Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]([NH2:15])=[CH:7][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[CH3:16][N:17]([CH3:20])C=O>O>[CH:1]([N:4]1[C:5]2[CH:10]=[CH:9][C:8]([C:11]([F:13])([F:14])[F:12])=[CH:7][C:6]=2[N:15]=[C:11]1[C:8]1[CH:9]=[CH:20][N:17]=[CH:16][CH:7]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Nc1ccc(C(F)(F)F)cc1N
Reactant: CN(C)C=O
Solvent: O
Product: CC(C)n1c(-c2ccncc2)nc2cc(C(F)(F)F)ccc21
Temperature: 150 °C
Reaction time: 1 h

Procedure:
A mixture of 0.44 g of N1-isopropyl-4-trifluoromethylbenzene-1,2-diamine, 0.51 g of isonicotinealdehyde-bisulfite adduct and 4 ml of N,N-dimethylformamide was stirred for 1 hour at 150° C. The reaction mixture was allowed to cool to room temperature, and water was poured into this, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, then, concentrated under reduced pressure to obtain a solid residue. The residue was washed with hexane, to obtain 0.50 g of 1-isopropyl-2-(pyridin-4-yl-)-5-trifluoromethyl-1H-benzimidazole (hereinafter, referred to as present active compound 219).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][NH:5][C:4](=[O:11])[CH:3]=1.[Br:12]Br>O>[Br:12][C:3]1[C:4](=[O:11])[NH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[CH3:1]
Reactant: BrBr
Reactant: Cc1cc(=O)[nH]cc1[N+](=O)[O-]
Solvent: O
Product: Cc1c([N+](=O)[O-])c[nH]c(=O)c1Br
Temperature: 10 °C
Reaction time: 4 h

Procedure:
In a 1000 ml three-necked round-bottomed flask, 5.00 g of 4-methyl-5-nitro-1H-pyridin-2-one (CA registry number: 21901-41-7) is suspended in 500 ml of water. Under stirring, the mixture is kept at a temperature of 40° C. while 1.83 ml of elemental bromine is added dropwise. Stirring at 40° C. is continued for an additional 4 hours. Afterwards, the mixture is cooled to 10° C. and the resulting precipitate collected by filtration and washed with water (4×). After drying, 6.65 g of the title compound is obtained in the form of a beige solid (MP: 237-240° C.).
Reaction SMILES: [CH2:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH:2]([CH3:4])[CH3:3].CCN(CC)CC.[C:28](Cl)(=[O:30])[CH3:29]>C(Cl)Cl>[C:28]([N:18]1[CH2:19][CH2:20][N:15]([C:12]2[CH:11]=[CH:10][C:9]([S:6]([NH:5][CH2:1][CH:2]([CH3:4])[CH3:3])(=[O:8])=[O:7])=[CH:14][CH:13]=2)[CH2:16][CH2:17]1)(=[O:30])[CH3:29]
Reactant: CC(C)CNS(=O)(=O)c1ccc(N2CCNCC2)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(c2ccc(S(=O)(=O)NCC(C)C)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
A solution of N-isobutyl-4-piperazin-1-yl-benzenesulfonamide (1.14 g, 3.83 mmol) and Et3N (795 μL, 5.75 mmol) in DCM (25 mL) was treated with acetyl chloride (340 mL, 4.79 mmol) and stirred at room temperature for 30 minutes. The mixture was diluted with DCM, washed with 1 N aqueous HCl, saturated aqueous NaHCO3, water and brine, dried over Na2SO4 and concentrated under vacuum. Purification by silica gel column chromatography (60-75% EtOAc in DCM) gave 4-(4-acetyl-piperazin-1-yl)-N-isobutyl-benzenesulfonamide (1.23 g, 95%) as a white solid. 1H NMR (400 MHz, DMSO) δ 7.58 (d, J=8.8 Hz, 2H), 7.27 (t, J=6.2 Hz, 1H), 7.04 (d, J=8.8 Hz, 2H), 3.62-3.54 (m, 4H), 3.38-3.26 (m, 8H), 2.49-2.43 (m, 2H), 2.04 (s, 3H), 1.65-1.54 (m, 1H), 0.80 (d, J=6.7 Hz, 6H). LCMS (m/z, Method B) ES+ 340.0 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:16]=[CH:15][N:14]=[C:13]3[C:8]=2[C:9]2[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=2[C:11](=[O:17])[NH:12]3)=[C:4]([F:24])[CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38](O)=[O:39])[C:33]2=[O:41])=[CH:28][CH:27]=1>>[F:24][C:4]1[CH:3]=[C:2]([NH:1][C:38]([C:34]2[C:33](=[O:41])[N:32]([C:29]3[CH:28]=[CH:27][C:26]([F:25])=[CH:31][CH:30]=3)[CH:37]=[CH:36][CH:35]=2)=[O:39])[CH:23]=[CH:22][C:5]=1[O:6][C:7]1[CH:16]=[CH:15][N:14]=[C:13]2[C:8]=1[C:9]1[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=1[C:11](=[O:17])[NH:12]2
Reactant: O=C(O)c1cccn(-c2ccc(F)cc2)c1=O
Reactant: Nc1ccc(Oc2ccnc3[nH]c(=O)c4ccccc4c23)c(F)c1
Product: O=C(Nc1ccc(Oc2ccnc3[nH]c(=O)c4ccccc4c23)c(F)c1)c1cccn(-c2ccc(F)cc2)c1=O
Yield: 87.4 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 181 using Compound 182 (50 mg, 0.16 mmol) and 1-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid (44 mg, 0.19 mmol) to provide 184 (75 mg, 90% yield) as a dark solid. LC-MS (M+H=537, obsd.=537).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.C([O-])(=O)C.[Na+].[I:14]Cl>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([I:14])=[CH:4][N:3]=1
Reactant: Nc1ccnc(Cl)c1
Reactant: ClI
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1cc(Cl)ncc1I
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A 100 mL round bottom flask was charged with 2-chloro-4-amino pyridine (3.0 g, 23.34 mmol), sodium acetate (11.49 g, 140 mmol) and acetic acid (60 mL). To this iodine monochloride (3.98 g, 24.50 mmol) was added and the reaction mixture stirred at 60° C. for 2 h. The reaction was cooled to room temperature and quenched with 1N saturated sodium bis-sulfite solution and extracted with DCM. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude was purified by silica gel flash chromatography using DCM-MeOH:95-5. 2-Chloro-5-iodo-pyridin-4-ylamine was obtained as a white color solid. ESI-MS: m/z 255.0 (M+H)+
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]1[C:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:8]([O:25]C)[C:9](=[O:24])[N:10]([CH2:12][CH2:13][C@@:14]([CH3:23])([S:19]([CH3:22])(=[O:21])=[O:20])[C:15]([NH:17][OH:18])=[O:16])[CH:11]=1>C(Cl)Cl>[F:5][C:6]1[C:7]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[C:8]([OH:25])[C:9](=[O:24])[N:10]([CH2:12][CH2:13][C@@:14]([CH3:23])([S:19]([CH3:22])(=[O:21])=[O:20])[C:15]([NH:17][OH:18])=[O:16])[CH:11]=1
Reactant: COc1c(-c2ccccc2)c(F)cn(CC[C@](C)(C(=O)NO)S(C)(=O)=O)c1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: C[C@@](CCn1cc(F)c(-c2ccccc2)c(O)c1=O)(C(=O)NO)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.9 %

Procedure:
Boron tribromide (760 μL, 0.76 mmol, 1.0 M in dichloromethane) was added to a solution of (2R)-4-(5-fluoro-3-methoxy-2-oxo-4-phenylpyridin-1(2H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide (156 mg, 0.378 mmol) in DCM (16.0 mL) at 0° C. The reaction was allowed to warm to rt and stirred overnight. The reaction mixture was concentrated to afford a brown solid. The crude product was purified via prepratory HPLC to afford the title compound as a yellow solid (25.4 mg, 16.9%). MS (LCMS) m/z 399.0 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.59 (s, 3 H) 2.11-2.25 (m, 1 H) 3.07 (s, 1 H) 3.13 (s, 2 H) 3.70-3.88 (m, 1 H) 4.02-4.26 (m, 1 H) 7.11 (d, J=7.81 Hz, 1 H) 7.37-7.65 (m, 5 H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.C(N(CC)CC)C.O=[C:30]([NH:41][NH:42][C:43](=[O:46])[CH2:44][CH3:45])[CH2:31][CH2:32][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37]>ClCCl>[CH2:44]([C:43]1[O:46][C:30]([CH2:31][CH2:32][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[N:41][N:42]=1)[CH3:45]
Reactant: CCC(=O)NNC(=O)CCNC(=O)OC(C)(C)C
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nnc(CCNC(=O)OC(C)(C)C)o1
Temperature: 25 °C
Reaction time: 0.1 h

Procedure:
11.49 g (24.70 mmol) PS-triphenylphosphine are placed in 240 ml dichloromethane, 6.27 g (24.70 mmol) iodine are added. The mixture is stirred for 0.1 hours at ambient temperature, then 7.00 ml (50.50 mmol) triethylamine are added dropwise. 3.20 g (12.34 mmol) tert-butyl [3-oxo-3-(N′-propionyl-hydrazino)-propyl]-carbamate dissolved in 150 ml dichloromethane are added. The reaction mixture is stirred for 24 hours at ambient temperature, then the precipitate is filtered off. The filtrate is evaporated down and purified by chromatography.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH:16]=3)[C:11]([OH:26])=[C:10]([C:27]([O:29]CC)=O)[C:9]2=[O:32])=[CH:4][CH:3]=1.[CH3:33][NH2:34]>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH:16]=3)[C:11]([OH:26])=[C:10]([C:27]([NH:34][CH3:33])=[O:29])[C:9]2=[O:32])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(-c2ccc(F)cc2)c1=O
Reactant: CN
Solvent: CCO
Product: CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(-c2ccc(F)cc2)c1=O
Yield: 29 %

Procedure:
In a similar manner to that described in example 196, from ethyl 1-(4-fluorophenyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (22 mg, 0.0504 mmol) and methylamine (0.1 mL of a 8 M solution in ethanol) was prepared 1-(4-fluorophenyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (6 mg, 29% yield) as a tan solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 9.87 (br s, 1 H), 8.52 (s, 1 H), 7.30-7.24 (m, 2 H), 7.20-7.16 (m, 2 H), 7.01-6.91 (m, 4 H), 6.71 (s, 1 H), 3.94 (s, 2 H), 2.96 (d, J=4.8 Hz, 3 H); MS m/z 422 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[CH:12]2.[OH-].[K+].C1C(=O)N([Br:27])C(=O)C1.O>CN(C=O)C>[Br:27][C:12]1[C:11]2[C:15](=[CH:16][CH:17]=[C:9]([C:3]3[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[CH:10]=2)[NH:14][N:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Fc1cccc(F)c1-c1ccc2[nH]ncc2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cccc(F)c1-c1ccc2[nH]nc(Br)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.6 %

Procedure:
To a solution of 5-(2,6-difluoro-phenyl)-1H-indazole (1 g, 4.35 mmol) in DMF (13 ml) were added KOH (488 mg, 8.7 mmol) and NBS (1.15 g, 6.48 mmol) at RT. The reaction mixture was stirred for 2 h at RT. Water was added to the reaction mixture and extracted with EtOAc (2×20 ml). Combined organic layers were washed with brine and dried over Na2SO4. The organic layer was concentrated and purified by column using silica (100-200 mesh) and 0-15 EtOAc-hexane to provide 3-bromo-5-(2,6-difluoro-phenyl)-1H-indazole (600 mg, 45% yield). MS (ESI, pos. ion) m/z: 306.9 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([F:11])[C:3]=1[N:12]1[CH2:17][CH2:16][Si:15]([CH3:19])([CH3:18])[CH2:14][CH2:13]1.C([O-])(O)=O.[Na+].[C:25](Cl)([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>C1COCC1.[Pd]>[CH2:28]([O:27][C:25](=[O:26])[NH:8][C:6]1[CH:7]=[C:2]([F:1])[C:3]([N:12]2[CH2:17][CH2:16][Si:15]([CH3:19])([CH3:18])[CH2:14][CH2:13]2)=[C:4]([F:11])[CH:5]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[Si]1(C)CCN(c2c(F)cc([N+](=O)[O-])cc2F)CC1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si]1(C)CCN(c2c(F)cc(NC(=O)OCc3ccccc3)cc2F)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 69.4 %

Procedure:
To a solution of 9a (1.32 g, 4.61 mmol) in THF, Pd/C is added for hydrogenation under a pressure of 35 psi in a par hydrogenator. The reaction mixture is filtered through celite. To the filtrate, saturated NaHCO3 (1.16 g, 13.84 mmol), CBzCl (1.17 g, 6.93 mmol) are added and stirred at 25° C. for 5 h. The solvent is removed, 10 mL water is then added and the aqueous layer is extracted with EtOAc. The crude mixture is then subjected to column chromatography on silica gel using hexane-DCM mixtures to afford the product 10a as a viscous liquid (1.25 g) in 69% yield.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH3:34][N:35]1[CH:39]=[CH:38][N:37]=[C:36]1[CH2:40][CH2:41]O.[C:43]([OH:51])(=[S:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>O1CCCC1.C(OCC)(=O)C>[C:43]([S:50][CH2:41][CH2:40][C:36]1[N:35]([CH3:34])[CH:39]=[CH:38][N:37]=1)(=[O:51])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: Cn1ccnc1CCO
Reactant: OC(=S)c1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1ccnc1CCSC(=O)c1ccccc1
Reaction time: 0.25 h

Procedure:
Triphenylphosphine (10.48 g) was dissolved in tetrahydrofuran (120 ml). To the solution were added diisopropyl azodicarboxylate (8.07 g) at 0° C. The mixture was stirred for 15 minutes at the same temperature. To the mixture were added a solution of 2-(1-methyl-2-imidazolyl)ethanol (2.52 g) in tetrahydrofuran (10 ml) and thiobenzoic acid (4.7 ml) in the order mentioned. The mixture was stirred for 2.5 hours at 0° C. and then for 1 hour at room temperature. The reaction mixture was diluted with ethyl acetate, then washed with saturated solution of sodium hydrogencarbonate in water and saturated solution of sodium chloride in water in the order mentioned. The residue was dried over anhydrous sodium sulfate and concentrated under reduced pressure, which was then subjected to column chloromatography on silica gel (developing solvent: ethyl acetate-methanol: 100:0→93:7) to give the title compound (3.52 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:3]=1.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([CH2:41][C:42]2[CH:43]=[C:44](B(O)O)[C:45]([F:48])=[N:46][CH:47]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].C([O-])(=O)C.[K+].O1CCOCC1>O>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:4]2[N:5]=[C:6]([CH3:8])[N:7]=[C:2]([C:44]3[CH:43]=[C:42]([CH2:41][N:38]4[CH2:39][CH2:40][N:35]([C:33]([O:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:34])[CH2:36][CH2:37]4)[CH:47]=[N:46][C:45]=3[F:48])[N:3]=2)=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cnc(F)c(B(O)O)c2)CC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(Cl)n2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(C(=O)OC(C)(C)C)CC4)cnc3F)n2)cc1
Temperature: 120 °C
Yield: 79 %

Procedure:
A microwave vial (80 mL) was charged with 4-chloro-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (2.496 g, 6.49 mmol), 5-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-2-fluoropyridin-3-ylboronic acid (2.000 g, 5.90 mmol), potassium acetate (1.777 g, 18.10 mmol), Am-Phos (0.403 g, 0.649 mmol), dioxane (20 mL) and water (3.00 mL, 167 mmol). The vial was heated in a CEM Voyager Microwave (Large-Scale Unit) for 25 minutes at 120° C. while 100 Watts of energy was supplied via Powermax (Simultaneous heating while cooling technology). The reaction mixture was diluted with water (15 mL) and extracted with Chloroform (3×50 mL). The organic extracts were combined and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude product as a yellow oil. The crude product was adsorbed onto a plug of silica gel and purified by chromatography through a SiliCycle SiliaSep pre-packed silica gel column (220 g) with a gradient of 10% to 100% ethyl acetate/hexanes over 45 min to give tert-butyl 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-fluoropyridin-3-yl)methyl)piperazine-1-carboxylate (3.000 g, 4.66 mmol, 79% yield) as a yellow oil. 1H NMR (400 MHz, d6-DMSO) δ 8.50 (dd, J=9.39, 2.35 Hz, 1H); 8.28 (d, J=1.37 Hz, 1H); 7.25 (d, J=8.61 Hz, 4H); 6.89 (dd, J=11.15, 8.61 Hz, 4H); 6.70-6.81 (m, 1H); 4.77 (d, J=4.69 Hz, 4H); 3.65-3.82 (m, 6H); 3.58 (s, 2H); 3.24-3.37 (m, 4H); 2.47 (s, 3H); 2.28-2.38 (m, 4H); 1.33-1.50 (m, 9H). m/z (ESI, +ve ion) 644.2 (M+H)+.
Reaction SMILES: Br[CH:2](C)[C:3](OC)(OC)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.NC(N)=O.[C:21](=O)([O-:23])[O-:22].[Ca+2]>CN(C)C=O>[CH3:11][O:10][C:7]1[CH:6]=[CH:5][C:4]([CH:3]([CH3:2])[C:21]([OH:23])=[O:22])=[CH:9][CH:8]=1
Reactant: COc1ccc(C(OC)(OC)C(C)Br)cc1
Reactant: O=C([O-])[O-]
Agent: NC(N)=O
Agent: [Ca+2]
Solvent: CN(C)C=O
Product: COc1ccc(C(C)C(=O)O)cc1
Temperature: 95 °C
Reaction time: 32 h
Yield: 92 %

Procedure:
A mixture of 2-bromo-1,1-dimethoxy-1-(4-methoxyphenyl)-propane (2.9 g; 10 mmol), N,N-dimethylformamide (13 g), urea (6 g) and calcium carbonate (1.2 g; 12 mmol) is heated at 95° C. under stirring for 32 h. The reaction mixture is worked up as described in example 1a to give 2-(4-methoxyphenyl)-propionic acid (1.7 g; 9.2 mmol; yield 92%), m.p. 56°-57° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:20]=[C:19]([S:21][CH3:22])[CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([NH:30][C:31](=[O:40])[C:32]2[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=2[NH2:39])=[N:28][CH:29]=1>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:20]=[C:19]([S:21][CH3:22])[CH:18]=[CH:17][C:13]=1[C:14]([NH:39][C:33]1[CH:34]=[CH:35][C:36]([Cl:38])=[CH:37][C:32]=1[C:31]([NH:30][C:27]1[CH:26]=[CH:25][C:24]([Cl:23])=[CH:29][N:28]=1)=[O:40])=[O:16])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CSc1ccc(C(=O)O)c(OCCNC(=O)OC(C)(C)C)c1
Reactant: Nc1ccc(Cl)cc1C(=O)Nc1ccc(Cl)cn1
Product: CSc1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)c(OCCNC(=O)OC(C)(C)C)c1

Procedure:
2-[2-[2-(tert-Butoxycarbonylamino)ethoxy]-4-(methylthio)benzoylamino]-5-chloro-N-(5-chloropyridin-2-yl)benzamide was prepared by methods described in example 4-E from 2-[2-(tert-butoxycarbonylamino)ethoxy]-4-(methylthio)benzoic acid and N-(5-chloropyridin-2-yl)-2-amino-5-chlorobenzamide (3 g, 92%). IR (CHCl3): 1665, 1500, 1375, 1296 cm−1.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:33][CH3:34])=[C:5]([C:10]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[CH2:24][CH2:25][CH2:26][CH2:27]OS(C)(=O)=O)(=[O:16])=[O:15])=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])[CH3:2].[CH3:35][CH:36]1[CH2:40][CH2:39][CH2:38][NH:37]1>CC#N>[CH2:1]([C:3]1[C:4]([O:33][CH3:34])=[C:5]([C:10]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[CH2:24][CH2:25][CH2:26][CH2:27][N:37]2[CH2:38][CH2:39][CH2:40][CH:36]2[CH3:35])(=[O:16])=[O:15])=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])[CH3:2]
Reactant: CC1CCCN1
Reactant: CCc1ccc(NS(=O)(=O)c2ccc(F)cc2CCCCOS(C)(=O)=O)c(C(=O)OC)c1OC
Solvent: CC#N
Product: CCc1ccc(NS(=O)(=O)c2ccc(F)cc2CCCCN2CCCC2C)c(C(=O)OC)c1OC

Procedure:
A solution of Example 615D (0.165 g, 0.31 mmol) and 2-methylpyrrolidine (70 mg, 0.8 mmol) in anhydrous CH3CN (3.0 mL) was heated at 50° C. for 10 hours. The mixture was directly purified on a silica gel column, eluting with ethyl acetate, then 5% methanol in CH2Cl2, giving the desired product. 85 mg, 52.7%. MS (ESI(−)) m/e 505 (M−H)−.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH:5]1[C:17]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1.[C:18]1(=[O:24])[O:23][C:21](=[O:22])[CH2:20][CH2:19]1.Cl>ClCCCl>[C:21]([CH2:20][CH2:19][C:18]([C:13]1[CH:12]=[CH:11][C:10]2[C:9]3[C:17](=[CH:5][C:6]([C:21](=[O:22])[CH2:20][CH2:19][C:18]([OH:23])=[O:24])=[CH:7][CH:8]=3)[CH2:16][C:15]=2[CH:14]=1)=[O:24])([OH:23])=[O:22]
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C(O)CCC(=O)c1ccc2c(c1)Cc1cc(C(=O)CCC(=O)O)ccc1-2
Reaction time: 16 h

Procedure:
In a dry agon-purged round bottom flask, anhydrous AlCl3 (98 g, 0.735 mol) was suspended in anhydrous 1,2-dichloroethane (140 mL). In a separate flask, fluorene (23 g, 0.138 mol) was dissolved in anh. 1,2-dichloroethane (125 mL) then added to the AlCl3 suspension. The reaction flask was placed in a room temperature bath and succinic anhydride (34.5 g, 0.345 mol) was carefully added. The reaction was stirred for 16 hours and then very carefully quenched by slow addition to cold 3 M HCl (Caution! The reaction can react violently when HCl is added too rapidly.) The final well mixed suspension was acidic and not reactive to additional HCl solution. The organic solvent was removed at reduced pressure then the product was filtered and washed well with water. The crude product was dissolved in warm NaOH solution (approximately <1M NaOH), filtered and precipitated with the addition of concentrated HCl. The product was filtered, washed with water and then dried at reduced pressure in the presence of P2O5. The product was a pale yellow solid (49.3 g, 97%). 1H-NMR (CD3OD): δ (ppm) 8.3 (s, 2H, Ar); 8.2 (m, 2H, Ar); 8.1 (m, 2H, Ar); 4.1 (s, 2H, CH2); 3.5 (t, 4H, CH2); 2.8 (t, 4H, CH2).
Reaction SMILES: N([O-])=O.[Na+].[N+]([O-])(O)=O.[CH3:9][O:10][C:11]([C:13]1[N:17]([CH:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C:19]2([CH3:28])[CH3:27])[C:16](S)=[N:15][CH:14]=1)=[O:12].[OH-].[Na+]>O>[CH3:9][O:10][C:11]([C:13]1[N:17]([CH:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C:19]2([CH3:28])[CH3:27])[CH:16]=[N:15][CH:14]=1)=[O:12]
Reactant: COC(=O)c1cnc(S)n1C1c2ccccc2CC1(C)C
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Solvent: O
Product: COC(=O)c1cncn1C1c2ccccc2CC1(C)C
Reaction time: 0.33 h
Yield: 96.7 %

Procedure:
2 g of sodium nitrite and 17.4 ml of nitric acid are solved in 140 ml of deionisized water. Within 20 min. 28 g of 1-(2,2-dimethyl-indan-1-yl)-2-mercapto-5-imidazolecarboxylic acid methyl ester are added portionwise at a temperature between 30° C. and 50° C. The reaction mixture is treated with conc. aqueous sodium hydroxide solution. Extracting the aqueous phase with chloroform, and evaporating the organic solvent yields 24.2 g of 1-(2,2-dimethyl-indan-1-yl)-5-imidazolecarboxylic acid methyl ester as a colourless product (m.p. 96°-97° C.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.Br[CH:39]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[C:40]([O:42][CH2:43][CH3:44])=[O:41].C(=O)([O-])O.[Na+]>CN(C=O)C>[CH2:43]([O:42][C:40](=[O:41])[CH:39]([N:16]([CH2:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][NH:7][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:28])=[CH:14][CH:13]=1)[CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:22][CH2:23][CH3:24])[CH2:25][CH2:26][CH3:27])[C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH3:44]
Reactant: CCCN(CCC)CCCCNCc1ccc(CNC(=O)OC(C)(C)C)cc1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(CCC)CCCCN(Cc1ccc(CNC(=O)OC(C)(C)C)cc1)C(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound (520 mg) obtained in Example 23-4 was dissolved in anhydrous DMF (10 ml) and added with diisopropylethylamine (463 μl) and diethyl bromomalonate (340 μl) and the whole was stirred at room temperature for 2 hours. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added thereto and the whole was stirred for a while. The solution was subjected to extraction with chloroform and washed with a saturated saline solution. The organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off. The residue was purified through silica gel column chromatography (hexane/ethyl acetate), thereby obtaining the subject compound (421 mg) as a colorless oily substance.
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].C(O)[C:13]1[CH:18]=[CH:17]C=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[CH3:3][CH:2]([CH3:4])[C:1](=[O:5])[CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=1)=[O:8]
Reactant: CCOC(=O)CC(=O)C(C)C
Reactant: OCc1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)C(=O)CC(=O)OCc1ccccc1
Reaction time: 0.08 h

Procedure:
3 g of molecular sieve (4 Å) were activated in a microwave oven at 100 W for 5 min. The molecular sieve obtained in this manner was then initially charged, and 200 ml of anhydrous toluene were added. 4.9 g (30.97 mmol) of ethyl isobutyrylacetate and 4.02 g (37.2 mmol) of benzyl alcohol were then added. The reaction mixture was heated at reflux temperature for 6 h. After cooling, the molecular sieve was filtered off and the solvent was distilled off under reduced pressure. The residue was chromatographed on silica gel (mobile phase: cyclohexane/ethyl acetate 10/1). This gave 4.70 g (65% of theory) of the target compound.