Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:30]=[CH:29][C:6]2[O:7][C:8]([CH3:28])([CH3:27])[CH:9]=[C:10]([N:11]3[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][Si](C(C)(C)C)(C)C)[C:12]3=[O:26])[C:5]=2[CH:4]=1)#[N:2].Cl.O>CO.O1CCOCC1>[C:1]([C:3]1[CH:30]=[CH:29][C:6]2[O:7][C:8]([CH3:27])([CH3:28])[CH:9]=[C:10]([N:11]3[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][OH:18])[C:12]3=[O:26])[C:5]=2[CH:4]=1)#[N:2]
Reactant: CC1(C)C=C(n2cccc(CO[Si](C)(C)C(C)(C)C)c2=O)c2cc(C#N)ccc2O1
Agent: Cl
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)C=C(n2cccc(CO)c2=O)c2cc(C#N)ccc2O1
Yield: 73.8 %

Procedure:
In 9.00 ml of methanol, is dissolved 877 mg of 6-cyano-2,2-dimethyl-4-(1,2-dihydro-2-oxo-3-t-butyldimethylsilyloxymethyl-1-pyridinyl)-2H-benzz[b]pyran obtained in Example 17. Then, 2.20 ml of 4N hydrochloric acid in dioxane is added to the solution at 0° C. and reacted at room temperature for one hour. After stopping the reaction by adding water, the reaction mixture is extracted with ethyl acetate. The organic layer is washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The inorganic matter is filtered off, and the filtrate is concentrated under reduced pressure. The residue thus obtained is purified by silica gel column chromatography using 1/20 mixture of methanol/methylene chloride as a developing solvent and further by silica gel column chromatography using 1/1 mixture of ethyl acetate/n-hexane as a developing solvent. Thus, 472 mg of 6-cyano-2,2-dimethyl-4-(1,2-dihydro-2-oxo-3-hydroxymethyl-1-pyridinyl)-2H-benzo[b]pyran is obtained.
Reaction SMILES: [CH3:1][CH:2]([CH3:59])[C@H:3]([NH:54][C:55](=[O:58])[O:56][CH3:57])[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[C:11]1[NH:12][CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[N:29]=[C:30]([CH:33]5[CH2:37][C:36]6([CH2:42][CH2:41][NH:40][CH2:39][CH2:38]6)[CH2:35][N:34]5[C:43](=[O:53])[C@@H:44]([NH:48][C:49]([O:51][CH3:52])=[O:50])[CH:45]([CH3:47])[CH3:46])[NH:31][CH:32]=4)=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)[N:15]=1)=[O:5].C(N(CC)CC)C.[C:67](Cl)(=[O:69])[CH3:68].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[C:67]([N:40]1[CH2:39][CH2:38][C:36]2([CH2:35][N:34]([C:43](=[O:53])[C@@H:44]([NH:48][C:49]([O:51][CH3:52])=[O:50])[CH:45]([CH3:46])[CH3:47])[CH:33]([C:30]3[NH:31][CH:32]=[C:28]([C:25]4[CH:24]=[CH:23][C:22]([C:19]5[CH:20]=[CH:21][C:16]([C:14]6[N:15]=[C:11]([C@@H:7]7[CH2:8][CH2:9][CH2:10][N:6]7[C:4]([C@@H:3]([NH:54][C:55](=[O:58])[O:56][CH3:57])[CH:2]([CH3:59])[CH3:1])=[O:5])[NH:12][CH:13]=6)=[CH:17][CH:18]=5)=[CH:27][CH:26]=4)[N:29]=3)[CH2:37]2)[CH2:42][CH2:41]1)(=[O:69])[CH3:68]
Reactant: COC(=O)N[C@H](C(=O)N1CC2(CCNCC2)CC1c1nc(-c2ccc(-c3ccc(-c4c[nH]c([C@@H]5CCCN5C(=O)[C@@H](NC(=O)OC)C(C)C)n4)cc3)cc2)c[nH]1)C(C)C
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N1CC2(CCN(C(C)=O)CC2)CC1c1nc(-c2ccc(-c3ccc(-c4c[nH]c([C@@H]5CCCN5C(=O)[C@@H](NC(=O)OC)C(C)C)n4)cc3)cc2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 105.9 %

Procedure:
To a solution of methyl [(1S)-2-methyl-1-({(2S)-2-[4-(4′-{2-[2-((2S)-3-methyl-2-{[(methyloxy)carbonyl]amino}butanoyl)-2,8-diazaspiro[4.5]dec-3-yl]-1H-imidazol-4-yl}-4-biphenylyl)-1H-imidazol-2-yl]-1-pyrrolidinyl}carbonyl)propyl]carbamate (Example 20) (19 mg, 0.02 mmol) in anhydrous CH2Cl2 (0.5 mL) was added triethylamine (0.016 mL, 0.12 mmol) followed by acetyl chloride (0.01 mL, 0.14 mmol) and the reaction stirred at room temperature for 1 h. The reaction is concentrated in vacuo and dissolved in methanol (0.7 mL) to which was added potassium carbonate (30 mg, 0.22 mmol) and the reaction was stirred at room temperature for 2 h. The reaction was concentrated in vacuo and partitioned between CH2Cl2 and water (3 mL each) and the aqueous layer extracted with CH2Cl2 (3 mL) and the organic layers combined and dried (MgSO4) and concentrated in vacuo to afford the title compound as a yellow solid (18 mg, 90% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.54-7.88 (m, 10H) 7.32 (br. s., 2H) 5.05-5.23 (m, 2H) 4.03-4.34 (m, 2H) 3.71-4.03 (m, 3H) 3.56-3.71 (m, 8H) 3.34-3.56 (m, 2H) 2.14-2.46 (m, 4H) 1.89-2.14 (m, 6H) 1.46-1.83 (m, 4H) 1.19-1.32 (m, 2H) 0.78-1.07 (m, 14H). HRMS for C46H60N9O7 (M+H)+ calc: 850.4616, found: 850.4617. Purity (LC-MS): 94%.
Reaction SMILES: Br[C:2]1[S:18][C:5]2[N:6]=[C:7]([CH2:10][CH2:11][N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:8]=[CH:9][C:4]=2[CH:3]=1.[CH:19]1([NH:22][C:23](=[O:40])[C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26](B3OC(C)(C)C(C)(C)O3)[CH:25]=2)[CH2:21][CH2:20]1.[F-].[Cs+].O1CCOCC1>CCOC(C)=O.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.O>[CH:19]1([NH:22][C:23](=[O:40])[C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([C:2]3[S:18][C:5]4[N:6]=[C:7]([CH2:10][CH2:11][N:12]5[CH2:17][CH2:16][O:15][CH2:14][CH2:13]5)[N:8]=[CH:9][C:4]=4[CH:3]=3)[CH:25]=2)[CH2:20][CH2:21]1
Reactant: Brc1cc2cnc(CCN3CCOCC3)nc2s1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1cc2cnc(CCN3CCOCC3)nc2s1
Temperature: 150 °C

Procedure:
A 5 ml glass microwave reaction vessel was charged with 6-bromo-2-(2-morpholinoethyl)thieno[2,3-d]pyrimidine. (0.200 g, 0.582 mmol), N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.135 g, 0.582 mmol), cesium fluoride (0.277 g, 1.75 mmol), tetrakis(triphenylphosphine)palladium(0) (0.046 g, 0.040 mmol), 1,4-dioxane (1 mL, 57 mmol) and water (1 ml). The reaction mixture was heated in a Smith Synthesizer microwave reactor (Personal Chemistry, Inc., Upssala, Sweden) at 150° C. for 20 min. The reaction mixture was diluted with EtOAc and filtered through Celite®. The organic solutions were evaporated under reduced pressure. The crude residue was suspended in DCM and washed with saturated sodium bicarbonate (1×25 mL) followed by brine (1×25 mL), water (1×25 mL) and dried over MgSO4. The organic solutions were evaporated under reduced pressure and the residue was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 5% to 95% MeOH in DCM to provide the title compound (0.095 g) MS (ES+): 438 (M+H)+.
Reaction SMILES: C(N[C:9]1[CH:10]=[C:11]2[C:16](=[N:17][CH:18]=1)[NH:15][C:14](=[O:19])[C:13]1[CH:20]=[CH:21][CH:22]=[CH:23][C:12]2=1)C1C=CC=CC=1.C([O-])=O.[NH4+:27]>CO.[Pd]>[CH2:11]([NH:27][C:21]1[CH:22]=[CH:23][C:12]2[C:11]3[C:16](=[N:17][CH:18]=[CH:9][CH:10]=3)[NH:15][C:14](=[O:19])[C:13]=2[CH:20]=1)[C:12]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:13]=1
Reactant: O=c1[nH]c2ncc(NCc3ccccc3)cc2c2ccccc12
Reactant: [NH4+]
Agent: [Pd]
Agent: O=C[O-]
Solvent: CO
Product: O=c1[nH]c2ncccc2c2ccc(NCc3ccccc3)cc12
Temperature: 60 °C
Reaction time: 8 h
Yield: 20.1 %

Procedure:
2-Benzylamino-5H-benzo[c][1,8]naphthyridin-6-one (100 mg, 0.33 mmol), ammonium formate (209 mg, 3.30 mmol), and palladium/carbon (200 mg, 10% weight) were suspended in MeOH (6 mL) and stirred overnight at 60° C. The reaction mixture was filtered through celite, and the celite was washed with methanol. The filtrate was concentrated, and the crude product was purified via prep-LC-MS to provide 19 (10 mg, 14% yield) as a yellow solid. LC-MS (M+H=212, obsd.=212). 1H NMR (400 MHz, d6-DMSO): δ 11.63 (s, 1H), 8.31 (d, 1H), 8.28 (d, 1H), 7.96 (d, 1H), 7.85 (m, 2H), 7.64 (t, 1H), 7.31 (m, 1H), 7.24 (m, 1H).
Reaction SMILES: F[C:2](F)(F)[C:3](O)=[O:4].[N+:8]([C:11]1[CH:12]=[C:13]([CH:31]=[CH:32][CH:33]=1)[CH2:14][NH:15][CH2:16][C:17]1[CH:18]=[C:19]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:20]=[CH:21][CH:22]=1)([O-:10])=[O:9].N1C=CC=CC=1.C(OC(=O)C)(=O)C>C(#N)C.CN(C)C1C=CN=CC=1>[C:3]([N:15]([CH2:16][C:17]1[CH:18]=[C:19]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:29])[CH3:27])[CH:20]=[CH:21][CH:22]=1)[CH2:14][C:13]1[CH:31]=[CH:32][CH:33]=[C:11]([N+:8]([O-:10])=[O:9])[CH:12]=1)(=[O:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cccc(CNCc2cccc([N+](=O)[O-])c2)c1
Reactant: O=C(O)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N(Cc1cccc(NC(=O)OC(C)(C)C)c1)Cc1cccc([N+](=O)[O-])c1
Temperature: 20 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
A solution of tert-butyl (3-{[(3-nitrobenzyl)amino]methyl}phenyl)carbamate trifluoroacetate (0.16 g, 0.34 mmol) in acetonitrile (5.2 mL) was treated with 4-dimethylaminopyridine (8.3 mg, 68 μmol), pyridine (0.14 mL, 1.7 mmol), and acetic anhydride (35 μL, 0.37 mmol) and stirred at 20° C. for 16 h. The reaction mixture was purified by preparative LCMS to give the desired product (95 mg, 70%). LCMS for C21H25N3O5Na (M+Na)+: m/z=422.0.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[CH:16][C:3]=12.[I:17]N1C(=O)CCC1=O>C(#N)C>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([I:17])[C:3]=12
Reactant: Clc1c(-c2ccccc2)nnc2[nH]ncc12
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: Clc1c(-c2ccccc2)nnc2[nH]nc(I)c12

Procedure:
A suspension of 4-chloro-5-phenyl-1H-pyrazolo[3,4-c]pyridazine (2.44 g, 10.6 mmol) and N-iodosuccinimide (3.58 g, 15.9 mmol) in acetonitrile (106 mL) was heated at reflux for 1 d. The yellow solid was collected by filtration while warm to provide a mixture of the title compound and starting material (9:1, 4 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[C:11](Cl)(=[O:15])[C:12]([Cl:14])=[O:13]>CCOCC>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C:11](=[O:15])[C:12]([Cl:14])=[O:13])=[CH:5][NH:6]2
Reactant: Fc1cccc2[nH]ccc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Product: O=C(Cl)C(=O)c1c[nH]c2cccc(F)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.9 %

Procedure:
To a stirred solution of 4-fluoroindole (2.00 g, 14.8 mmol) in ether (15 mL), at 0° C. under Ar, was added oxalyl chloride (1.55 mL, 17.8 mmol) dropwise. The resulting suspension was stirred at room temperature for 1 h and then it was filtered and the filtercake was washed with ether. The resulting solid was dried in vacuo to give the title compound (2.60 g, 78%) as a yellow powder:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([CH2:15][N:16](C(OCC3C=CC=CC=3)=O)[CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:33][N:34](C(OCC1C=CC=CC=1)=O)[CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>CO.[Pd]>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([CH2:15][NH:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:33][NH:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: COc1ccc2c(OC)c(CN(C(=O)OCc3ccccc3)C3CCCCC3)ccc2c1CN(C(=O)OCc1ccccc1)C1CCCCC1
Agent: [Pd]
Solvent: CO
Product: COc1ccc2c(OC)c(CNC3CCCCC3)ccc2c1CNC1CCCCC1

Procedure:
A solution of 1,6-dimethoxy-2,5-bis-[N-(cyclohexyl)benzyloxycarbonylaminomethyl)-naphthalene (250 mg) in methanol (10 ml) was hydrogenated at atmospheric pressure in the presence of 5% palladium-on-charcoal (50 mg) for 2 hours at room temperature. The catalyst was removed by filtration through Celite, and the filtrate was evaporated to afford the product as a yellow syrup; yield 60 mg (37%).
Reaction SMILES: [I:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[N:4]=[C:5](Cl)[C:6](Cl)=[N:7]2.[CH3:15][O-:16].[Na+].[CH3:18][OH:19]>>[Cl:12][C:10]1[CH:9]=[C:8]2[C:3]([N:4]=[C:5]([O:19][CH3:18])[C:6]([O:16][CH3:15])=[N:7]2)=[C:2]([I:1])[CH:11]=1
Reactant: CO
Reactant: C[O-]
Reactant: Clc1cc(I)c2nc(Cl)c(Cl)nc2c1
Agent: [Na+]
Product: COc1nc2cc(Cl)cc(I)c2nc1OC
Temperature: 0 °C
Reaction time: 18 h
Yield: 48.8 %

Procedure:
205 g (0.828 mol) of 5-iodo-2,3,7-trichloro-quinoxaline are placed in 2255 ml of methanol at room temperature, and 463.9 ml of an approximately 5.4 molar solution of sodium methanolate in methanol are added. The reaction mixture is then heated to reflux and stirred for 18 hours. The reaction mixture is cooled to 0° C. and the suspension is filtered with suction. The filter residue is then washed with methanol and dried in vacuo at 60° C., and the crude product is purified by means of continuous extraction with diethyl ether. 96.4 g (48.8%) of 7-chloro-2,3-dimethoxy-5-iodo-quinoxaline having a melting point of 94-96° C. are obtained.
Reaction SMILES: C(N(CC)C(C)C)(C)C.ClCCl.[I:13][C:14]1[C:15]([OH:22])=[N:16][C:17]([CH3:21])=[N:18][C:19]=1[CH3:20].[CH3:23][O:24][CH2:25]Cl>O>[I:13][C:14]1[C:15](=[O:22])[N:16]([CH2:23][O:24][CH3:25])[C:17]([CH3:21])=[N:18][C:19]=1[CH3:20].[I:13][C:14]1[C:15]([O:22][CH2:23][O:24][CH3:25])=[N:16][C:17]([CH3:21])=[N:18][C:19]=1[CH3:20]
Reactant: COCCl
Reactant: Cc1nc(C)c(I)c(O)n1
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1nc(C)nc(C)c1I
Product: COCn1c(C)nc(C)c(I)c1=O
Temperature: -40 °C

Procedure:
N,N-diisopropylethylamine (13.1 ml) was added to a dichloromethane (100 ml) solution of the compound 326-2 (14.5 g). Chloromethyl methyl ether (4.85 ml) was added to the reaction solution, while the solution was stirred at −40° C. The obtained mixture was stirred at room temperature for 15 hours. Water was added to the reaction solution, and the mixture was extracted with dichloromethane. The obtained organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=19:1 to 0:1), so as to obtain the title compound (10.6 g) and 5-iodo-4-(methoxymethoxy)-2,6-dimethylpyrimidine (2.55 g).
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].CC[O-].[Na+].C(O)C.Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1>ClCCl>[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][S:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:19][CH:18]=1
Reactant: Cc1ccc(CBr)cc1
Reactant: CCOC(=O)CS
Agent: CC[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)CSCc1ccc(C)cc1

Procedure:
Ethyl 2-mercaptoacetate (8.5 cc) is added in the course of 15 minutes at a temperature in the region of 20° C. to a stirred solution, through which a stream of nitrogen is passed, of a 2M ethanolic solution of sodium ethylate (37.5 cc) and ethanol (50 cc). The mixture is left with stirring for 15 minutes at the same temperature, and α-bromo-p-xylene (13.9 g) is then added in the course of 20 minutes at a temperature in the region of 20° C. Stirring is maintained for 60 minutes at this temperature, and the reaction mixture is then evaporated to dryness at 50° C. under reduced pressure (20 mm Hg; 2.7 kPa). The residue obtained is dissolved in dichloromethane (100 cc), and the organic phase is dried over anhydrous magnesium sulphate, filtered and concentrated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). Ethyl (4-methylbenzylthio)acetate (15.6 g) is thereby obtained, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH2:6][C:7]3[NH:12][C:11]4[N:13]=[CH:14][CH:15]=[CH:16][C:10]=4[C:8]=32)[CH2:3][CH2:2]1.[H-].[Na+].CC1C=CC(S(O[CH2:30][CH2:31][C:32]2[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=2)(=O)=O)=CC=1>CN(C=O)C.O>[CH3:38][C:35]1[N:34]=[CH:33][C:32]([CH2:31][CH2:30][N:12]2[C:7]3[CH2:6][CH2:5][N:4]4[CH:9]([C:8]=3[C:10]3[CH:16]=[CH:15][CH:14]=[N:13][C:11]2=3)[CH2:1][CH2:2][CH2:3]4)=[CH:37][CH:36]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(C)nc2)cc1
Reactant: c1cnc2[nH]c3c(c2c1)C1CCCN1CC3
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(CCn2c3c(c4cccnc42)C2CCCN2CC3)cn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2,3,5,6,7,11c-hexahydro-1H-pyrido[3′,2′:4,5]pyrrolo[2,3-g]indolizine (120 mg, 0.565 mmol) in DMF (1 mL) was added a suspension of NaH (68.0 mg, 1.69 mmol) in DMF (1 mL). After stirring for 5 min at rt, a solution of 2-(6-methylpyridin-3-yl)ethyl 4-methylbenzenesulfonate (492 mg, 1.69 mmol) in DMF (1 mL) was added dropwise into the reaction mixture and stirring continued for another 2 h at RT. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3×25 mL). The organic layer was washed with water (3×20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by silica gel flash chromatography (MeOH-DCM) to yield 7-(2-(6-methylpyridin-3-yl)ethyl)-2,3,5,6,7,11c-hexahydro-1H-pyrido[3′,2′:4,5]pyrrolo[2,3-g]indolizine;
Reaction SMILES: ClC(Cl)(Cl)COC(NC([N:12]1[CH2:15][CH:14]([NH:16][C:17](=[O:25])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]1=[O:26])C(C)C)=O.C(=O)(O)[O-].[Na+]>C(O)(=O)C.[Zn]>[C:19]1([CH2:18][C:17]([NH:16][CH:14]2[CH2:15][NH:12][C:13]2=[O:26])=[O:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)C(NC(=O)OCC(Cl)(Cl)Cl)N1CC(NC(=O)Cc2ccccc2)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C(Cc1ccccc1)NC1CNC1=O
Reaction time: 0.5 h
Yield: 58.6 %

Procedure:
1-[1-(2,2,2-Trichloroethoxycarbonylamino)-2-methylpropyl]-3-(2-phenylacetamido)-2-azetidinone (1.13 g.) was dissolved in a 90% acetic acid aqueous solution (20 ml.), and the solution was cooled to 5° C. (Zinc powder (1.62 g.) was added dropwise to said solution in 5 minutes, and the mixture was stirred for 30 minutes. Furthermore, zinc powder (1.62 g.) was added to said mixture, and the mixture was stirred for 2 days. The reaction mixture was neutralized with a sodium bicarbonate aqueous solution, and extracted with methylene chloride. The extract was washed with water and dried over anhydrous magnesium sulfate, and then the solvent was distilled off from the solution. The residue (0.65 g.) was subjected to preparative thin layer chromatography using silica.gel [developing solvent; a mixed solvent of ethyl acetate, ethyl methyl ketone, water and formic acid (volume ratio 5:3:1:1)], isolated and purified to give 3-(2-phenylacetamido)-2-azetidinone (0.3 g.). Mp 190° to 192° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=2)=O)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C(OP([CH2:31][C:32]#[N:33])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O1C2C=CC(C(C3C=C(OC)C=C(OC)C=3)=CC#N)=CC=2OCC1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=2)=[CH:31][C:32]#[N:33])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1cc(OC)cc(C(=O)c2cc(OC)cc(OC)c2)c1
Reactant: CCOP(=O)(CC#N)OCC
Agent: COc1cc(OC)cc(C(=CC#N)c2ccc3c(c2)OCCO3)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C(=CC#N)c2cc(OC)cc(OC)c2)c1
Yield: 76.3 %

Procedure:
Bis-(3,5-dimethoxyphenyl)methanone (1.29 g, 4.27 mmol), cyanomethylphosphonic acid diethyl ester (1.34 ml, 8.53 mmol) in anhydrous THF (10 ml), and lithium bis (trimethylsilyl)amide (1.0 M solution in THF, 8.53 ml, 8.53 mmol) were treated in the same manner as described above for the synthesis of 3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxyphenyl)acrylonitrile. The crude material was purified via flash column chromatography (5% EtOAc in hexane gradient to 40% EtOAc in hexane in about 45 min.) to give 3,3-bis-(3,5-dimethoxy-phenyl)-acrylonitrile as an off-white solid (1.06 g, 76%): mp, 149-151° C.; 1HNMR (DMSO-d6) δ 6.66-6.62 (m, 2H, Ar), 6.50-6.47 (m, 4H, Ar), 6.39 (s, 1H, double bond proton), 3.76 (s, 6H, 2OCH3), 3.74 (s, 6H, 2OCH3); 13C NMR(CDCl3) δ 163.0, 160.9, 160.8, 140.8, 138.7, 117.7, 107.8, 106.9, 102.4, 102.2, 95.5, 55.6; Anal. Calcd. For C19H19NO4: C, 70.14; H, 5.89; N, 4.30. Found: C, 69.93; H, 5.96;N, 4.18.
Reaction SMILES: C([N:8]1[CH:12]([CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:11][CH2:10][CH:9]1[CH2:22][OH:23])C1C=CC=CC=1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[Si:15]([O:14][CH2:13][CH:12]1[NH:8][CH:9]([CH2:22][OH:23])[CH2:10][CH2:11]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)OCC1CCC(CO)N1Cc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCC1CCC(CO)N1
Yield: 86.8 %

Procedure:
To a solution of 1-benzyl-5-t-butyldimethylsilyloxymethyl-2-hydroxymethylpyrrolidine (6.3 g) in methanol (63 ml) was added palladium hydroxide on carbon (630 mg) under nitrogen atmosphere. The apparatus was evacuated to remove nitrogen, then filled with hydrogen, and the mixture was stirred under hydrogen atmosphere until 19 mmol of hydrogen was absorbed. The palladium hydroxide on carbon was filtered off and the solvent was removed under reduced pressure to give 5-t-butyldimethylsilyloxymethyl-2-hydroxymethylpyrrolidine (4.0 g). To a solution of this residue in tetrahydrofuran (60 ml) and water (30 ml) were added sodium bicarbonate (4.10 g) and then allyl chloroformate (1.42 ml) at room temperature. After stirring for 2 hours, sodium bicarbonate (2.1 g) and allyloxycarbonyl chloride (1.42 ml) was added. After stirring for an hour, ethyl acetate (100 ml) and water (50 ml) were added and the aqueous layer was separated and extracted twice with ethyl acetate. The combined organic layer was washed with 1N hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine successively, dried over magnesium sulfate and evaporated under reduced pressure. The residue was column chromatographed on silica gel (eluent: hexane/ethyl acetate, 9:1-4:1 V/V) to give 1-allyloxycarbonyl-5-t- butyldimethylsilyloxymethyl-2-hydroxymethylpyrrolidine (4.91 g).
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([NH2:9])[CH:6]=[CH:5][C:4]=1[C:10]#[C:11][Si](C)(C)C)[CH3:2].C([O-])([O-])=O.[K+].[K+]>CO>[CH2:1]([C:3]1[N:8]=[C:7]([NH2:9])[CH:6]=[CH:5][C:4]=1[C:10]#[CH:11])[CH3:2]
Reactant: CCc1nc(N)ccc1C#C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(N)nc1CC

Procedure:
The title compound is synthesized according to general procedure GP3 starting from to 12.23 g (56 mmol) 6-ethyl-5-trimethylsilanylethynyl-pyridin-2-ylamine and 3.87 g (28 mmol) K2CO3 in 120 mL MeOH. The product is purified by chromatography on silica gel using a DCM/MeOH gradient. Yield: 4.5 g (85%).
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:13](OC)=[O:14]>C1COCC1.CO>[CH3:3][C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[CH2:13][OH:14]
Reactant: COC(=O)c1nc2ccccn2c1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(CO)nc2ccccn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
Sodium borohydride (1.5 g, 41.6 mmol) was added to a solution of methyl 3-methylimidazo[1,2-a]pyridine-2-carboxylate (2.0 g, 10.5 mmol) in THF (50 mL) and methanol (2.5 ml) at RT. The reaction mixture was stirred at RT for 2 h (the reaction was monitored by TLC) upon which the mixture was concentrated under reduced pressure. The residue was diluted with water and extracted with EtOAc. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford (3-methylimidazo[1,2-a]pyridin-2-yl)methanol (0.8 g, 47.05%,) as off-white solid. 1H NMR: 200 MHz, CDCl3: δ 7.45 (d, 1H), 7.6 (d, 1H), 7.2 (t, 1H), 6.8 (t, 1H), 4.85 (s, 2H), 2.45 (s, 3H). MS: [M+H]+: m/z=162.9.