmol) in pyridine (62 mL) was added acetic anhydride (3 ml, 31.5 mmol). The reaction was stirred at room temperature for 16 h. Ethanol was added and the mixture was concentrated in vacuo. The crude residue was purified by column chromatography (silica gel, gradient 10 to 100% ethyl acetate/isohexane) yielding ethyl 2-(5-acetamido-3-(4-fluorophenyl)-1H-pyrazol-1-yl)acetate as a solid (7.6 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([C:14](OC)=[O:15])[O:11][C:10]2=[O:18])[CH:5]=[CH:6][C:7]=1[I:8].[OH-].[NH4+:20]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([C:14]([NH2:20])=[O:15])[O:11][C:10]2=[O:18])[CH:5]=[CH:6][C:7]=1[I:8]
Reactant: [NH4+]
Reactant: COC(=O)[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Agent: [OH-]
Solvent: CC#N
Product: NC(=O)[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (−)-methyl (5R)-3-[3-fluoro-4-iodophenyl]-2-oxo-5-oxazolidinecarboxylate (Step 2, 6.23 g, 17.1 mmol) in acetonitrile (85 mL) is treated with concentrated ammonium hydroxide (85 mL), and the resulting mixture is stirred at ambient temperature for 1 h. The mixture is then diluted with saline (100 mL) and extracted with methylene chloride (3×100 mL), and the combined organic phase is washed with saline (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product is diluted with hot ethyl acetate (200 mL) and filtered to remove inorganic residue, and the filtrate is diluted with hexanes (300 mL). The resulting precipitate is isolated by filtration to give the title compound, mp 176-178° C.; MS (ESI+) for C10H8FIN2O3 m/z 351 (M+H)+; [α]25D=−19 (c 0.97, DMSO).
Reaction SMILES: [I:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-])=O)=[CH:4][CH:3]=1.[NH4+].[Cl-]>[Fe]>[I:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[CH:4][CH:3]=1
Reactant: Nc1nc(I)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Product: Nc1ccc(I)nc1N

Procedure:
To a solution of 5-2 (2.0 g, 7.55 mmol) and NH4Cl (0.202 g, 3.78 mmol) in 2:1 EtOH-H20 (37.8 mL) at 90° C. was added iron powder (2.11 g, 37.8 mmol) in three equal portions over ten minutes. The reaction turned very dark in color. After sixty minutes the hot mixture was filtered through Celite then concentrated. The residue was partitioned between EtOAc and saturated NaHCO3 solution. The organic phase was washed with sat. NaHCO3 solution and brine, then dried with MgSO4 and concentrated to yield a brown solid.
Reaction SMILES: [CH2:1](OCC)C.[CH2:6]([O:13][C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][C@@H:21]([C:30]([OH:32])=[O:31])[NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N+](=C)=[N-]>C(Cl)(Cl)Cl.C(OCC)(=O)C>[CH3:1][O:31][C:30](=[O:32])[C@H:21]([CH2:20][CH2:19][CH2:18][CH2:17][NH:16][C:14]([O:13][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:15])[NH:22][C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24]
Reactant: CCOCC
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Agent: C=[N+]=[N-]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
An ethyl ether solution of 1.48 g (3.9 mmol) of Nε -benzyloxycarbonyl-Nα -(tert-butoxycarbonyl)-L-lysine was combined with an ethyl ether solution of diazomethane at 0° C. The reaction mixture was evaporated to give a colorless oil in nearly quantitative yield (1.54 g). TLC Rf =0.38 (chloroform/ethyl acetate, 5:1). IR (neat) ν 3340, 1710, 1530 cm-1. NMR (CDCl3) δ 7.3 (5H, s), 7.25 (1H, m), 5.05 (2H, s), 5.0 (1H, m), 4.1 (1H, m), 3.8 (3H, s), 3.1 (2H, m), 2.0-1.1 (6H, m), 1.4 (9H, s). The product has the structural formula: ##STR82##
Reaction SMILES: C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([OH:27])[CH2:20][CH2:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:15][CH:14]=1>ClCCl>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:27])[CH2:20][CH2:21][CH2:22][C:23]([F:25])([F:26])[F:24])=[CH:15][CH:14]=1
Reactant: OC(CCCC(F)(F)F)c1ccc(Br)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C(CCCC(F)(F)F)c1ccc(Br)cc1
Reaction time: 4 h
Yield: 96 %

Procedure:
PCC (9.29 g, 43.1 mmol) was admixed with 9 g SiO2 and ground with mortar & pestle before being added in one portion to a solution of 1-(4-bromophenyl)-5,5,5-trifluoropentan-1-ol (6.4 g, 21.54 mmol) dissolved in dichloromethane (350 mL). The reaction was stirred 4 h, filtered through diatomaceous earth (Celite®), concentrated, and applied to a 160 g Thomson® silica gel column. Elution: 10-60% B over 1.5 L (A/B Hexanes/EtOAc) gave Example 5b, 1-(4-bromophenyl)-5,5,5-trifluoropentan-1-one 6.1 g (86%). 1H NMR (500 MHz, CDCl3) δ 7.81 (d, J=8.5 Hz, 2H), 7.61 (d, J=8.3 Hz, 2H), 3.04 (t, J=7.0 Hz, 2H), 2.25-2.16 (m, 2H), 2.05-1.99 (m, 2H). RT=2.1 minutes (condition 1). LCMS: Anal. Calcd. For C11H11BrF3O: 295.00. found: 295.00 (M+H).
Reaction SMILES: [CH3:1][C:2]([CH3:18])=[CH:3][CH2:4][C@H:5]1[O:7][C@@:6]1([C@@H:9]1[C@:14]2([O:16][CH2:15]2)[CH2:13][CH2:12][C@@H:11]([OH:17])[CH2:10]1)[CH3:8].[CH3:19][S-:20].O>CN(C=O)C>[O:7]1[CH:5]([CH2:4][CH:3]=[C:2]([CH3:18])[CH3:1])[C:6]1([CH:9]1[CH2:10][CH:11]([OH:17])[CH2:12][CH2:13][C:14]1([CH2:15][S:20][CH3:19])[OH:16])[CH3:8]
Reactant: C[S-]
Reactant: CC(C)=CC[C@H]1O[C@]1(C)[C@H]1C[C@H](O)CC[C@]12CO2
Solvent: O
Solvent: CN(C)C=O
Product: CSCC1(O)CCC(O)CC1C1(C)OC1CC=C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
To a solution of 5-demethoxyfumagillol (280 mg) in N,N'-dimethylformamide (2 ml), thiomethoxide (220 mg) was added, and the mixture was stirred at room temperature for 1 hour. After adding water (20 ml) thereto, the reaction mixture was extracted with isopropyl ether (50 ml). The organic layer was washed with saturated sodium hydrogen carbonate solution (10 ml) and brine (20 ml), dried over anhydrous magnesium sulfate, and filtered. The residue after distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2) to obtain 180 mg of the title compound as white solid.
Reaction SMILES: [NH2:1][C:2]1[C:28]([Br:29])=[CH:27][C:5]2[C:6]([C:23]([NH:25][CH3:26])=[O:24])=[C:7]([C:9]3[CH:10]=[N:11][C:12]([O:15][C:16]4[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=4)=[CH:13][CH:14]=3)[O:8][C:4]=2[CH:3]=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[Br:29][C:28]1[C:2]([NH:1][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:3][C:4]2[O:8][C:7]([C:9]3[CH:10]=[N:11][C:12]([O:15][C:16]4[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=4)=[CH:13][CH:14]=3)=[C:6]([C:23]([NH:25][CH3:26])=[O:24])[C:5]=2[CH:27]=1
Reactant: CNC(=O)c1c(-c2ccc(Oc3ccc(F)cc3)nc2)oc2cc(N)c(Br)cc12
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CNC(=O)c1c(-c2ccc(Oc3ccc(F)cc3)nc2)oc2cc(NS(C)(=O)=O)c(Br)cc12
Temperature: 20 °C
Reaction time: 15 h
Yield: 85.1 %

Procedure:
To a degassed solution of 6-amino-5-bromo-2-(6-(4-fluorophenoxy)pyridin-3-yl)-N-methylbenzofuran-3-carboxamide (100 mg, 0.22 mmol) and DMAP (10 mg, 0.02 mmol) in Pyridine (5 ml) under N2 was added MsCl (32 mg, 0.38 mmol) at 0° C. Then it was stirred at 20° C. for 15 h. The reaction mixture was concentrated and extracted with DCM. After it was washed with brine, dried over Na2SO4 and concentrated, the residue was purified by prep-TLC to give 5-bromo-2-(6-(4-fluorophenoxy)pyridin-3-yl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (100 mg, yield: 85%). 1H-NMR (CDCl3, 400 MHz) δ 9.65 (s, 1H), 8.73 (s, 1H), 8.54 (d, J=4.8 Hz, 1H), 8.39 (d, J=2.8 Hz, 1H), 8.03 (s, 1H), 7.84 (s, 1H), 7.33˜7.38 (m, 4H), 7.28 (d, J=8.8 Hz, 1H). (M+H)+: 534/536.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[CH3:27][N:28]([CH3:38])[C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1>>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:33]2[CH:32]=[CH:31][CH:30]=[C:29]([N:28]([CH3:38])[CH3:27])[CH:34]=2)=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)c1cccc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)NC(C(=O)c1ccc(I)cc1)c1ccc(Cl)c(Cl)c1
Product: CN(C)c1cccc(-c2ccc(C(=O)C(NC(=O)OC(C)(C)C)c3ccc(Cl)c(Cl)c3)cc2)c1

Procedure:
The title compound was prepared from rac-[1-(3,4-dichloro-phenyl)-2-(4-iodo-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester and 3-(dimethylamino)phenylboronic acid in analogy to Example 1b): MS (ISP): 499.1 and 501.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:18][CH3:19])[CH2:4][CH2:5][N:6]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([N+:15]([O-])=O)[CH:11]=[CH:12]2)=[N:7]1.[NH4+].[Cl-]>CCO.O.[Fe]>[CH3:19][O:18][CH:3]([O:2][CH3:1])[CH2:4][CH2:5][N:6]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([NH2:15])[CH:11]=[CH:12]2)=[N:7]1
Reactant: COC(CCn1cc2ccc([N+](=O)[O-])cc2n1)OC
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COC(CCn1cc2ccc(N)cc2n1)OC

Procedure:
To a stirred solution of 2-(3,3-dimethoxypropyl)-6-nitro-2H-indazole (1.5 g, 5.66 mmol) and NH4Cl (254 mg, 4.53 mmol) in EtOH/H2O (2:1, 56 mL) at room temperature was added Fe (962 mg, 17.8 mmol) in a single poroom temperature ion and the resulting mixture was heated for 2 h at 70 C. The heating bath was removed and upon reaching room temperature the mixture was filtered through a pad of celite. The residue was washed with hot Methanol (5×20 mL) and the combined eluent was concentrated under reduced pressure. The residue was diluted with Ethyl acetate (30 mL) and filtered. Concentration of the organic layer under reduced pressure gave 2-(3,3-dimethoxypropyl)-2H-indazole-6-ylamine as an amber oil. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.12 (m, 2 H), 3.24 (s, 6 H), 4.26 (m, 2 H), 4.32 (t, J=5.59 Hz, 1 H), 5.18 (m, 2 H), 6.52 (m, 2 H), 7.35 (d, J=8.48 Hz, 1 H) and 8.04 (s, 1 H).
Reaction SMILES: ClCC(O)=O.[OH:6][CH:7]1[CH2:13][O:12]C(C)(C)[O:10][CH2:9][CH:8]1[N:16]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.[OH-].[Na+].Cl>O>[OH:10][CH2:9][CH:8]([N:16]1[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][NH:22][CH2:23][CH2:24][NH:25][CH2:26][CH2:27]1)[CH:7]([OH:6])[CH2:13][OH:12]
Reactant: CC1(C)OCC(O)C(N2CCNCCNCCNCC2)CO1
Agent: Cl
Agent: O=C(O)CCl
Agent: [Na+]
Solvent: O
Product: OCC(O)C(CO)N1CCNCCNCCNCC1
Temperature: 70 °C
Reaction time: 4 h
Yield: 128.5 %

Procedure:
72.7 g (767 mmol) of chloroacetic acid is added under ice/water cooling and nitrogen atmosphere to 60.7 g (192 mmol) of the crude product obtained from example 3a in 500 ml of deionized water. Then, the pH is adjusted to 9.5 with about 42 ml of 10 molar sodium hydroxide solution. The reaction solution is heated to 70° C. and the pH is kept at 9.1-9.5 by adding 10 molar sodium hydroxide solution. For 4 hours of additional stirring time, the pH is maintained at 70° C. The reaction mixture is cooled to 30° C. and acidified with 97 ml of conc. HCl to pH=0.8, heated to 60° C. and stirred for one more hour at this temperature. Then, it is evaporated to dryness in a vacuum at this temperature. The residue is mixed twice with 310 ml of MeOH/EtOH each and in each case again evaporated to dryness. The residue is then mixed with 620 ml of methanol and stirred at 50° C. for 30 minutes, cooled in ice/water and suctioned off, NaCl residue is rewashed with ice-cold methanol. The filtrate is evaporated to dryness in a vacuum. The thus obtained crude product is dissolved in 133 ml of deionized water, added on a column (2.0 l of Amberlite® AMB 252c). The column is washed with deionized water until a conductivity of 23 μS is detected in the eluate. Then, the product is eluted with water/NH3. The fractions containing product are combined and evaporated to dryness. 68.2 g (78% of theory) of 10-(1-hydroxymethyl- 2,3-dihydroxypropyl)-1,4,7,10-tetraazacyclododecane is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][C@@H:17]3[CH2:19][C@H:14]2[CH2:15][O:16]3)=[CH:5][CH:4]=1.C(N(C(C)C)C(C)C)C.Cl.[CH3:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][N:39]=1)[C:34](Cl)=[O:35]>C1COCC1.ClCCl>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:34](=[O:35])[C:33]3[CH:37]=[CH:38][N:39]=[C:31]([CH3:30])[CH:32]=3)[S:11][C:7]=2[C:6]([N:13]2[CH2:18][C@@H:17]3[CH2:19][C@H:14]2[CH2:15][O:16]3)=[CH:5][CH:4]=1
Reactant: Cc1cc(C(=O)Cl)ccn1
Reactant: COc1ccc(N2C[C@@H]3C[C@H]2CO3)c2sc(N)nc12
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N2C[C@@H]3C[C@H]2CO3)c2sc(NC(=O)c3ccnc(C)c3)nc12
Reaction time: 24 h
Yield: 89.5 %

Procedure:
To a stirred solution of 111 mg (0.40 mmol) 4-methoxy-7-{(1S,4S)-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl)}-benzothiazol-2-ylamine and 0.26 ml (1.50 mmol) N-ethyldiisopropylamine in 20 ml THF at room temperature was added dropwise a solution of 127 mg (0.66 mmol) 2-methyl-isonicotinoyl chloride hydrochloride in 20 ml dichloromethane and stirring continued at room temperature for 24 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (3/97 methanol/ethyl acetate) followed by trituration in ether afforded 142 mg (90%) N-[4-methoxy-7-{(1S,4S)-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl)}-benzothiazol-2-yl]-2-methyl-isonicotinamide as a yellow crystalline solid. ES-MS m/e (%): 419 (M+Na+, 17), 397 (M+H+, 100).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)C(C)C)C.Cl[C:25]1[N:30]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:28]=[C:27]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:26]=1.CCCCCCC>C1COCC1.C(O)C.ClCCl>[C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][C:25]2[N:30]=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:28]=[C:27]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:26]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccccc1Nc1ccccc1
Reactant: Clc1nc(-c2ccccc2)nc(-c2ccccc2)n1
Solvent: CCO
Solvent: ClCCl
Solvent: CCCCCCC
Product: c1ccc(Nc2ccccc2Nc2nc(-c3ccccc3)nc(-c3ccccc3)n2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
44.3 g (240 mmol) of N-phenyl-o-phenylenediamine are initially introduced in THF and cooled to 0° C., and 136.4 ml (818 mmol) of N-ethyldiisopropylamine are added dropwise. The mixture is subsequently stirred at room temperature for a further 1 h. A solution of 64.4 g (240 mmol) of 2-chloro-4,6-diphenyl-1,3,5-triazine, dissolved in 1600 ml of THF, is then added dropwise, and the mixture is stirred at 60° C. for 96 h. After cooling, the solution is stirred with 400 ml of heptane, 80 ml of dichloromethane and 100 ml of ethanol. The solid is washed with toluene and washed by stirring with hot heptane, giving 87.7 g (211 mmol) of a crystalline solid. The overall yield is 88%.
Reaction SMILES: [NH2:1][C:2](=[O:38])[CH2:3][O:4][C:5]([C:7]1[CH:8]=[C:9]([CH:35]=[CH:36][CH:37]=1)[CH2:10][N:11]1[C:15](=[O:16])[C:14]2([CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)[N:13]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:12]1)=[O:6].Cl>O1CCOCC1>[O:16]=[C:15]1[C:14]2([CH2:17][CH2:18][NH:19][CH2:20][CH2:21]2)[N:13]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:12][N:11]1[CH2:10][C:9]1[CH:8]=[C:7]([CH:37]=[CH:36][CH:35]=1)[C:5]([O:4][CH2:3][C:2]([NH2:1])=[O:38])=[O:6]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)N(Cc1cccc(C(=O)OCC(N)=O)c1)CN2c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)COC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To tert-butyl 3-(3-((2-amino-2-oxoethoxy)carbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.22 g, 0.42 mmol) was added 4M solution of HCl in dioxane (4 mL). After stirring at room temperature for 2 hours, the reaction mixture was concentrated in vacuo to obtain 2-amino-2-oxoethyl 3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate as a hydrochloride salt.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[NH:14][CH:15]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:24][O:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29]>C1(C)C=CC=CC=1>[CH3:24][O:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28]([C:15]1[NH:14][C:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[CH:12][C:11]=1[C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=1)=[O:29]
Reactant: COc1ccc(-c2cc(-c3ccc(C(C)(C)C)cc3)c[nH]2)cc1
Reactant: COc1ccccc1C(=O)Cl
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cc(-c3ccc(C(C)(C)C)cc3)c(C(=O)c3ccccc3OC)[nH]2)cc1
Temperature: 25 °C
Yield: 60.2 %

Procedure:
A mixed solution of 300 mg of 4-(4-tert-butylphenyl)-2-(4-methoxyphenyl)pyrrole, 201 mg of 2-methoxybenzoylchloride, and 10 mL of toluene was heated at 120° C. for 6 hours under a nitrogen flow. After cooling to room temperature, evaporation was performed. After washing with 20 mL of ethanol and vacuum drying, 260 mg of 2-(2-methoxybenzoyl)-3-(4-tert-butylphenyl)-5-(4-methoxyphenyl)pyrrole was obtained.