Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4](Cl)[CH:3]=1.[C:12]1([NH2:19])[C:13]([NH2:18])=[CH:14][CH:15]=[CH:16][CH:17]=1>ClC1C=CC=CC=1.[Cu]>[Br:1][C:2]1[CH:10]=[CH:9][C:5]2[C:6](=[O:8])[NH:19][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[NH:18][C:4]=2[CH:3]=1
Reactant: Nc1ccccc1N
Reactant: O=C(O)c1ccc(Br)cc1Cl
Agent: [Cu]
Solvent: Clc1ccccc1
Product: O=C1Nc2ccccc2Nc2cc(Br)ccc21
Yield: 41.5 %

Procedure:
A mixture of 4-bromo-2-chlorobenzoic acid (2.35 g, 10 mmol), 1,2-benzenediamine (1.08 g, 10 mmol) and copper (0.63 g, 10 mmol) in chlorobenzene (150 mL) was heated to reflux for 48 hours and filtered. The filter cake was washed with ethyl acetate several times. The combined filtrates were concentrated under vacuum and the residue was purified by flash column chromatography on silica gel with 8:2 hexanes/ethyl acetate to provide 1.20 g (22%) of the desired product. MS (DCI) m/e 289 (M+H)+, 307 (M+NH4)+; 1H NMR (500 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.02 (s, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.24 (d, J=1.8 Hz, 1H), 7.06 (dd, J=8.4, 1.8 Hz, 1H), 6.92-6.95 (m, 5H).
Reaction SMILES: [Br:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([CH3:9])=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][C:12]=1[C:21]([F:24])([F:23])[F:22]>N1C=CC=CC=1>[Br:1][C:2]1[C:7]([NH:8][S:17]([C:14]2[CH:15]=[CH:16][C:11]([Cl:10])=[C:12]([C:21]([F:24])([F:22])[F:23])[CH:13]=2)(=[O:19])=[O:18])=[CH:6][C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: Cc1cnc(Br)c(N)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Solvent: c1ccncc1
Product: Cc1cnc(Br)c(NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1
Yield: 61.4 %

Procedure:
A solution of 2-bromo-5-methyl-pyridin-3-ylamine (1 g, 5.38 mmol) and 4-chloro-3-trifluoromethylbenzenesulfonylchloride (1.8 g, 6.46 mmol) in pyridine (5 mL) was stirred at 60° C. for 12 h. The mixture was concentrated under reduced pressure and to it, was added 1:1 EtOAc-10% aqueous HCl (50 mL). Aqueous layer was separated and extracted with EtOAc (2×50 mL). Combined EtOAc layers were washed with 10% aqueous HCl (50 mL), dried (anhydrous Na2SO4), concentrated and column purified (SiO2, 50% EtOAc-hexanes) to obtain N-(2-bromo-5-methyl-pyridin-3-yl)-4-chloro-3-trifluoromethyl-benzenesulfonamide (1.42 g) in 84% yield as a half white solid. ESMS m/z (relative intensity): 429 (M+H)+ (100).
Reaction SMILES: [C:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH:6]1C(O)=O)(=O)[CH2:2][CH3:3].[C:17]([C:23]([O:25][CH3:26])=[O:24])#[C:18][C:19]([O:21][CH3:22])=[O:20].C(=O)=O>C(OC(=O)C)(=O)C>[CH3:22][O:21][C:19]([C:18]1[C:17]([C:23]([O:25][CH3:26])=[O:24])=[C:1]([CH2:2][CH3:3])[N:5]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[CH2:7][C:6]=12)=[O:20]
Reactant: COC(=O)C#CC(=O)OC
Reactant: CCC(=O)N1c2ccccc2CC1C(=O)O
Agent: O=C=O
Solvent: CC(=O)OC(C)=O
Product: CCc1c(C(=O)OC)c(C(=O)OC)c2n1-c1ccccc1C2
Temperature: 120 °C

Procedure:
A mixture of 1-propionyl-2,3-dihydro-1H-indole-2-carboxylic acid (4.49 g, 20.5 mmol) and dimethyl acetylenedicarboxylate (5.68 g, 40 mmol) in acetic anhydride (40 mL) was stirred in a flask equipped with a reflux condenser and a gas bubbler to monitor carbon dioxide evolution during the reaction. The mixture was heated to 120° C. for 4 hours until no gas was eliminated. The dark solution was concentrated in vacuo to dryness and the solid residue was recrystallized from methanol to yield 3-ethyl-8H-3a-aza-cyclopenta[a]indene-1,2-dicarboxylic acid dimethyl ester, 4.61 g (75%): mp 86-88° C.; 1H NMR (DMSO-d6) δ 1.22 (3H, t, J=7.4 Hz, Me), 3.08 (2H, q, J=7.4 Hz, CH2), 3.75 and 3.76 (each 3H, s, 2×OMe), 4.07 (2H, s, CH2), 7.27-7.31 (1H, m, ArH), 7.43-7.47 (1H, m, ArH), 7.59-7.64 (2H, m, ArH). Anal. Calcd. for C17H17NO4: C, 68.21; H, 5.72; N, 4.68. Found: C, 68.22; H, 5.74; N, 4.65.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[C:23]4[CH:24]=[CH:25][C:26]([C:28]5[N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH:30]=[CH:31][CH:32]=5)=[CH:27][C:22]=4[C:21]([CH3:41])([CH3:40])[O:20][CH:19]3[CH3:42])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.ClS([N:47]=[C:48]=O)(=O)=O>>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[C:23]4[CH:24]=[CH:25][C:26]([C:28]5[N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:30]([C:48]#[N:47])=[CH:31][CH:32]=5)=[CH:27][C:22]=4[C:21]([CH3:41])([CH3:40])[O:20][CH:19]3[CH3:42])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC1OC(C)(C)c2cc(-c3cccn3C(=O)OC(C)(C)C)ccc2N1C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: O=C=NS(=O)(=O)Cl
Product: CC1OC(C)(C)c2cc(-c3ccc(C#N)n3C(=O)OC(C)(C)C)ccc2N1C(=O)OCC1c2ccccc2-c2ccccc21
Yield: 64.6 %

Procedure:
Using the procedure for Example 18, the title compound (0.8 g, 65%) was prepared from 9H-fluoren-9-ylmethyl-6-[1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl]-2,4,4-trimethyl-2H-3,1-benzoxazine-1(4H)carboxylate (1.2 g, 2.1 mmol) and chlorosulfonyl isocyanate (0.28 mL, 3.1 mmol). A white solid: mp 135-136° C.; 1H-NMR (DMSO-d6) δ 7.90 (t, 2H, J=6.7 Hz), 7.64 (d, 1H, J=7.5 Hz), 7.59 (d, 1H, J=7.1 Hz), 7.40 (td, 2H, J=7.2, 2.0 Hz), 7.31-7.34 (m, 3H), 7.29 (d, 1H, J=1.2 Hz), 7.04-7.09 (m, 2H), 6.44 (d, 1H, J=3.57 Hz), 5.30 (q, 1H, J=5.6 Hz), 4.86 (dd, 1H, J=10.7, 5.2 Hz), 4.64 (dd, 1H, J=10.8, 5.2 Hz), 4.33 (t, 1H, J=4.7 Hz). 1.50 (s, 3H), 1.30 (s, 9H), 1.20 (s, 3H), 1.03 (d, 3H, J=5.6 Hz); MS (ESI) m/z 590 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([O:5][CH2:6][CH2:7][OH:8])[CH2:4][CH2:3]1.[OH-].[Na+].[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>O1CCCC1.ClCCl>[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([O:8][CH2:7][CH2:6][O:5][C:2]2([CH3:1])[CH2:4][CH2:3]2)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(OCCO)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCOC2(C)CC2)cc1
Temperature: 2.5 °C
Reaction time: 3 h

Procedure:
To the crude 2-(1-methylcyclopropoxy)ethanol from the previous step (0.32 g) in a mixture of 4.6N sodium hydroxide (6.3 mL, 2.52 mmol) and tetrahydrofuran (3 mL) was added 4-methylbenzene-1-sulfonyl chloride (2.1 g, 11.2 mmol) in dichloromethane (6 mL) at 0-5° C. The solution was stirred for 3 h at 0-5° C., and then extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to obtain crude product (100 mg), which was used in the next step without further purification.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1)OC1C=CC=CC=1)#[N:2].[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]2[N:37]=[C:36]([NH:38][NH2:39])[CH:35]=[CH:34][N:33]=2)[CH2:28][CH2:27]1>CN1CCCC1=O>[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]2[N:37]=[C:36]([N:38]3[C:1]([NH2:2])=[N:3][C:4]([NH:12][C:13]4[CH:14]=[CH:15][C:16]([N:19]5[CH2:20][CH2:21][O:22][CH2:23][CH2:24]5)=[CH:17][CH:18]=4)=[N:39]3)[CH:35]=[CH:34][N:33]=2)[CH2:28][CH2:27]1
Reactant: CN1CCN(c2nccc(NN)n2)CC1
Reactant: N#CNC(=Nc1ccc(N2CCOCC2)cc1)Oc1ccccc1
Solvent: CN1CCCC1=O
Product: CN1CCN(c2nccc(-n3nc(Nc4ccc(N5CCOCC5)cc4)nc3N)n2)CC1
Temperature: 220 °C
Yield: 66.5 %

Procedure:
A mixture of N-cyano-N′-(4-morpholinopheny)-O-phenylisourea (0.10 g, 0.31 mmol) and [2-(4-Methyl-piperazin-1-yl)-pyrimidin-4-yl]-hydrazine (0.08 g, 0.34 mmol) in N-methylpyrrolidinone (3 mL) was heated in the microwave apparatus at 220° C. for 5 min. Purification by semi-preparative HPLC provided the title compound (0.09 g, 2% yield).
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[C:12]([CH2:15]O)[CH:11]=[C:10]([C:17]([NH:19][CH2:20][C:21]4[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=4[CH3:27])=[O:18])[C:9]=3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:50]>C(Cl)Cl>[Br:50][CH2:15][C:12]1[CH:11]=[C:10]([C:17]([NH:19][CH2:20][C:21]2[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=2[CH3:27])=[O:18])[C:9]2[CH:8]=[N:7][N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C:14]=2[CH:13]=1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(CO)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(CBr)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Temperature: 0 °C
Yield: 51.8 %

Procedure:
To a stirred solution of 1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(hydroxymethyl)-1H-indazole-4-carboxamide (0.75 g, 1.90 mmol) in DCM (10 mL), triphenyl phosphine (0.998 g, 3.807 mmol) was added at room temperature. The mixture was cooled to 0° C. after 5 minutes then carbon tetrabromide (1.26 g, 3.80 mmol) was added. On completion, reaction mixture was evaporated under reduced pressure and the crude residue purified by column chromatography over silica gel to afford desired 6-(bromomethyl)-1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydro pyridine-3-yl)methyl)-1H-indazole-4-carboxamide (0.45 g, 51.84%).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Li+].[H-].[CH:13]([OH:16])([CH3:15])[CH3:14].[CH3:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>C(OCC)C>[CH2:19]([C@@H:20]1[CH2:21][CH2:22][CH2:15][C@H:13]([OH:16])[CH2:14]1)[CH:18]=[CH2:17]
Reactant: CCCCCC
Reactant: CC(C)O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: C=CC[C@@H]1CCC[C@H](O)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
87 ml of a 1 molar solution of lithium diisobutylaluminum hydride in n-hexane are dissolved in 100 ml of diethyl ether, and 7 ml of isopropanol are added at 0° C. After the evolution of gas has ceased, 12.4 g of cis-3-allylcylohexanone, dissolved in 50 ml of diethyl ether, are added. The mixture is stirred at room temperature for 48 hours. The reaction mixture is quenched by addition of 1M HCl and the aqueous phase is saturated with sodium chloride and extracted five times with in each case 200 ml of ethyl acetate. The combined organic phases are washed with 2N NaOH and dried over MgSO4, and the solvent is then removed under reduced pressure. The residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate=15:1=>5:1. This gives 6.8 g of cis-3-allylcyclohexanol as an oil. C9H160 (140.23), MS(ESI): 141 (M+H+), Rf(n-heptane:ethyl acetate=2:1)=0.22.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8](O)=[O:9])[C:5]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:26][C:27]=3[CH3:28])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[N:4]1)[CH3:2].[CH3:35][CH2:36][N:37]=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.Cl.C(N)C>C(Cl)Cl.C(OCC)(=O)C>[CH2:36]([NH:37][C:8]([C:6]1[C:5]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:26][C:27]=3[CH3:28])=[CH:17][CH:16]=2)(=[O:13])=[O:14])=[N:4][N:3]([CH2:1][CH3:2])[CH:7]=1)=[O:9])[CH3:35]
Reactant: CCN=C=NCCCN(C)C
Reactant: CCn1cc(C(=O)O)c(NS(=O)(=O)c2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)n1
Agent: CCN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCNC(=O)c1cn(CC)nc1NS(=O)(=O)c1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Reaction time: 16 h

Procedure:
To a solution of the title compound of Example 3 (0.15 g, 0.31 mmol), EDCl (0.12 g, 0.62 mmol), 1-hydroxybenzotriazole (0.42 g, 0.31 mmol) and TEA (0.2 g, 1.5 mmol) in DCM, is added ethylamine hydrochloride (0.5 g, 0.62 mmol) at RT. The reaction mixture is stirred for 16 h. The reaction mixture is diluted with ethyl acetate, washed with 1N hydrochloric acid, water and brine. The organic filtrate is concentrated, the crude is chromatographed using 25% ethyl acetate in hexanes to provide 1-ethyl-3-{4-[5-methyl-2-phenyl-oxazol-4-ylmethoxy]-benzenesulfonylamino}-1H-pyrazole-4-carboxylic acid ethyl amide as a crystalline solid: MS [m/z] 508.1 [M-1]−.
Reaction SMILES: [I:1]I.[Cl:3][C:4]1[CH:28]=[CH:27][C:7]([O:8][CH2:9][C:10]2[N:19]([CH2:20][CH2:21][CH2:22]O)[C:18](=[O:24])[C:17]3[C:12](=[C:13]([O:25][CH3:26])[CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[CH:6][CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:3][C:4]1[CH:28]=[CH:27][C:7]([O:8][CH2:9][C:10]2[N:19]([CH2:20][CH2:21][CH2:22][I:1])[C:18](=[O:24])[C:17]3[C:12](=[C:13]([O:25][CH3:26])[CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[CH:6][CH:5]=1
Reactant: II
Reactant: COc1cccc2c(=O)n(CCCO)c(COc3ccc(Cl)cc3)nc12
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1cccc2c(=O)n(CCCI)c(COc3ccc(Cl)cc3)nc12
Temperature: 25 °C
Reaction time: 17 h
Yield: 35 %

Procedure:
Iodine (1016 mg, 4 mmol) was added to a mixture of the product from Step A above, triphenylphosphine (1050 mg, 4 mmol) and imidazole (545 mg, 8 mmol) in toluene (20 mL) at 0° C. The reaction mixture was slowly allowed to warm to room temperature and was stirred for 17 h and diluted with CHCl3. The organic solution was washed with sat'd aq NaHCO3, sat'd aq NaCl, dried and concentrated. The crude residue was chromatographed on SiO2-gel using 30% EtOAc/hexanes to yield the product as a yellow oil (450 mg, 35%). API-MS: 485 (M+1). 1H NMR (300 MHz, CDCl3): d 7.8 (d, 1 H), 7.35 (t, 1 H), 7.2 (d, 2 H), 7.1 (d, 1 H), 6.9 (d, 2 H), 5.15 (s, 2 H), 4.1 (t, 2 H), 3.93 (s, 3 H), 3.9 (s, 3 H), 3.15 (t, 2 H), 2.23 (m, 2 H).
Reaction SMILES: [OH-:1].[Na+].BrBr.[C:5]([C:8]1[CH:9]=[CH:10][C:11]([O:16][CH2:17][CH2:18][CH3:19])=[C:12]([CH:15]=1)[C:13]#[N:14])(=[O:7])C.Cl>O.O1CCOCC1>[C:13]([C:12]1[CH:15]=[C:8]([CH:9]=[CH:10][C:11]=1[O:16][CH2:17][CH2:18][CH3:19])[C:5]([OH:7])=[O:1])#[N:14]
Reactant: CCCOc1ccc(C(C)=O)cc1C#N
Reactant: [OH-]
Agent: BrBr
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCCOc1ccc(C(=O)O)cc1C#N
Reaction time: 2 h
Yield: 93.2 %

Procedure:
NaOH (5.52 g, 0.138 mol) was dissolved in water (35 ml) under ice-bath, followed by slow addition of liquid bromine (3.5 ml, 0.068 mol) under cooling. After a solution of 5-acetyl-2-n-propoxybenzonitrile (7 g, 0.034 mol) in dioxane (35 ml) was slowly added dropwise thereto, the reaction continued for 2 h. The reaction mixture was adjusted slowly to a pH of about 2 with a diluted hydrochloric acid to generate a large amount of light yellow solid. After filtered, the resultant solid was washed with ethyl acetate, and filtered to obtain the title compound (6.5 g, yield: 92%). 1H NMR (CDCl3) δ: 13.21 (1H, br), 8.18 (1H, d), 8.15 (1H, dd), 7.34 (1H, d), 4.18 (2H, t), 1.79 (2H, m), 1.00 (3H, t).
Reaction SMILES: [OH:1][N:2]1[C:6]([Br:7])=[C:5]([Br:8])[C:4]([Br:9])=[N:3]1.[N:10]1([C:16](Cl)=[O:17])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>>[Br:9][C:4]1[C:5]([Br:8])=[C:6]([Br:7])[N:2]([O:1][C:16]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:17])[N:3]=1
Reactant: On1nc(Br)c(Br)c1Br
Reactant: O=C(Cl)N1CCOCC1
Product: O=C(On1nc(Br)c(Br)c1Br)N1CCOCC1

Procedure:
The title compound was prepared from 1-hydroxy-3,4,5-tribromopyrazole and 4-morpholine carbonyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (90%, crystals).
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]1[C:8]([CH2:9][CH3:10])=[CH:7][C:6]([PH:11](=O)[C:12]2[CH:17]=[C:16]([CH2:18][CH3:19])[C:15]([N:20]([CH3:22])[CH3:21])=[C:14]([CH2:23][CH3:24])[CH:13]=2)=[CH:5][C:4]=1[CH2:26][CH3:27].[BH3:29].O1CCCC1>C1(C)C=CC=CC=1>[CH3:28][N:2]([CH3:1])[C:3]1[C:8]([CH2:9][CH3:10])=[CH:7][C:6]([PH:11][C:12]2[CH:17]=[C:16]([CH2:18][CH3:19])[C:15]([N:20]([CH3:21])[CH3:22])=[C:14]([CH2:23][CH3:24])[CH:13]=2)=[CH:5][C:4]=1[CH2:26][CH3:27].[BH3:29]
Reactant: CCc1cc([PH](=O)c2cc(CC)c(N(C)C)c(CC)c2)cc(CC)c1N(C)C
Agent: B
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCc1cc(Pc2cc(CC)c(N(C)C)c(CC)c2)cc(CC)c1N(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
Under an argon atmosphere, to a solution of bis(4-dimethylamino-3,5-diethylphenyl)phosphine oxide (8.12 g, 20 mmoL) synthesized in Example 4 in toluene (48 mL) was added borane-tetrahydrofuran solution (68 mL, 3.5 equivalents) at 25° C. to 30° C. over 2 hr. Then, silica gel (8.3 g, 7.0 equivalents) was added to the mixture, and the mixture was stirred at room temperature for 1 hr. The silica gel was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 50 g, toluene) to give the title compound (5.1 g, colorless oil). yield 64%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]4[C:19](=[O:20])[N:18]([CH2:21][CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[C:17](=[O:29])[C:15]4=3)[N:10]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:46](Cl)(=[O:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>ClCCl>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:10]2[C:11]3=[N:12][CH:13]=[C:14]4[C:19](=[O:20])[N:18]([CH2:21][CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[C:17](=[O:29])[C:15]4=[C:16]3[C:8]([C:4]3[CH:3]=[C:2]([NH:1][C:46](=[O:53])[C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[CH:7]=[CH:6][CH:5]=3)=[N:9]2)=[CH:36][CH:35]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc(Cn2nc(-c3cccc(N)c3)c3c4c(cnc32)C(=O)N(CCc2ccccc2)C4=O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Cn2nc(-c3cccc(NC(=O)c4ccccc4)c3)c3c4c(cnc32)C(=O)N(CCc2ccccc2)C4=O)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 9.1 %

Procedure:
To an ice cooled solution of 1-(3-aminophenyl)-3-(4-methoxybenzyl)-7-phenethylpyrazolo[3,4-b]pyrrolo[3,4-d]pyridine-6,8(3H,7H)-dione (200 mg) in dichloromethane (6 ml), triethylamine (0.08 ml, 0.59 mmol) and Benzoyl chloride (0.05 ml, 0.59 mmol) were added. The reaction mixture was warmed to room temperature and stirred for 2-3 hours. After completion of reaction (TLC, LCMS), the reaction mixture was diluted with dichloromethane (15 ml) and was washed with water (10 ml). The dichloromethane layer was dried over sodium sulfate and evaporated under reduced pressure. The crude compound was purified by reverse phase HPLC on a C-18 column to give N-(3-(3-(4-methoxybenzyl)-6,8-dioxo-7-phenethyl-3,6,7,8-tetrahydropyrazolo[3,4-b]pyrrolo[3,4-d]pyridin-1-yl)phenyl)benzamide (22 mg, 11%) as a solid.
Reaction SMILES: C([Li])CCC.C(N)(C)C.[C:10]([CH:12]([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:11].Cl[CH2:20][S:21][CH2:22]Cl>CCOCC>[C:10]([C:12]([CH3:18])([CH2:20][S:21][CH3:22])[C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:11]
Reactant: CCOC(=O)C(C)C#N
Reactant: ClCSCCl
Agent: [Li]CCCC
Solvent: CC(C)N
Solvent: CCOCC
Product: CCOC(=O)C(C)(C#N)CSC
Temperature: 10 °C
Reaction time: 1.5 h

Procedure:
n-Butyllithium (24.2 mL, 60 mmol, 2.5 M solution in hexanes) was added to a solution of iso-propylamine (8.1 mL, 58 mmol) in dry ether (70 mL) under nitrogen at a rate needed to maintain temperature below −60° C. Upon completion, the reaction was allowed to warm to 10° C., re-cooled to −78° C. before addition of ethyl 2-cyanopropanoate (7 g, 55 mmol). After stirring at −78° C. for 90 minutes, chloromethylsulfide (4.61 mL, 55 mmol) was added and the mixture was warmed to room temperature over 14 hours, diluted with ether (350 mL), washed with water (100 mL), brine (100 mL), dried over MgSO4, concentrated under reduced pressure and distilled at 0.04 mm Hg. Yield of yellow liquid 3.95 g. (38%): by 145° C.; IR (KBr thin film) 1751 cm−1; 1H NMR (400 MHz, CDCl3) δ 4.30 (q, J=7.1 Hz, 2H), 3.08 (d, J=13.9 Hz, 1H), 2.91 (d, J=13.9 Hz, 1H), 2.30 (s, 3H), 1.67 (s, 3H), 1.35 (t, J=7.4 Hz, 3H); EIMS m/z 187.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.I[CH3:12].[H-].[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH3:12])=[CH:4][CH:3]=1
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 105.8 %

Procedure:
5.00 g of 6-bromoindole was added to 25 ml of N,N-dimethylformamide. To the mixture was added 4.37 g of iodomethane in the presence of 1.12 g of sodium hydride (purity: 60%). The resulting mixture was stirred for 1 hour at room temperature to obtain 5.67 g of 6-bromo-1-methylindole. 2.10 g of this compound was dissolved in 21 ml of diethyl ether. Into the solution was dropwise added 7.0 ml of a 1.5M n-hexane solution of n-butyllithium at -45° to -40° C. in a nitrogen atmosphere. The resulting mixture was stirred for 1 hour at room temperature. To the reaction mixture was added 1.46 g of N,N-dimethylformamide at -30° to -20° C. The mixture was stirred for 30 minutes at the same temperature. The temperature of the reaction mixture was elevated to room temperature. 30 ml of water and 10 ml of ethyl acetate were added thereto. The mixture was adjusted to pH 8.0 with dilute hydrochloric acid. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (eluant: n-hexane/ethyl acetate=10/1) to obtain 1.09 g of light brown solid 6-formyl-1-methylindole.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]1[O:21][CH:6]1[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)[CH3:2].[H][H]>[Pd].O1CCOCC1>[OH:21][CH:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:22]
Reactant: CCOC(=O)C1OC1c1ccc(OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Product: CCOC(=O)C(O)Cc1ccc(OCc2ccccc2)cc1
Yield: 80 %

Procedure:
A mixture of ethyl-2,3-epoxy-3-(4-benzyloxyphenyl)propionate of the formula (9) (125 g) obtained according to the procedure described in step (ii) above, 5% Pd/C catalyst (12.5 g) and 1,4-dioxane (750 ml) was hydrogenated at room temperature at 5–10 psi of hydrogen pressure for a period of 10–15 h The progress of the reaction was monitored by TLC. After completion of the reaction, the catalyst was filtered and the solvent was removed under reduced pressure to afford the title compound of the formula (10) (100–105 g, 80–83%).
Reaction SMILES: [CH2:1]([N:4]([CH2:25][CH2:26][CH3:27])[C:5]1[NH:6][C:7](=[O:24])[C:8]2[C:13]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[CH3:22])=[CH:12][N:11]([CH3:23])[C:9]=2[N:10]=1)[CH2:2][CH3:3].CN(C)C=O.[H-].[Na+].[CH2:35](Cl)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>O>[CH2:35]([N:6]1[C:7](=[O:24])[C:8]2[C:13]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[CH3:22])=[CH:12][N:11]([CH3:23])[C:9]=2[N:10]=[C:5]1[N:4]([CH2:1][CH2:2][CH3:3])[CH2:25][CH2:26][CH3:27])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CCCN(CCC)c1nc2c(c(-c3c(C)cc(C)cc3C)cn2C)c(=O)[nH]1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCN(CCC)c1nc2c(c(-c3c(C)cc(C)cc3C)cn2C)c(=O)n1Cc1ccccc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 17.2 %

Procedure:
To a solution of 2-(dipropylamino)-5-mesityl-7-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (50 mg, 0.14 mmol) and dimethylformamide (3 ml) was added sodium hydride (60% in oil, 10 mg, 0.25 mmol) at 0° C. and stirred for 0.5 hour. After stirring at room temperature for 0.5 hour, to the mixture was added a solution of benzylchloride (64 mg, 0.50 mmol) and dimethylformamide (2 ml) at 0° C. and stirred for 0.5 hour. After stirring at room temperature for 1 hour, the mixture was heated at 80° C. After cooling to room temperature, the mixture was diluted with water (20 ml) and extracted with ethyl acetate (50 ml×3). The extracts were combined, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (20:1) to give 11 mg (17%) of the title compound.