Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]([F:13])=[C:4]([N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[N:3]=1.[CH:21]1([NH2:24])[CH2:23][CH2:22]1>CC(N(C)C)=O.ClCCl>[CH:21]1([NH:24][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]([F:13])=[C:4]([N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)[N:3]=2)[CH2:23][CH2:22]1
Reactant: CCOC(=O)c1cc(F)c(N2CCN(C)CC2)nc1Cl
Reactant: NC1CC1
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cc(F)c(N2CCN(C)CC2)nc1NC1CC1
Temperature: 90 °C

Procedure:
A solution of ethyl 2-chloro-5-fluoro-6-(4-methylpiperazinyl)-3-pyridine-carboxylate (Example D-2, 1.00 g, 3.314 mmol) and cyclopropylamine (2 mL) in DMA (1 mL) was sealed in a pressure bottle and heated at 90° C. for 60 hours. The reaction mixture was diluted with dichloromethane (30 mL), washed with water, and dried on sodium sulfate. Flash chromatography on silica gel column using dichloromethane as eluent provided compound 0.85 g of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][C:16](=[O:24])[CH2:15][CH2:14]1)(=[O:12])=[O:11].Br[CH2:26]Br.C([Li])CCC.CCCCCC.[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[CH2:14][CH2:15][C:16]2([O:24][CH2:26]2)[CH:17]=[C:18]1[C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[O:12])=[O:11]
Reactant: BrCBr
Reactant: CCOC(=O)C1=CC(=O)CCC1S(=O)(=O)Nc1ccc(F)cc1Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C1=CC2(CCC1S(=O)(=O)Nc1ccc(F)cc1Cl)CO2
Temperature: 25 °C
Reaction time: 4 h
Yield: 13.5 %

Procedure:
50 mg (0.133 mmol) of ethyl 6-[1-(2-chloro-4-fluorophenyl)sulfamoyl]-3-oxo-1-cyclohexene-1-carboxylate obtained in Example 7 and 0.01 ml (0.146 mmol) of dibromomethane were dissolved in 1 ml of tetrahydrofuran, and 0.18 ml (0.279 mmol) of n-butyllithium/hexane solution (1.58 M) was added dropwise thereto at −78° C., followed by stirring at room temperature for 4 hours. After the reaction solution was cooled with ice, a saturated aqueous ammonium chloride solution was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel thin layer chromatography (solvent; hexane:ethyl acetate=2:1) to give 7 mg of the title compound as a yellow oil (yield: 14%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5](C(OC)=O)=[N:6][CH:7]=1.C[Mg]Br.C([O:17][CH2:18][CH3:19])C.[CH2:20](Cl)Cl.C1CCCCC1>O1CCCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:18]([OH:17])([CH3:19])[CH3:20])=[N:6][CH:7]=1
Reactant: ClCCl
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: CCOCC
Agent: C[Mg]Br
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(O)c1cnc(Cl)cn1
Reaction time: 1 h
Yield: 25 %

Procedure:
A well-stirring solution of methyl 5-chloropyrazine-2-carboxylate (23.5 g, 136 mmol) in Tetrahydrofuran (THF) (172 ml) under nitrogen was cooled to −10° C. and became a thick tan suspension. Added methylmagnesium bromide, 3M in diethyl ether (100 ml, 300 mmol) slowly making sure the temperature did not rise above 0° C. After 1 hour, the reaction now at 0° C. was quenched with saturated NH4Cl (100 mL) slowly, followed by EtOAc (100 mL), and the dark mixture was stirred overnight. The mixture was diluted with 400 mL water and 100 mL EtOAc, and the layers were separated. The aqueous layer was extracted with EtOAc (2×300 mL). The combined EtOAc extracts were dried over MgSO4, filtered, and concentrated to give a dark residue, which was divided into two batches. Each batch was loaded (with 10% CH2Cl2/cyclohexane) onto a pre-equilibrated (with hexanes) 330 g silica cartridge and purified using normal phase chromatography CISCO): 0-25% ethyl acetate/hexanes (30 min), 25% (15 min). Product began eluting at 33 minutes. Product fractions were concentrated to afford 2-(5-chloropyrazin-2-yl)propan-2-ol (6.232 g, 25%) as a low viscosity orange oil. MS (m/z) 173.1 (M+H+).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][OH:20])=[N:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:21]C1C=CC(CCl)=CC=1.O>C1(C)C=CC=CC=1>[Cl:21][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH2:19][OH:20])=[N:11]2)=[CH:9][CH:8]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: OCc1nn(Cc2ccccc2)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: OCc1nn(Cc2ccc(Cl)cc2)c2ccccc12
Temperature: 25 °C
Yield: 23 %

Procedure:
To a suspension of 60% NaH (2.7 g; 0.07 mol) in toluene (200 ml) was added 1-benzyl-3-hydroxymethylindazole (10 g; 0.07 mol). The mixture was brought to the boiling point and left stirring at reflux for 1 hour. 4-chlorobenzyl chloride (14.4 g; 0.09 mol) was then added. The mixture was then stirred at reflux for 4 hours. The reaction was stopped by cooling the mixture to room temperature and adding water (50 ml). The organic phase was separated out and washed, respectively, with 2N HCl (50 ml) and water (5×50 ml). The solvent was evaporated off under reduced pressure. The crude residue thus obtained was purified by flash chromatography on silica gel, using as eluent a 3/1 hexane/ethyl acetate mixture. The product obtained was crystallized from a 5/1 hexane/ethyl acetate mixture to give 4.4 g of [1-(4-chlorobenzyl)-1H-indazol-3-yl]methanol.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:5][S:4][C:3]=1[C:13]([O:15]C)=O.[CH:17](OCC)(OCC)OCC.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(O)(=O)C>CCOC(C)=O.C(OCC)C>[C:28]1([N:27]2[C:13](=[O:15])[C:3]3[S:4][CH:5]=[C:6]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:2]=3[N:1]=[CH:17]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Reactant: CCOC(OCC)OCC
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Temperature: 160 °C
Reaction time: 18 h
Yield: 33 %

Procedure:
Methyl 3-amino-4-phenylthiophene-2-carboxylate (100 mg, 0.43 mmol), triethyl orthoformate (1 ml), aniline (76 mg, 0.81 mmol), and acetic acid (0.1 ml) were placed in a pressure bottle. The mixture was heated with stirring at 160° C. for 18 hr. After the completion of the reaction was confirmed by TLC, the reaction mixture was cooled to room temperature and solidified with diethyl ether and EtOAc to give 42 mg (0.14 mmol, 33% yield) of the title compound as a final product.
Reaction SMILES: C(OC[O:5][CH:6]1[CH2:23][CH:22]2[CH:8]([C:9](=[O:35])[N:10]([CH3:34])[CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH:16][CH:17]3[C:19]([C:25]([NH:27][S:28]([CH:31]4[CH2:33][CH2:32]4)(=[O:30])=[O:29])=[O:26])([NH:20][C:21]2=[O:24])[CH2:18]3)[CH2:7]1)C.C([O-])(O)=O.[Na+]>C1COCC1.CO.O.Cl>[OH:5][CH:6]1[CH2:23][CH:22]2[CH:8]([C:9](=[O:35])[N:10]([CH3:34])[CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH:16][CH:17]3[C:19]([C:25]([NH:27][S:28]([CH:31]4[CH2:32][CH2:33]4)(=[O:30])=[O:29])=[O:26])([NH:20][C:21]2=[O:24])[CH2:18]3)[CH2:7]1
Reactant: CCOCOC1CC2C(=O)NC3(C(=O)NS(=O)(=O)C4CC4)CC3C=CCCCCN(C)C(=O)C2C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CN1CCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O)CC2C1=O

Procedure:
The ethoxy ether 1g was dissolved in a mixture of THF/MeOH/water (1:1:1, total volume 30 ml) whereafter 2.5 ml conc. hydrochloric acid was added while stirring. The reaction was stirred overnight at room temperature and was monitored by LC-MS. The reaction mixture was then poured into sat. aq. NaHCO3 (50 ml) and concentrated to half of the volume by rotary evaporation. The resulting mixture was acidified with 10% citric acid and extracted into DCM (3×20 ml). The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated by rotary evaporation and dried at high vacuum overnight. The product was used without additional purification.
Reaction SMILES: O1[CH:6]=[CH:5][C:4](=[O:7])[CH:3]=[CH:2]1.[C:8]([O:12][C:13](=[O:16])[NH:14][NH2:15])([CH3:11])([CH3:10])[CH3:9]>C(O)C>[C:8]([O:12][C:13]([NH:14][N:15]1[CH:6]=[CH:5][C:4](=[O:7])[CH:3]=[CH:2]1)=[O:16])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=c1ccocc1
Solvent: CCO
Product: CC(C)(C)OC(=O)Nn1ccc(=O)cc1
Yield: 55.2 %

Procedure:
4-Pyranone (1 g, 10.4 mmol) and t-butylcarbazate (1.32 g, 10 mmol) were heated at reflux in ethanol for 48 h. The solvent was gradually allowed to distil from the mixture and the residue was chromatographed on silica gel 60, eluting with ethanol, dichloromethane (1:19) to give the title compound (1.16 g, 50%); υmax (KBr) 1723, 1630, and 1550 cm-1 ; δH 1.54 (9H, s), 6.47 (2H, d), and 7.60 (2H, d); M+ 210.
Reaction SMILES: [Br:1][CH2:2][C:3](=[O:8])[C:4]([F:7])([F:6])[F:5].[NH2:9][C:10]1N=[C:14]([Br:16])[CH:13]=[CH:12][N:11]=1.[CH3:17]OCCOC>>[BrH:1].[Br:16][C:14]1[CH:13]=[CH:12][N:11]2[CH2:2][C:3]([C:4]([F:7])([F:6])[F:5])([OH:8])[N:9]=[C:10]2[CH:17]=1
Reactant: Nc1nccc(Br)n1
Reactant: COCCOC
Reactant: O=C(CBr)C(F)(F)F
Product: Br
Product: OC1(C(F)(F)F)CN2C=CC(Br)=CC2=N1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 1.14 g of 3-bromo-1,1,1-trifluoropropan-2-one and 10 ml of DME was added to a mixture of 1.04 g of 2-amino-4-bromopyrimidine and 10 ml of DME, and the mixture was stirred at room temperature for 1 day. The precipitated solid was taken by filtration, washed with 10 ml of DME, and dried to obtain 1.92 g of 7-bromo-2-trifluoromethyl-2,3-dihydroimidazo[1,2-a]pyridin-2-ol hydrobromide.
Reaction SMILES: [CH:1]1([C:6]2[N:14]3[C:9]([C:10](=[O:24])[NH:11][C:12]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-])=O)[CH:16]=4)=[N:13]3)=[C:8]([CH2:25][CH3:26])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[NH2:21][C:17]1[CH:16]=[C:15]([C:12]2[NH:11][C:10](=[O:24])[C:9]3=[C:8]([CH2:25][CH3:26])[N:7]=[C:6]([CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[N:14]3[N:13]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: CCc1nc(C2CCCC2)n2nc(-c3cccc([N+](=O)[O-])c3)[nH]c(=O)c12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCc1nc(C2CCCC2)n2nc(-c3cccc(N)c3)[nH]c(=O)c12

Procedure:
1.8 g (5.1 mmol) 7-cyclopentyl-5-ethyl-2-(3-nitrophenyl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one (Example 21A) are dissolved in 100 ml methanol, and 200 mg palladium (10% on charcoal) are added. The mixture is exposed to an hydrogen atmosphere until no more hydrogen is absorbed. Then the palladium/charcoal is removed by filtration and the filtrate is evaporated to dryness in vacuo. The product is purified by chromatography (flash or column chromatography).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:16]=[C:15]([NH2:17])[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1.N1C=CC=CC=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:16]=[C:15]([NH:17][S:26]([CH3:25])(=[O:28])=[O:27])[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCCN(C)C(=O)c1cc(N)cc(C(=O)OC)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCN(C)C(=O)c1cc(NS(C)(=O)=O)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Dissolve 5-amino-N-methyl-N-propyl-isophthalamic acid methyl ester (1.64 g, 6.55 mmol) in dichloromethane (20 mL) and add pyridine (620 mg, 6.88 mmol) and methanesulfonyl chloride (788 mg, 6.88 mmol). Stir at room temperature for 72 h, dilute with dichloromethane, wash with 0.1 N citric acid and saturated aqueous sodium chloride. Dry (magnesium sulfate) and concentrate to give the title compound as an oil.
Reaction SMILES: [C:1]1([CH2:7][C:8]([C:10]2[CH:14]=[CH:13][N:12]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:11]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:24]([O:26][C:27]1[CH:28]=[C:29]([CH:32]=[C:33]([N+:36]([O-:38])=[O:37])[C:34]=1[OH:35])[CH:30]=O)[CH3:25].[NH2:39][C:40]([NH2:42])=[O:41].Cl>C(O)C>[CH2:24]([O:26][C:27]1[CH:28]=[C:29]([CH:30]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:8]([C:10]3[CH:14]=[CH:13][N:12]([S:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)(=[O:17])=[O:16])[CH:11]=3)[NH:42][C:40](=[O:41])[NH:39]2)[CH:32]=[C:33]([N+:36]([O-:38])=[O:37])[C:34]=1[OH:35])[CH3:25]
Reactant: NC(N)=O
Reactant: O=C(Cc1ccccc1)c1ccn(S(=O)(=O)c2ccccc2)c1
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3ccn(S(=O)(=O)c4ccccc4)c3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Yield: 28.2 %

Procedure:
To a solution of 2-phenyl-1-(1-(phenylsulfonyl)-1H-pyrrol-3-yl)ethanone (Intermediate 52) (200 mg, 0.6 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (130 mg, 0.6 mmol), and urea (108 mg, 1.8 mmol) in 10 mL of ethanol was added 0.2 mL of concentrated HCl solution. The mixture refluxed overnight, concentrated in vacuo, and purified by TLC (PE: EtOAc=1:2) to afford the Compound 107 (95 mg, yield 27.6%). 1H NMR (DMSO-d6 400 MHz): δ 10.25 (s, 1H), 8.53 (s, 1H), 7.86 (d, J=7.6 Hz, 2H), 7.77 (t, J=7.6 Hz, 1H), 7.65 (t, J=8.0 Hz, 2H), 7.49 (s, 1H), 7.36 (s, 1H), 7.31 (d, J=2.0 Hz, 1H), 7.17-7.14 (m, 3H), 7.12 (t, J=2.8 Hz, 1H), 7.00 (d, J=2.0 Hz, 1H), 6.91-6.89 (m, 2H), 5.70 (m, 1H), 5.10 (d, J=2.4 Hz, 1H), 4.05-3.90 (m, 2H), 1.29 (t, J=7.2 Hz, 3H); MS (ESI): m/z 561.3 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24](Cl)[C:25]([F:28])([F:27])[F:26])=[CH:4][CH:3]=1.[N-:30]=[N+:31]=[N-:32].[Na+]>CS(C)=O.C(OCC)(=O)C>[N:30]([CH:24]([C:5]1[C:6]2[N:7]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]4[C:16]([Cl:23])=[CH:17][C:18]([Cl:22])=[CH:19][C:20]=4[Cl:21])[C:8]3=[N:9][C:10]=2[C:2]([Cl:1])=[CH:3][CH:4]=1)[C:25]([F:27])([F:28])[F:26])=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: FC(F)(F)C(Cl)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: [N-]=[N+]=NC(c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl)C(F)(F)F
Temperature: 100 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
A mixture of 9-chloro-6-(1-chloro-2,2,2-trifluoroethyl)-1-(2,4,6-trichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole (290 mg, 0.576 mmol) and sodium azide (74.9 mg, 1.15 mmol) in dimethylsulfoxide (2.8 mL) was stirred at 100° C. for 2 h. After the mixture was diluted with ethyl acetate, the resultant mixture was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 0-30% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless amorphous solid (286 mg, 0.560 mmol, 97%).
Reaction SMILES: [C:1]([OH:21])(=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].CN(C)C=O.[C:27]1([CH3:33])[CH:32]=CC=C[CH:28]=1>>[C:27]([O:18][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:21])=[O:20])([CH3:33])([CH3:32])[CH3:28]
Reactant: Cc1ccccc1
Reactant: O=C(O)CCCCCCCCCCCCCCCC(=O)O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
The crude heptadecanedioic acid (0.99 g, 3.3 mmol) was dissolved in toluene (15 ml) at 115° C. N,N-dimethylformamide di-tert-butylacetale (0.79 ml, 3.3 mmol) was added dropwise over 10 min. After refluxing for 1 h more N,N-dimethylformamide di-tert-butylacetale (0.79 ml) was added over 10 min. After refluxing for another 1 h, a last eq of N,N-dimethylformamide di-tert-butylacetale (0.79 ml) was added over 10 min. Reflux was continued for 1 h. On cooling to RT a precipitate appeared, this was filtered off (diacid). The mother liqueour was extracted with water (25 ml) and DCM (25 ml). The organic layer was dried and concentrated. The residue was purified by flash chromatography using DCM/MeOH 15:1 as eluent. Heptadecanedioic acid mono-tert-butyl ester was isolated in 33% yield (0.330 g). HPLC-MS: 379 (M+Na), rt 6.11. 1H-NMR (DMSO-d6): δ 1.22 (br s, 22H), 1.39 (s, 9H), 1.47 (m, 4H), 2.16 (t, 2H), 2.19 ppm (t, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]2[O:10][CH2:11][O:12][C:4]=2[CH:3]=1.[Mg].Br[CH2:15][CH3:16].[Cl-].[NH4+]>O1CCCC1>[CH3:1][C:2]1[C:7]([CH:8]([OH:9])[CH2:15][CH3:16])=[CH:6][C:5]2[O:10][CH2:11][O:12][C:4]=2[CH:3]=1
Reactant: CCBr
Reactant: Cc1cc2c(cc1C=O)OCO2
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)c1cc2c(cc1C)OCO2
Reaction time: 2 h
Yield: 95.9 %

Procedure:
A solution of 2.0 g of (6-methyl-1,3-benzodioxol-5-yl)carboxaldehyde in 15 ml of anhydrous tetrahydrofuran was added dropwise at room temperature to a Grignard reagent prepared from 0.32 g of magnesium ribbon, 20 ml of anhydrous tetrahydrofuran and 1.4 g of bromoethane. The mixture was stirred for 2 h. A saturated ammonium chloride solution was added to the reaction mixture. The solvent was distilled off. After extraction with ethyl acetate followed by drying over magnesium sulfate and concentration under reduced pressure, the residue was purified according to silica gel column chromatography (ethyl acetate/hexane=2:8) to obtain 2.27 g of the intended compound in the form of white crystals.
Reaction SMILES: Br[C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].BrC(Br)C.[CH:14]12[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH:15]1C=O)[CH2:21]2.B(OC)(OC)[O:27][CH3:28].Cl>[Zn].C(OCC)(=O)C.O1CCCC1>[C:14]12([CH:28]([OH:27])[C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:15][CH:16]3[CH2:17][CH:18]([CH2:19][CH:20]([CH2:22]3)[CH2:21]1)[CH2:23]2
Reactant: O=CC1C2CC3CC(C2)CC1C3
Reactant: CCOC(=O)C(F)(F)Br
Reactant: COB(OC)OC
Agent: CC(Br)Br
Agent: Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(F)(F)C(O)C12CC3CC(CC(C3)C1)C2
Temperature: 60 °C
Reaction time: 10 h
Yield: 54 %

Procedure:
A mixture of 40 g of ethyl bromodifluoroacetate, 3.7 g of dibromoethane and 50 g of tetrahydrofuran was added dropwise to a mixture of 13 g of zinc, 29 g of 2-adamantanecarbaldehyde, 60 mL of trimethyl borate, and 50 g of tetrahydrofuran at a temperature of 50° C., followed by stirring for 10 hours at 60° C. Thereafter, 100 g of 5 wt % hydrochloric acid was added to quench the reaction. Ethyl acetate, 200 g, was added to the reaction solution, from which the organic layer was extracted. The organic layer was washed with saturated sodium chloride water and then with water. The reaction solution after washing was concentrated under reduced pressure, obtaining 23 g of the target compound, ethyl 3-(1-adamantyl)-2,2-difluoro-3-hydroxypropionate as oily matter (yield 54%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:44])[NH:10][C@H:11]([C:16](=[O:43])[NH:17][C@@:18]1([C:33](=[O:42])[NH:34][C@H:35]([C:40]#[N:41])[CH2:36][CH:37]([CH3:39])[CH3:38])[CH2:30][C:29]2[C:28]3[C:23](=[C:24]([Cl:32])[CH:25]=[C:26]([Cl:31])[CH:27]=3)[NH:22][C:21]=2[CH2:20][CH2:19]1)[CH:12]([CH3:15])[CH2:13][CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:45]=[N+:46]=[N-:47].[Na+].[Cl-].[NH4+]>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:44])[NH:10][C@H:11]([C:16](=[O:43])[NH:17][C@@:18]1([C:33](=[O:42])[NH:34][C@H:35]([C:40]2[NH:47][N:46]=[N:45][N:41]=2)[CH2:36][CH:37]([CH3:38])[CH3:39])[CH2:30][C:29]2[C:28]3[C:23](=[C:24]([Cl:32])[CH:25]=[C:26]([Cl:31])[CH:27]=3)[NH:22][C:21]=2[CH2:20][CH2:19]1)[CH:12]([CH3:15])[CH2:13][CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CCC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@]1(C(=O)N[C@H](C#N)CC(C)C)CCc2[nH]c3c(Cl)cc(Cl)cc3c2C1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@]1(C(=O)N[C@@H](CC(C)C)c2nnn[nH]2)CCc2[nH]c3c(Cl)cc(Cl)cc3c2C1
Reaction time: 6 h

Procedure:
0.122 g (0.19 mmol) of {(5)-1-[(R)-6,8-Dichloro-3-((S)-1-cyano-3-methyl-butylcarbamoyl)-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methyl-butyl}-carbamic acid benzyl ester synthesized according to 84 (see below), 0.028 g (0.44 mmol) of sodium azide and 0.026 (0.48 mmol) of ammonium chloride were heated in 2 mL of DMF in a microwave at 110° C. and 100 watt for 6 h. The reaction solution was separated on a preparative HPLC column.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([NH2:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:26]([O:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36]Br)=[CH:32][C:31]=1[F:38])[CH:27]=[CH2:28]>CN(C=O)C.CCOC(C)=O>[CH2:26]([O:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][N:11]([C@H:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([NH2:15])=[O:14])[S:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)(=[O:9])=[O:10])=[CH:32][C:31]=1[F:38])[CH:27]=[CH2:28]
Reactant: C=CCOc1ccc(CBr)cc1F
Reactant: CC(C)C[C@@H](NS(=O)(=O)c1ccc(Cl)cc1)C(N)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOc1ccc(CN([C@H](CC(C)C)C(N)=O)S(=O)(=O)c2ccc(Cl)cc2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 25.5 %

Procedure:
To a solution of (2R)-2-(4-chlorobenzenesulfonylamino)-4-methyl-pentanoic acid amide (1.00 g, 3.29 mmol), and Cs2CO3 (1.29 g, 3.95 mmol) in DMF (25 mL) was added 1-allyloxy-4-bromomethyl-2-fluorobenzene (ref.: Graham, Samuel L; et al., Eur. Pat. Appl. (1992): EP 487270; 0.88 g, 3.67 mmol). The resulting solution was stirred at rt for 18 h. The reaction was then diluted with 9:1 EtOAc:hexanes (350 mL) and washed with H2O (4×200 mL), brine, and dried over Na2SO4, to afford the titled compound (393 mg) as a white solid in 26% yield. MS (ESI), (M+H)+469.1; 1H NMR (CDCl3) δ7.66 (d, 2H, J=8.1), 7.45 (d, 2H, J=8.1), 7.11 (d, 1H, J=12.0), 6.98 (m, 1H), 6.84 (t, 1H, J=8.0), 6.22 (br s, 1H), 6.04 (m, 2H), 5.42 (m, 1H), 5.16 (br s, 1H), 4.59 (m, 2H), 4.40 (m, 3H), 1.83 (m, 1H), 1.32 (m, 1H), 1.14 (m, 1H), 0.76 (d, 3H, J=7.0), 0.68 (d, 3H, J=7.0).
Reaction SMILES: [CH2:1]([C:8]1([C:12]2[CH:13]=[C:14]([CH:28]=[CH:29][CH:30]=2)[O:15][CH2:16][CH2:17][NH:18][S:19]([C:22]2[N:23]=[CH:24][N:25]([CH3:27])[CH:26]=2)(=[O:21])=[O:20])[CH2:11][NH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(NC(C)C)(C)C.[F:38][CH2:39][C:40](Cl)=[O:41]>ClCCl>[CH2:1]([C:8]1([C:12]2[CH:13]=[C:14]([CH:28]=[CH:29][CH:30]=2)[O:15][CH2:16][CH2:17][NH:18][S:19]([C:22]2[N:23]=[CH:24][N:25]([CH3:27])[CH:26]=2)(=[O:21])=[O:20])[CH2:11][N:10]([C:40](=[O:41])[CH2:39][F:38])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)CF
Reactant: Cn1cnc(S(=O)(=O)NCCOc2cccc(C3(Cc4ccccc4)CNC3)c2)c1
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: Cn1cnc(S(=O)(=O)NCCOc2cccc(C3(Cc4ccccc4)CN(C(=O)CF)C3)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of N-(2-(3-(3-benzylazetidin-3-yl)phenoxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide (81 mg, 0.190 mmol) in dry dichloromethane (1.5 ml) containing diisopropylamine (0,066 ml, 0,380 mmol) under argon was added fluoroacetyl chloride (0.022 ml, 0.285 mmol) and stirred at room temperature for 1 h. Washed with 1N HCl, sodium bicarbonate and brine, dried over MgSO4, filtered, evaporated and the crude material was purified by flash silica gel chromatography on 4 g SiO2-cartridge using 5% MeOH in dichloromethane affording 68.7 mg of a white solid.