Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[C:17]2[N:18]=[CH:19][N:20]([CH2:21][CH2:22][O:23][CH2:24][C:25]#[CH:26])[C:16]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[C:28]1[S:29][CH:30]=[CH:31][CH:32]=1>>[O:1]([C:8]1[C:17]2[N:18]=[CH:19][N:20]([CH2:21][CH2:22][O:23][CH2:24][C:25]#[C:26][C:32]3[CH:31]=[CH:30][S:29][CH:28]=3)[C:16]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Ic1cccs1
Reactant: C#CCOCCn1cnc2c(Oc3ccccc3)nc3ccccc3c21
Product: C(#Cc1ccsc1)COCCn1cnc2c(Oc3ccccc3)nc3ccccc3c21
Yield: 42.4 %

Procedure:
Using the general method of Example 3 Part A, 4-phenoxy-1-[2-(prop-2-ynyloxy)ethyl]-1H-imidazo[4,5-c]quinoline (10 g, 29.4 mmol) was reacted with 2-iodothiophene (3.6 mL, 32.3 mmol). The glassy solid obtained from purification by chromatography over silica gel (98/2 dichloromethane/methanol) was triturated with ether to provide 5.3 g of 4-phenoxy-1-{2-[(3-thien-3-ylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinoline as a gray powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:15]=[CH:14][C:11](C=O)=[CH:10][CH:9]=2)[CH:2]=1.[C:16](NC1C=CC(S(N=[N+]=[N-])(=O)=O)=CC=1)(=O)[CH3:17].C(=O)([O-])[O-].[K+].[K+].N#N>CC#N.CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]#[C:15][C:14]2[CH:11]=[CH:10][CH:9]=[CH:17][CH:16]=2)[CH:2]=1
Reactant: O=Cc1ccc(Oc2cccnc2)cc1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CO
Product: C(#Cc1ccccc1)Oc1cccnc1

Procedure:
4-(Pyridine-3-yloxy)benzaldehyde (0.500 g, 2.510 mmol), 4-acetamidobenzene sulfonyl azide (0.724 g, 3.01 mmol), dimethyl (2-oxopropyl) phosphonate (0.412 mL, 3.01 mmol), and potassium carbonate (1.041 g, 7.53 mmol) in MeCN (10.5 mL) and MeOH (2.1 mL) was heated to 40° C. for 16 h while under N2. The solvent was removed and residue was redissolved in EtOAc and washed with water (3×) and brine (1×). The organic phase was separated, dried with Na2SO4 and evaporated to afford an oil. This material was chromatographed on silica (0-80% EtOAc in hexanes) to yield 0.238 g as an oil.
Reaction SMILES: [CH:1]12[CH2:7][NH:6][CH:5]1[CH2:4][N:3]([C:8]1C=N[C:15]3[C:10](=CC=[CH:13][CH:14]=3)[N:9]=1)[CH2:2]2.ClC1N=C(C)C=C[N:20]=1>>[CH3:13][C:14]1[CH:15]=[CH:10][N:9]=[C:8]([N:3]2[CH2:4][CH:5]3[CH:1]([CH2:7][NH:6]3)[CH2:2]2)[N:20]=1
Reactant: c1ccc2nc(N3CC4CNC4C3)cnc2c1
Reactant: Cc1ccnc(Cl)n1
Product: Cc1ccnc(N2CC3CNC3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 8, using 2-chloro-4-methyl pyrimidine. MS (ESI) mass calcd. for C10H14N4, 190.25; m/z found 191.2 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[N:10]=[C:9]([C:11]([OH:13])=O)[CH:8]=[CH:7][CH:6]=1)[CH3:3].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[NH:47]1[C:55]2[C:50](=[C:51]([C:56]3[CH:57]=[C:58]([NH2:71])[C:59]4[C:63]([CH:64]=3)=[N:62][N:61](C3CCCCO3)[CH:60]=4)[CH:52]=[CH:53][CH:54]=2)[CH:49]=[CH:48]1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH3:3][N:2]([CH2:4][C:5]1[N:10]=[C:9]([C:11]([NH:71][C:58]2[CH:57]=[C:56]([C:51]3[CH:52]=[CH:53][CH:54]=[C:55]4[C:50]=3[CH:49]=[CH:48][NH:47]4)[CH:64]=[C:63]3[C:59]=2[CH:60]=[N:61][NH:62]3)=[O:13])[CH:8]=[CH:7][CH:6]=1)[CH3:1]
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2nn(C3CCCCO3)cc12
Reactant: CN(C)Cc1cccc(C(=O)O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)Cc1cccc(C(=O)Nc2cc(-c3cccc4[nH]ccc34)cc3[nH]ncc23)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 53.6 %

Procedure:
A solution of 6-[(dimethylamino)methyl]-2-pyridinecarboxylic acid (27 mg, 0.15 mmol) in DMF (0.0008 ml) was treated with O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (72 mg, 0.19 mmol) and DIPEA (0.052 ml). After 5 minutes the resulting solution was added to 6-(1H-indol-4-yl)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-amine (33 mg, 0.10 mmol). After stirring for 90 mins at room temperature the mixture was treated with saturated sodium bicarbonate solution (10 ml) and extracted with dichloromethane (3×10 ml). The extracts were passed through a hydrophobic frit, combined and the solvent was evaporated under nitrogen flow. The residue was dissolved in methanol (2 ml) and hydrochloric acid (2M, 0.080 ml) was added. The solvents were evaporated under nitrogen stream to give a crude product which was purified by Mass Directed Automated Preparative HPLC (Method B). Fractions containing pure product were evaporated under a nitrogen stream to give the title compound (22 mg) as a pale solid.
Reaction SMILES: [C:1]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[C:11]([OH:22])[CH:10]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].C1([O-])C=CC=CC=1.[Na+].[C:34](Cl)(=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36]>>[C:1]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[C:11]([O:22][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])[CH:10]=1)=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(C)(C)NCC(=O)c1ccc(OC(=O)C(C)(C)C)c(O)c1
Agent: C[O-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Product: CC(C)(C)NCC(=O)c1ccc(OC(=O)C(C)(C)C)c(OC(=O)C(C)(C)C)c1

Procedure:
Following a procedure similar to that described in Example 2A above, when 3-hydroxy-4-(pivalyloxy)phenyl tert-butylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is reacted with pivalyl chloride there is obtained 3,4-bis(pivalyloxy)phenyl tert-butylaminomethyl ketone, which reacts with hydrochloric acid to yield the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 2B, there is obtained 3,4-bis(pivalyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride. The ketone intermediate and the alcohol product obtained in this manner are identical with the ketone and the alcohol described above in Example 5A and 5B, respectively.
Reaction SMILES: F[B-](F)(F)F.[CH3:6][O+](C)C.F[B-](F)(F)F.[F:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[CH:18][C:17]=1[CH:26]([NH:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[N:41]=[C:40]([CH3:42])[O:39][N:38]=2)=[CH:33][CH:32]=1)[C:27]([NH2:29])=[S:28].C(=O)([O-])O.[Na+]>ClCCl>[CH3:6][S:28][C:27](=[NH:29])[CH:26]([C:17]1[CH:18]=[C:19]([O:24][CH3:25])[C:20]([O:22][CH3:23])=[CH:21][C:16]=1[F:15])[NH:30][C:31]1[CH:32]=[CH:33][C:34]([C:37]2[N:41]=[C:40]([CH3:42])[O:39][N:38]=2)=[CH:35][CH:36]=1
Reactant: COc1cc(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)C(N)=S)cc1OC
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)C(=N)SC)cc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 100 %

Procedure:
After adding 3.62 g of trimethyloxonium tetrafluoroborate (hereinafter, “Me3O+BF4−”) to a solution of 8.59 g of 2-(2-fluoro-4,5-dimethoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]thioacetamide in 400 ml of dichloromethane under a nitrogen atmosphere, the mixture was stirred at room temperature for 15 hours. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with dichloromethane. After washing the organic layer with saturated brine, it was dried over anhydrous sodium sulfate. The desiccating agent was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (8.89 g, crude product) as an oil.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[N:13]=[N:12][C:11]([NH2:14])=[N:10][CH:9]=1.[CH2:15]([O:17][CH:18]([N:20]1[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=[N:21]1)[CH3:19])[CH3:16]>O.C1(C)C=CC=CC=1.C(O)C.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>[CH2:15]([O:17][CH:18]([N:20]1[CH:24]=[C:23]([C:8]2[N:13]=[N:12][C:11]([NH2:14])=[N:10][CH:9]=2)[CH:22]=[N:21]1)[CH3:19])[CH3:16]
Reactant: CCOC(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Nc1ncc(Br)nn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(C)n1cc(-c2cnc(N)nn2)cn1
Temperature: 110 °C
Yield: 69.4 %

Procedure:
Sodium carbonate (510 mg, 4.8 mmol) in water (1 mL) was added to a mixture of 6-bromo-1,2,4-triazin-3-amine (0.420 g, 2.40 mmol), 1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.766 g, 2.88 mmol), and tetrakis(triphenylphosphine)palladium (100 mg, 0.1 mmol) in toluene (7 mL) and ethanol (5 mL). The resulting mixture was heated at 110° C. for 2 h. The mixture was cooled to RT, diluted with water, and extracted with chloroform. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was treated with CH2Cl2/Et2O and filtered to give the desired product (0.39 g, 69%). LCMS: (M+H)=235.4.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:22]5[CH:23]=[N:24][N:25]([C:27]([CH3:32])([CH3:31])[C:28](O)=[O:29])[CH:26]=5)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:33]=2)=[N:7][C:6](C)=[N:5]1)([CH3:3])[CH3:2].C([N:38](CC)C(C)C)(C)C.[Cl-].[NH4+].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:22]5[CH:23]=[N:24][N:25]([C:27]([CH3:31])([CH3:32])[C:28]([NH2:38])=[O:29])[CH:26]=5)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:33]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(-c4cnn(C(C)(C)C(=O)O)c4)cc2OCC3)n(C(C)C)n1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(-c3cnn(C(C)(C)C(N)=O)c3)cc1OCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
2-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanoic acid (100 mg, 0.22 mmol) was dissolved in DMF (1 mL) and treated sequentially with N,N-diisopropylethylamine (0.3 mL, 2.0 mmol), ammonium chloride (50 mg, 0.9 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (HATU, 200 mg, 0.6 mmol). The resulting mixture was stirred at room temp for an overnight period. Saturated sodium bicarbonate was added, and the mixture was extracted with EtOAc. The combined organics were dried over sodium sulfate, concentrated, and purified by rp-HPLC to provide 53 mg (54% yield) of 215. LC/MS (ESI+): m/z 447 (M+H). 1H NMR (400 MHz, DMSO) δ 8.41 (s, 1H), 8.39 (s, 0H), 8.37 (s, 1H), 8.02 (s, 1H), 7.46 (dd, J=8.4, 1.7, 1H), 7.35 (t, J=7.2, 1H), 7.20 (s, 1H), 6.85 (s, 1H), 5.90 (hept, J=6.6, 1H), 4.53 (q, J=5.9, 4H), 1.74 (s, 6H), 1.50 (d, J=6.6, 6H)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]1.CC1(C)C(C)(C)OB([C:40]2[CH:41]=[N:42][C:43]([C:46]#[N:47])=[N:44][CH:45]=2)O1>>[C:46]([C:43]1[N:44]=[CH:45][C:40]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[C:5]3[NH:17][C@H:18]2[CH2:19][CH2:20][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:28])[CH3:29])[CH2:22][CH2:23]2)=[CH:41][N:42]=1)#[N:47]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Reactant: CC1(C)OB(c2cnc(C#N)nc2)OC1(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4cnc(C#N)nc4)cc23)CC1

Procedure:
Following general procedure D, tert-butyl trans-4-[6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino]cyclohexylcarbamate (49 mg, 0.100 mmol) was reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine-2-carbonitrile (46 mg, 0.200 mmol) to afford the crude product (52 mg): ESI MS m/z 513 [C29H32N6O3+H]+.
Reaction SMILES: O1CCCCC1[O:7][CH:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][N:19]=[CH:18]3)[CH2:10][CH2:9]1>CO>[NH:20]1[C:21]2[C:17](=[CH:16][C:15]([O:14][CH:11]3[CH2:12][CH2:13][CH:8]([OH:7])[CH2:9][CH2:10]3)=[CH:23][CH:22]=2)[CH:18]=[N:19]1
Reactant: c1cc2[nH]ncc2cc1OC1CCC(OC2CCCCO2)CC1
Solvent: CO
Product: OC1CCC(Oc2ccc3[nH]ncc3c2)CC1
Temperature: 50 °C
Reaction time: 5 h
Yield: 77528.5 %

Procedure:
An acidic resin (Dowex 50W×8, trade name, Dow Chemical Company, 46 mg) was added to a solution of 5-{[4-(tetrahydro-2H-pyran-2-yloxy)cyclohexyl]oxy}-1H-indazole (232 mg, 0.733 mmol) in methanol (10 ml), and the resulting mixture was heated to 50° C. After 5 hours, the reaction solution was filtered by the use of Celite and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol) to obtain 4-(1H-indazol-5-yloxy)cyclohexanol (132 g, 78%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[C:13]12([CH2:23][CH2:24][C:25]3[NH:29][C:28]([CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[N:27][C:26]=3[C:36](O)=[O:37])[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2>>[C:13]12([CH2:23][CH2:24][C:25]3[NH:29][C:28]([CH:30]4[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]4)=[N:27][C:26]=3[C:36]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:7]=3)=[O:37])[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2
Reactant: O=C(O)c1nc(C2CCCCC2)[nH]c1CCC12CC3CC(CC(C3)C1)C2
Reactant: Nc1ccc(CCC(=O)O)cc1
Product: O=C(O)CCc1ccc(NC(=O)c2nc(C3CCCCC3)[nH]c2CCC23CC4CC(CC(C4)C2)C3)cc1

Procedure:
3-(4-Amino-phenyl)-propionic acid acid benzyl ester (prepared in two steps from 4-nitrocinnamic acid) was reacted with 5-(2-adamantan-1-yl-ethyl)-2-cyclohexyl-1H-imidazole-4-carboxylic acid (Example 252) according to the procedure of Example 20, step d. The benzyl ester was hydrogenolysed using the same procedure as in Example 1, step e to afford the title compound. 1H NMR (300 MHz, d6-DMSO) 12.00 (1H, br s), 9.28 (1H, br s), 7.63 (1H, d), 7.14 (1H, d), 2.86 (2H, m), 2.76 (2H, t), 2.64 (1H, m), 2.62 (2H, m), 2.49 (2H, m), 1.93-1.30 (27H, m). The acid was converted to the N-methyl-D-glucamine salt and lyophilised from water/dioxan. Found: C, 60.77; H, 8.69; N, 7.49%; C38H58N4O8.3.0 H2O requires: C, 60.62; H, 8.57; N, 7.44%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]([CH3:31])[C:16](=[O:30])[C:17](Cl)=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[C:22]([F:28])[CH:21]=3)[N:19]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:33][N:34](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:32])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]([CH3:31])[C:16](=[O:30])[C:17]([C:33]#[N:34])=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[C:22]([F:28])[CH:21]=3)[N:19]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: Cn1c(N2CCC(NC(=O)OC(C)(C)C)CC2)nc(-c2ccc(C#N)c(F)c2)c(Cl)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cn1c(N2CCC(NC(=O)OC(C)(C)C)CC2)nc(-c2ccc(C#N)c(F)c2)c(C#N)c1=O
Temperature: 150 °C
Reaction time: 4 h
Yield: 33 %

Procedure:
A mixture of {1-[5-chloro-4-(4-cyano-3-fluoro-phenyl)-1-methyl-6-oxo-1,6-dihydro-pyrimidin-2-yl]-piperidin-4-yl}-carbamic acid tert-butyl ester (460 mg, 1 mmol), Zn(CN)2 (175 mg, 1.5 mmol) and Pd(PPh3)4 (116 mg, 0.0.1 mmol) in DMF (5 mL) was stirred for 4 h at 150° C. under N2 atmosphere. The reaction mixture was cooled to RT and filtered. The filtrate was concentrated in vacuo, and the residue was purified by preparative HPLC to give 150 mg of the title product as a yellow solid (33%). [M+H] Calc'd for C23H25FN6O3, 453. Found, 453.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[N:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[C:10]=1[CH2:11][CH2:12][NH:13][CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:5])C.[OH-].[K+]>CCO>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([C:8]2[N:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:10]([CH2:11][CH2:12][NH:13][CH:14]3[CH2:15][CH2:16][CH2:17][CH2:18]3)=[C:6]([C:4]([OH:5])=[O:3])[N:7]=2)=[CH:27][CH:28]=1
Reactant: CCOC(=O)c1nc(-c2ccc(Cl)cc2)n(-c2ccccc2Cl)c1CCNC1CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1nc(-c2ccc(Cl)cc2)n(-c2ccccc2Cl)c1CCNC1CCCC1
Temperature: 85 °C

Procedure:
To a solution of 2-(4-chloro-phenyl)-1-(2-chloro-phenyl)-5-(2-cyclopentylamino-ethyl)-1H-imidazole-4-carboxylic acid ethyl ester I-5i (22 mg, 0.46 mmol) in absolute EtOH (2 ml) was added 1N KOH (500 μl). The reaction mixture was heated to 85° C. for 4 hours and then was concentrated to a quarter fraction of the original volume. The pH of the solution was adjusted to approximately 3.5 using 10% HCl. The aqueous ethanolic solution was concentrated to dryness to give the I-5i as a solid (20 mg): +APCI MS (M+1) 444.4.
Reaction SMILES: C([O:9][C@@H:10]1[C@:14]([C:16]#[CH:17])([OH:15])[C@H:13]([O:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@H:12]([CH2:27][O:28][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:11]1)(=O)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CO.C1COCC1>[C:19]([O:18][C@@H:13]1[C@@H:12]([CH2:27][O:28][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:11][C@@H:10]([OH:9])[C@:14]1([C:16]#[CH:17])[OH:15])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C#C[C@]1(O)[C@@H](OC(=O)c2ccccc2)O[C@H](COC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: C#C[C@]1(O)[C@H](O)O[C@H](COC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Intermediate (2R,3R,4R,5R)-2,4-dibenzoyloxy-5-benzoyloxymethyl-3-ethynyl-tetrahydro-furan-3-ol (2.048 g, 4.21 mmol, 1.0 equiv.) is dissolved in methanol (10 ml) and THF (10 ml). K2CO3 (176 mg, 1.26 mmol, 0.3 equiv.) is added, The reaction is stirred at ambient temperature for 2 h, filtered on silica gel, concentrated and purified by flash chromatography to give (2R,3R,4R,5R)-4-benzoyloxy-5-benzoyloxymethyl-3-ethynyl-tetrahydrofuran-2,3-diol as a foam. 1H-NMR (400 MHz, CDCl3): δ 8.06-7.96 (m, 4H), 7.54-7.26 (m, 6H), 5.88 (d, 0.26H, J=6.4 Hz), 5.54 (s, 0.72H), 5.53 (d, 0.72H, J=5.2 Hz), 5.41 (s, 0.28H), 5.28 (bs, 1H), 4.67-4.49 (m, 3H), 4.22 (bs, 1H), 2.67 (s, 0.26H), 2.59 (s, 0.71H); 13C-NMR (100 MHz, CDCl3): δ 166.74, 166.61, 165.74, 165.66, 133.79, 133.71, 133.52, 133.33, 133.24, 130.11, 130.05, 130.02, 129.89, 129.81, 129.44, 129.41, 128.86, 128.75, 128.57, 128.41, 128.36, 81.87, 80.07, 79.23, 77.89, 77.21, 76.61, 76.39, 75.77, 75.58, 72.83, 65.29, 64.26.
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][C@@H:6]([N:13]1[C:21](=[O:22])[N:20]([CH2:23][C:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][C:31]=3[CH3:33])[N:26]([CH3:34])[CH:25]=2)[C:19]2[C:14]1=[N:15][C:16]([CH:35]1[CH2:37][CH2:36]1)=[N:17][CH:18]=2)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.[Li+].[OH-].Cl>C1COCC1.O>[CH:35]1([C:16]2[N:15]=[C:14]3[C:19]([N:20]([CH2:23][C:24]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][C:31]=5[CH3:33])[N:26]([CH3:34])[CH:25]=4)[C:21](=[O:22])[N:13]3[C@@H:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:5][C:4]([OH:38])=[O:3])=[CH:18][N:17]=2)[CH2:36][CH2:37]1
Reactant: CCOC(=O)C[C@H](c1ccccc1)n1c(=O)n(Cc2cn(C)c3cccc(C)c23)c2cnc(C3CC3)nc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc2c1c(Cn1c(=O)n([C@H](CC(=O)O)c3ccccc3)c3nc(C4CC4)ncc31)cn2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.3 %

Procedure:
(R)-3-[2-Cyclopropyl-7-(1,4-dimethyl-1H-indol-3-ylmethyl)-8-oxo-7,8-dihydro-purin-9-yl]-3-phenyl-propionic acid ethyl ester (130 mg, 0.255 mmol) was dissolved in THF (3 ml). To the solution a concentrated solution of LiOH in water (2 ml) was added. The mixture was stirred at room temperature for 1 hour. The reaction was monitored by TLC. The reaction mixture was neutralized with 1N HCl, and then extracted with ethyl acetate 3×. The organic layer was dried over MgSO4, filtered and evaporated to dryness. The white solid obtained was purified by prep TLC, eluded with 10% methanol in dichloromethane to give the title compound (52 mg, 43%). LCMS, M++1, m/z: 481.54
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:16]=[C:15]2[C:11]([CH:12]=[C:13]([C:17]3[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:25])[NH:14]2)=[CH:10][CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:25][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=1[C:13]1[NH:14][C:15]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([NH2:7])[CH:16]=2
Reactant: COc1cccc(Cl)c1-c1cc2ccc(NC(=O)OC(C)(C)C)cc2[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(Cl)c1-c1cc2ccc(N)cc2[nH]1
Yield: 91.7 %

Procedure:
A solution of [2-(2-chloro-6-methoxy-phenyl)-1H-indol-6-yl]-carbamic acid tert-butyl ester (120 mg, 0.32 mmol) in CH2Cl2 (5 mL) was added 2,2,2-trifluoroacetic acid (0.5 mL) at 25° C. The solution was heated to reflux for 3 h, concentrated and poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration followed by concentration in vacuo gave a brown solid. Flash chromatography (70/30 hexanes/ethyl acetate) afforded 2-(2-chloro-6-methoxy-phenyl)-1H-indol-6-ylamine (80 mg, 91%) as a white solid. MH+ 272.9.
Reaction SMILES: CN(C)[C:3](=[O:6])[CH:4]=[CH2:5].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[S:23]1[CH:27]=[CH:26][CH:25]=[CH:24]1>ClC(Cl)C>[S:23]1[CH:27]=[CH:26][C:25]2[C:3](=[O:6])[CH2:4][CH2:5][C:24]1=2
Reactant: c1ccsc1
Reactant: C=CC(=O)N(C)C
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CC(Cl)Cl
Product: O=C1CCc2sccc21
Yield: 38.7 %

Procedure:
To a solution of N,N-dimethylacrylamide (6.6 g, 71 mmol) in dichloroethane (400 ml) was gradually added dropwise a solution of trifluoromethanesulfonic acid anhydride (20 g, 71 mmol) in dichloroethane (50 mL) under ice-cooling. A solution of thiophene (6.0 g, 71 mmol) in dichloroethane (50 mL) was added to the mixture, and the mixture was heated under reflux for 15 hrs. The reaction mixture was concentrated under reduced pressure, saturated sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9:5 to 4:1) to give the title compound (3.8 g, yield 39%) as a white powder.
Reaction SMILES: [CH:1]([N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[C:7]([C:16]2[S:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[N:6]1)([CH2:3][CH3:4])[CH3:2].ClC1C=CC=C(C(OO)=[O:30])C=1.S([O-])([O-])=O.[Na+].[Na+]>ClCCl>[CH:1]([N:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][N+:13]([O-:30])=[CH:14][CH:15]=2)[C:7]([C:16]2[S:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[N:6]1)([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)n1cc(-c2ccncc2)c(-c2ccc(Cl)s2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCC(C)n1cc(-c2cc[n+]([O-])cc2)c(-c2ccc(Cl)s2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.6 %

Procedure:
To a solution of 4-[1-sec-butyl-3-(5-chloro-2-thienyl)-1H-pyrazol-4-yl]pyridine (1 eq, 7.2 mmol) in 23 mL of dichloromethane was added metachloroperbenzoic acid 70% (1.5 eq, 10.9 mmol) in small portion at 0° C. The reaction was then stirred at room temperature overnight. Sodium sulfite (1.5 eq, 10.9 mmol) was then added and the organic layer was then washed with a 2M solution of potassium carbonate, dried over MgSO4, filtered and concentrated to afford 2.25 g of 4-[1-sec-butyl-3-(5-chloro-2-thienyl)-1H-pyrazol-4-yl]pyridine N oxide (83% yield) which was used in the next step without further purification.