Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:10]([O:20][C@H:21]3[CH2:30][O:29][C@H:28]4[C@@H:23]([O:24][CH:25]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[O:26][CH2:27]4)[CH2:22]3)=[N:9][C:5]2=[N:6][C:7]=1I.[B:37]1([C:46]2[CH:51]=[CH:50][C:49](B3OC(C)(C)C(C)(C)O3)=[CH:48][CH:47]=2)[O:41][C:40]([CH3:43])([CH3:42])[C:39]([CH3:45])([CH3:44])[O:38]1>C1COCC1.CCOC(C)=O.C(=O)([O-])[O-].[Ag+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:10]([O:20][C@H:21]3[CH2:30][O:29][C@H:28]4[C@@H:23]([O:24][CH:25]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[O:26][CH2:27]4)[CH2:22]3)=[N:9][C:5]2=[N:6][C:7]=1[C:49]1[CH:50]=[CH:51][C:46]([B:37]2[O:41][C:40]([CH3:43])([CH3:42])[C:39]([CH3:45])([CH3:44])[O:38]2)=[CH:47][CH:48]=1
Reactant: C[Si](C)(C)CCOCn1c(O[C@H]2CO[C@@H]3COC(c4ccccc4)O[C@H]3C2)nc2nc(I)c(Cl)cc21
Reactant: CC1(C)OB(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)OC1(C)C
Agent: [Ag+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc(-c3nc4nc(O[C@H]5CO[C@@H]6COC(c7ccccc7)O[C@H]6C5)n(COCC[Si](C)(C)C)c4cc3Cl)cc2)OC1(C)C
Temperature: -78 °C
Reaction time: 21 h

Procedure:
To a stirred solution of 6-chloro-5-iodo-2-(((4aR,7R,8aS)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine (4.29 g, 9.31 mmol) under nitrogen in anhydrous THF (30 mL) was added silver carbonate (3.08 g, 11.18 mmol), Pd(PPh3)4 (538 mg, 0.466 mmol), and 1,4-benzenediboronic acid bis(pinacol) ester (9.22 g, 27.9 mmol). The mixture was cooled to −78° C., a hard vacuum was pulled, and nitrogen was introduced (3×). The mixture was allowed to warm to room temperature, then heated to reflux. After 21 hours, the mixture was cooled to room temperature and diluted with EtOAc (80 mL). The mixture was filtered through celite with EtOAc rinse until filtrate was colorless. The filtrate was concentrated under reduced pressure. The resultant residue was chromatographed using a Biotage™ 150 g (100 g+50 g in series) silica gel cartridge eluted with 0-30% EtOAc in 1:1 Hexane/DCM over 15 column volumes. The product fractions were combined and concentrated under reduced pressure, then the resultant oil was dissolved in MeCN and water, frozen at −78° C., and lyophilized to dryness to provide the title compound as a yellow solid. LC-MS: calculated for C37H47BClN3O7Si 719.30, observed m/e: 720.43 (M+H)+ (Rt 3.25/4 min).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:8][NH:9][C:10]1[C:15]([F:16])=[CH:14][N:13]=[C:12]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([Cl:26])[CH:24]=3)[N:19](S(C3C=CC(C)=CC=3)(=O)=O)[CH:18]=2)[N:11]=1.CCN(C(C)C)C(C)C.[CH3:46][O:47][CH2:48][C:49](Cl)=[O:50]>C(Cl)Cl>[Cl:26][C:23]1[CH:24]=[C:25]2[C:17]([C:12]3[N:11]=[C:10]([NH:9][CH2:8][C@@H:3]4[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]4[NH:1][C:49](=[O:50])[CH2:48][O:47][CH3:46])[C:15]([F:16])=[CH:14][N:13]=3)=[CH:18][NH:19][C:20]2=[N:21][CH:22]=1
Reactant: COCC(=O)Cl
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC[C@@H]4CCCC[C@H]4N)n3)c3cc(Cl)cnc32)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCC(=O)N[C@@H]1CCCC[C@H]1CNc1nc(-c2c[nH]c3ncc(Cl)cc23)ncc1F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a cooled mixture of N-((trans-2-aminocyclohexyl)methyl)-2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-amine (0.060 g, 0.093 mmol) and iPr2NEt (0.057 mL, 0.330 mmol) in CH2Cl2 (2 mL) at 0° C., was added 2-methoxyacetyl chloride (0.010 g, 0.098 mmol). After 5 min, the solution was allowed to warm to room temperature. After 3 hours, the mixture was concentrated in vacuo, taken up in THF (1 mL) and treated with LiOH (0.326 mL, 1.0 M solution) at 120° C. for 10 min. The resulting mixture was cooled to room temperature and partitioned and the aqueous layer extracted with EtOAc and the combined organics were concentrated in vacuo. Preparative HPLC provided the desired product, 556, as a racemic mixture of TFA salts (8.6 mg, 17% yield).
Reaction SMILES: [I:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C@H:9]1[CH2:33][CH2:32][C@@:31]2([CH3:34])[C:11](=[CH:12][CH2:13][C@@H:14]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:35])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[C@H:19]([CH3:26])[CH2:20][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:10]1.S(CCCCCCO[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2[C@H](C)C=C[C@H](C(C)C)CC)C1)[C@@H:37]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H:38]1O>>[I:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C@H:9]1[CH2:33][CH2:32][C@@:31]2([CH3:34])[C:11](=[CH:12][CH2:13][C@@H:14]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:35])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[C@H:19]([CH3:26])[CH:20]=[CH:21][C@H:22]([CH:23]([CH3:25])[CH3:24])[CH2:37][CH3:38])[CH2:10]1
Reactant: CC[C@H](C=C[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCS[C@@H]5O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]5O)CC[C@]4(C)[C@H]3CC[C@]12C)C(C)C
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCI)CC[C@]4(C)[C@H]3CC[C@]12C
Product: CC[C@H](C=C[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCI)CC[C@]4(C)[C@H]3CC[C@]12C)C(C)C

Procedure:
Employing the procedure substantially as described in Example 2, but substituting for cholest-5-en-3β-yl 6-iodohexyl ether, an equivalent amount of stigmasta-5,22-dien-3β-yl 6-iodohexyl ether, there was prepared 6-(stigmasta-5,22-dien-3β-yloxy)hexyl 1-thio-β-D-mannopyranoside (Step D). TLC data and Rf values are given in the above Table.
Reaction SMILES: [CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([OH:22])=[C:11]4[O:12][C@H:13]5[C:14]([O:20]C)=[CH:15][CH:16]=[C:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1.C(OO)(=[O:25])C>CC(O)=O.O>[CH3:1][N:2]1[C@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([OH:22])=[C:11]4[O:12][C@H:13]5[C:14]([CH:15]=[CH:16][C@:17]2([OH:25])[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:20]
Reactant: CC(=O)OO
Reactant: COC1=CC=C2[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3C)[C@H]1O5
Solvent: CC(=O)O
Solvent: O
Product: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)C=C[C@@]3(O)[C@@H]1C5
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 200 mL flask, dried oripavine (10.00 g, 95% wt/wt %) was dissolved in HOAc/H2O (1:4, 100 mL) and cooled to 5° C. to 10° C. Peroxyacetic acid, CH3CO3H, (9.1 mL, 32% wt/wt %) was added over 3 minutes and the reaction mixture was stirred at 5° C. to 10° C. for 30 minutes. HPLC data showed that the reaction was completed. The reaction mixture was allowed to warm to 25° C. for 30 minutes. H2C2O4 (3.0 g) was added to the reaction mixture, and was stirred at room temperature for 30 minutes and then heated to 50° C. for 30 minutes. The solution was assayed by HPLC and >99% conversion was observed.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:15][N:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: Cn1cc(Br)cc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cn2)c1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(Br)cc(Nc2ccc(C3CCNCC3)cn2)c1=O
Yield: 100 %

Procedure:
Following Example 121c, 264a (0.58 g, 1.25 mmol), trifluoroacetic acid (0.96 mL, 12.5 mmol) and methylene chloride (20 mL) were reacted. Work-up and concentrated to afford a quantitative yield of 264b (454 mg) as yellow oil, which was used without purification in the next step. MS (ESI+) m/z 365.2 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])[CH3:2].[I:14]I.S(=O)(=O)(O)O>CC(O)=O>[CH2:1]([C:3]1[CH:12]=[C:11]([CH3:13])[C:10]([I:14])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])[CH3:2]
Reactant: II
Reactant: CCc1cc(C)ccc1C(=O)OC
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCc1cc(C)c(I)cc1C(=O)OC
Temperature: 110 °C
Reaction time: 12 h

Procedure:
To a round-bottom flask was added a solution of methyl 2-ethyl-4-methylbenzoate (compound 48.1, 12.5 g, 70.1 mmol, 1.00 equiv) in AcOH (100 mL). NaIO4 (7.51 g, 35.1 mmol, 0.50 equiv) and I2 (21.4 g, 84.3 mmol, 1.20 equiv) were added in portions at 25° C. Sulfuric acid (1.60 g, 16.3 mmol, 0.20 equiv) was then added to the reaction mixture dropwise at 25° C. The resulting solution was stirred for 12 h at 110° C. in an oil bath, and then cooled to ambient temperature. The reaction was quenched with 150 mL of Na2S2O3 (aq., sat.). The aqueous phase was extracted with 2×200 mL of ethyl acetate. The combined organic layers were washed with 3×300 mL of sodium bicarbonate (aq.) and 1×150 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. This resulted in 20.0 g (94%) of methyl 2-ethyl-5-iodo-4-methylbenzoate as a yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]([CH3:17])[CH3:16])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:3]=1.[F-:24].[Cs+].CS(C)=O.CCCCCC>CCOC(C)=O>[F:24][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]([CH3:17])[CH3:16])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:3]=1
Reactant: CC(C)Oc1ccc(-c2cc(Cl)cc(-c3ccccn3)n2)cc1
Reactant: [F-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CS(C)=O
Product: CC(C)Oc1ccc(-c2cc(F)cc(-c3ccccn3)n2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a 2 dram vial equipped with a stir bar and charged with 4-chloro-6-(4-isopropoxyphenyl)-2,2′-bipyridine (all material from step 1) was added cesium fluoride (200 mg, 1.32 mmol) and DMSO (0.7 mL). The vial was sealed with a septum cap and then placed in a 140° C. heating block with stirring for 18 h. The reaction mixture was allowed to cool to room temperature. The mixture was transfered to a 125 mL separatory funnel and was diluted with EtOAc (50 mL) and then twice washed with water:brine (25 mL:25 mL). The organic solution was dried over MgSO4; filtered; then concentrated in vacuo to afford an amber solid residue which was subjected to silica gel chromatography (hexane:EtOAc) to afford 4-fluoro-6-(4-isopropoxyphenyl)-2,2′-bipyridine as a colorless solid (16 mg, 29% over two steps). 1H-NMR (400 MHz, CDCl3) δ 8.72-8.67 (m, 1H), 8.62 (dt, J=7.8, 1.0 Hz, 1H), 8.10-8.05 (m, 3H), 7.86 (td, J=7.8, 1.8 Hz, 1H), 7.41 (dd, J=10.0, 2.3 Hz, 1H), 7.35 (ddd, J=7.5, 4.8, 1.3 Hz, 1H), 7.04-6.99 (m, 2H), 4.66 (spt, J=6.1 Hz, 1H), 1.40 (d, J=6.0 Hz, 6H); MS: MS m/z 309.2 (M++1).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([CH2:7][CH3:8])[NH:4][N:3]=1.CN(C)[CH:11]=[CH:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1)=O>C(O)(=O)C>[CH2:7]([C:5]1[N:6]=[C:2]2[N:1]=[CH:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:23])[F:24])[CH:16]=3)[N:3]2[N:4]=1)[CH3:8]
Reactant: CCc1nc(N)n[nH]1
Reactant: CN(C)C=CC(=O)c1cccc(C(F)(F)F)c1
Solvent: CC(=O)O
Product: CCc1nc2nccc(-c3cccc(C(F)(F)F)c3)n2n1

Procedure:
A mixture of 2.24 g. of 3-amino-5-ethyl-1,2,4-triazole and 4.86 g. of 3-dimethylamino-3'-trifluoromethylacrylophenone in 50 ml. of glacial acetic acid is refluxed for 16 hours. The resulting mixture is worked up as described in Example 54 to give the product of the Example, m.p. 132°-134° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]([F:13])([F:12])[F:11])[NH2:5].[I:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][S:21]([C:18]2[CH:19]=[CH:20][C:15]([I:14])=[CH:16][CH:17]=2)(=[O:23])=[O:22])[CH:6]=[CH:7][C:8]=1[O:9][C:10]([F:11])([F:12])[F:13]
Reactant: Nc1ccc(OC(F)(F)F)c(Br)c1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Product: O=S(=O)(Nc1ccc(OC(F)(F)F)c(Br)c1)c1ccc(I)cc1

Procedure:
The title compound was prepared from 3-bromo-4-[(trifluoromethyl)oxy]aniline and 4-iodobenzenesulfonyl chloride using a similar method to that described for Examples 82-100. MS (ES−) m/e 520/522 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:35]=[CH:34][C:23]([O:24][C:25]3[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=3)[C:28]([OH:30])=[O:29])=[C:22]([F:36])[CH:21]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=O)=[C:4]([CH3:37])[CH:3]=1.Cl.[NH2:39][OH:40].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:35]=[CH:34][C:23]([O:24][C:25]3[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=3)[C:28]([OH:30])=[O:29])=[C:22]([F:36])[CH:21]=2)[CH2:9]/[C:10](=[N:39]\[OH:40])/[C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[C:4]([CH3:37])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(Oc2cccc(C(=O)O)c2)c(F)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(Cl)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(Oc2cccc(C(=O)O)c2)c(F)c1

Procedure:
In analogy to example 151, step 3, 3-{4-[1-(4-chloro-2-methyl-phenyl)-3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-propyl]-2-fluoro-phenoxy}-benzoic acid was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound containing less than 10% of the corresponding Z isomer as a colourless solid, MS (ESI−): m/z=532.9 [M−H]−.
Reaction SMILES: [CH:1]1([NH:7][C:8]([NH2:10])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([C:14]1[CH:20]=[CH:19][C:17](C)=[CH:16][CH:15]=1)(=O)=O>>[CH2:4]1[CH2:5][CH2:6][CH:1]([N:7]=[C:8]=[N:10][CH:14]2[CH2:20][CH2:19][CH2:17][CH2:16][CH2:15]2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NC(=O)NC1CCCCC1
Product: C(=NC1CCCCC1)=NC1CCCCC1
Reaction time: 9 h

Procedure:
The polymer bound cyclohexylurea (PS-DCU; 1 g of 1.25 mmol/g) recovered after N-acylation is suspended in dimethylformamide (DMF; 10 ml) in a two-necked round-bottom flask (50 ml) equipped with a silicone rubber septum and a reverse filter funnel under exclusion of moisture and air. Tosyl chloride (TsCl; 0.47 g, 2.5 mmol) is added slowly over a period of 20 minutes to the above suspension of PS-DCU. The mixture is shaken gently for 8-10 hours and supernatant is removed by reverse filtration and replaced by 10% aqueous NaOH (5 ml) and tetrahydrofuran (20 ml). The suspension is shaken for 1 hour and supernatant is removed. The polymer is washed with tetrahydrofuran (2×25 ml) to remove excess of water, DMF and base and dried under vacuum to furnish PS-DCC.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:35]=O)=[C:5]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:6]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:9].Cl.[NH2:38][OH:39].C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:1][C:2]1[NH:3][C:4]([CH:35]=[N:38][OH:39])=[C:5]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:6]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:9]
Reactant: CCOC(=O)C1=C(C=O)NC(C)=C(C(=O)OCCOCc2ccccc2)C1c1cccc([N+](=O)[O-])c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)C1=C(C=NO)NC(C)=C(C(=O)OCCOCc2ccccc2)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
A mixture of 2-benzyloxyethyl 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate (2.44 g), hydroxylamine hydrochloride (377 mg) and sodium acetate (526 mg) in acetic acid (15 ml) was stirred at room temperature for an hour to form 2-benzyloxyethyl 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-hydroxyiminomethyl-1,4-dihydropyridine-3-carboxylate. To the reaction mixture was added acetic anhydride (1.66 g) and the mixture was stirred at room temperature for an hour and then heated at 100° C. for 3 hours with stirring. After removal of the acetic acid, the residue was adjusted to pH 7.5 with aqueous sodium bicarbonate solution and extracted twice with ethyl acetate. The extracts were washed twice with water, and saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to dryness in vacuo. The residual brown oil (2.6 g) was chromatographed on a column of silica-gel (78 g) and eluted with a mixture of benzene and ethyl acetate (12:1, v/v) to give an oil (1.45 g). The oil was crystallized by triturating with a small amount of mixture of diisopropyl ether and diethyl ether, and recrystallized from a mixture of diisopropyl ether (9 ml) and ethanol (1 ml) to give pure crystals of 2-benzyloxyethyl 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-cyano-1,4-dihydropyridine-3-carboxylate (840 mg), mp 114° to 115° C. An additional crop (560 mg) was recovered from the filtrate by concentrating the filtrate and allowing to stand the residue in a refrigerator.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]([C:11](=[O:31])[NH:12][C:13]1[N:18]=[C:17]2[N:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C:20](=[O:22])[NH:21][C:16]2=[CH:15][CH:14]=1)[CH3:10])C)(C)(C)C.Cl>C1COCC1.CCOC(C)=O>[ClH:30].[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][N:19]2[C:17]3=[N:18][C:13]([NH:12][C:11](=[O:31])[CH:9]([NH:7][CH3:6])[CH3:10])=[CH:14][CH:15]=[C:16]3[NH:21][C:20]2=[O:22])=[CH:29][CH:28]=1
Reactant: CC(C(=O)Nc1ccc2[nH]c(=O)n(Cc3ccc(Cl)cc3)c2n1)N(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC(C)C(=O)Nc1ccc2[nH]c(=O)n(Cc3ccc(Cl)cc3)c2n1
Reaction time: 2 h

Procedure:
The product from Step 4 was dissolved in THF (2 mL) and then added to a solution of saturated HCl in EtOAc. After 2 hours, the resulting precipitate was collected by filtration and washed with EtOAc to give the title compound as a white solid (30 mg). 1H NMR (400 MHz, DMSO-d6): 11.31-11.23 (1H, m), 10.87 (1H, s), 9.37 (1H, br), 8.99 (1H, br), 7.78 (1H, d), 7.47-7.35 (3H, m), 7.31 (2H, d), 5.00 (2H, s), 4.08-3.95 (1H, m), 2.57-2.53 (3H, m), 1.47 (3H, d). MS: [M+H]+ 360.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][NH:18][C:19]([CH3:21])([CH3:20])[C:12]2=[N:11][C:10]=1[C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:39](Br)[C:40]#[CH:41]>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][N:18]([CH2:41][C:40]#[CH:39])[C:19]([CH3:21])([CH3:20])[C:12]2=[N:11][C:10]=1[C:22]([NH:24][CH2:25][C:26]1[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=1)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#CCBr
Reactant: CC1(C)NCCn2c1nc(C(=O)NCc1ccc(F)cc1)c(OCc1ccccc1)c2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCN1CCn2c(nc(C(=O)NCc3ccc(F)cc3)c(OCc3ccccc3)c2=O)C1(C)C
Temperature: 45 °C

Procedure:
A mixture of 3-(benzyloxy)-N-(4-fluorobenzyl)-9,9-dimethyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrazino[1,2-a]pyrimidine-2-carboxamide (prepared as described in Example 3, Step 1) (1 eq.), K2CO3 (2 eq.), propargyl bromide (2.5 eq.) in DMF was heated at 45° C. overnight and then cooled at room temperature. The solvent was removed under reduced pressure and the residue was taken up in EtOAc and washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to yield the titled acetylene. MS (ES) C27H27FN4O3 requires 474. Found: 475 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:16]1([O:22][C:23](Cl)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>C(Cl)Cl>[C:16]1([O:22][C:23](=[O:24])[NH:9][C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1ccc(N)cn1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(NC(=O)Oc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
6-Methoxy-pyridin-3-ylamine (1.0 g, 8.06 mmol) and pyridine (18 ml) are stirred in dry CH2Cl2. To this mixture phenylchloroformate (1.9 g, 12.0 mmol) is added and stirred for 24 hours at room temperature. Water and a solution of 1:1 EtOAc/hexanes is added to the mixture and the organic layer is separated. The organic layer is washed with 1N HCl three times and with brine once. The organic layer is dried over Na2SO4, filtered, and evaporated in vacuo. Purify by flash column chromatography (0-10% EtOAc/CH2Cl2) to obtain (6-methoxy-pyridin-3-yl)-carbamic acid phenyl ester. Mass spec.: m+1=245 (AP+). B. 1′-(6-methoxy-pyridin-3-yl-carbamoyl)-spiroisobenzofuran-1,4′-piperidine
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[CH3:22][C:23]1[N:24]=[N:25][N:26]([CH:29]2[CH2:33][CH2:32][NH:31][CH2:30]2)[C:27]=1[CH3:28].C1CCN2C(=NCCC2)CC1>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:31]4[CH2:32][CH2:33][CH:29]([N:26]5[C:27]([CH3:28])=[C:23]([CH3:22])[N:24]=[N:25]5)[CH2:30]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: Cc1nnn(C2CCNC2)c1C
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: Cc1nnn(C2CCN(c3c(F)cc4c(=O)c(C(=O)O)cn(C5CC5)c4c3F)C2)c1C

Procedure:
1-Cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (100 mg, 0.36 mmol) was reacted with 3-(4 , 5-dimethyl-1,2,3-triazol-1-yl)pyrrolidine hydrochloride (182 mg, 0.9 mmol) in 8 ml of dry pyridine in the presence of 137 mg (0.9 mmol) of DBU at 115° C. for five days. The small amount of the solid was filtered off and the supernatant was evaporated to dryness. To the residue, water and a few drops of acetonitrile were added. The solid was collected to afford after drying 125 mg (81%) of the desired product as a gray solid. m.p. 230-232 ° C. (dec). 1H NMR (CDCl3) δ: 8.74 (s, 1H), 7.84 (d, J=13.2Hz, 1H), 5.07-4.8 (m, 1H), 4.4-3.85 (m, 5H), 2.8-2.14 (m, 8H, singlet at 2.29, 6H), 1.4-1.0 (m, 4H). Anal. calcd. for C21H12F2N5O3.1/2 H2O: C, 57.52; H, 4.83; N, 15.97. Found: C, 57.68; H, 4.81; N, 15.68.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH3:12])[CH:9]=[C:10](I)[C:3]=12.[CH3:13][N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20](B3OC(C)(C)C(C)(C)O3)[CH:21]=2)[CH2:16][CH2:15]1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.CN(C=O)C.C(Cl)Cl.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>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH3:12])[CH:9]=[C:10]([C:20]3[CH:21]=[C:22]4[C:17]([CH2:16][CH2:15][N:14]4[CH3:13])=[CH:18][CH:19]=3)[C:3]=12
Reactant: CN1CCc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Reactant: Cn1cc(I)c2c(Br)ccnc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: CN1CCc2ccc(-c3cn(C)c4nccc(Br)c34)cc21
Temperature: 55 °C
Yield: 48.8 %

Procedure:
To a stirred solution of 4-bromo-3-iodo-1-methyl-1H-pyrrolo[2,3-b]pyridine (D7) (5 g, 14.84 mmol) and 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indoline (4.61 g, 17.81 mmol) in ACN (40 mL), DMF (40 mL) and DCM (20 mL) was added 2M sodium carbonate aq. solution (74.2 mL, 148 mmol). Bis(triphenylphosphine)palladium(II) chloride (1.250 g, 1.781 mmol) was then added to the solution and the resulting mixture was heated at 55° C. for ca. 1.5 hour. The reaction mixture was diluted with DCM (100 mL) and water (150 mL). The organic phase was separated and the aqueous phase was further extracted with DCM (100 mL×3). The combined organics were dried and concentrated. The residue was purified by chromatography on silica, eluting with a gradient of 0-20% ethyl acetate in cyclohexane. The corresponding fractions were combined and concentrated to give the title compound (2.48 g). LCMS (A): m/z (M+H)+ 342/344, C17H16BrN3 requires 341/343 (acidic).