Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][C@@H:14]2[CH2:16][C@@H:15]2[CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[N:9][CH:10]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[C:30](=O)([O:36]N1C(=O)CCC1=O)[O:31][CH2:32][CH:33]1[CH2:35][CH2:34]1>ClCCl.[NH4+].[Cl-]>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][C@@H:14]2[CH2:16][C@@H:15]2[CH:17]2[CH2:22][CH2:21][N:20]([C:30]([O:31][CH2:32][CH:33]3[CH2:35][CH2:34]3)=[O:36])[CH2:19][CH2:18]2)=[N:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: O=C(OCC1CC1)ON1C(=O)CCC1=O
Reactant: CS(=O)(=O)c1ccc(OCC[C@@H]2C[C@@H]2C2CCNCC2)nc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(OCC[C@@H]2C[C@@H]2C2CCN(C(=O)OCC3CC3)CC2)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 5-(methylsulfonyl)-2-(2-((1S,2R)-2-(piperidin-4-yl)cyclopropyl)ethoxy)pyridine (Step A, Example 11; 0.30 g, 0.93 mmol) in dichloromethane (4.6 mL) under a nitrogen atmosphere was added triethylamine (0.36 mL, 2.6 mmol) and cyclopropylmethyl 2,5-dioxopyrrolidin-1-yl carbonate (0.35 g, 1.67 mmol). The resulting solution was stirred for 18 h at ambient temperature. The solution was diluted with saturated NH4Cl(aq.) (10 mL). The resulting layers were separated and the aqueous phase extracted with dichloromethane (2×30 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification of the obtained residue by CombiFlash chromatography (12 g silica gel, 0 to 25% EtOAc in heptane) provided the title compound as an off white semi-solid: 1H NMR (500 MHz, CDCl3) δ 8.72 (d, J=2.0 Hz, 1 h), 8.03 (m, 1H), 6.84 (d, J=8.5 Hz, 1H), 4.49 (m, 2H), 4.15 (m, 2H), 3.90 (d, J=7.0 Hz, 2H), 3.07 (s, 3H), 2.80-2.68 (m, 2H), 2.10 (m, 1H), 1.75 (m, 2H) 1.52 (m, 1H), 1.37-1.29 (m, 2H), 1.13 (m, 1H), 1.01-0.87 (m, 2H), 0.70-0.53 (m, 4H), 0.27 (m, 2H), −0.11 (q, J=5.0 Hz, 1H); MS (ESI) m/z 423 [M+H]+.
Reaction SMILES: [C:1]([O:7][C@@H:8]([C:13]([Cl:16])([Cl:15])[Cl:14])[CH:9]=[C:10]([CH3:12])[CH3:11])(=[O:6])[CH2:2]C(C)=O.C(N(CC)CC)C.S([N:34]=[N+:35]=[N-])(C1C=CC(C)=CC=1)(=O)=O.[OH-].[Na+]>C(#N)C>[N+:34](=[CH:2][C:1]([O:7][C@@H:8]([C:13]([Cl:16])([Cl:15])[Cl:14])[CH:9]=[C:10]([CH3:12])[CH3:11])=[O:6])=[N-:35]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: CC(=O)CC(=O)O[C@H](C=C(C)C)C(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)=C[C@@H](OC(=O)C=[N+]=[N-])C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.2 %

Procedure:
To a solution of (1R)-3-methyl-1-trichloromethyl-2-butenyl acetoacetate (1.63 g., 5.68 mmole) from Example IA.2.(a) and triethylamine (0.57 g, 5.68 mmole) in 10 ml of acetonitrile was added dropwise in small portions at 7-10 minute intervals over a total period of 30 minutes a solution of tosyl azide (1.12 g, 5.68 mmole) in 2 ml of acetonitrile. After stirring at room temperature for 21/4 hours, the mixture was poured into 17 ml of aqueous 1N NaOH. After stirring an additional 45 minutes, the mixture was extracted three times with ether, and the combined ethereal extracts were dried over MgSO4. The dried solution was concentrated to give an orange oil. The oil was chromatographed on 8 (20×20 cm) preparative tlc plates (silica gel) with CH2Cl2 as eluent to afford (1R)-3-methyl-1-trichloromethyl-2-butenyl diazoacetate (0.96 g, 62% isolated yield) as a yellow oil; [α]D31 =+59° (hexane).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:15])=[C:6]([NH:8][S:9]([CH2:12][CH2:13][CH3:14])(=[O:11])=[O:10])[CH:7]=1.Cl[C:17]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=2)[N:20]=[CH:19][N:18]=1.C([O-])(O)=O.[Na+]>CN(C=O)C.O>[CH3:15][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=3)[N:20]=[CH:19][N:18]=2)=[CH:7][C:6]=1[NH:8][S:9]([CH2:12][CH2:13][CH3:14])(=[O:11])=[O:10]
Reactant: CCCS(=O)(=O)Nc1cc(N)ccc1C
Reactant: O=[N+]([O-])c1cccc(-c2cc(Cl)ncn2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCS(=O)(=O)Nc1cc(Nc2cc(-c3cccc([N+](=O)[O-])c3)ncn2)ccc1C
Temperature: 80 °C

Procedure:
A mixture of propane-1-sulfonic acid (5-amino-2-methyl-phenyl)-amide (5.5 g, 24 mmol) and 4-chloro-6-(3-nitro-phenyl)-pyrimidine (5.52 g, 23.4 mmol) in DMFA (50 mL) was stirred at 80° C. till the reaction completion (TLC control), the reaction mixture was diluted with water (200 mL), treated with NaHCO3 (4.2 g, 50 mmol). The formed precipitate was filtered out, washed with water (2×200 mL), dried, washed with chloroform (2×50 ml), dried to yield propane-1-sulfonic acid {2-methyl-5-[6-(3-nitro-phenyl)-pyrimidin-4-ylamino]-phenyl}-amide as yellow powder.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH2:11][O:12][C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[CH:14]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].O.[O-2].[O-2].[O-2].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.[Al+3].[Al+3]>C1(C)C=CC=CC=1>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[C:15]([CH3:20])=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=3[O:12][CH:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc(C)cc(OCC(=O)c2ccc(C(C)C)cc2)c1
Agent: O=[Si]=O
Agent: [Al+3]
Agent: [O-2]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(C)c2c(-c3ccc(C(C)C)cc3)coc2c1
Temperature: 95 °C
Yield: 100 %

Procedure:
A solution of 1-(4-isopropylphenyl)-2-(3,5-dimethylphenoxy)ethanone obtained in Reference Example 142 (38.1 g, 135 mmol) and Montmorillonite KSF (57.2 g) in toluene (400 mL) was heated at 95° C., and was reacted for 16 hours. The reaction solution was cooled to room temperature, and then Montmorillonite KSF was filtered off. The solution was purified by silica gel column chromatography (ethyl acetate:hexane=1:9), and the solvent was distilled off under reduced pressure to obtain 35.6 g (yield 100%) of the title compound as an oily matter. The oily matter was, if necessary, crystallized with methanol. Melting point: 44-45° C.
Reaction SMILES: [Cl:1][C:2]([O-:4])=[O:3].[C:5]1(C)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C1C=CC=CC=1>[C:5]1([O:3][C:2]([Cl:1])=[O:4])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Cc1ccccc1
Reactant: O=C([O-])Cl
Solvent: c1ccccc1
Product: O=C(Cl)Oc1ccccc1

Procedure:
Alternatively, a compound of formula II can be treated with a chloroformate, e.g., an alkylchloroformate or phenylchloroformate, at a temperature of 25°-125° C. in a solvent such as toluene or benzene to provide the corresponding N-alkoxycarbonyl or N-phenoxycarbonyl compound.
Reaction SMILES: [Cl-].COC1C=C(C=CC=1OC)C[NH:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[C:12]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:11]([CH3:27])[NH+:10]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:20][O:19][C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[C:9]([NH2:8])=[N:10][C:11]([CH3:27])=[C:12]2[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1ccc2c(NCc3ccc(OC)c(OC)c3)[nH+]c(C)c(-c3ccccc3)c2c1
Agent: [Cl-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(N)nc(C)c(-c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The free base of 1-[(3,4-dimethoxybenzyl)amino]-6-methoxy-3-methyl-4-phenylisoquinolinium chloride was treated with 5 mL of CH2Cl2 and 10 mL of trifluoroacetic acid. The reaction was stirred at room temp for 2 h, then concentrated to dryness. The residue was combined with saturated aqueous sodium carbonate, and the mixture was extracted with EtOAc (3×). The combined organic solutions were dried (Na2SO4) and concentrated. Recrystallization from EtOAc/hexanes gave a solid which was further purified by flash chromatography (0-1% MeOH/ammonia-saturated CHCl3). The solid thus obtained was triturated with hexanes to give the titled compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([I:15])[CH:12]=[CH:11][C:10]=1[NH2:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:21][C:22](=[O:25])[CH2:23]Br)([CH3:20])([CH3:19])[CH3:18].C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C>[C:17]([O:21][C:22](=[O:25])[CH2:23][NH:16][C:10]1[CH:11]=[CH:12][C:13]([I:15])=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Nc1ccc(I)cc1OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CNc1ccc(I)cc1OCc1ccccc1
Temperature: 50 °C

Procedure:
To a solution of 2-benzyloxy-4-iodophenylamine (2.35 g, 7.23 mmol) in DMF (15 mL) is added bromoacetic acid tert-butyl ester (1.76 g, 9.04 mmol) and K2CO3 (5.0 g, 36.2 mmol) and the mixture is heated at 50° C. for 4 h. 2N HCl solution (200 mL) is added with cooling and it is then extracted with EtOAc. The organic layer is then washed with brine, dried and concentrated. The residue is then purified by column chromatography to give the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4]O.C(N(CC)CC)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C(Cl)Cl>[CH3:1][N:2]([CH2:3][CH2:4][S:15]([CH3:14])(=[O:17])=[O:16])[CH3:6]
Reactant: CS(=O)(=O)Cl
Reactant: CN(C)CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)CCS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of N,N-dimethylethanolamine (890 mg, 10 mmol) and triethylamine (1520 mg, 15 mmol) in anhydrous CH2Cl2, kept under nitrogen atmosphere, at 0° C., methansulphonyl chloride (1220 mg, 11 mmol) was added. The mixture was kept under stirring and at 0° C. for 1 hour, and then concentrated by evaporation. The residue was dissolved in CH2Cl2, washed with Na2CO3 saturated solution and with deionized water. The organic phase was dried under Na2SO4 and the solvent removed by evaporation. The product was used as obtained, without purification, for the following step b) (1330 mg, yield 80%).
Reaction SMILES: Cl.[OH:2][C@@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.[N+:8]([C:11]1[CH:21]=[CH:20][C:14]([CH2:15][O:16][C:17](Cl)=[O:18])=[CH:13][CH:12]=1)([O-:10])=[O:9].C(N(CC)CC)C>C(Cl)Cl>[OH:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:17]([O:16][CH2:15][C:14]2[CH:13]=[CH:12][C:11]([N+:8]([O-:10])=[O:9])=[CH:21][CH:20]=2)=[O:18])[CH2:4]1
Reactant: O[C@@H]1CCNC1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CC[C@@H](O)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.2 %

Procedure:
To a suspension of (3R)-3-hydroxypyrrolidine hydrochloride (7.00 g, 56.6 mmol) in methylene chloride (210 ml) were added chloroformic acid p-nitrobenzyl ester (13.4 g, 62.3 mmol) and triethylamine (17.4 ml, 125 mmol) in an ice bath. The mixture was stirred at room temperature for 5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The obtained organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (1:1)→ethyl acetate as the eluant to afford (3R)-3-hydroxy-1-(p-nitrobenzyloxycarbonyl)-pyrrolidine (13.6 g, yield 90%) as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:52]([CH:55]2[CH2:57][CH2:56]2)(=[O:54])=[O:53])=[C:6]([CH2:8][N:9]([CH3:51])[C:10]([CH:12]([NH:25][C:26]2[CH:27]=[C:28]3[C:33](=[CH:34][CH:35]=2)[C:32]([N:36]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[N:31][CH:30]=[CH:29]3)[C:13]2[CH:18]=[CH:17][C:16]([C@H:19]([CH2:22][OH:23])[CH2:20][F:21])=[C:15]([CH3:24])[CH:14]=2)=[O:11])[CH:7]=1.[C:58](Cl)(Cl)=[O:59]>C(#N)C.ClCCl>[C:39]([O:38][C:37]([N:36]([C:32]1[C:33]2[C:28](=[CH:27][C:26]([NH:25][C@H:12]3[C:10](=[O:11])[N:9]([CH3:51])[CH2:8][C:6]4[CH:7]=[C:2]([CH:3]=[CH:4][C:5]=4[S:52]([CH:55]4[CH2:56][CH2:57]4)(=[O:53])=[O:54])[NH:1][C:58](=[O:59])[O:23][CH2:22][C@H:19]([CH2:20][F:21])[C:16]4[CH:17]=[CH:18][C:13]3=[CH:14][C:15]=4[CH3:24])=[CH:35][CH:34]=2)[CH:29]=[CH:30][N:31]=1)[C:44](=[O:45])[O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:43])([CH3:42])([CH3:41])[CH3:40]
Reactant: O=C(Cl)Cl
Reactant: Cc1cc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)C(=O)N(C)Cc2cc(N)ccc2S(=O)(=O)C2CC2)ccc1[C@H](CO)CF
Solvent: CC#N
Solvent: ClCCl
Product: Cc1cc2ccc1[C@@H](CF)COC(=O)Nc1ccc(S(=O)(=O)C3CC3)c(c1)CN(C)C(=O)[C@@H]2Nc1ccc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36.8 %

Procedure:
To a solution of 24E (0.1 g, 0.124 mmol) in acetonitrile (5 mL) and dichloromethane (2.5 mL) at 0° C., was added phosgene solution (20% in toluene, 0.072 mL, 0.136 mmol) dropwise. The mixture was stirred at 0° C. for 30 min. Extra phosgene was removed by bubbling Ar for 20 min. The crude was then added dropwise via syringe pump into a solution of TEA (0.138 mL, 0.993 mmol) in dichloromethane (60 mL) at rt over 3.0 h. The solution was stirred at rt over night. Solvent was removed, and the crude product was purified by flash chromatography (0-80% EtOAc/hexanes) to give a mixture of diastereoisomers (0.1 g, 0.120 mmol, 97% yield). The diastereomers were separated by a prep chiral HPLC (R,R-Whelk-O column 21.1×250 mm) to give 24F (38 mg, 76% yield). MS (ESI) (m/z): 831.9 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:16]=[N:17][C:18]([N+:21]([O-])=O)=[CH:19][CH:20]=2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].O1CCCC1>C(OCC)(=O)C.[C].[Pd]>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:16]=[N:17][C:18]([NH2:21])=[CH:19][CH:20]=2)[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccc(Oc2ccc([N+](=O)[O-])nc2)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1cccc(Oc2ccc(N)nc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 108.2 %

Procedure:
To a solution of tert-butyl{3-[(6-nitropyridin-3-yl)oxy]phenyl}carbamate (6.00 g, 18.1 mmol) in ethyl acetate (500 mL)/tetrahydrofuran (150 mL) was added 10% palladium-carbon (600 mg), and the mixture was stirred at room temperature for 16 hr under a hydrogen atmosphere (1.0 atm). The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (5.9 g, quantitative) as a brown oil. The obtained compound was used for the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([C:9]([OH:11])=O)[CH:3]=1.[CH:12]1([N:15]2[CH:19]=[N:18][N:17]=[C:16]2[C:20]2[N:25]=[C:24]([NH2:26])[CH:23]=[CH:22][CH:21]=2)[CH2:14][CH2:13]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([C:9]([NH:26][C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([C:16]3[N:15]([CH:12]4[CH2:14][CH2:13]4)[CH:19]=[N:18][N:17]=3)[N:25]=2)=[O:11])[CH:3]=1
Reactant: Nc1cccc(-c2nncn2C2CC2)n1
Reactant: Cc1cnc(C(=O)O)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1cnc(C(=O)Nc2cccc(-c3nncn3C3CC3)n2)cc1Cl
Yield: 47 %

Procedure:
A solution of 4-chloro-5-methylpicolinic acid (159 mg, 0.924 mmol), 6-(4-Cyclopropyl-4H-[1,2,4]triazol-3-yl)-pyridin-2-ylamine (169 mg, 0.840 mmol), (2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (383 mg, 1.01 mmol), and N-methylmorpholine (11 μL, 1.01 mmol) in N,N-dimethylformamide was stirred at 65° C. for 1.2 hours. The solvent was removed under reduced pressure, the residue was suspended in acetonitrile, and the solid product was isolated by filtration, washed with water (80 mL), acetonitrile (80 mL), diethyl ether (80 mL), and dried under vacuum to afford 4-chloro-N-(6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-5-methylpicolinamide as a white powder (140 mg, 47% yield).
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].Cl.[NH2:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([C:14]([C:17]([C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[C:21]([O:28][CH3:29])[CH:20]=3)=[O:18])=[N:15][CH:16]=2)[CH:13]=1>N1C=CC=CC=1.Cl>[CH3:29][O:28][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][C:22]=1[N+:25]([O-:27])=[O:26])[C:17]([C:14]1[N:12]2[CH:13]=[C:8]([NH:7][S:1]([CH3:4])(=[O:3])=[O:2])[CH:9]=[CH:10][C:11]2=[CH:16][N:15]=1)=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(C(=O)c2ncc3ccc(N)cn23)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: c1ccncc1
Product: COc1cc(C(=O)c2ncc3ccc(NS(C)(=O)=O)cn23)ccc1[N+](=O)[O-]
Temperature: 5 °C
Reaction time: 18 h
Yield: 91.6 %

Procedure:
0.107 ml (1.38 mmol) of mesyl chloride is added to 0.40 g (1.15 mmol) of (6-aminoimidazo[1,5-a]pyridin-3-yl)(3-methoxy-4-nitrophenyl)methanone hydrochloride in 10 ml of pyridine cooled to 5° C. and the mixture is allowed to return to ambient temperature and is stirred for 18 hours. The medium is taken up in 130 ml of 1N hydrochloric acid and extracted with ethyl acetate. The organic phase is washed with a saturated aqueous sodium chloride solution, then dried over sodium sulfate and concentrated under reduced pressure. The residue is taken up in isopropyl ether, filtered off, washed with isopropyl ether and then dried. 411 mg of a yellow solid are obtained. Melting point: 249° C.; 1H NMR (d6-DMSO): 3.14 (3H, s), 4.02 (3H, s), 7.39 (1H, d), 7.94 (1H, s), 8.02-8.11 (3H, m), 8.13 (1H, s), 9.88 (1H, s)
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[F:5][C:6]([F:16])([F:15])[C:7](=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]>O.C(O)(=O)C>[F:5][C:6]([F:15])([F:16])[C:7](=[O:14])[C:8](=[N:1][OH:3])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: O=N[O-]
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(=NO)C(=O)C(F)(F)F
Temperature: 15 °C
Reaction time: 2 h

Procedure:
A solution of sodium nitrite (0.29 mmol) in 35 mL of water was added dropwise over 50 minutes to a stirred, ice-cooled solution of 22.8 g of ethyl 4,4,4-trifluoroacetoacetate (0.12 mmol) in 30 mL of acetic acid. The reaction was continued for 2 hours, with gradual warming to 15° C. Water and acetic acid were removed under reduced pressure (azeotroped with toluene). The crude product was partitioned between ethyl acetate and saturated aqueous potassium hydrogen carbonate solution. The layers were separated. The ethyl acetate layer was washed with saturated aqueous potassium hydrogen carbonate solution and brine, dried over sodium sulfate and concentrated to yield 21.4 g of the title A compound as a light yellow oil.
Reaction SMILES: I[C:2]1[C:10]2[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:3]=1.[CH3:25][N:26]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[N:27]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:25][N:26]1[CH:30]=[C:29]([C:2]2[C:10]3[C:9]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:3]=2)[CH:28]=[N:27]1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(N3CCOCC3)ncnc21
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cn1cc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N4CCOCC4)c23)cn1
Temperature: 100 °C

Procedure:
To a solution of 5-iodo-4-(morpholin-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (P1) (500 mg, 1.1 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (272 mg, 1.31 mmol) in a mixture of ethanol and water (4:1, 10 mL) were added dichlorobis(triphenylphosphine)palladium(II) (41 mg, 58 μmol) and potassium carbonate (447 mg, 3.23 mmol). The reaction mixture was degassed and purged with nitrogen; this procedure was carried out a total of three times. It was then heated at 100° C. for 18 hours. After concentration in vacuo, the residue was purified via chromatography on silica gel (Eluent: 1:1 ethyl acetate/petroleum ether) to provide the product as a yellow solid. Yield: 200 mg, 0.48 mmol, 44%. 1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 7.86 (s, 1H), 7.59 (s, 1H), 7.52 (s, 1H), 5.57 (s, 2H), 3.90 (s, 3H), 3.50-3.58 (m, 6H), 3.20-3.27 (m, 4H), 0.83 (dd, J=8.0, 7.9 Hz, 2H), −0.09 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([OH:14])=[CH:12][C:11]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[N:10]1.[CH3:20][O:21][CH2:22][C:23](Cl)=[O:24].Cl>O1CCOCC1.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([OH:14])=[C:12]([C:23](=[O:24])[CH2:22][O:21][CH3:20])[C:11]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[N:10]1
Reactant: COC(=O)Cc1cc(O)n(-c2ccc(F)cc2Cl)n1
Reactant: COCC(=O)Cl
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COCC(=O)c1c(CC(=O)OC)nn(-c2ccc(F)cc2Cl)c1O
Yield: 74 %

Procedure:
The mixture of the above obtained methyl [1-(2-chloro-4-fluorophenyl)-5-hydroxy-1H-pyrazol-3-yl]acetate (Compound of Formula (IV), 0.600 g, 2.11 mmol, 1 eq.), was suspended in dioxane (10 mL) and Ca(OH)2 (0.313 g, 4.22 mmol, 2eq.) and methoxyacetyl chloride (0.229 g, 2.11 mmol, 1 eq.) under nitrogen, was heated at 70° C. for 45-60 minutes. The resulting solution was concentrated in vacuo and the residue was partitioned between dichloromethane (50 ml) and a mixture of brine (10 ml) and 2N hydrochloric acid (1 ml, 2.00 mmol). The dichloromethane phase was collected. The aqueous phase was extracted with more dichloromethane (50 ml) and then ethyl acetate (50 ml). The combined organic phases were dried over Na2SO4 and the solvent evaporated to give methyl [1-(2-chloro-4-fluorophenyl)-5-hydroxy-4-(methoxyacetyl)-1H-pyrazol-3-yl]acetate as a beige solid (550 mg, 1.55 mmol, 74% yield, 92% HPLC) that can be used in the following step without further purification. MS(ESI+): 357.7; MS(ESI−): 355.8.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].[CH2:6](O)C.[O:9]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:12](=[O:13])[CH:11]([C:20]2[CH:21]=[CH:22][CH:23]=[C:24]3[C:29]=2[O:28][CH:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26][C:25]3=[O:36])[CH:10]1[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CC(C)=O>[O:9]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:12](=[O:13])[CH:11]([C:20]2[CH:21]=[CH:22][CH:23]=[C:24]3[C:29]=2[O:28][CH:27]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:26][C:25]3=[O:36])[CH:10]1[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1.[CH3:2][C:1]1([CH3:6])[O:4][O:3]1
Reactant: CC(=O)[O-]
Reactant: CCO
Agent: O=C1CC(c2ccccc2)Oc2c1cccc2C1C(=O)c2ccccc2OC1c1ccccc1
Agent: [Na+]
Solvent: CC(C)=O
Product: CC1(C)OO1

Procedure:
Donnelly and co-workers (Donnelly, D. M. X.; Fitzpatrick, B. M.; Ryan, S. M.; Finet, J.-P. J. Chem. Soc., Perkin Trans. I 1994, 1794-1801) synthesized the biflavonoids (46) and (47) via arylation of a 3-phenylsulfanylflavanone (48) with an 8-triacetoxyplumbylflavan derivative (49) (2:1 mixture of cis and trans). The dioxolane ring, of the intermediate (50) was cleaved during acid workup. Desulfurization of the intermediate (50) with nickel boride (NaBH4/H2O, NiCl26H2O/EtOH) yielded a chalcone (51) (in a 1.1:1 ratio of E/Z) that was cyclised with anhydrous sodium acetate in refluxing ethanol to the 3,8-biflavanone (46) in 73% yield (only the 2,3-trans isomer was isolated from a mixture of diastereoisomers with an α/β ratio of 1.4:1). Oxidation of (46) with dimethyldioxirane in acetone yielded (47) in 47% yield (Scheme 3). The end products are however not optically active and constitute a racemic mixture.