Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1.ClC1C=CC=C(C(OO)=[O:21])C=1>C(Cl)Cl>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[CH2:7][CH2:8][O:12][C:9](=[O:21])[CH2:10][CH2:11]1
Reactant: O=C1CCC(CCCCO)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C1CCC(CCCCO)CCO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4.47 g of 4-(4-hydroxybutyl) cyclohexanone in 80 mL methylene chloride is added 6.81 g of 80-85% m-chloroperbenzoic acid and the mixture is stirred at room temperature for 3 hours. The reaction is quenched by addition of saturated aqueous sodium sulfite solution. The mixture is then poured onto a 10% solution of sodium bicarbonate and the layers are separated. The organic phase is dried, filtered and evaporated to dryness to yield 4-(4-hydroxybutyl)-epsilon-caprolactone as a clear oil.
Reaction SMILES: Br[CH2:2][C:3]#[N:4].[CH3:5][C:6]1[NH:7][C:8]2[C:13]([C:14]=1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])=[CH:12][C:11]([OH:25])=[CH:10][CH:9]=2.C(=O)([O-])[O-].[K+].[K+].CCCCCC.C(OCC)(=O)C>C(#N)C>[CH2:18]([O:17][C:15]([C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:25][CH2:2][C:3]#[N:4])[CH:12]=2)[NH:7][C:6]=1[CH3:5])=[O:16])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: N#CCBr
Reactant: Cc1[nH]c2ccc(O)cc2c1C(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCCCCC
Product: Cc1[nH]c2ccc(OCC#N)cc2c1C(=O)OCc1ccccc1
Reaction time: 6 h
Yield: 51 %

Procedure:
α-Bromoacetonitrile (0.209 mL, 3.00 mmol, 1.0 eq.) was dissolved in dry acetonitrile (30 mL) and treated with 2-methyl-3-benzyloxycarbonyl-5-hydroxyindole (0.972 g, 3.46 mmol, 1.2 eq.) and potassium carbonate (0.690 g, 5.0 mmol, 1.7 eq.). The reaction was heated to reflux and followed by TLC (hexane/ethyl acetate 3/2). After 6 hours, the reaction was quenched with water and extracted with ethyl acetate. The resulting organic layers were concentrated, taken up in methylene chloride, and filtered. The filtrate was evaporated to afford a brown solid: 0.490 g (51% yield).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:12][C:13]3[CH:17]=[CH:16][NH:15][N:14]=3)[N:3]=2)=[CH:21][CH:20]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Product: Clc1ccc(-c2nc(Nc3cc[nH]n3)cc3ccccc23)cc1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 4-chloro-phenylboronic acid to give [1-(4-chloro-phenyl)-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 321(MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]#[C:10][C:11]1[N:16]=[C:15]([NH2:17])[C:14]([N+:18]([O-:20])=[O:19])=[CH:13][CH:12]=1.P([O-])(O)(O)=O.[Na+].P([O-])([O-])(O)=O.[Na+].[Na+].[Mn]([O-])(=O)(=O)=O.[K+].[OH2:40].[OH2:41].O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>O.CC(C)=O>[NH2:17][C:15]1[N:16]=[C:11]([C:10](=[O:41])[C:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[O:40])[CH:12]=[CH:13][C:14]=1[N+:18]([O-:20])=[O:19]
Reactant: O
Reactant: Nc1nc(C#Cc2ccc(F)cc2F)ccc1[N+](=O)[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: O=P([O-])(O)O
Agent: O=P([O-])([O-])O
Solvent: CC(C)=O
Product: Nc1nc(C(=O)C(=O)c2ccc(F)cc2F)ccc1[N+](=O)[O-]
Temperature: 5 °C
Yield: 75.8 %

Procedure:
6-[2-(2,4-Difluorophenyl)ethynyl]-3-nitro-pyridin-2-amine (2.0 kg, 7.3 mol) and acetone (40.5 L) are added to a reactor under a nitrogen atmosphere and the mixture is cooled to 0-10° C. with stirring. A buffering solution of water (38.3 L), sodium dihydrogen phosphate (3.3 kg), and disodium hydrogen phosphate (0.7 kg) is added at 0-15° C. The mixture is cooled to 3-6° C. and is charged with solid potassium permanganate (4.1 kg, 25.9 mol) at 3-6° C. The mixture is stirred for 3 h to 5 h, and then portions of the reaction mixture are transferred to a vessel containing water (9.3 L) and sodium thiosulfate pentahydrate (3.6 kg) at 15-20° C. The mixture is stirred at 15-25° C. Water (50 L) is added and the mixture stirred for 0.5-1 h and is filtered. The filtrate is concentrated under reduced pressure below 45° C. When the distillation of solvent is complete, water (40 L) is added at 20-25° C. and the mixture is stirred for 0.5-1 h. The solids are collected by filtration and the filtercake is dried below 40° C. to obtain the title compound as a yellow solid (1.7 kg, 75%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([CH3:19])([CH3:18])[CH2:10][CH:11]([OH:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[CH:7][CH:8]=1.CS(C)=O.C(N(CC)CC)C>ClCCl>[CH2:15]([O:14][C:12](=[O:13])[C:11](=[O:17])[CH2:10][C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)([CH3:19])[CH3:18])[CH3:16]
Reactant: CCOC(=O)C(O)CC(C)(C)c1cccc(OC)c1
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)CC(C)(C)c1cccc(OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.2 %

Procedure:
2019 g (78.47 mmol) of ethyl 4-(3-methoxyphenyl)-2-hydroxy-4-methyl-pentanoate is dissolved in 820 ml of dichloromethane and mixed with 273 ml of dimethyl sulfoxide. After 39.7 g (392.36 mmol) of triethylamine is added, the batch is mixed in portions with 31.2 g (196.18 mmol) of SO3/pyridine complex and then stirred for 16 hours at room temperature. About 400 ml of dichloromethane is drawn off in a rotary evaporator. Then, the reaction mixture is mixed with 312 ml of saturated ammonium chloride solution while being cooled slightly, and it is stirred vigorously for 20 minutes. After 2× extraction with diethyl ether (800 ml each), the combined organic phases are washed with water and brine. The residue that remains after the solvent is spun off is chromatographed on silica gel (mobile solvent ethyl acetate/hexane). 15.59 g (75.3%) of the desired compound is isolated.
Reaction SMILES: C([N:4]([CH2:8][CH3:9])[CH:5](C)C)(C)C.Cl.Cl.Cl.[CH3:13][C:14]([CH3:51])([CH3:50])[C@H:15]([NH:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:29]=[N:30][C:31]3[N:32]([C:34]([C:37]4([C:40]5[CH:41]=[C:42]6[C:47](=[CH:48][CH:49]=5)[N:46]=[CH:45][CH:44]=[CH:43]6)[CH2:39][CH2:38]4)=[CH:35][N:36]=3)[CH:33]=2)=[CH:24][N:23]=1)=[O:21])[C:16](O)=[O:17].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.Cl.N1CCC1>CN(C)C=O.CO>[N:4]1([C:16]([C@@H:15]([NH:19][C:20]([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:29]=[N:30][C:31]4[N:32]([C:34]([C:37]5([C:40]6[CH:41]=[C:42]7[C:47](=[CH:48][CH:49]=6)[N:46]=[CH:45][CH:44]=[CH:43]7)[CH2:39][CH2:38]5)=[CH:35][N:36]=4)[CH:33]=3)=[CH:24][N:23]=2)=[O:21])[C:14]([CH3:50])([CH3:13])[CH3:51])=[O:17])[CH2:5][CH2:9][CH2:8]1
Reactant: CC(C)(C)[C@H](NC(=O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)cn1)C(=O)O
Reactant: CCN(C(C)C)C(C)C
Agent: C1CNC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)(C)[C@H](NC(=O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)cn1)C(=O)N1CCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N,N-Diisopropylethylamine (30 μL, 0.172 mmol) was added to a mixture of (2S)-3,3-dimethyl-2-[(5-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]pyridin-2-ylcarbonyl)amino]butanoic acid trihydrochloride (16.4 mg, 0.026 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (12.6 mg, 0.0286 mmol) and azetidine hydrochloride (3.65 mg, 0.039 mmol) in N,N-dimethylformamide (1.0 mL). The mixture was stirred at RT for 3 h, and was diluted with methanol (0.8 mL). The resulting solution was purified by RP-HPLC (pH 10) to give the desired product. LCMS: (M+H)=560.2.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[CH:18]([N:19]([CH3:27])[C:20](=[O:26])[C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[CH2:17][NH:16][CH2:15][CH2:14][N:13]3[C:28](=[O:31])[C:29]=2[OH:30])=[O:9])=[CH:4][C:3]=1[CH3:34].C(N(CC)CC)C.C(O[C:45]1(O[Si](C)(C)C)[CH2:47][CH2:46]1)C.[BH3-]C#N.[Na+]>CO.C(O)(=O)C>[CH:45]1([N:16]2[CH2:17][CH:18]([N:19]([CH3:27])[C:20](=[O:26])[C:21]([N:23]([CH3:24])[CH3:25])=[O:22])[C:12]3=[N:11][C:10]([C:8]([NH:7][CH2:6][C:5]4[CH:32]=[CH:33][C:2]([F:1])=[C:3]([CH3:34])[CH:4]=4)=[O:9])=[C:29]([OH:30])[C:28](=[O:31])[N:13]3[CH2:14][CH2:15]2)[CH2:47][CH2:46]1
Reactant: Cc1cc(CNC(=O)c2nc3n(c(=O)c2O)CCNCC3N(C)C(=O)C(=O)N(C)C)ccc1F
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: Cc1cc(CNC(=O)c2nc3n(c(=O)c2O)CCN(C2CC2)CC3N(C)C(=O)C(=O)N(C)C)ccc1F
Temperature: 25 °C

Procedure:
N-(2-{[(4-fluoro-3-methylbenzyl)amino]carbonyl}-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydropyrimido[1,2-d][1,4]diazepin-10-yl)-N,N′,N′-trimethylethanediamide (prepared as described in Example 11, Step 1-7) was dissolved in methanol and treated with triethylamine (2 eq.), [(1-ethoxycyclopropyl)oxy](trimethyl)silane and acetic acid pH=5.5. To the mixture was then added NaCNBH3 (4 eq.) and reaction was refluxed overnight. After cooling to room temperature, mixture was concentrated under reduced pressure and purified by prep RP HPLC (C18, 5 μM, H2O/MeCN with 1% of TFA as eluant) affording desired compound as a white solid. 1H NMR (300 MHz, CD3CN) δ 12.67 (bs, 1H), 10.01 (bs, 1H), 7.49 (d, J=7.52 Hz, 1H), 7.45-7.40 (m, 1H), 7.21 (t, J=8.62 Hz, 1H), 5.51-5.41 (m, 2H), 4.76 (dd, J=14.6 Hz, J=6.86 Hz, 1H), 4.66 (dd, J=14.6 Hz, J=6.41 Hz, 1H), 4.27-4.00 (m, 4H), 3.51-3.36 (m, 2H), 3.27 (s, 3H), 3.19 (s, 3H), 3.17 (s, 3H), 2.46 (s, 3H), 1.37-1.31 (m, 2H), 1.19-1.10 (m, 2H); MS (ES) C25H31FN6O5 requires 514. Found: 515 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[NH:22][C:23](CC(C(F)(F)F)CC(O)=O)=[O:24].S(Cl)(Cl)=O.[O:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1>>[Cl:1][C:2]1[C:3]([N:22]2[C:43](=[O:39])[CH2:42][CH:41]([C:16]([F:19])([F:18])[F:17])[CH2:40][C:23]2=[O:24])=[CH:4][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:6]([F:8])[CH:7]=1
Reactant: C1CCOC1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(NC(=O)CC(CC(=O)O)C(F)(F)F)c(Cl)cc2F)c1=O
Solvent: O=S(Cl)Cl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(N3C(=O)CC(C(F)(F)F)CC3=O)c(Cl)cc2F)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 0.50 g of 4-(N-(2-chloro-4-fluoro-5(1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedion-3-yl)phenyl)carbamoyl)-3-trifluoromethylbutyric acid and 7 ml of dry tetrahydrofuran was added dropwise 0.23 g of thionyl chloride at room temperature. After stirring for 2 hours under reflux, the temperature was cooled to room temperature, and the solvent was removed by distillation under reduced pressure. The resulting crude product was extracted with ethyl acetate, washed successively with water, a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution, and dried over anhydrous sodium sulfate followed by removing ethyl acetate by distillation to obtain 0.50 g of the desired compound as crystal.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([O:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[N:6][CH:7]=1.CC1(C)C(C)(C)[O:22][B:21](B2OC(C)(C)C(C)(C)O2)[O:20]1.CC([O-])=O.[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][O:8][C:5]2[N:4]=[CH:3][C:2]([B:21]([OH:22])[OH:20])=[CH:7][N:6]=2)=[CH:12][CH:13]=1
Reactant: Fc1ccc(CCOc2ncc(Br)cn2)cc1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: OB(O)c1cnc(OCCc2ccc(F)cc2)nc1
Temperature: 85 °C
Reaction time: 24 h
Yield: 39.7 %

Procedure:
A mixture of 5-bromo-2-(4-fluorophenethoxy)pyrimidine (200 mg), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (256 mg), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (24.63 mg) and KOAc (198 mg) in 1,4-dioxane (8 mL) in a sealed tube was degassed with nitrogen for 2 minutes and then heated at 85° C. for 4 hours, followed by being stirred at room temperature for 24 h. The mixture was diluted with EtOAc, washed with water, brine, dried over MgSO4 and concentrated under vacuum. The residue was purified by silica gel column (Hex/EtOAc=10:1) to give (2-(4-fluorophenethoxy)pyrimidin-5-yl)boronic acid (70 mg). LCMS (M+H)=263.1.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[N:12]=2)=[CH:4][C:3]=1[N+:24]([O-])=O.CO.[F:29][C:30]([F:41])([F:40])[C:31]1[CH:36]=[CH:35][C:34]([N:37]=[C:38]=S)=[CH:33][CH:32]=1>[C].[Pd].[Fe](Cl)(Cl)Cl.C(OCC)(=O)C>[F:29][C:30]([F:40])([F:41])[C:31]1[CH:32]=[CH:33][C:34]([NH:37][C:38]2[NH:24][C:3]3[CH:4]=[C:5]([O:6][C:7]4[CH:8]=[CH:9][C:10]5[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]6[CH2:21][CH2:20]6)=[O:18])[N:15]=5)[N:12]=4)[CH:22]=[CH:23][C:2]=3[N:1]=2)=[CH:35][CH:36]=1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1[N+](=O)[O-]
Reactant: FC(F)(F)c1ccc(N=C=S)cc1
Agent: Cl[Fe](Cl)Cl
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(Nc1cn2nc(Oc3ccc4nc(Nc5ccc(C(F)(F)F)cc5)[nH]c4c3)ccc2n1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 126.1 %

Procedure:
A suspension of N-[6-(4-amino-3-nitrophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (499 mg, 1.38 mmol), 10% palladium carbon (100 mg) and methanol (20.0 mL) was stirred under a hydrogen atmosphere (up to 1 atm) at room temperature overnight. The insoluble material was filtered through celite, and the filtrate was evaporated under reduced pressure. The residue was dissolved in methanol (10 mL), 4-(trifluoromethyl)phenylisothiocyanate (120 mg, 0.59 mmol) was added to the mixture, and the mixture was stirred at room temperature for 1 hr. Iron (III) chloride (177 mg, 1.1 mmol) was added to the reaction mixture, and the mixture was further stirred at room temperature for 1.5 hr. Ethyl acetate was added to the reaction mixture, and the mixture was washed with saturated aqueous sodium hydrogencarbonate solution, dried over anhydrous magnesium sulfate, and filtrated. Dichloromethane (20 mL) was added to the residue, and the precipitate was collected by filtration to give the title compound (367 mg, 52%). The filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate alone→ethyl acetate/methanol=9:1). Ethyl acetate was added to the obtained oily substance, and the precipitate was collected by filtration to give the title compound (116 mg, 32%) as a pale-yellow solid.
Reaction SMILES: [Br-].[CH2:2]([O:4][C:5]([CH2:7][N+:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6])[CH3:3].CSC(SC)=C[N+]([O-])=O.[CH3:23][CH2:24][N:25](CC)[CH2:26]C>C(O)C>[CH3:26][NH:25][C:24]1[CH:23]=[C:13]2[N:8]([C:7]=1[C:5]([O:4][CH2:2][CH3:3])=[O:6])[CH:9]=[CH:10][CH:11]=[CH:12]2
Reactant: CCN(CC)CC
Reactant: CCOC(=O)C[n+]1ccccc1
Agent: CSC(=C[N+](=O)[O-])SC
Agent: [Br-]
Solvent: CCO
Product: CCOC(=O)c1c(NC)cc2ccccn12

Procedure:
A mixture of 1-ethoxycarbonylmethylpyridinium bromide 5 (1 g, 4.1 mmol), 1,1-bismethylthio-2-nitroethene (1.2 g; 8.1 mmol) and Et3N (4.1 g, 40.6 mmol) in ethanol (30 mL) was heated at reflux for 12 h. The solvents and the triethylamine were then evaporated under vacuum. The oil obtained was extracted with water (50 mL) and toluene (3×50 mL). The combined extracts were dried over anhydrous magnesium sulphate, filtered and then concentrated under vacuum. The residue was chromatographed on a column of silica with an elution gradient of 1/1 to 4/1 of ethyl acetate/petroleum ether. This gave 0.5 g of ethyl 2-methylaminoindolizine-3-carboxylate 6 in the form of an oil. 1H NMR (DMSO-d6) δ: 9.11 (br s, 1H), 7.32 (d, J=8.8 Hz, 1H), 7.07-7.01 (m, 1H), 6.71-6.66 (m, 1H), 5.88 (br s, 1H), 5.85 (s, 1H), 4.32 (q, J=7.0 Hz, 2H), 2.85 (d, J=5.1 Hz, 3H), 1.34 (t, J=7.0 Hz, 1H), 13C NMR (CDCl3) δ: 161.0, 148.9, 138.2, 127.0, 123.4, 115.8, 109.9, 98.6, 84.3, 58.7, 31.0, 14.7.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]2[C:9](I)=[N:10][N:11]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]=2[CH:3]=1.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.CC(C)([O-])C.[Na+].COC(C)(C)C>O1CCOCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]2[C:9]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[N:10][N:11]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]=2[CH:3]=1
Reactant: C1COCCN1
Reactant: Cc1nc(Cl)cc2c1c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: COC(C)(C)C
Product: Cc1nc(Cl)cc2c1c(N1CCOCC1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 60 °C

Procedure:
6-Chloro-3-iodo-4-methyl-1-trityl-1H-pyrazolo[4,3-c]pyridine (Intermediate 1C; 2 g, 3.73 mmol), morpholine (0.488 mL, 5.60 mmol), sodium tert-butoxide (0.538 g, 5.60 mmol), and chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-t-butylether adduct (0.152 g, 0.187 mmol) was dissolved in dioxane (10 mL) and degassed under argon for five minutes. The reaction mixture was heated to 60° C. for 30 min under microwave irradation. The reaction mixture was diluted with ethyl acetate and washed with saturated ammonium chloride and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo while loading onto silica gel. Purification by flash chromatography (5-30% EtOAc/Hexanes) gave 4-(6-chloro-4-methyl-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)morpholine. MS ESI calc'd. For C30H28ClN4O [M+H]+ 495. found 495.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[N:6]2[CH:9]=[N:10][C:11]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=O)=[C:5]2[N:4]=[N:3]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22].C[Si](C)(C)O[Si](C)(C)C>C(Cl)Cl>[CH3:1][N:2]1[C:7](=[O:8])[N:6]2[CH:9]=[N:10][C:11]([C:12](=[S:22])[NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:5]2[N:4]=[N:3]1
Reactant: Cn1nnc2c(C(=O)Nc3ccccc3)ncn2c1=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: C[Si](C)(C)O[Si](C)(C)C
Solvent: ClCCl
Product: Cn1nnc2c(C(=S)Nc3ccccc3)ncn2c1=O
Yield: 270.7 %

Procedure:
A mixture of 3-methyl-4-oxo-N-phenyl-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide (430 mg, 1.59 mmol), phosphorus pentasulfide (212 mg, 0.48 mmol) and hexamethyldisiloxane (680 μL, 3.18 mmol) in DCM (20 mL) was refluxed overnight. The crude product was absorbed on silica and was purified by flash chromatography using a gradient elution of DCM:MeOH (100:0 to 98:2) to give 372 mg of 3-methyl-4-oxo-N-phenyl-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carbothioamide as a 1.5:1 inseparable mixture with the starting material.
Reaction SMILES: [CH2:1]([C@H:7]1[C@H:10]([CH2:11][C@H:12]([OH:18])[CH2:13][CH2:14][CH:15]=[CH:16][CH3:17])[O:9][C:8]1=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(N=C=NCCCN(C)C)C.[CH:31]([NH:33][CH2:34][C:35](O)=[O:36])=[O:32]>CN(C)C1C=CN=CC=1.C1(C)C(C)=CC=CC=1>[CH:31]([NH:33][CH2:34][C:35]([O:18][C@H:12]([CH2:13][CH2:14][CH:15]=[CH:16][CH3:17])[CH2:11][C@H:10]1[C@H:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:8](=[O:19])[O:9]1)=[O:36])=[O:32]
Reactant: O=CNCC(=O)O
Reactant: CC=CCC[C@@H](O)C[C@@H]1OC(=O)[C@H]1CCCCCC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1C
Product: CC=CCC[C@H](C[C@@H]1OC(=O)[C@H]1CCCCCC)OC(=O)CNC=O
Yield: 57.1 %

Procedure:
Prepared according to representative procedure described in Example 48 above (i.e., acylation) using hydroxy β-lactone 13k (15.6 mg, 0.058 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (14.4 mg, 0.075 mmol), 4-dimethylaminopyridine (8.7 mg, 0.070 mmol), 0.5 mL of xylene were azeotroped in vacuo for 1.0 h. The residue was then dissolved in CH2Cl2 (1.5 mL) and N-formyl glycine (9.0 mg, 0.087 mmol) was added. After twelve hours resulting mixture was purified by chromatography (SiO2, gradient 10-40% EtOAc:hexanes) to afford β-lactone 17g (11.7 mg, 57%).
Reaction SMILES: [C:1]1([CH:7]([NH:11]C(=O)OC(C)(C)C)[CH2:8][C:9]#[CH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>ClCCl>[C:1]1([CH:7]([NH2:11])[CH2:8][C:9]#[CH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#CCC(NC(=O)OC(C)(C)C)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C#CCC(N)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
To a solution of 1.03 g of tert-butyl 1-phenylbut-3-ynylcarbamate (Formula 16) in 15 mL of dichloromethane was added 3 mL of trifluoroacetic acid. The mixture was stirred at room temperature for 1 hour. Then, dichloromethane was removed. The residue was diluted with water and extracted with ethyl acetate. Combined ethyl acetate was washed with brine, dried over sodium sulfate and concentrated. Column chromatography (60% ethyl acetate/hexane) gave 564 mg (93%) of 1-phenylbut-3-yn-1-amine (Formula 17) as a clear oil. 1H NMR (300 MHz, CDCl3) δ 2.04-2.05 (m, 1H), 2.43-2.63 (m, 2H), 4.14-4.19 (m, 1H), 7.24-7.40 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6](=[O:20])[C:7]3[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.[CH3:23]C(O)C>Cl>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6](=[O:20])[C:7]3[C:14]([C:15]([O:17][CH:18]([CH3:23])[CH3:19])=[O:16])=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1
Reactant: CCOC(=O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Reactant: CC(C)O
Agent: Cl
Product: CC(C)OC(=O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Reaction time: 8 h
Yield: 48 %

Procedure:
A solution of 7-chloro-3-(ethoxycarbonyl)pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione (500 mg, 1.56 mmol), 2-propanol (60 mL), and concentrated hydrochloric acid (3 drops) was subjected to three cycles of partial solvent removal by slow distillation (over 6 hours) followed by overnight reflux. After the third cycle, solvent was removed by rotary evaporation and the crude product was purified by flash chromatography eluting with dichloromethane:2-propanol (95:5-85:15) to yield the title compound as a white solid (256 mg, 48%, m.p. 291° C.). Alternatively, the title compound can be prepared as described in Example 18 shown hereinbelow in Table 1.
Reaction SMILES: Cl[CH2:2][CH:3]=O.C([O-])(O)=O.[Na+].[CH:10]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([CH3:21])[CH3:20])[C:14]=1[NH:22][C:23]([C:25]1[CH:26]=[C:27]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1)=[NH:24])([CH3:12])[CH3:11].C(N)(C)C>O.C(OCC)(=O)C>[CH:19]([C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH:10]([CH3:11])[CH3:12])[C:14]=1[N:22]1[CH:3]=[CH:2][N:24]=[C:23]1[C:25]1[CH:26]=[C:27]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1)([CH3:21])[CH3:20]
Reactant: O=CCCl
Reactant: COc1cc(C(=N)Nc2c(C(C)C)cccc2C(C)C)cc(-c2ccccc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)N
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(-c2ccccc2)cc(-c2nccn2-c2c(C(C)C)cccc2C(C)C)c1
Yield: 98.4 %

Procedure:
To a 250 mL round bottom flask was mixed 2-chloroacetaldehyde (5.36 g, 34.2 mmol), NaHCO3 (2.87 g, 34.2 mmol), N-(2,6-diisopropylphenyl)-5-methoxy-[1,1′-biphenyl]-3-carboximidamide (6.6 g, 17.08 mmol) were charged in a flask and 100 mL of iso-propyl amine was added. The reaction mixture was heated up to reflux for 3 hours. The reaction mixture was diluted with water and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. After silica gel chromatography with 10% ethyl acetate in hexane as solvent, 6.9 g of product was obtained.