Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.C(NC(C)C)(C)C.[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=1)#[CH:18]>C1COCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:9][S:8][C:4]1[N:3]=[C:2]([C:18]#[C:17][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[CH:7]=[CH:6][N:5]=1
Reactant: C#Cc1cccc([N+](=O)[O-])c1
Reactant: CSc1nccc(I)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CSc1nccc(C#Cc2cccc([N+](=O)[O-])c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
4-Iodo-2-(methylthio)pyrimidine (39.7 g, 0.157 mol) and diisopropylamine (44.2 mL, 0.315 mol) are dissolved in dry THF (720 mL) and argon gas is bubbled through the solution for 20 min. Copper(I) iodide (2.99 g, 14.3 mmol) and bis(triphenylphosphine)palladium dichloride (5.51 g, 7.85 mmol) are added and then 1-ethynyl-3-nitrobenzene (25.4 g, 0.173 mol) in dry THF (100 mL) is added dropwise over about 30 min with the temperature being maintained at about 25° C. Following complete addition, the mixture is stirred at rt for overnight. The mixture is filtered and washed with THF. The filtrate is concentrated under reduced pressure. The residue is washed with EtOAc/MeOH to give pale-yellow solid (42 g).
Reaction SMILES: [CH2:1]([C:3]1([CH2:18][CH3:19])[C:8]2[CH:9]=[C:10](B(O)O)[CH:11]=[CH:12][C:7]=2[N:6]([CH3:16])[C:5](=[O:17])[O:4]1)[CH3:2].C(=O)(O)[O-:21].[Na+].OOS([O-])=O.[K+].S(=O)(O)[O-].[Na+]>O.CC(C)=O>[CH2:1]([C:3]1([CH2:18][CH3:19])[C:8]2[CH:9]=[C:10]([OH:21])[CH:11]=[CH:12][C:7]=2[N:6]([CH3:16])[C:5](=[O:17])[O:4]1)[CH3:2]
Reactant: O=C([O-])O
Reactant: CCC1(CC)OC(=O)N(C)c2ccc(B(O)O)cc21
Agent: O=S([O-])O
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCC1(CC)OC(=O)N(C)c2ccc(O)cc21
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 69 %

Procedure:
To a stirred suspension of 4,4-diethyl-1-methyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl boronic acid (3.97 g, 15.09 mmol) in a 15% acetone and 85% water mixture solution (80 mL) was added sodium bicarbonate (3.80 g, 45.27 mmol). The resulting suspension was cooled to 0° C. and Oxone (9.09 g, 14.80 mmol) was added portionwise over 20 minutes. After 45 minutes, sodium bisulfite (4.25 g, 4.10 mmol) was added. The solution was stirred for an additional 10 minutes, diluted with water and extracted several times with ethyl acetate. The organic layers were dried over magnesium sulfate and concentrated. Trituration with ether gave 4,4-diethyl-6-hydroxy-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one as a white solid (2.45 g, 69%). 1H NMR (DMSO-d6): δ 9.32 (s, 2H), 6.90 (d, J=8.8 Hz, 1H), 6.75 (dd, J=8.7, 2.6 Hz, 1H), 6.58 (d, J=2.7 Hz, 1H), 3.22 (s, 3H), 1.99 (m, 4H), 0.79 (t, J=7.3 Hz, 6H). MS (ESI) m/z 236 ([M+H]+); MS (ESI) m/z 234 ([M−H]−); Anal. calcd for C13H17NO3: C, 66.36; H, 7.28; N, 5.95. Found: C, 66.02; H, 7.34; N, 5.74.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][O:5][CH2:4][C@H:3]1[OH:7].C(=O)([O-])[O-].[Na+].[Na+].O1CCCC1.Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>O>[OH:7][C@@H:3]1[CH2:4][O:5][CH2:6][C@H:2]1[NH:1][C:20](=[O:21])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@@H]1COC[C@H]1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(N[C@@H]1COC[C@H]1O)OCc1ccccc1
Temperature: 0 °C
Yield: 59 %

Procedure:
A mixture of the crude trans-4-aminotetrahydrofuran-3-ol (from Step 1), sodium carbonate (7.68 g, 72.5 mmol), tetrahydrofuran (100 mL) and water (100 mL) was cooled to 0° C. and stirred vigorously. Benzyl chloroformate (9.48 mL, 66.4 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 2 h. The organic solvent was removed in vacuo. The aqueous residue was diluted with water (50 mL) and extracted with ethyl acetate (3×70 mL). The combined extracts were dried (MgSO4) and concentrated. Silica gel chromatography, eluting with 30-100% ethyl acetate in hexanes, gave benzyl trans-4-hydroxytetrahydrofuran-3-ylcarbamate as a white solid (8.43 g, 59% yield for 2 steps). 1H NMR (400 MHz, chloroform-d) δ ppm 7.28-7.51 (5 H, m), 5.11 (2 H, br. s.), 4.92 (1 H, br. s.), 4.32 (1 H, br. s.), 3.93-4.17 (3 H, m), 3.50-3.80 (2 H, m), 2.69 (1 H, br. s.); MS (ES+) m/z: 238.1 (M+H); LC retention time: 2.595 min (analytical HPLC Method H).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:28]([OH:30])=O)[CH2:19][C:20]3[CH:21]=[N:22][C:23]([NH2:27])=[C:24]([CH3:26])[CH:25]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:31]=[CH:32][CH:33]=[CH:34][C:4]=2[NH:3]1.[CH3:35][N:36]1[CH2:41][CH2:40][N:39]([CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH2:38][CH2:37]1>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:21]=[N:22][C:23]([NH2:27])=[C:24]([CH3:26])[CH:25]=3)[C:28]([N:45]3[CH2:44][CH2:43][CH:42]([N:39]4[CH2:38][CH2:37][N:36]([CH3:35])[CH2:41][CH2:40]4)[CH2:47][CH2:46]3)=[O:30])=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:34]2[CH:33]=[CH:32][CH:31]=[CH:5][C:4]=2[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cnc1N
Reactant: CN1CCN(C2CCNCC2)CC1
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCN(C)CC3)CC2)cnc1N

Procedure:
Analogously to Example 1 h the product was obtained from 50 mg (0.11 mmol) of (R)-2-(6-amino-5-methyl-pyridin-3-yl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 20 mg (0.11 mmol) 1-methyl-4-piperidin-4-yl-piperazine.
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[N:17]=[CH:16][CH:15]=[C:14]2[O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]2[S:35][CH:36]=[CH:37][N:38]=2)=[O:32])=[C:26]([F:39])[CH:25]=1)C1C=CC=CC=1.FC(F)(F)C(O)=O.C1(SC)C=CC=CC=1>>[NH2:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[N:17]=[CH:16][CH:15]=[C:14]2[O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]2[S:35][CH:36]=[CH:37][N:38]=2)=[O:32])=[C:26]([F:39])[CH:25]=1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)Nc4nccs4)c(F)c3)c2cc1NC(=O)OCc1ccccc1
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4nccs4)c(F)c3)c2cc1N
Temperature: 60 °C
Reaction time: 2 h
Yield: 30.3 %

Procedure:
After adding {4-[3-fluoro-4-(3-(thiazol-2-yl)ureido)phenoxy]-7-methoxyquinolin-6-yl}carbamic acid benzyl ester (100 mg) to a mixture of trifluoroacetic acid (3 ml) and thioanisole (0.1 ml), the mixture was heated and stirred at 60° C. for 2 hours. The solvent was distilled off and the residue was subjected to NH silica gel column chromatography for elution with a solvent (ethyl acetate:methanol=10:1) to obtain the title compound (23 mg) as a solid.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N+:4]=1[O-:9].[N+:12]([O-])([OH:14])=[O:13]>OS(O)(=O)=O>[N+:12]([C:7]1[CH:6]=[CH:5][N+:4]([O-:9])=[C:3]([C:2]([F:1])([F:10])[F:11])[CH:8]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: [O-][n+]1ccccc1C(F)(F)F
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc[n+]([O-])c(C(F)(F)F)c1
Temperature: 130 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
To a stirred solution of 2-trifluoromethyl-pyridine 1-oxide (0.43 g, 2.43 mmol) in concentrated H2SO4 (2 mL) is added 70% HNO3 (1.6 mL) dropwise at 0° C. Reaction mixture is allowed to stir for 2 h at 130° C. After completion of reaction it is quenched with ice (˜200 g) and pH is adjusted 7 with solid K2CO3 (15-20 g) and extracted with EtOAc (3×20 mL). Organic part is washed with water, brine and dried over anhydrous MgSO4. Solution is concentrated under reduced pressure. The residue is purified by column chromatography (silica-gel, 100-200 mesh, eluent; 20% EtOAc in hexane) to afford 4-nitro-2-trifluoromethyl-pyridine 1-oxide (0.1 g, 20%).
Reaction SMILES: [OH:1][C:2]1[C:7](C(O)=O)=[CH:6][N:5]=[C:4]2[NH:11][N:12]=[CH:13][C:3]=12>C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:11][N:12]=[CH:13][C:3]=12
Reactant: O=C(O)c1cnc2[nH]ncc2c1O
Solvent: CCO
Product: Oc1ccnc2[nH]ncc12

Procedure:
An alternative synthesis of intermediates 19 has been described by Misra et al. (Bioorg. Med. Chem. Lett, Vol. 13(14), 2003, p. 2405). Suitably protected 4-Hydroxy-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (22, Y═OH, Z═OH) can be decarboxylated at temperatures above 200° C. Bromination of the resulting 4-Hydroxy-1H-pyrazolo[3,4-b]pyridine using elemental bromine in ethanol affords 19a (X═OH). Chlorination using phosphorus oxychloride affords 5-bromo-4-chloro-1H-pyrazolo[3,4-b]pyridine 19b (X═Cl).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][NH:10][C:9]2[CH:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=[CH:15][C:8]=2[O:7]1)=[O:5])C.[OH-].[Na+].ClC(OCC1C=CC=CC=1)=O.Cl>O1CCOCC1.O>[F:19][C:16]([F:17])([F:18])[C:13]1[CH:14]=[CH:15][C:8]2[O:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][NH:10][C:9]=2[CH:12]=1
Reactant: CCOC(=O)C1CNc2cc(C(F)(F)F)ccc2O1
Agent: Cl
Agent: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)C1CNc2cc(C(F)(F)F)ccc2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.8 %

Procedure:
6-Trifluoromethyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid ethyl ester (500 mg, 2 mmol) was dissolved in 1,4-dioxane (20 mL). Sodium hydroxide (109 mg, 2.7 mmol) was added, followed by benzyl chloroformate (311 μL, 2.2 mmol), and the reaction stirred overnight at room temperature. The reaction mixture was acidified with 2N HCl and diluted with water (20 mL), then extracted with EtOAc (3×30 mL). The combined organics were washed with brine (2×40 mL), dried (MgSO4), filtered and concentrated. Trituration using DCM/hexanes gave the title compound (330 mg, 10%) as a pale brown solid. m/z=245.7 (M−1), r.t.=2.78 mins. 1H NMR (400 MHz; CDCl3) δ 7.01 (2H, s), 6.86 (1H, s), 4.94 (1H, t), 3.66 (2H, dd).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)[O:3]1.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:16])([CH3:1])[O:3][B:4]([C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[N:13][CH:14]=2)[O:5]1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 0 °C
Yield: 57.5 %

Procedure:
5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (0.5 g, 2.27 mmol), pivaloyl chloride (0.277 g, 2.20 mmol) and triethylamine (0.248 g, 2.45 mmol) in pyridine (10 mL) were stirred at room temperature overnight. The mixture was diluted with ethyl acetate and ice/water and the layers were separated. The aqueous phase was extracted with ethyl acetate and the combined extracts dried over sodium sulfate. Purification by chromatography (1:1 ethyl acetate in hexanes) gave the product (0.385 g, 56% yield) as a white solid. 1H-NMR (300 MHz, CDCl3) δ 8.60 (s, 1H), 8.23 (d, 1H), 8.06 (d, 2H), 1.33 (s, 12H), 1.31 (s, 9H). MS (ES+) m/z 305 (M+1).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].CN(C)C=O.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][NH:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[C:1](=[O:2])[O:25][C:20]([C:21]([CH3:24])([CH3:23])[CH3:22])=[N:19]2)=[CH:16][CH:17]=1
Reactant: COc1ccc(NNC(=O)C(C)(C)C)cc1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(-n2nc(C(C)(C)C)oc2=O)cc1

Procedure:
12 ml of a (20%) solution of phosgene in toluene are added dropwise, at room temperature, to a mixture of 50 ml of toluene, 0.1 ml of N,N-dimethylformamide and 2.3 g of N-(4-methoxyphenyl)-N′-pivaloyl-hydrazine. The reaction mixture is stirred at reflux for 7 hours and then concentrated. After purification of the residue on silica gel, 1-methoxy-4-(5-oxo-2-tert-butyl-3,4-diaza-1-oxa-cyclopent-2-en-4-yl)-benzene is obtained in the form of a colourless oil.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([N:10]([CH2:12][C:13]1[S:17][CH:16]=[C:15]([C:18]2[CH:19]=[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=2)[NH:23][CH:22]=[C:21]3[CH:30]2[CH2:35][CH2:34][N:33]([S:36]([CH2:39][CH3:40])(=[O:38])=[O:37])[CH2:32][CH2:31]2)[CH:14]=1)[CH3:11])[CH3:9].[CH3:41][NH:42][CH2:43][CH3:44]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:39]([S:36]([N:33]1[CH2:34][CH2:35][CH:30]([C:21]2[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=[C:18]([C:15]4[CH:14]=[C:13]([CH2:12][N:10]([CH3:11])[CH2:8][C:9]5[CH:2]=[CH:41][N:42]=[CH:43][CH:44]=5)[S:17][CH:16]=4)[CH:19]=3)[NH:23][CH:22]=2)[CH2:31][CH2:32]1)(=[O:37])=[O:38])[CH3:40]
Reactant: CCN(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Reactant: CCNC
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN(C)Cc5ccncc5)c4)cc23)CC1
Yield: 46.6 %

Procedure:
The title compound was prepared according to the general procedure of 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting methyl(4-pyridinylmethyl)amine (122 mg, 1.0 mmol) for N-methylethanamine to afford 31.0 mg of the title compound (46.6%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:17])=[CH:4][C:5]2[C:14]3[NH:13][C:12](=O)[CH2:11][CH2:10][C:9]=3[N:8]=[CH:7][C:6]=2[CH:16]=1.B>O1CCCC1>[Cl:1][C:2]1[C:3]([Cl:17])=[CH:4][C:5]2[C:14]3[NH:13][CH2:12][CH2:11][CH2:10][C:9]=3[N:8]=[CH:7][C:6]=2[CH:16]=1
Reactant: O=C1CCc2ncc3cc(Cl)c(Cl)cc3c2N1
Agent: B
Solvent: C1CCOC1
Product: Clc1cc2cnc3c(c2cc1Cl)NCCC3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4.00 g of 8,9-dichloro-1,4-dihydrobenzo[c]-1,5-naphthyridin-2(3H)-one in tetrahydrofuran (800 ml) was added 60 ml of borane solution (1.0M in tetrahydrofuran) over approximately one minute. A solution formed after the borane addition was complete. The solution was stirred overnight at ambient temperature.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:10][C:9](=[O:11])[NH:8][C:5]2=[N:6][CH:7]=1.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH:21]=O)[CH:19]=2)[CH:14]=[N:13]1>>[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH:21]=[C:10]3[C:4]4[C:5](=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=4)[NH:8][C:9]3=[O:11])[CH:19]=2)[CH:14]=[N:13]1
Reactant: O=Cc1ccc2cn[nH]c2c1
Reactant: O=C1Cc2cc(Br)cnc2N1
Product: O=C1Nc2ncc(Br)cc2C1=Cc1ccc2cn[nH]c2c1
Yield: 146.6 %

Procedure:
The title compound (50 mg, 95%) was synthesized as a green solid according to the method described for (E/Z)-3-((3-iodo-1H-indazol-6-yl)methylene)-5-methoxyindolin-2-one using 5-bromo-1H-pyrrolo[2,3-b]pyridin-2(3H)-one (21.3 mg, 0.1 mmol) and 1H-indazole-6-carbaldehyde (14.6 mg, 0.1 mmol). 1H NMR indicated 56:44 mixture of E/Z isomers. E isomer: 1H NMR (400 MHz, DMSO-d6) δ 13.38 (s, 1H, NH), 11.45 (s, 1H, NH), 8.38 (d, J=2.0 Hz, 1H), 8.25 (d, J=2.0 Hz, 1H), 8.19 (s, 1H), 8.01 (s, 1H), 7.93 (s, 1H), 7.90 (d, J=2.0 Hz, 1H), 7.45 (dd, J=8.4 Hz, 2.0 Hz, 1H); Z isomer: δ 13.46 (s, 1H, NH), 11.45 (s, 1H, NH), 8.94 (s, 1H), 8.21 (d, J=2.0 Hz, 1H), 8.19 (s, 1H), 8.15 (s, 1H), 7.99 (dd, J=8.8 Hz, 1.6 Hz, 1H), 7.94 (d, J=8.4 Hz, 1H), 7.85 (d, J=8.0 Hz, 1H); MS ESI 341.0 [M+H]+, calcd for [C15H9BrN4O+H]+ 341.1.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:13]([N:15]([C:19]1[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=1)[CH2:16][CH2:17][NH2:18])[CH3:14].[BH4-].[Na+].O>CO>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:18][CH2:17][CH2:16][N:15]([CH2:13][CH3:14])[C:19]2[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CCN)c1cccc(C)c1
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCN(CCNCc1ccc(C(C)(C)C)cc1)c1cccc(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
1.62 g (10 mmol) of 4-tert-butyl benzaldehyde and 1.78 g (10 mmol) of N*1*-ethyl-N*1* -m-tolyl-ethane-1,2-diamine were dissolved in 20 ml methanol and the solution was stirred for 2 h at rt. 567 mg (15 mmol) of sodium borohydride were added in portions under nitrogen. The reaction mixture was stirred at rt over night. Water was added and the solvent was evaporated. The reaction mixture was extracted with diethyl ether and the organic layer was washed with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and the solvent was evaporated to leave the 3.08 g (95%) product as a light yellow oil. 1H NMR (DMSO-d6, 300 MHz): δ 7.33 (d, 2H), 7.24 (d, 2H), 7.09 (dd, 1H), 6.51 (m, 3H), 3.78 (s, 2H), 3.42 (t, 2H), 3.34 (q, 2H), 2.85 (t, 2H), 2.29 (s, 3H), 1.31 (s, 9H), 1.11 (t, 3H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:9][C@@H:8]([CH2:10][OH:11])[O:7][C@H:6]1[N:12]1[CH:19]=[CH:18][C:16](=[O:17])[NH:15][C:13]1=[O:14])(=[O:3])[CH3:2].[N+]([O-])([O-])=O.[Ce+4].[NH4+].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[I:47]I>C(#N)C>[C:1]([O:4][C@@H:5]1[CH2:9][C@@H:8]([CH:10]([I:47])[OH:11])[O:7][C@H:6]1[N:12]1[CH:19]=[CH:18][C:16](=[O:17])[NH:15][C:13]1=[O:14])(=[O:3])[CH3:2]
Reactant: II
Reactant: CC(=O)O[C@@H]1C[C@@H](CO)O[C@H]1n1ccc(=O)[nH]c1=O
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Product: CC(=O)O[C@@H]1C[C@@H](C(O)I)O[C@H]1n1ccc(=O)[nH]c1=O
Yield: 155.3 %

Procedure:
To a solution of 2'-O-acetyl-3'-deoxyuridine (2.47 g) in acetonitrile (150 ml), diammonium cerium (IV) nitrate (2.51 g) and iodine (1.39 g) were added and allowed to react at 80° C. for one hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, the obtained residue w s extracted with ethyl acetate, and the extract was washed with 5% aqueous solution of sodium bisulfite and saturated brine. The ethyl acetate layer was dried with anhydrous magnesium sulfate, and the solvent was evaporated to afford 2'-O-acetyl-3'-deoxy-5'-iodouridine (3.37 g, yield: 93.1%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[N:14]3[N:15]=[N:16][N:17]=[C:13]3[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11]([CH3:28])=[C:10]2[C:29](O)=[O:30])=[CH:5][CH:4]=1)#[N:2].[Cl-].[NH4+].C[N:35](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[N:14]3[N:15]=[N:16][N:17]=[C:13]3[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:25])[F:27])[CH:19]=3)[C:11]([CH3:28])=[C:10]2[C:29]([NH2:35])=[O:30])=[CH:7][CH:8]=1)#[N:2]
Reactant: CC1=C(C(=O)O)[C@@H](c2ccc(C#N)cc2)n2nnnc2N1c1cccc(C(F)(F)F)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1=C(C(N)=O)[C@@H](c2ccc(C#N)cc2)n2nnnc2N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The reaction was carried out under argon. (7R)-7-(4-Cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxylic acid (62 mg, 145 μmol) and ammonium chloride (116.7 mg, 2.2 mmol, 15 eq.) were initially charged in dry DMF (3.5 ml) at 0° C., and HATU (415 mg, 1.8 mmol, 7.5 eq.) and triethylamine (147 mg, 1.45 mmol, 10 eq.) were added. The mixture was stirred for 12 h, during which time it gradually warmed to RT. The reaction mixture was then concentrated, and the residue was taken up in acetonitrile (with 0.1% TFA) and then purified by preparative HPLC (Gromsil C18 column, 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). The product was obtained as a colorless amorphous solid (36 mg, 58% of theory).
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@H:23]4[C@H:19]([O:20]C(C)(C)[O:22]4)[C@@H:18]([CH2:26][N:27]([CH3:47])[CH:28]4[CH2:31][CH:30]([CH2:32][CH2:33][C:34]5[NH:38][C:37]6[CH:39]=[CH:40][C:41]([CH:43]7[CH2:46][O:45][CH2:44]7)=[CH:42][C:36]=6[N:35]=5)[CH2:29]4)[CH2:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.FC(F)(F)C(O)=O.O>>[NH2:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@@H:16]3[CH2:17][C@H:18]([CH2:26][N:27]([CH3:47])[CH:28]4[CH2:31][CH:30]([CH2:32][CH2:33][C:34]5[NH:38][C:37]6[CH:39]=[CH:40][C:41]([CH:43]7[CH2:44][O:45][CH2:46]7)=[CH:42][C:36]=6[N:35]=5)[CH2:29]4)[C@@H:19]([OH:20])[C@H:23]3[OH:22])[C:9]=2[N:10]=[CH:11][N:12]=1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C)C3CC(CCc4nc5cc(C6COC6)ccc5[nH]4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CN(C[C@H]1C[C@@H](n2ccc3c(N)ncnc32)[C@H](O)[C@@H]1O)C1CC(CCc2nc3cc(C4COC4)ccc3[nH]2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 43.8 %

Procedure:
N-(2,4-dimethoxybenzyl)-7-((3aS,4R,6R,6aR)-2,2-dimethyl-6-((methyl(3-(2-(5-(oxetan-3-yl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)amino)methyl)tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (115 mg, 0.159 mmol) was dissolved in a mixture of Trifluoroacetic Acid (4.00 ml, 51.9 mmol) and Water (0.40 ml, 22 mmol) which had been pre-cooled at 0° C. in an ice bath. The solution was stirred at 0° C. for 2 h, the reaction mixture was allowed to warm to RT. After 1 the reaction mixture was concentrated in vacuo. The residue was taken up in 6 ml MeOH, concentrated and the process was repeated twice. The resultant residue was placed on high vacuum. The crude residue was diluted with 2 ml MeOH, treated with 140 mg K2CO3 and 10 drops of H2O and allowed to stir at RT until the solution was basic by pH paper. The solution was filtered through a fine frit and the solids washed with MeOH. The filtrate was concentrated to a solid that was placed on high vacuum overnight. The crude material was purified by prep TLC on two 20 cm×20 cm×1.0 mm prep TLC plate, eluting with 14% 7N NH3 in CH3OH/CH2Cl2 to give the product as a colorless glass (37 mg) 1H NMR (400 MHz, MeOD) δH ppm 8.06 (s, 1 H), 7.52 (br. s., 1 H), 7.48 (d, J=8.29 Hz, 1 H), 7.28 (m, 1 H), 7.20 (t, J=3.42 Hz, 1 H), 6.60 (d, J=3.52 Hz, 1 H), 5.12 (m, 2 H), 4.80 (m, 2 H), 4.38 (m, 1 H), 4.32 (m, 1 H), 3.89 (q, J=5.60 Hz, 1 H), 3.04 (m, 1 H), 2.85 (m, 2 H), 2.70 (m, 1 H), 2.52 (m, 1 H), 2.41 (m. 2 H), 2.27 (dd, J=10.99, 6.63 Hz, 2 H), 2.19 (s, 3 H), 2.17 (s, 3 H), 2.14 (m, 1 H), 2.03 (d, J=7.88 Hz, 1 H), 1.91 (m, 3 H), 1.62 (m, 1 H), 1.51 (m, 1 H).
Reaction SMILES: O1CCCC1.C[O:7][C:8]([C:10]1[CH:15]=[N:14][C:13]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[N:11]=1)=[O:9].[OH-].[Li+].Cl>O>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C:12]2[N:11]=[C:10]([C:8]([OH:9])=[O:7])[CH:15]=[N:14][C:13]=2[N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:23][CH:24]=1
Reactant: COC(=O)c1cnc(N2CCCCC2)c(-c2ccc(F)cc2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnc(N2CCCCC2)c(-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a tetrahydrofuran (5 ml) solution of 6-(4-fluoro-phenyl)-5-piperidin-1-yl-pyrazine-2-carboxylic acid methyl ester (0.48 g, 1.52 mmol, 1.0 eq) was added a solution of lithium hydroxide (1M, 1.52 ml, 1.52 mmol, 1.0 eq) in water. The mixture was stirred overnight at room temperature after which time the resulting solution was acidified with hydrochloric acid (pH˜5) and aqueous phase extracted with ethyl acetate (2×10 ml). The organic phase was dried over magnesium sulfate and concentrated in vacuo to afford 6-(4-fluoro-phenyl)-5-piperidin-1-yl-pyrazine-2-carboxylic acid as white crystals. Yield=0.42 g (91%). 1H NMR (400 MHz, DMSO): δ 1.46-1.53 (6H, m), 3.22-3.25 (4H, m), 7.32 (2H, t, J=8.87 Hz), 7.82-7.86 (2H, m), 8.62 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.NC1C(C(OCC)=O)=CNN=1.[CH3:18][C:19](=O)[CH2:20][C:21](=O)[CH3:22]>>[CH3:18][C:19]1[CH:20]=[C:21]([CH3:22])[N:3]2[N:4]=[CH:5][CH:6]=[C:2]2[N:1]=1
Reactant: Nc1cc[nH]n1
Reactant: CC(=O)CC(C)=O
Agent: CCOC(=O)c1c[nH]nc1N
Product: Cc1cc(C)n2nccc2n1

Procedure:
The procedure for preparation of the 5,7-dialkyl compounds of this invention follows generally that reported by Y. Makisumi, Chem. Pharm. Bull. (Tokyo) 10, 612 (1962) wherein 3-aminopyrazole or 3-amino-4-carbethoxypyrazole is condensed with pentane-2,4-dione to provide 5,7-dimethylpyrazolo[1,5-a]pyrimidine or the 3-carbethoxy derivative.