Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:14]O>OS(O)(=O)=O>[CH3:14][O:12][C:11]([C:6]1[C:5]2[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:8][CH:7]=1)=[O:13]
Reactant: CO
Reactant: O=C(O)c1c[nH]c2cc(Cl)ccc12
Agent: O=S(=O)(O)O
Product: COC(=O)c1c[nH]c2cc(Cl)ccc12

Procedure:
1 g of 6-chloro-1H-indole-3-carboxylic acid were heated at reflux in MeOH with 3 drop of concentrated H2SO4 overnight. Concentration in vacuo afforded the title compound in quantitative yield.
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]([NH:12][C:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][C:14]=2[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=2)=[O:23])=[O:11])[CH2:6][CH2:5]1.CO[CH:34]1[CH2:38][CH2:37][CH:36](OC)O1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[N:3]1([C@H:4]2[CH2:9][CH2:8][C@H:7]([C:10]([NH:12][C:13]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[O:15][C:14]=3[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=3)=[O:23])=[O:11])[CH2:6][CH2:5]2)[CH:34]=[CH:38][CH:37]=[CH:36]1
Reactant: COC1CCC(OC)O1
Reactant: N[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccccc23)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(Nc1ccc(Cl)cn1)c1oc2ccccc2c1NC(=O)[C@H]1CC[C@H](n2cccc2)CC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Trans-3-(4-aminocyclohexylcarbonylamino)-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide dihydrochloride (200 mg) obtained in Example 219, tetrahydro-2,5-dimethoxyfuran (53 μl), sodium acetate (68 mg) are stirred at 80° C. for 2 hours in acetic acid (3 ml). To the mixture is added tetrahydro-2,5-dimethoxyfuran (26 μl), and the mixture is further stirred at 80° C. for 2 hours. After cooling, the reaction solution is poured into ice-water, and the mixture is extracted with chloroform. The organic layer is washed with a saturated aqueous sodium hydrogen carbonate solution, a saturated brine, and dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (eluent: ethyl acetate/hexane=1/5→ethyl acetate/hexane=1/3) to give the title compound (96 mg).
Reaction SMILES: CC(C)([O-:4])C.[K+].[CH2:7]([O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[C:8]#[C:9][CH3:10].[CH2:19]1[CH2:23][O:22]C[CH2:20]1>C1COCC1.CN(C=O)C>[CH2:7]([O:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:20][CH2:19][C:23]([OH:22])=[O:4])=[CH:16][CH:17]=1)[C:8]#[C:9][CH3:10]
Reactant: CC#CCOc1ccc(O)cc1
Reactant: CC(C)(C)[O-]
Reactant: C1CCOC1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(OCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a 0° C. solution of 1.015 g (8.60 mmol) of potassium t-butoxide suspended in 10 mL of dry THF was added a solution of 1.40 g (8.60 mmol) of 4-but-2-ynyloxy-phenol, dissolved in 30 mL of THF/DMF (5:1). The reaction was stirred at room temperature for 10 minutes and then recooled to 0° C. followed by the addition of 0.66 mL (9.46 mmol) of neat •-propiolactone. The resulting mixture was stirred overnight at room temperature and then concentrated in vacuo. The residue was diluted with ethyl acetate and extracted with saturated sodium bicarbonate solution. The alkaline aqueous extracts were acidified to pH2 with concentrated HCl solution and the precipitated solid was collected by filtration, washed with water and dried in vacuo to provide 0.089 g of the carboxylic acid as a black solid; m.p. 88-92° C. Electrospray Mass Spec: 232.9 (M−H)−
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][C:6]([CH3:11])([CH2:9][OH:10])[CH2:7][OH:8].Cl.C(=O)=O>ClCCl>[CH3:5][C:6]1([CH3:11])[CH2:9][O:10][C:1](=[O:2])[O:8][CH2:7]1
Reactant: O=C(Cl)Cl
Reactant: CC(C)(CO)CO
Agent: Cl
Agent: O=C=O
Solvent: ClCCl
Product: CC1(C)COC(=O)OC1
Temperature: 110 °C
Yield: 45 %

Procedure:
198 g (2.00 mol) phosgene were introduced over a period of 1,5 h at 0° to 5° C. into a suspension of 208 g (2.00 mol) 2,2-dimethylpropane-1,3-diol and 600 ml dry dichloromethane, followed by stirring at that temperature until the initially vigorous evolution of hydrogen chloride had abated. The discharge of phosgene was prevented by an effective reflux condenser (dry ice). The solvent was then removed in vacuo, 500 mg (0.2% by weight) imidazole and 500 ml toluene were added and the reaction was completed by slowly increasing the temperature to 110° C. until the evolution of hydrogen chloride had stopped (3 hours). Residues of hydrogen chloride were then removed by application of a low vacuum. Removal of the toluene and fractionation of the residue in vacuo left 121 g (93%) of a solid product (boiling point 142° to 146° C./10 mbar). Recrystallization from ethyl acetate gave 117 g (90%) of product (Mp. 108° to 109° C.). Further working up is unnecessary.
Reaction SMILES: C(OC[C@@H](OC(C)(C)C)C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1C)N=C(N1CCOCC1)C=C2)(=[O:6])C(C)(C)C.[C:39]([O:43][C@@H:44]([C:47]1[C:48]([C:61]2[CH:66]=[CH:65][C:64]([Cl:67])=[CH:63][CH:62]=2)=[C:49]2[C:54](=[CH:55][C:56]=1[CH3:57])[N:53]1[CH:58]=[N:59][N:60]=[C:52]1[CH:51]=[CH:50]2)[CH2:45][OH:46])([CH3:42])([CH3:41])[CH3:40].C(O[C@@H](C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1C)N=C(N1CCOCC1)C=C2)CO)(C)(C)C>>[C:39]([O:43][C@@H:44]([C:47]1[C:48]([C:61]2[CH:66]=[CH:65][C:64]([Cl:67])=[CH:63][CH:62]=2)=[C:49]2[C:54](=[CH:55][C:56]=1[CH3:57])[N:53]1[CH:58]=[N:59][N:60]=[C:52]1[CH:51]=[CH:50]2)[C:45]([OH:6])=[O:46])([CH3:42])([CH3:40])[CH3:41]
Reactant: Cc1cc2c(ccc3nncn32)c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Reactant: Cc1cc2nc(N3CCOCC3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: Cc1cc2nc(N3CCOCC3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Product: Cc1cc2c(ccc3nncn32)c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(S)-2-tert-butoxy-2-(6-(4-chlorophenyl)-8-methyl-[1,2,4]triazolo[4,3-a]quinolin-7-yl)acetic acid was prepared in a similar manner as compound ((S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-yl)acetic acid of Example 29 except using (S)-2-tert-butoxy-2-(6-(4-chlorophenyl)-8-methyl-[1,2,4]triazolo[4,3-a]quinolin-7-yl)ethanol instead of ((S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-yl)ethanol. 1H-NMR 400 MHz (CD3OD) δ 9.95 (s, 1 H), 8.34 (s, 1 H), 7.6 (m, 3 H), 7.54 (m, 1 H), 7.35 (m, 2 H), 5.17 (s, 1 H), 2.75 (s, 3 H), 0.99 (s, 9 H); LCMS-ESI+ (m/z): [M+H]+ calcd for C23H23ClN3O3: 424.1. Found: 424.2; LCMS-EST (m/z): [M−H]− calcd for C23H21ClN3O3: 422.1Found: 421.9.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:5])[CH3:2].F[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+]>CS(C)=O>[CH2:1]([O:3][C:4](=[O:5])[CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[CH2:9][CH2:8]1)[CH3:2]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCOC(=O)CC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)CC1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C

Procedure:
A mixture of 4-(ethoxycarbonylmethyl)piperidine (0.011 mol) and 1-fluoro-4-nitrobenzene (0.011 mol) in DMSO (20 ml) was stirred in the presence of Na2CO3 (0.044 mol) during 2 hours at a temperature of 60° C. The reaction mixture was cooled to room temperature and poured into an ice/water mixture. The resulting precipitate was filtered and washed with water. The reaction product was purified by recrystallisation from a mixture of ethyl acetate and hexane, yielding [1-(4-nitro-phenyl)-piperidin-4-yl]-acetic acid ethyl ester (intermediate 3, mp. 83-85° C.).
Reaction SMILES: [NH2:1][CH:2]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])[OH:4].[C:24]1([CH2:30][CH2:31][C:32](Cl)=[O:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:12][C:6]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=1[CH:3]([OH:4])[CH:2]([NH:1][C:32](=[O:33])[CH2:31][CH2:30][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1F
Reactant: O=C(Cl)CCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(CCc1ccccc1)NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(2,4-difluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (400 mg, 1.21 mmol) in ethyl acetate (20 ml) were added 3-phenylpropionyl chloride (269 ml, 1.81 mmol) and saturated aqueous sodium hydrogen carbonate (20 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (498 mg, 89%).
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:6]([CH2:7][NH:8][C:9](=[O:29])[CH:10]([C:14]2[C:19]([F:20])=[CH:18][C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[OH:27])=[CH:16][C:15]=2[F:28])[O:11][CH2:12][CH3:13])=[CH:5][CH:4]=1)#[N:2].I[CH2:33][C:34]([NH2:36])=[O:35].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[NH2:44][OH:45]>CN(C=O)C>[C:34]([CH2:33][O:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:17]1[CH:16]=[C:15]([F:28])[C:14]([CH:10]([O:11][CH2:12][CH3:13])[C:9]([NH:8][CH2:7][C:6]2[CH:5]=[CH:4][C:3]([C:1](=[NH:2])[NH:44][OH:45])=[CH:31][CH:30]=2)=[O:29])=[C:19]([F:20])[CH:18]=1)(=[O:35])[NH2:36]
Reactant: NO
Reactant: NC(=O)CI
Reactant: CCOC(C(=O)NCc1ccc(C#N)cc1)c1c(F)cc(-c2ccccc2O)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(C(=O)NCc1ccc(C(=N)NO)cc1)c1c(F)cc(-c2ccccc2OCC(N)=O)cc1F

Procedure:
In analogy to example 16.4, (RS)-N-(4-cyano-benzyl)-2-(3,5-difluoro-2′-hydroxy-biphenyl-4-yl)-2-ethoxy-acetamide (example 256.1) was alkylated with iodoacetamide and cesium carbonate in DMF. The product of this reaction was reacted with hydroxylamine hydrochloride in analogy to example 15.5 to give (RS)-2-(2′-carbamoylmethoxy-3,5-difluoro-biphenyl-4-yl)-2-ethoxy-N-[4-(N-hydroxycarbamimidoyl)-benzyl]-acetamide. Colorless solid. MS 513.1 ([M+H]+)
Reaction SMILES: CN(C)C=O.[CH2:6]([O:13][C:14]1[CH:15]=[CH:16][C:17]([OH:22])=[C:18]([CH:21]=1)[CH:19]=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:23]([O:26][CH2:27][CH2:28]Br)(=[O:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+]>O>[CH2:27]([O:26][C:23]([C:24]1[O:22][C:17]2[CH:16]=[CH:15][C:14]([O:13][CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:21][C:18]=2[CH:19]=1)=[O:25])[CH3:28]
Reactant: O=Cc1cc(OCc2ccccc2)ccc1O
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2o1
Temperature: 120 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
To a N,N-dimethylformamide (10 mL) solution of 5-benzyloxy-2-hydroxy-benzaldehyde (830 mg, 3.64 mmol) described in Production Example 7-1-2 were added bromoethyl acetate (446 μL, 4.00 mmol) and potassium carbonate (1.01 g, 7.28 mmol) at room temperature, which was stirred at 120° C. for 8 hours. Water was added to the reaction solution at 0° C. followed by extraction with ethyl acetate. The organic layer was washed with water and sat. NaCl followed by drying over anhydrous magnesium sulfate and filtering. The filtrate was concentrated under a reduced pressure and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=2:1) to obtain the title compound (890 mg, 83%) as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][C@H:17]([OH:32])[CH2:18][O:19][C:20]4[CH:25]=[C:24]([O:26]C)[CH:23]=[CH:22][C:21]=4[NH:28][C:29](=[O:31])[CH3:30])[CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.B(Br)(Br)Br.O>ClCCl>[F:1][C:2]1[CH:34]=[CH:33][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][C@H:17]([OH:32])[CH2:18][O:19][C:20]4[CH:25]=[C:24]([OH:26])[CH:23]=[CH:22][C:21]=4[NH:28][C:29](=[O:31])[CH3:30])[CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: COc1ccc(NC(C)=O)c(OC[C@@H](O)CN2CCC(n3c(=O)[nH]c4cc(F)ccc43)CC2)c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CC(=O)Nc1ccc(O)cc1OC[C@@H](O)CN1CCC(n2c(=O)[nH]c3cc(F)ccc32)CC1
Temperature: 21 °C
Yield: 49 %

Procedure:
N-[2-({(2S)-3-[4-(5-Fluoro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-piperidinyl]-2-hydroxypropyl}oxy)-4-methoxyphenyl]acetamide, obtained in Example 32iii), (300 mg, 0.6 mmol) was dissolved in dichloromethane (5 ml) and stirred under nitrogen (N2) at ambient (20-22° C.) temperature. Boron tribromide solution (1 M in dichloromethane, 2 ml, 2 mmol) was added dropwise. After stirring at ambient temperature for 17 hr dichloromethane (5 ml) and water (5 ml) were added. After 1 hr the solvent was removed in vacuo. The residue was purified by gradient flash chromatography on silica gel (CH2Cl2/MeOH, 100/0 to 70/30) and lyophilized yielding the title compound as a white solid (134 mg, 49%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:11]([N:14]=[CH:15][N:16]([CH3:18])[CH3:17])(=[O:13])=[O:12])[CH:5]=[C:6]([F:10])[C:7]=1[CH2:8][OH:9].CCN(CC)CC.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[CH3:26][S:27]([O:9][CH2:8][C:7]1[C:2]([F:1])=[CH:3][C:4]([S:11](=[O:12])(=[O:13])[N:14]=[CH:15][N:16]([CH3:18])[CH3:17])=[CH:5][C:6]=1[F:10])(=[O:29])=[O:28]
Reactant: CN(C)C=NS(=O)(=O)c1cc(F)c(CO)c(F)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C=NS(=O)(=O)c1cc(F)c(COS(C)(=O)=O)c(F)c1
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
To a solution of N′-(3,5-difluoro-4-(hydroxymethyl)phenylsulfonyl)-N,N-dimethyl-formimidamide (80 g, 287 mmol) in DCM (500 mL) was added Et3N (121 mL, 862 mmol, 3 eq) and methanesulfonylchloride (27 mL, 245 mmol, 1.2 eq) successively at 0° C. After 30 min, the reaction mixture was extracted with DCM (300 mL×3). The combined extracts were washed with water (1 L), dried over MgSO4, concentrated and then purified by chromatography (silica, DCM/EtOAc, 1:1) to give 4-(N-((dimethylamino)methylene)sulfamoyl)-2,6-difluorobenzyl methanesulfonate (77.5 g, 28% over 4 steps) as a ivory solid. 1H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 7.59-7.39 (m, 2H), 5.32 (s, 2H), 3.18 (s, 3H), 3.09 (s, 3H), 3.08 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=[O:5].[CH2:11]([Mg]Cl)[CH3:12].C1COCC1>C1COCC1>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]([OH:5])[CH2:11][CH3:12]
Reactant: CC[Mg]Cl
Reactant: O=Cc1c(Cl)cccc1Cl
Solvent: C1CCOC1
Product: CCC(O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,6-dichlorobenzaldehyde (880 mg, 5.03 mmol) in THF (10 mL) was added EtMgCl/THF (2.0 M, 3 mL, 6.0 mmol) at 0° C. under nitrogen, the resulting mixture was allowed to warm to rt and stirred at rt overnight. The mixture was quenched with sat. aq. NH4Cl (5 mL) at 0° C., then diluted with Et2O (50 mL), the organic phase was washed with brine (20 mL), and dried over anhydrous sodium sulfate. The residue was purified by silica gel chromatography (Hex:EtOAc=80:20) to give the title compound as a colorless oil. 1H NMR (CDCl3): δ=1.00 (t, J=7.4 Hz, 3H), 1.95-2.11 (m, 2H), 2.82 (d, J=10.4 Hz, 1H, —OH), 5.34 (m, 1H), 7.13 (t, J=7.6 Hz, 1H), 7.29 (d, J=7.8 Hz, 2H.)
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:24](=[O:25])[N:13]2[CH2:14][CH2:15][O:16][CH2:17][C:18]3([CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:12]2=[N:11][C:10]=1[C:26](O)=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=1[N:38]1[C:42](=[O:43])[N:41]([CH3:44])[CH:40]=[N:39]1.C(N(C(C)C)CC)(C)C.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.Cl>CC#N>[CH2:1]([O:8][C:9]1[C:24](=[O:25])[N:13]2[CH2:14][CH2:15][O:16][CH2:17][C:18]3([CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:12]2=[N:11][C:10]=1[C:26]([NH:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=1[N:38]1[C:42](=[O:43])[N:41]([CH3:44])[CH:40]=[N:39]1)=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1nc2n(c(=O)c1OCc1ccccc1)CCOCC21CCOCC1
Reactant: Cn1cnn(-c2cc(F)ccc2CN)c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cnn(-c2cc(F)ccc2CNC(=O)c2nc3n(c(=O)c2OCc2ccccc2)CCOCC32CCOCC2)c1=O
Temperature: 23 °C
Reaction time: 18 h
Yield: 89.5 %

Procedure:
To a solution of 3′-(benzyloxy)-4′-oxo-2,3,4′,5,6,6′,7′,9′-octahydrospiro[pyran-4,10′-pyrimido[1,2-d][1,4]oxazepine]-2′-carboxylic acid (0.095 g, 0.246 mmol) in CH3CN (15 mL) was added 1-(2-(aminomethyl)-5-fluorophenyl)-4-methyl-1H-1,2,4-triazol-5(4H)-one (0.070 g, 0.271 mmol), diisopropylethylamine (0.171 mL, 0.984 mmol) and O-(7-azabenzotriazole-1yl)-N,N,N′,N′-tetramethyluronium (0.103 g, 0.271 mmol). The reaction mixture was stirred at 23° C. for 18 hours. HCl (1N, 50 mL) was added and the organic material was extracted with EtOAc (3×50 mL). The combined organic phases were washed with H2O (50 mL), brine (50 mL), dried over MgSO4 and concentrated in vacuo. The crude material was purified on Silica gel column (Biotage™), eluted with EtOAc:Hex (1:1) to EtOAc 100% to afford the title compound as a white solid (0.130 g, 77%): 1H NMR (400 MHz, CDCl3) δ 8.54 (1 H, brs), 7.67 (1H, dd, J=8.7, 6.2 Hz), 7.52 (2H, m), 7.45 (1H, s), 7.27-7.36 (3H, m), 7.22 (1H, dd, J=9.3, 2.5 Hz), 7.08 (1H, td, J=8.2, 2.5 Hz), 5.31 (2H, s), 4.54 (2 H, d, J=6.3 Hz), 4.1-3.6 (10H, m), 3.36 (3H, s), 2.4-2.2 (1H, brm), 2.1-1.6 (2H, brs). LCMS (+ESI, M+H+) m/z 591.
Reaction SMILES: [N:1]([CH:4]1[CH2:13][CH2:12][C:11]2[CH:10]=[C:9]([C:14]#[N:15])[CH:8]=[CH:7][C:6]=2[CH:5]1[OH:16])=[N+:2]=[N-:3].Cl.[NH2:18][OH:19].C(=O)(O)[O-].[Na+].CCOC(C)=O>CC(O)C>[N:1]([CH:4]1[CH2:13][CH2:12][C:11]2[CH:10]=[C:9]([C:14](=[N:18][OH:19])[NH2:15])[CH:8]=[CH:7][C:6]=2[CH:5]1[OH:16])=[N+:2]=[N-:3]
Reactant: NO
Reactant: N#Cc1ccc2c(c1)CCC(N=[N+]=[N-])C2O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NC1CCc2cc(C(N)=NO)ccc2C1O
Temperature: 25 °C
Yield: 94.7 %

Procedure:
Racemic (5S*,6R*)-6-azido-5-hydroxy-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (400 mg, 1.9 mmol) and hydroxylamine hydrochloride (260 mg, 3.7 mmol) were mixed in 2-propanol (7.5 mL). To this suspended solution was added sodium bicarbonate (627 mg, 7.5 mmol) and the solution was heated at reflux for 2 hr. Then the reaction mixture was cooled to room temperature and diluted by EtOAc (50 mL) and washed with water and brine. The combined aqueous layers were extracted again by EtOAc. The combined organic layers were dried (MgSO4) and concentrated to afford pure racemic (5S*,6R*,E/Z)-6-azido-N′,5-dihydroxy-5,6,7,8-tetrahydronaphthalene-2-carboximidamide (445 mg, 1.8 mmol, 96% yield).
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[S:3])[NH2:2].[Cl:14][CH2:15][C:16]([CH2:18]Cl)=O>C1COCC1>[Cl:14][CH2:15][C:16]1[N:2]=[C:1]([CH2:4][C:5]2[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=2)[S:3][CH:18]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=S)Cc1ccc(C(=O)O)cc1
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Cc2nc(CCl)cs2)cc1
Yield: 82.8 %

Procedure:
A solution of 250 (729 mg, 3.73 mmol) and 1,3-dichloroacetone (474 mg, 3.73 mmol) in THF (30 ml) was stirred at 40° C. during 48h. The solvent was evaporated then the residue was dissolved in ethyl acetate, washed with brine, dried over anhydrous MgSO4, filtered and concentrated. The crude residue was purified by flash chromatography on silica gel (2-4% MeOH/CH2Cl2) to afford the title compound (827 mg, 83% yield) as a white solid. 1H NMR (DMSO) δ (ppm): 12.93 (bs, 1H), 7.91 (d, J=8.1 Hz, 2H), 7.63 (s, 1H), 7.46 (d, J=8.1 Hz, 2H), 4.78 (s, 2H), 4.42 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37][NH2:38]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:30])([F:29])[F:31])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:38][CH2:37][C:36]3[CH:39]=[CH:40][CH:41]=[C:34]([O:33][CH3:32])[CH:35]=3)=[O:22])=[CH:17][C:9]1=2
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Reactant: COc1cccc(CN)c1
Product: COc1cccc(CNC(=O)c2cccc(-c3cnc4c(c3)N(Cc3cc(Cl)ccc3C(F)(F)F)CCN4)c2)c1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 3-methoxybenzylamine as in General Procedure 10 to give the title compound. LCMS: m/z=566.99 (M+H+); retention time=0.93 minutes.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([CH2:10][C:11](=P(OCC)OCC)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:9])([CH3:6])([CH3:5])[CH3:4].[Br:24][C:25]1[CH:32]=[CH:31][C:30](OC(C)C)=[CH:29][C:26]=1[CH:27]=O.[CH2:37]1[CH2:41]OC[CH2:38]1>>[C:3]([O:7][C:8](=[O:9])[CH2:10]/[C:11](/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:27]\[C:26]1[CH:29]=[C:30]([CH:37]([CH3:41])[CH3:38])[CH:31]=[CH:32][C:25]=1[Br:24])([CH3:4])([CH3:5])[CH3:6]
Reactant: CC(C)Oc1ccc(Br)c(C=O)c1
Reactant: CCOC(=O)C(CC(=O)OC(C)(C)C)=[PH](OCC)OCC
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)/C(=C/c1cc(C(C)C)ccc1Br)CC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 6 h
Yield: 61 %

Procedure:
To a suspension of 1.85 g (77.1 mmol) NaH in 130 mL dry THF, 25.4 g (75.1 mmol) tert-butoxycarbonyl-1-ethoxycarbonylethylidendiethoxy-phosphorane (2) was added dropwise at 0° C., The reaction mixture was stirred for 6 h at 0° C. under Ar. This solution was added under Ar dropwise at 0° C. to 15.5 g (63.5 mmol) 2-bromo-5-isopropoxy-benzaldehyde (1), dissolved in 80 mL dry THF. The cooling bath was removed and the reaction mixture was stirred overnight at room temperature. 20 mL water was added and the solvent was removed under reduced pressure. The residue was partitioned between water and dichloromethane. The organic layers were dried (MgSo4), filtered and the solvent was removed under reduced pressure to afford 16.5 g (61%) (E)-3-carboethoxy-4-(2'-bromo-5-isopropylphenyl)-3-butenic acid-tert-butyl ester as a yellow oil.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH2:6][C:7]([C:9]([F:12])([F:11])[F:10])=[O:8])=[O:5].CC(O[Na])=O.O.[Cl-].[C:20]1([N+:26]#[N:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[C:20]1([NH:26][N:27]=[C:6]([C:7](=[O:8])[C:9]([F:10])([F:11])[F:12])[C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N#[N+]c1ccccc1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: CC(=O)O[Na]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(=NNc1ccccc1)C(=O)C(F)(F)F
Yield: 60 %

Procedure:
7.3 ml (0.05 mol) of ethyl 3-oxo-4,4,4-trifluoroacetoacetate, 6 g (0.073 mol) of CH3COONa, 20 ml of water, 37.5 ml of ethanol and a solution of 0.05 mol of phenyldiazonium chloride were treated as described in preparation 2. The crude product was purified by chromatography on silica gel (hexane/Et2O 0%→25%) obtaining 8.65 g of the title compound. M.p.=78°-80° C.