Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15](Cl)=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:19])[NH:7][C:6](=[O:20])[N:5]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:4]=2[N:3]=1.Br[CH2:30][CH2:31][CH2:32][O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:11]([N:10]1[C:9]2[C:8](=[O:19])[N:7]([CH2:30][CH2:31][CH2:32][O:33][Si:34]([C:37]([CH3:38])([CH3:40])[CH3:39])([CH3:35])[CH3:36])[C:6](=[O:20])[N:5]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:4]=2[N:3]=[C:2]1[Cl:1])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C[Si](C)(C)CCOCn1c(=O)[nH]c(=O)c2c1nc(Cl)n2Cc1ccc(Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCn1c(=O)c2c(nc(Cl)n2Cc2ccccc2)n(COCC[Si](C)(C)C)c1=O
Temperature: 70 °C
Reaction time: 8 h
Yield: 103.3 %

Procedure:
To a solution of 8-chloro-7-(4-chlorobenzyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione (250 mg, 0.568 mmol) in DMF (30 mL) was added (3-bromopropoxy)(tert-butyl)dimethylsilane (0.2 g, 0.794 mmol), followed by potassium carbonate (160 mg, 1.13 mmol). The mixture was stirred at 70° C. overnight. The reaction was cooled and partitioned between ethyl acetate and water. The combined organic phase was washed with brine, dried over sodium sulfate, and concentrated to give 7-benzyl-1-(3-(tert-butyldimethylsilyloxy)propyl)-8-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione (340 mg, 97.4% yield) as colorless oil. LCMS retention time 4.675 min; LCMS MH+ 613.
Reaction SMILES: [CH2:1]1[O:29][C:4]2=[CH:5][C:6]3[C:12]([C:13]4[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=4)=[N:11][N:10]([CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[C:9](=[O:27])[CH2:8][C:7]=3[CH:28]=[C:3]2[O:2]1.O.NN>C(O)C.Cl.[Ni]>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[C:6]3[CH:5]=[C:4]4[O:29][CH2:1][O:2][C:3]4=[CH:28][C:7]=3[CH2:8][C:9](=[O:27])[N:10]([CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[N:11]=2)=[CH:14][CH:15]=1
Reactant: CCC(CC)N1N=C(c2ccc([N+](=O)[O-])cc2)c2cc3c(cc2CC1=O)OCO3
Agent: [Ni]
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: CCC(CC)N1N=C(c2ccc(N)cc2)c2cc3c(cc2CC1=O)OCO3
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.4 %

Procedure:
To a solution of 7,8-methylenedioxy-1-(4-nitrophenyl)-3-(3-pentyl)-3,5-dihydro-2,3-benzodiazepin-4(4H)-one (48 mg, 0.123 mmol) in ethanol (10 mL) was added hydrazine hydrate (0.5 mL), 3 drops of conc. HCl, and excess amount of Raney Ni and the mixture obtained was stirred at room temperature for 1.5 h. Then the Raney Ni was removed by decanting. The crude product obtained by removal of the solvent was purified by flash chromatography (1:1 of hex:EtOAc) to give the product (42 mg, 94%), 1H NMR (CDCl3) 7.46 (d, J=8.3, 2H), 6.69 (d, J=8.3, 2H), 6.85 (s, 1H), 6.70 (s, 1H), 6.04, (bs, 1H), 6.01 (bs, 1H), 4.49 (heptet, J=4.9, 1H), 3.92 (bs, 2H), 3.50 (d, J=16.3, 1H), 3.29 (d, J=16.3, 1H), 2.10 (m, 1H), 1.72 (m, 1H), 1.48 (m, 21H), 0.98 (t, J=7.2, 3H), 0.48 (t, J=7.2, 3H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH:12]=[O:13])[NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:20]1[O:23][CH:21]1[CH3:22]>C(O)C>[OH:23][CH:21]([CH3:22])[CH2:20][N:10]1[CH:11]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[C:9]1[CH:12]=[O:13]
Reactant: CC1CO1
Reactant: O=Cc1nc(-c2ccccc2)c[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)Cn1cc(-c2ccccc2)nc1C=O
Temperature: 100 °C

Procedure:
In a closed vessel a slurry of 4-phenyl-1H-imidazole-2-carbaldehyde (200 mg, 1.16 mmol) and sodium carbonate (60 mg, 0.6 mmol) in ethanol (4 mL) was treated with propylene oxide (170 μL, 2.4 mmol) and heated at 100° C. for 3 h. The cooled solution was filtered and the solids washed with DCM. The volatiles were removed in vacuo to yield the crude title compound which was used without further purification (250 mg, 63%). LC-MS: m/z=231.5 (MH+), tR=0.41 min, method A
Reaction SMILES: COP([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])(OC)=O.[H-].[Na+].[F:17][C:18]([F:24])([F:23])[CH:19]([CH3:22])[CH:20]=O>C1COCC1>[F:17][C:18]([F:24])([F:23])[CH:19]([CH3:22])/[CH:20]=[CH:7]/[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: CC(C=O)C(F)(F)F
Reactant: COP(=O)(CC(=O)OC(C)(C)C)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(/C=C/C(=O)OC(C)(C)C)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 40.6 %

Procedure:
A solution of tert-butyl 2-(dimethoxyphosphoryl)acetate (9.78 g, 43.6 mmol) in THF (10 mL) was slowly transferred to a suspension of NaH (60% dispersion in mineral oil) (1.903 g, 47.6 mmol) in THF (30 mL) at 0° C. under a nitrogen atmosphere. After the addition was complete, the reaction mixture was stirred at 0° C. for 10 min, and then warmed to room temperature. After being stirred for 30 min, the reaction mixture was cooled to 0° C. again, and a solution of 3,3,3-trifluoro-2-methylpropanal (5 g, 39.7 mmol) in THF (10 mL) was added, and the ice bath was removed. After 12 h at 25° C., the mixture was partitioned between water (60 mL) and EtOAc (60 mL). The aqueous layer was extracted with EtOAc (60 mL), and the combined organic layers were successively washed with water (60 mL) and brine. The resulting solution was dried over MgSO4, concentration under reduced pressure, and purified by silica gel flash chromatography (330 g column, 0% to 15% EtOAc in hexane over 20 min) to obtain Intermediate S-5A (3.61 g, 16.10 mmol, 40.6% yield). 1H NMR (400 MHz, chloroform-d) δ 6.77 (dd, J=15.8, 7.7 Hz, 1H), 5.95 (dd, J=15.7, 0.6 Hz, 1H), 3.12-2.93 (m, 1H), 1.56-1.47 (m, 9H), 1.37-1.27 (m, 3H).
Reaction SMILES: [CH2:1]([N:8]1[C@H:13]([CH3:14])[CH2:12][N:11]([C@@H:15]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=2)[C:16]2[CH:25]=[C:24]3[C:19]([CH2:20][CH2:21][N:22]([CH2:26][C:27]([O:29]C)=[O:28])[CH2:23]3)=[CH:18][CH:17]=2)[C@@H:10]([CH3:39])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>O1CCOCC1.CO>[CH2:1]([N:8]1[C@@H:13]([CH3:14])[CH2:12][N:11]([C@@H:15]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=2)[C:16]2[CH:25]=[C:24]3[C:19]([CH2:20][CH2:21][N:22]([CH2:26][C:27]([OH:29])=[O:28])[CH2:23]3)=[CH:18][CH:17]=2)[C@@H:10]([CH3:39])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CN1CCc2ccc([C@H](c3cccc(OC)c3)N3C[C@@H](C)N(Cc4ccccc4)C[C@@H]3C)cc2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: COc1cccc([C@@H](c2ccc3c(c2)CN(CC(=O)O)CC3)N2C[C@H](C)N(Cc3ccccc3)C[C@@H]2C)c1
Reaction time: 16 h
Yield: 78.6 %

Procedure:
To a solution of the compound of Example 104 (0.85 g) in dioxan (20 ml) and methanol (10 ml) was added an aqueous solution of sodium hydroxide (2N, 5 ml). After 16 hours, the pH of the reaction was adjusted to pH5 using 1N aqueous hydrochloric acid solution and the solvent removed under reduced pressure. The crude product was purified on silica gel, eluting with a solvent gradient of 90:10:2 to 80:20:3 dichloromethane: methanol:ammonia solution. The fractions containing the product were pooled and the solvent removed under reduced pressure. The residue was taken up in a mixture of water and 1 drop of aqueous ammonium hydroxide solution and freeze-dried to give the title compound (0.65 g, 65%).
Reaction SMILES: [CH:1]([CH:3]=[O:4])=[O:2].[CH3:5][C:6]([CH3:11])([CH2:9]O)[CH2:7][OH:8].C1(C)C=CC(S(O)(=O)=O)=CC=1.[O-]S([O-])(=O)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C1C=CC=CC=1>[CH:1]([CH:3]1[O:8][CH2:7][C:6]([CH3:11])([CH3:9])[CH2:5][O:4]1)=[O:2]
Reactant: O=CC=O
Reactant: CC(C)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: c1ccccc1
Product: CC1(C)COC(C=O)OC1
Yield: 50 %

Procedure:
Streamlined Synthesis of 5-(5,5-Dimethyl-1,3-dioxan-2-yl)dipyrromethane (2). A mixture of glyoxal (10.0 g of 40 wt. % aqueous solution, 0.070 mol), 2,2-dimethyl 1,3-propanediol (7.28 g, 0.070 mol) and p-toluenesulfonic acid (0.260 g, 1.36 mmol) in benzene (140 mL) was refluxed for 4 h in a flask fitted with a Soxhlet extractor containing Na2SO4. Then the reaction mixture was treated with solid NaHCO3 (0.250 g, 2.90 mmol) and filtered. The filtrate was concentrated, affording crude 2-formyl-5,5-dimethyl-1,3-dioxane (1). The crude 1 was treated with pyrrole (223 mL, 3.45 mol; an amount corresponding to an assumed yield of 50% for the glyoxal monoacetal) and the standard reaction for dipyrromethane formation20 was carried out. InCl3 (0.762 g, 3.45 mmol) was added and the mixture was stirred under argon at room temperature for 1.5 h. The reaction mixture was worked up by addition of NaOH (4.13 g, 103 mmol), filtration, recovery of excess pyrrole from the filtrate, trituration of the resulting residue with hexanes to remove traces of pyrrole, and chromatography [silica, hexanes/CH2Cl2/ethyl acetate (7:2:1)], affording a pale yellow solid (2.84 g, 32%): mp 112-114° C.; 1H NMR δ 0.74 (s, 3H), 1.15 (s, 3H), 3.51 (d, J=11 Hz, 2H), 3.57 (d, J=11 Hz, 2H), 4.42 (d, J=2 Hz, 1H), 4.85 (d, J=2 Hz, 1H), 5.92 (m, 2H), 6.13 (m, 2H), 6.73 (m, 2H), 8.75 (s, 2H); Anal. Calcd for C15H20N2O2: C, 69.20; H, 7.74; N, 10.76. Found: C, 69.18; H, 7.77; N, 10.71.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:4]=1[CH2:5][N:6]1[C:11](=[O:12])[CH:10]2[C:8]([CH:13]=[O:14])([CH2:9]2)[CH2:7]1.O.O.P([O-])(O)(O)=[O:24].[Na+].CC(=CC)C.Cl([O-])=O.[Na+]>C(O)(C)(C)C.O1CCCC1.O.O>[CH3:1][O:2][C:3]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:4]=1[CH2:5][N:6]1[C:11](=[O:12])[CH:10]2[C:8]([C:13]([OH:24])=[O:14])([CH2:9]2)[CH2:7]1
Reactant: O=P([O-])(O)O
Reactant: COc1ccc(CN2CC3(C=O)CC3C2=O)c(OC)c1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Solvent: O
Product: COc1ccc(CN2CC3(C(=O)O)CC3C2=O)c(OC)c1
Temperature: 0 °C
Reaction time: 24 h
Yield: 32.4 %

Procedure:
Under argon atmosphere, to a solution of 3-(2,4-dimethoxybenzyl)-4-oxo-3-azabicyclo[3.1.0]hexane-1-carbaldehyde (10.8 mg) in tert-butanol/tetrahydrofuran/water (4/3/1, 0.5 ml) was added sodium dihydrogenphosphate dihydrate (20.2 mg) at room temperature. This reaction mixture was cooled to 0° C., 2-methyl-2-butene (18 μl) and sodium chlorite (9.0 mg) were sequentially added thereto, and then the mixture was stirred at room temperature for 24 hours. This reaction mixture was cooled to 0° C., and then water was added thereto, and the mixture was extracted with ethyl acetate. This organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel thin-layer chromatography (eluent: chloroform/methanol=9/1) to give the titled compound (3.7 mg).
Reaction SMILES: C1([Si](OC)(OC)OC)C=CC=CC=1.C(O[Si](OCC)(OCC)OCC)C.C[Si](OCC)(OCC)OCC.[F:38][C:39]([F:44])([F:43])[C:40]([O-:42])=[O:41].C(O[Si](CCC[NH+:58]1[CH2:62][CH2:61][N:60]=[CH:59]1)(OCC)OCC)C.Cl.C(OCC(O)C)C>O.CC(C)=O.CO.C(O)C>[F:38][C:39]([F:44])([F:43])[C:40]([O-:42])=[O:41].[NH+:58]1[CH:62]=[CH:61][NH:60][CH:59]=1
Reactant: CCO[Si](CCC[NH+]1C=NCC1)(OCC)OCC
Agent: CCOCC(C)O
Agent: CCO[Si](C)(OCC)OCC
Agent: CCO[Si](OCC)(OCC)OCC
Solvent: CO
Solvent: CC(C)=O
Solvent: O
Product: c1c[nH+]c[nH]1
Temperature: 25 °C

Procedure:
4.92 g of phenyltrimethoxysilane, 72.40 g of tetraethoxysilane, 22.04 g of methyltriethoxysilane, 0.64 g of the 30% ethanol solution of triethoxysilylpropyl-4,5-dihydroimidazolium trifluoroacetate, and 150 g of acetone were charged into a 500 mL flask to be dissolved and the resultant mixed solution was warmed while stirring the mixed solution with a magnetic stirrer to reflux. Next, 33.10 g of 0.01 M hydrochloric acid was added to the mixed solution. The mixed solution was subjected to the reaction for 240 minutes and then the resultant reaction solution was cooled down to room temperature. Then, 200 g of propylene glycol monoethyl ether was added to the reaction solution, and ethanol and methanol as reaction by-products, acetone, water, and hydrochloric acid were distilled off under reduced pressure to obtain a hydrolysis-condensation product. The polymer thus obtained corresponded to Formula (VII-9):
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]2[C:5]([O:6][CH2:7][CH2:8][N:9]3[C:13]2=[N:12][C:11]([C:16]2[N:20]([CH:21]([CH3:23])[CH3:22])[N:19]=[C:18]([CH3:24])[N:17]=2)=[CH:10]3)=[CH:4][C:3]=1[CH3:25].C([Sn](CCCC)(CCCC)[C:31]([O:33][CH2:34][CH3:35])=[CH2:32])CCC.[Li+].[Cl-].[F-].[K+]>C1COCC1.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>[CH2:34]([O:33][C:31]([C:2]1[CH:15]=[C:14]2[C:5]([O:6][CH2:7][CH2:8][N:9]3[C:13]2=[N:12][C:11]([C:16]2[N:20]([CH:21]([CH3:22])[CH3:23])[N:19]=[C:18]([CH3:24])[N:17]=2)=[CH:10]3)=[CH:4][C:3]=1[CH3:25])=[CH2:32])[CH3:35]
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(Br)c(C)cc2OCC3)n(C(C)C)n1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: C=C(OCC)c1cc2c(cc1C)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2
Temperature: 80 °C
Reaction time: 16 h
Yield: 136.3 %

Procedure:
A mixture of 13-bromo-12-methyl-4-[3-methyl-1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaene (1.50 g, 3.73 mmol), tributyl(1-ethoxyvinyl)stannane (1.35 g, 3.74 mmol), LiCl (472 mg, 11.2 mmol), Pd(PPh3)4 (130 mg, 0.120 mmol) in THF (30 mL) was stirred at 80° C. for 16 hrs under N2 atmosphere in a sealed tube. After being cooled to room temperature, the mixture was treated with aq. KF (2.0 M, 50.0 mL). The resulting mixture was stirred at room temperature for 1 h and then filtered. The filtrate was extracted with ethyl acetate (5×50 mL). The combined organic layer was washed with brine and dried over MgSO4. Removal of the solvent gave the crude product (2.0 g, over 100% yield) as pale yellow oil, which was used directly in the next step without further purification. LCMS m/z [M+H]+ 395.3.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=3)[N:15]=[C:14]2[CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.[NH2:44][C:45]1[C:50]([C:51]#[N:52])=[C:49](Cl)[N:48]=[CH:47][N:46]=1>C(#N)C>[NH2:44][C:45]1[N:46]=[CH:47][N:48]=[C:49]([N:32]2[CH2:33][CH2:34][CH:29]([C:14]3[N:13]([CH:10]4[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]4)[CH:17]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[C:20]([C:25]([F:27])([F:26])[F:28])[CH:19]=4)[N:15]=3)[CH2:30][CH2:31]2)[C:50]=1[C:51]#[N:52]
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3ccc(F)c(C(F)(F)F)c3)nc2C2CCNCC2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3ccc(F)c(C(F)(F)F)c3)nc2C2CCN(c3ncnc(N)c3C#N)CC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-[4-(4-fluoro-3-trifluoromethyl-phenyl)-2-piperidin-4-yl-imidazol-1-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (109.27 mg; 0.23 mmol; 1.00 eq.) in acetonitrile 2 ml was added ethyl-diisopropyl-amine (0.08 ml; 0.45 mmol; 2.00 eq.) and 4-amino-6-chloro-pyrimidine-5-carbonitrile (35.00 mg; 0.23 mmol; 1.00 eq.), the reaction mixture was stirred at RT for 1 hr, lc-ms showed desired as major product, removed off solvent, got residue, which as title compound directly using for the next step reaction.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)=[C:15]([C:22](O)=[O:23])[N:14]=[N:13]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[CH:25]1([NH2:28])[CH2:27][CH2:26]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(N(CC)CC)C>[CH:25]1([NH:28][C:22]([C:15]2[N:14]=[N:13][N:12]([C:9]3[CH:10]=[CH:11][C:6]([C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=3)[C:16]=2[C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)=[O:23])[CH2:27][CH2:26]1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2-c2cccs2)cc1
Reactant: NC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2-c2cccs2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
To a solution of 1-{4-[(ethylamino)carbonyl]phenyl}-5-(2-thienyl)-1H-1,2,3-triazole-4-carboxylic acid (764 mg) obtained in Example 336a) in DMF (5 ml) were sequentially added cyclopropylamine (0.23 ml), triethylamine (0.46 ml), HOBt (170 mg) and WSC (640 mg), and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column (ethyl acetate/hexane=4/6 to ethyl acetate) and recrystallized from ethyl acetate to give the title compound as a colorless powder (543 mg, 64%).
Reaction SMILES: C1COCC1.[C:6]([NH:9][CH2:10][CH:11]([O:14][C:15](=[O:17])C)[CH2:12]Cl)(=[O:8])[CH3:7].C(OC(=O)[NH:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH:39]=[CH:38][C:37](=[O:40])[CH2:36][CH2:35]2)=[CH:30][CH:29]=1)C1C=CC=CC=1>CN(C=O)C.CO>[O:17]=[C:15]1[N:27]([C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH:35]=[CH:36][C:37](=[O:40])[CH2:38][CH2:39]3)=[CH:30][CH:29]=2)[CH2:12][CH:11]([CH2:10][NH:9][C:6](=[O:8])[CH3:7])[O:14]1
Reactant: CC(=O)NCC(CCl)OC(C)=O
Reactant: O=C1C=CN(c2ccc(NC(=O)OCc3ccccc3)cc2)CC1
Solvent: CO
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(=O)NCC1CN(c2ccc(N3C=CC(=O)CC3)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1.0 M LiOBu-t in THF (5 mL, 5 mmol) is added dropwise with stirring to a solution of acetic acid 1-(acetylamino-methyl)-2-chloro-ethyl ester (0.600 g, 3.10 mmol) in DMF (1 mL) and MeOH (0.127 mL) under nitrogen atmosphere at 0° C. [4-(4-Oxo-3,4-dihydro-2H-pyridin-1-yl)-phenyl]-carbamic acid benzyl ester (0.500 g, 1.55 mmol; prepared as described for Example 8), is added, and the mixture is allowed to gradually warm up to r.t. and stirred for additional 24 h. The mixture is quenched with saturated aq. NH4Cl (20 mL), diluted with aq. NaCl, and extracted with EtOAc (3×). The organic layers are combined and washed with brine, and dried over MgSO4. The solvent is removed under vacuum, and the crude product purified by silica gel flash chromatography (gradient 20% to 100% EtOAc—hexanes) to afford the title compound as a white solid. Yield 137 mg (26%). MS (m/z): 330 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 8.24 (br. t, J=5.8 Hz, 1H), 7.72 (d, J=7.7, 1H), 7.53 (d, J=9.1, 2H), 7.27 (d, J=9.1, 2H), 4.97 (d, J=7.7 Hz, 1H), 4.72–4.67 (m, 1H), 4.10 (t, J=9.1 Hz, 2H), 3.75–3.69 (m, 1H), 3.40 (t, J=5.5 Hz, 2H), 2.50–2.49 (m, 2H), 1.82 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[N:30]1([C:34]([C@H:36]2[CH2:40][CH2:39][NH:38][CH2:37]2)=[O:35])[CH2:33][CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[N:30]1([C:34]([C@H:36]2[CH2:40][CH2:39][N:38]([CH2:18][C:13]3[N:14]([CH3:17])[C:15]4[C:11]([N:12]=3)=[C:10]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[N:9]=[C:8]([N:7]3[C:6]5[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=5[N:4]=[C:3]3[CH2:1][CH3:2])[N:16]=4)[CH2:37]2)=[O:35])[CH2:31][CH2:32][CH2:33]1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: O=C([C@H]1CCNC1)N1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC[C@H](C(=O)N4CCC4)C3)n(C)c2n1
Reaction time: 18 h
Yield: 45 %

Procedure:
A solution of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (100 mg, 0.26 mmol) and azetidin-1-yl-(S)-pyrrolidin-3-ylmethanone (47 mg, 0.31 mmol) in DCE (5 mL) was stirred at ambient temperature for 4 h. Sodium triacetoxyborohydride (81 mg, 0.38 mmol) was added and the mixture stirred for 18 h, then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM: MeOH; gradient from 100:0 to 70:30) followed by reverse phase HPLC (Phenomenex Gemini 5u C18, 20 mM triethylamine in water on a gradient of acetonitrile 80:20 to 2:98) to afford 393 as a white solid (62 mg, 46%). LCMS (Method G): RT=5.93 min, M+H+=530. 1H NMR (CDCl3, 400 MHz) δ 8.02 (m, 1 H); 7.75 (m, 1 H); 7.29-7.22 (m, 2 H); 4.35 (m, 4 H); 4.22-4.08 (m, 2 H); 4.02 (t, J=7.9 Hz, 2H); 3.94 (s, 2H); 3.90-3.83 (m, 7 H); 3.35 (q, J=7.5 Hz, 2 H); 3.09-2.57 (m, 5 H); 2.33-2.23 (m, 2 H); 2.09 (m, 2 H) and 1.45 (t, J=7.5 Hz, 3 H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([N+:16]([O-])=O)[C:14]=1[F:15])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1>CO.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH2:16])[C:14]=1[F:15])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: O=[N+]([O-])c1c(F)c(Cl)cc2c1[nH]c1cnccc12
Agent: [Pd]
Solvent: CO
Product: Nc1c(F)c(Cl)cc2c1[nH]c1cnccc12
Reaction time: 6 h
Yield: 90.3 %

Procedure:
A slurry of 6-chloro-7-fluoro-8-nitro-9H-β-carboline (500 mg, 1.88 mmol) in MeOH (25 ml) was degassed with argon. Palladium on charcoal (20% w/w on C, 50 mg) was added and the reaction vessel was flushed with hydrogen. The slurry was stirred under a balloon of hydrogen for 6 hr, then filtered through celite and concentrated under reduced pressure to yield 6-chloro-7-fluoro-9H-β-carbolin-8-ylamine (400 mg) as a brown solid. 1H-NMR (300 MHz, DMSO-d6): δ 11.48 (br s, 1); 8.99-8.98 (m, 1); 8.37-8.35 (m, 1); 8.11-8.09 (m, 1); 7.74-7.72 (m, 1); 5.65 (br s, 2). HCOOH standard conditions. DAD Rf=1.00 min. MS (M+H+): 236.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C(O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10]
Reactant: OB(O)c1ccccc1Cl
Reactant: N#CCc1ccccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: N#CCc1ccccc1-c1ccccc1Cl
Reaction time: 0.5 h
Yield: 84.4 %

Procedure:
To a stirred solution of (2-bromophenyl)-acetonitrile (13) (5 g, 25.51 mmol) in a mixture of toluene and ethanol (1:1, 150 mL) was added 2-chloro phenyl boronic acid (14) (6 g, 38.2 mmol) and Na2CO3 (8.1 g, 76.53 mmol) at room temperature. Purging was conducting for 30 min with nitrogen. Then triphenyl phosphine (2.6 g, 10.2 mmol) was added followed by Pd(OAc)2 (0.287 g, 1.27 mmol) and further degassing was conducted for another 10 min. The reaction mixture was heated to reflux for 10 h. After completion of the reaction, the mixture was concentrated under reduced pressure to get a crude product which was purified using a silica column using 2% ethyl acetate in hexane to get (2′-chloro-biphenyl-2-yl)-acetonitrile (15) (4.9 g, 84.36%) as a yellow liquid.