Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)(C)(C)C.[F:15][C:16]([F:26])([F:25])[C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br.C(N(C(C)C)CC)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:15][C:16]([F:25])([F:26])[C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][N:11]1[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: FC(F)(F)c1cccc(CBr)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: NC1CCN(Cc2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.1 %

Procedure:
A mixture of piperidin-4-ylcarbamic acid tert-butyl ester (2.5 g, 12.4 mmol), 3-(trifluoromethyl)benzyl bromide (1.7 ml, 11.3 mmol) and diisoproylethylamine (2.9 ml, 16.9 mmol) in dichloromethane (25 ml) was stirred at room temperature for 2 h. After this period, trifluoroacetic acid (32 ml) was added and the reaction mixture was stirred for a further 2 h. The solvent was evaporated in vacuo and a saturated solution of sodium carbonate was added. The mixture was extracted with dichloromethane and the separated organic layers were dried (Na2SO4), filtered, and the solvent evaporated in vacuo. The residue was purified by column chromatography (silica gel; 5-10% ammonia in methanol (7 M)/dichloromethane) to yield D6 (1.9 g, 60%) as a solid. C13H12F3N2 requires 258. Found 259 (MH+)
Reaction SMILES: [Li+].[B-](CC)(CC)CC.[Cl:9][C:10]1[CH:27]=[CH:26][C:13]2[N:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:15](=[O:18])[CH2:16][O:17][C:12]=2[CH:11]=1.C([O-])([O-])=O.[Na+].[Na+].OO>C1COCC1>[Cl:9][C:10]1[CH:27]=[CH:26][C:13]2[N:14]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH:15]([OH:18])[CH2:16][O:17][C:12]=2[CH:11]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)COc2cc(Cl)ccc21
Agent: CC[B-](CC)CC
Agent: O=C([O-])[O-]
Agent: OO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1c2ccc(Cl)cc2OCC1O
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 100.1 %

Procedure:
A 1 M solution of lithium triethylhydroborate (13.75 mL, 13.75 mmol) in THF was added dropwise to a solution of tert-butyl 7-chloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazine-4-carboxylate (Intermediate 16, 3.25 g, 11.5 mmol) in anhydrous THF (60 mL) at −78° C. under N2 (g). After stirring at −78° C. for 45 min, the mixture was treated with Na2CO3 (sat. aq., 25 mL); then H2O2 (35% in aq, 25 mL) was slowly added at −15° C. The mixture was stirred at rt over night, then filtered. The filtrate was concentrated in vacuo and the residue was extracted with EtOAc (2×100 mL). The organic phase was washed with brine (100 mL), dried by passage through a phase separator, and concentrated under reduced pressure giving the title compound (3.29 g, 101%) as an off-white solid that was used without further purification.
Reaction SMILES: O=[C:2]([CH3:21])[CH2:3][O:4][C:5]([CH:7]1[CH2:10][N:9]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:8]1)=O.C([NH2:25])(=O)C.B(F)(F)F.CCOCC>C1(C)C(C)=CC=CC=1>[CH2:14]([O:13][C:11]([N:9]1[CH2:10][CH:7]([C:5]2[O:4][CH:3]=[C:2]([CH3:21])[N:25]=2)[CH2:8]1)=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(=O)COC(=O)C1CN(C(=O)OCc2ccccc2)C1
Reactant: CC(N)=O
Agent: FB(F)F
Solvent: Cc1ccccc1C
Solvent: CCOCC
Product: Cc1coc(C2CN(C(=O)OCc3ccccc3)C2)n1
Temperature: 130 °C

Procedure:
To 130 mg (0.45 mmol) azetidine-1,3-dicarboxylic acid 1-benzyl ester 3-(2-oxo-propyl)ester in 4 mL xylene were added 132 mg (2.25 mmol) acetamide, 39 μL (0.31 mmol) boron trifluoride etherate and the mixture was heated at 130° C. for 24 hours. After cooling to room temperature and evaporation of the solvent the product was purified by chromatography (silica, hexane-EtOAc 6:4).
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][C:13]2[S:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)[CH2:8][CH2:7]1)=O)C>CCO.[OH-].[K+]>[S:14]1[C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=[C:13]1[CH2:12][CH:9]1[CH2:10][CH2:11][NH:6][CH2:7][CH2:8]1
Reactant: CCOC(=O)N1CCC(Cc2nc3ccccc3s2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: c1ccc2sc(CC3CCNCC3)nc2c1
Yield: 78.6 %

Procedure:
A solution of 300 mg of 1-ethoxycarbonyl-4-((benzothiazol-2-yl)methyl)piperidine (from EXAMPLE 163, Step E) in 5 mL of EtOH and 5 mL of KOH (50 wt. % solution) was refluxed for 18 h. The reaction mixture was partitioned between H2O and EtOAc. Aqueous phase was extracted with EtOAc (3×). The combined organic phases were washed with sat'd NaCl and dried over anhydrous MgSO4. Concentration afforded 180 mg of the title compound as a brown solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:8]#[N:9])[S:5][C:6]=1I.C([Mg]Cl)(C)C.[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1.[NH4+].[Cl-]>C1COCC1>[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]([OH:21])[C:6]2[S:5][C:4]([C:8]#[N:9])=[CH:3][C:2]=2[I:1])=[CH:18][CH:17]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: N#Cc1cc(I)c(I)s1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: N#Cc1cc(I)c(C(O)c2ccc(Cl)cc2)s1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
An oven-dried round-bottomed flask was charged with 4,5-diiodothiophene-2-carbonitrile (1.80 g, 5.0 mmol). After degassed, anhydrous THF (15 mL) was added through syringe. After cooled to −78° C., i-PrMgCl (3 mL, 2.0 M, 6.0 mmol) was added dropwise. The reaction was further stirred for 30 min at −78° C. after complete addition. 4-chlorobenzaldehyde (0.98 g, 7.0 mmol) in 5 mL THF was then added. After stirring for 10 min at −78° C. for 1 h, the reaction mixture was warmed to room temperature. 50 mL of saturated aqueous NH4Cl was added. The reaction mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulphate and then concentrated. The residue was purified by flash chromatography (hexane:EtOAc:CH2CL2=30:3:10). 1.39 g (74%) of product was obtained as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][O:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=2)=[C:11]([CH3:24])[N:10]=[N:9]1.[CH:25]1([CH2:28][NH2:29])[CH2:27][CH2:26]1>>[CH:25]1([CH2:28][NH:29][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:12]3[N:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[N:9]=[N:10][C:11]=3[CH3:24])=[N:16][CH:17]=2)[CH2:27][CH2:26]1
Reactant: Cc1nnn(-c2ccccc2F)c1COc1ccc(C(=O)O)cn1
Reactant: NCC1CC1
Product: Cc1nnn(-c2ccccc2F)c1COc1ccc(C(=O)NCC2CC2)cn1
Yield: 60 %

Procedure:
As described for example 67, 6-((1-(2-fluorophenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)nicotinic acid (78 mg, 0.24 mmol), was converted, using cyclopropylmethylamine instead of isopropylamine, to the title compound (54 mg, 60%) which was obtained as a white gum. MS: m/e=382.3 [M+H]+.
Reaction SMILES: CN1[CH:7]=[CH:6][C:5](=[O:8])N(C)C1=O.[C:11]([NH2:17])(=[O:16])[CH2:12][C:13]([NH2:15])=[O:14].[O-]CC.[Na+]>CCO>[OH:14][C:13]1[N:15]=[C:5]([OH:8])[CH:6]=[CH:7][C:12]=1[C:11]([NH2:17])=[O:16]
Reactant: NC(=O)CC(N)=O
Reactant: Cn1ccc(=O)n(C)c1=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1ccc(O)nc1O
Yield: 65 %

Procedure:
A mixture of compound 1,3-dimethylpyrimidine-2,4(1H,3H)-dione (14 g, 0.1 mol), malonamide (45 g, 0.44 mol) and sodium ethoxide (34 g, 0.4 mol) in EtOH (500 mL) was refluxed for 20 mins. The mixture was cooled to r.t, quenched by water and acidified with 1 M HCl to pH=1-2. The solid was filtered and the filter cake was concentrated in vacuo to afford compound 2,6-dihydroxynicotinamide. (10 g, yield: 65%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm) 7.90-7.88 (d, 1H), 5.66-5.64 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:23])=[CH:4][C:5]([CH3:22])=[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13](Cl)[CH:12]=3)[CH:7]=1.[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1>C(O)(=O)C>[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH:31][C:13]2[CH:12]=[C:11]3[C:16]([CH:17]=[C:8]([C:6]4[CH:7]=[C:2]([NH2:1])[C:3]([F:23])=[CH:4][C:5]=4[CH3:22])[C:9](=[O:21])[N:10]3[CH2:19][CH3:20])=[CH:15][N:14]=2)=[CH:28][CH:27]=1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2C)cc2cnc(Cl)cc21
Reactant: COc1ccc(CN)cc1
Solvent: CC(=O)O
Product: CCn1c(=O)c(-c2cc(N)c(F)cc2C)cc2cnc(NCc3ccc(OC)cc3)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of Example A6 (2.5 g, 7.5 mmol) and 4-methoxybenzylamine (30 mL) was refluxed at 140° C. for 2 h. After cooling to RT, the reaction mixture was poured into a 20% aq. solution of acetic acid and stirred for 0.5 h. The mixture was filtered to provide 7-(4-methoxybenzylamino)-3-(5-amino-4-fluoro-2-methylphenyl)-1-ethyl-1,6-naphthyridin-2(1H)-one.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27]Cl.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>>[CH2:1]([O:8][C:9](=[O:22])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:27][CH2:26][N:25]([CH3:29])[CH3:24])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)CCCl
Reactant: O=C(NCCCCc1ccc(O)cc1)OCc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: Cl
Agent: O=C([O-])[O-]
Product: CN(C)CCOc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 59.4 %

Procedure:
A mixture of [4-(4-hydroxyphenyl)butyl]carbamic acid benzyl ester (1.5 g, 5 mmol), 2-dimethylaminochloroethane hydrochloride (1.4 g, 10 mmol), potassium carbonate (2.76 g, 20 mmol) and 18-crown-6 ether (154 mg, 0.58 mmol) was stirred at 80° C. (oil bath) for 18 h. After this time, the solvent was removed under reduced pressure and the residue was purified by Flash™ (BIOTAGE, Inc) (90 g silica gel cartridge 40M, 10:1:0.1 chloroform/methanol/concentrated ammonium hydroxide) to provide 62 (1.1 g, 61%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.56 (m, 4H), 2.32 (s, 6H), 2.56 (m, 2H), 2.71 (t, 2H), 3.18 (m, 2H), 4.04 (t, 2H), 4.78 (br s, 1H), 5.08 (s, 2H), 6.83 (d, 2H), 7.06 (d, 2H), 7.35 (m, 5H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]=[C:10]=[O:11].[Cl:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([F:23])[C:14]=1[O:24][C:25]1[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=1.Cl>C(OCC)(=O)C>[CH3:8][NH:9][C:10]([N:27]1[C:28]([CH3:30])=[CH:29][C:25]([O:24][C:14]2[C:15]([F:23])=[CH:16][C:17]([C:19]([F:22])([F:20])[F:21])=[CH:18][C:13]=2[Cl:12])=[N:26]1)=[O:11]
Reactant: CN=C=O
Reactant: Cc1cc(Oc2c(F)cc(C(F)(F)F)cc2Cl)n[nH]1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CNC(=O)n1nc(Oc2c(F)cc(C(F)(F)F)cc2Cl)cc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.9 %

Procedure:
Triethylamine (0.13 g, 1.3 mmol) and methyl isocyanate (0.07 g, 1.2 mmol) were added to a solution of 3-(2-chloro-6-fluoro-4-trifluoromethylphenyloxy)-5-methylpyrazole (0.32 g, 1.1 mmol) in ethyl acetate (10 ml), and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate (10 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/10), to give a white solid of N-methyl-3-(2-chloro-6-fluoro-4-trifluoromethylphenyloxy)-5-methylpyrazole-1-carboxamide (0.22 g, yield: 56.9%). mp: 87-88° C.; 1H-NMR (CDCl3, TMS, ppm): δ 2.59 (s, 3H), 2.88 (d, J=5.0 Hz, 3H), 5.80 (s, 1H), 6.55-6.75 (m, 1H), 7.40 (dd, JHF=2.0 and 9.3 Hz, 1H), 7.56 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:13])[CH2:9][CH:10]([CH3:12])[CH3:11].[F:14][C:15]1[N:19]([CH3:20])[N:18]=[C:17]([CH3:21])[C:16]=1[C:22](Cl)=[O:23].C(N(CC)CC)C>O1CCCC1>[CH3:12][CH:10]([CH3:11])[CH2:9][C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:22]([C:16]1[C:17]([CH3:21])=[N:18][N:19]([CH3:20])[C:15]=1[F:14])=[O:23])=[O:13]
Reactant: Cc1nn(C)c(F)c1C(=O)Cl
Reactant: CC(C)CC(=O)c1ccccc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nn(C)c(F)c1C(=O)Nc1ccccc1C(=O)CC(C)C
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
At room temperature, 355.0 mg (2.0 mmol) of 1-(2-aminophenyl)-3-methylbutan-1-one are added to a solution comprising 388.5 mg (2.2 mmol) of 5-fluoro-1,3-dimethyl-1H-pyrazole-4-carbonyl chloride and 0.45 ml (3.2 mmol) of triethylamine in 20 ml of tetrahydrofuran. The reaction mixture is stirred at 60° C. for 1.5 h, filtered through silica gel and concentrated. Column chromatography (cyclohexane/ethyl acetate: 3/1) gives 577.7 mg (1.8 mmol, 88% of theory) of N-[2-(3-methylbutyryl)phenyl-5-fluoro-1,3-dimethyl-1H-pyrazole-4-carboxamide of logP (pH=2.3)=3.42.
Reaction SMILES: [C:1]([NH2:7])(=[NH:6])[CH2:2][CH2:3][CH2:4][CH3:5].[C:8]([CH:11]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:12](OCC)=[O:13])(=O)[CH3:9].[OH-].[K+].O>CO>[CH2:2]([C:1]1[N:7]=[C:12]([OH:13])[C:11]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:8]([CH3:9])[N:6]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(=N)N
Reactant: CCOC(=O)CC(C(C)=O)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCc1nc(C)c(CC(=O)OCC)c(O)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 82.1 %

Procedure:
1.41 kg of valeroamidine and 1.41 kg of diethyl acetylsuccinate were dissolved in 4.5 L of methanol and 1.16 kg of potassium hydroxide was added thereto. The mixture was stirred for 15 hours at room temperature, and then 14 L of water was added while stirring. The obtained solid was filtered, dried, and dissolved in 6 L of ethanol. Then, 840 g of thionyl chloride was added by drop for 2 hours and stirred for 12 hours at 60° C. To this mixture was added a solution of 1.22 kg of sodium bicarbonate in 15 L of water and the produced solid was filtered and dried to obtain 1.35 kg (47.8% yield) of the titled compound.
Reaction SMILES: [C:1]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:9]1[CH2:10][OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:22][S:23]([O:11][CH2:10][C@@H:9]1[CH2:12][CH2:13][CH2:14][N:8]1[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 101 %

Procedure:
N-Boc-(2S)-prolinol (6.04 g) in 100 mL of dichloromethane was treated with 4.04 g of triethylamine, cooled to 0° C., and treated with methanesulfonyl chloride (4.0 g) slowly. After stirring at 0° C. for 30 minutes, the reaction was allowed to warm to room temperature, washed with 5% aqueous NaHCO3 solution, dried over sodium sulfate, and concentrated to dryness to give the title compound as an off-white oil (8.47 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]([CH3:13])=[CH:4][C:3]=1[S:14][CH2:15][CH2:16][C:17]([OH:19])=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C(=O)([O-])[O-].[Na+].[Na+]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]([CH3:13])=[C:4]2[C:3]=1[S:14][CH2:15][CH2:16][C:17]2=[O:19]
Reactant: CCOC(=O)c1cc(Cl)c(SCCC(=O)O)cc1C
Agent: O=C([O-])[O-]
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Product: CCOC(=O)c1cc(Cl)c2c(c1C)C(=O)CCS2
Temperature: 25 °C
Yield: 92.4 %

Procedure:
47.7 Grams (157 mmol) of 3-(2-chloro-4-ethoxycarbonyl-5-methylphenylthio)propionic acid was added to 167 g of 20 wt % P2O5 -containing polyphosphoric acid heated at 80~85° C., and then the mixture was stirred under heat for 1 hour and 20 minutes. After allowed to cool to room temperature, the reaction mixture was gradually added to a mixture of 191 g (1.80 mol) of sodium carbonate and ice, and the mixture was stirred at room temperature until the sodium carbonate was almost dissolved. The mixture was extracted with ethyl acetate twice, and the extract was washed with a sodium carbonate aqueous solution twice, with water twice and with a saturated sodium chloride aqueous solution once, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 41.3 g (yield 85%) of 8-chloro-6-ethoxycarbonyl-5-methylthiochroman-4-one.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:26])[C@H:6]([NH:19][C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21])[CH2:7][S:8]SC[C@@H](N)C(OCC=C)=O)[CH:2]=[CH2:3].Cl>CO.[Zn]>[CH2:1]([O:4][C:5](=[O:26])[C@@H:6]([CH2:7][SH:8])[NH:19][C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N[C@H](CSSC[C@@H](N)C(=O)OCC=C)C(=O)OCC=C
Agent: Cl
Agent: [Zn]
Solvent: CO
Product: C=CCOC(=O)N[C@H](CS)C(=O)OCC=C
Reaction time: 0.03 h

Procedure:
A suspension of zinc dust (5.18 g) in a solution of bis(N-allyloxycarbonyl-D-cystine bis-allyl ester (5.18 g) in methanol (50 ml) at 0° C. is stirred vigorously while adding concentrated hydrochloric acid (3.5 ml) in one portion. After two minutes, the mixture is worked up as in the above Preparation B to afford the title product.
Reaction SMILES: [C:1]1([CH:14]=[CH:13][CH:12]=[CH:11]N=1)[S:2][S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.SCCCCC[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][OH:36]>CO>[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[S:3][S:2][CH2:1][CH2:14][CH2:13][CH2:12][CH2:11][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][OH:36]
Reactant: OCCOCCOCCOCCCCCCCCCCCS
Reactant: c1ccc(SSc2ccccn2)nc1
Solvent: CO
Product: OCCOCCOCCOCCCCCCCCCCCSSc1ccccn1
Temperature: 25 °C
Reaction time: 42 h
Yield: 80.5 %

Procedure:
Aldrithiol-2 (1.45 g, 6.59 mmol) was added to a solution of 2-{2-[2-(11-mercapto-undecyloxy)-ethoxy]-ethoxy}-ethanol (1.85 g, 5.49 mmol) in 30 mL of MeOH. After stirring the solution for 42 h at room temperature, the solvent was evaporated, and the residue was purified by flash chromatography (EtOAc) to afford compound S 1.97 g (81%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=2[C:14]2[C:15]3[NH:22][CH:21]=[C:20]([C:23]([OH:25])=O)[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.C(OC(=O)[NH:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([C:39](=[O:44])[NH:40][CH:41]2[CH2:43][CH2:42]2)[CH2:35][CH2:34]1)(C)(C)C>>[CH:41]1([NH:40][C:39]([C@H:36]2[CH2:37][CH2:38][C@H:33]([NH:32][C:23]([C:20]3[C:16]4[N:17]=[CH:18][N:19]=[C:14]([C:7]5[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[CH:11][C:6]=5[O:5][CH2:4][CH:1]5[CH2:2][CH2:3]5)[C:15]=4[NH:22][CH:21]=3)=[O:25])[CH2:34][CH2:35]2)=[O:44])[CH2:43][CH2:42]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)NC2CC2)CC1
Reactant: COc1ccc(-c2ncnc3c(C(=O)O)c[nH]c23)c(OCC2CC2)c1
Product: COc1ccc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](C(=O)NC5CC5)CC4)c[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A73) and trans-(4-cyclopropylcarbamoyl-cyclohexyl)-carbamic acid tert-butyl ester (A195) the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:37](O)=[O:38])=[N:11][C:12]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:21][CH2:20]2)=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:74][CH2:75][C:76]1[CH:86]=[CH:85][C:84]([F:87])=[CH:83][C:77]=1[C:78]([O:80][CH2:81][CH3:82])=[O:79]>ClCCl>[CH2:1]([O:8][C:9]1[C:10]([C:37]([NH:74][CH2:75][C:76]2[CH:86]=[CH:85][C:84]([F:87])=[CH:83][C:77]=2[C:78]([O:80][CH2:81][CH3:82])=[O:79])=[O:38])=[N:11][C:12]([N:19]2[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[CH2:23][CH2:24]2)=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCCCN1CCN(c2nc(C(=O)O)c(OCc3ccccc3)c3ncccc23)CC1
Reactant: CCOC(=O)c1cc(F)ccc1CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc(F)ccc1CNC(=O)c1nc(N2CCN(CCCCNC(=O)OC(C)(C)C)CC2)c2cccnc2c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96.9 %

Procedure:
8-(Benzyloxy)-5-(4-(4-(tert-butoxycarbonylamino)butyl)piperazin-1-yl)-1,6-naphthyridine-7-carboxylic acid (Example 4.2; 1.4 mmol) was dissolved in dichloro methane (14 ml). DIPEA (5.4 mmol) and HBTU (1.6 mmol) were added. The reaction mixture was stirred at room temperature during 5 min. Ethyl 2-(aminomethyl)-5-fluorobenzoate hydrochloride (Example 4; 1.6 mmol) was added portionwise at room temperature. The mixture was stirred overnight at room temperature. The mixture was diluted with CH2Cl2 and washed with a saturated aqueous Na2CO3 solution (2×) and H2O. The organic layer was separated, dried (MgSO4), filtered and evaporated. The residue was purified by flash column chromatography over silica gel (eluent: hexane/EtOAc 10:1 up to 1:1) to afford 0.97 gr of the title compound.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:28])([F:27])[O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[N:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23](=O)[CH2:24][CH3:25])=[CH:19][CH:18]=3)=[N:13]2)=[CH:8][CH:7]=1.[C:29]([O:32][CH2:33][CH3:34])(=[O:31])[CH3:30]>O.[Pd]>[F:28][C:4]([F:3])([F:27])[O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[N:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]([CH2:24][CH3:25])[CH2:30][C:29]([O:32][CH2:33][CH3:34])=[O:31])=[CH:19][CH:18]=3)=[N:13]2)=[CH:8][CH:7]=1
Reactant: CCOC(C)=O
Reactant: CCC(=O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Agent: [Pd]
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CC(CC)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reaction time: 2 h
Yield: 90 %

Procedure:
Sodium hydride (60% immersion in oil, 0.32 g, 7.9 mmol) was weighed into an oven-dried three neck round bottomed flask. The flask was placed under nitrogen and tetrahydrofuran (44 mL) was added. The stirring mixture was placed in an ice bath. Triethylphosphonoacetate (1.4 mL, 6.9 mmol) was added and the mixture was stirred for 2 hours. Added 1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-1-one (CA7) (2.4 g, 6.5 mmol) as a solid and warmed to room temperature overnight. The reaction was diluted with water and extracted with ethyl acetate/hexanes (1:1, 2×). The organic layers were dried over sodium sulfate, filtered, and concentrated. To the crude residue was added palladium on carbon (10 wt %, 0.70 g, 0.66 mmol) and dissolved in ethyl acetate (20 mL). The reaction was stirred under hydrogen by balloon overnight. The reaction mixture was filtered through Celite® and concentrated to give the title compound as a brown liquid (2.7 g, 90%): 1H NMR (400 MHz, CDCl3) δ 8.55 (d, J=0.6 Hz, 1H), 8.11 (dd, J=8.1, 6.0 Hz, 2H), 7.83-7.76 (m, 2H), 7.38 (dq, J=7.9, 1.0 Hz, 2H), 7.35-7.27 (m, 2H), 4.24-4.14 (m, 1H), 4.04 (qd, J=7.1, 1.6 Hz, 1H), 3.13-2.99 (m, 1H), 2.74-2.55 (m, 2H), 1.79-1.61 (m, 2H), 1.38-1.24 (m, 3H), 1.06 (dt, J=72.0, 7.2 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −58.03; ESIMS m/z 434 ([M+H]+).
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.C([O-])([O-])=O.[K+].[K+].[Cl:15][C:16]1[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:17]=1[CH2:18][N:19]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[S:22](=[O:30])(=[O:29])[N:21](CC2C=CC=CN=2)[C:20]1=[O:38]>>[Cl:15][C:16]1[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:17]=1[CH2:18][N:19]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[S:22](=[O:30])(=[O:29])[N:21]([CH2:2][CH:3]2[CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)[C:20]1=[O:38]
Reactant: BrCC1CCOCC1
Reactant: O=C1N(Cc2c(F)cccc2Cl)c2ccccc2S(=O)(=O)N1Cc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1N(Cc2c(F)cccc2Cl)c2ccccc2S(=O)(=O)N1CC1CCOCC1

Procedure:
The title compound (150 mg, 0.34 mmol) was prepared from (IntE1) (0.3 g, 0.88 mmol), 4-(bromomethyl)tetrahydro-2H-pyran (0.20 g, 1.05 mmol) and K2CO3 (0.36 g, 2.60 mmol) using the methods of (128).