Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([CH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[CH2:9][C:10]([CH3:16])([CH3:15])[C:11]([O:13][CH3:14])=[O:12])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[NH2:1][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([CH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[CH2:9][C:10]([CH3:16])([CH3:15])[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)C(C)(C)CC(CCCCN=[N+]=[N-])CCCc1cccnc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)CC(CCCCN)CCCc1cccnc1
Reaction time: 14 h

Procedure:
The crude azide (1.29 g) is dissolved in 7 ml dry tetrahydrofuran, and 0.82 g (3.1 mmol) triphenylphosphine is added followed by two boiling stones and 0.08 ml (4.4 mmol) water. The solution is stirred for 14 h. An additional 0.82 g triphenylphosphine and 0.08 ml water are added and the mixture is stirred for another 5 h. The reaction mixture is concentrated under vacuum and then purified by silica gel chromatography using first ethyl acetate to remove nonpolar impurities and triphenylphosphine oxide. Then the eluent is changed to 9:1 methanol/triethylamine to obtain methyl 8-amino-2,2-dimethyl-4-(3-[3-pyridyl)propyl]-octanoate as an oil; NMR (CDCl3): delta 3.59 (s,3H), 2.67 (t,2H), 2.54 (t,2H), 1.13 (s,6H).
Reaction SMILES: N[C:2]1[N:7]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])[C:6](=[O:17])[NH:5][C:4](=[O:18])[CH:3]=1.[ClH:19].[N+]([O-])([O-])=O.[Na+]>O>[Cl:19][C:2]1[N:7]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])[C:6](=[O:17])[NH:5][C:4](=[O:18])[CH:3]=1
Reactant: Cc1cccc(C)c1Nn1c(N)cc(=O)[nH]c1=O
Reactant: Cl
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cccc(C)c1Nn1c(Cl)cc(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 1 mole of 6-amino-1-(2,6-dimethylanilino)-2,4-pyrimidinedione dissolved in 3 moles of dilute aqueous hydrochloric acid cooled to 0°-5° in an ice bath is slowly added 1.1 mole of sodium nitrate (dissolved in water at 5°) with rapid stirring. After addition is complete, add dropwise but rapidly 1.1 mole cuprous chloride dissolved in water. Stir for 30 minutes, then heat to 50° for 1 hour. The mixture is cooled to RT and filtered to obtain 6-chloro-1-(2,6-dimethyl anilino)-2,4-pyrimidinedione.
Reaction SMILES: [CH2:1]([Si:3]([CH2:15][CH3:16])([CH2:13][CH3:14])[O:4][C:5]([CH3:12])([CH2:9][CH2:10][CH3:11])[CH2:6][C:7]#[CH:8])[CH3:2].N(C(C)(C)C#N)=NC(C)(C)C#N.[CH2:29]([SnH:33]([CH2:38][CH2:39][CH2:40][CH3:41])[CH2:34][CH2:35][CH2:36][CH3:37])[CH2:30][CH2:31][CH3:32]>>[CH2:15]([Si:3]([CH2:13][CH3:14])([CH2:1][CH3:2])[O:4][C:5]([CH3:12])([CH2:9][CH2:10][CH3:11])[CH2:6]/[CH:7]=[CH:8]/[Sn:33]([CH2:34][CH2:35][CH2:36][CH3:37])([CH2:38][CH2:39][CH2:40][CH3:41])[CH2:29][CH2:30][CH2:31][CH3:32])[CH3:16]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C#CCC(C)(CCC)O[Si](CC)(CC)CC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCCC[Sn](/C=C/CC(C)(CCC)O[Si](CC)(CC)CC)(CCCC)CCCC
Temperature: 25 °C

Procedure:
A solution of 40.0 g of 4-triethylsilyloxy-4-methyl-1-heptyne, 180 mg of azobisisobutyronitrile, and 50 ml of tri-n-butyltin hydride is stirred under an argon atmosphere at 130° C. for 2 hours, then allowed to cool to ambient temperature. The excess tin hydride is removed by distillation and the residue purified to provide 63.5 g of the (E)-4-triethylsilyloxy-4-methyl-1-tri-n-butylstannyl-1-heptene (b.p. 160°-88° C. at 0.6 mm).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]([NH2:9])=[N:7][CH:8]=1.[CH3:10][C:11]1([CH3:19])[CH2:17][C:16](=O)[O:15][C:13](=[O:14])[CH2:12]1>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]([N:9]2[C:13](=[O:14])[CH2:12][C:11]([CH3:19])([CH3:10])[CH2:17][C:16]2=[O:15])=[N:7][CH:8]=1
Reactant: COc1cnc(N)nc1
Reactant: CC1(C)CC(=O)OC(=O)C1
Solvent: ClCCl
Product: COc1cnc(N2C(=O)CC(C)(C)CC2=O)nc1
Temperature: 180 °C
Yield: 39.7 %

Procedure:
A mixture of 5-methoxy-pyrimidin-2-ylamine (1.00 g, 7.99 mmol) and 3,3-dimethylglutaric anhydride (1.14 g, 7.99 mmol) was heated at 180° C. for 9 hours. After cooling to room temperature the reaction mixture was dissolved in a small amount of dichloromethane and purified by flash column chromatography (SiO2, ethyl acetate:heptane 70:30), yielding the title compound (0.79 g, 40% yield) as a white solid.
Reaction SMILES: [N+:1]([C:4]([N+:13]([O-:15])=[O:14])([N+:10]([O-:12])=[O:11])[CH2:5][CH2:6][C:7](Cl)=[O:8])([O-:3])=[O:2].[F:16][C:17]([F:29])([C:25]([F:28])([F:27])[F:26])[C:18]([F:24])([F:23])[C:19]([NH:21][NH2:22])=[O:20].N1C=CC=CC=1.Cl>C(OCC)C.O>[N+:1]([C:4]([N+:13]([O-:15])=[O:14])([N+:10]([O-:12])=[O:11])[CH2:5][CH2:6][C:7]([NH:22][NH:21][C:19](=[O:20])[C:18]([F:23])([F:24])[C:17]([F:16])([F:29])[C:25]([F:27])([F:26])[F:28])=[O:8])([O-:3])=[O:2]
Reactant: O=C(Cl)CCC([N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-]
Reactant: NNC(=O)C(F)(F)C(F)(F)C(F)(F)F
Agent: Cl
Solvent: O
Solvent: CCOCC
Solvent: c1ccncc1
Product: O=C(CCC([N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-])NNC(=O)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
To a solution of 1.0 g (0.0041 mole) of 4,4,4-trinitrobutyryl chloride in anhydrous diethyl ether (10 mL) stirred at 20° C. (water bath) was added 0.9 g (0.0039 mole) of N-(heptafluorobutyryl)hydrazine. The mixture became thick with precipitate and sufficient ether (10 mL) was added to allow efficient stirring. Pyridine (0.35 ml, 0.0044 mole) was added dropwise and the mixture was stirred for 5 minutes before 5% hydrochloric acid (10 mL) was added. The ether layer was dried (Na2SO4), the volatiles were removed, and the residue was stirred with water to give 1.5 g, mp 146°-150° C. Crystallization from 1,2-dichloroethane gave the product, N-(4,4,4-trinitrobutyryl)-N'-(perfluorobutyryl)hydrazine, 1.2 g (70%) mp 154°-156° C.; 1H NMR (acetone-d6 +D2O): 2.98 (t, 2H), 3.87 (t, 2H).
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([O:26][C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:22][C:21]=3[NH:31][CH2:32][CH:33]([CH3:35])[CH3:34])[C@H:14]2[CH3:36])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1.CCOC(C)=O>[F:38][C:2]([F:1])([F:37])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([O:26][C:27]([F:28])([F:29])[F:30])[CH:23]=[CH:22][C:21]=3[N:31]([CH2:32][CH:33]([CH3:34])[CH3:35])[S:40]([CH3:39])(=[O:42])=[O:41])[C@H:14]2[CH3:36])[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: CC(C)CNc1ccc(OC(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)CN(c1ccc(OC(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C)S(C)(=O)=O
Temperature: 65 °C
Reaction time: 4 h

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(isobutylamino)-5-(trifluoromethoxy)benzyl]-4-methyl-1,3-oxazolidin-2-one (9.2 mg, 0.0165 mmol) in pyridine (300 μL) was added methanesulfonyl chloride (100 μL, 1.29 mmol) and excess 4-dimethylaminopyridine. The reaction was stirred at 65° C. for 4 hours and then diluted with EtOAc (15 mL), and washed with 1 N HCl (2×10 mL) and brine (10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by PTLC (60% EtOAc/hexanes) N-[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethoxy)phenyl]-N-isobutylmethanesulfonamide. Rf=0.25 (60% EtOAc/hexanes). LCMS=637.4 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.91 (s, 1H), 7.80 (s, 2H), 7.34-2.46 (m, 3H), 5.79-5.76 (m, 1H), 4.90-4.58 (m, 2H), 4.19-4.14 (m, 1H), 3.51-3.46 (m, 1H), 3.34-3.32 (m, 1H), 2.97 (m, 3H), 1.25 (m, 1H), 0.93-0.87 (m, 6H), 0.70-0.66 (m, 3H).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:16])=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([NH2:8])=[CH:6][CH:7]=1.C(OC([NH:24][C@@H:25]([CH3:29])[C:26](O)=O)=O)(C)(C)C.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.[ClH:47].CN(C)CCCN=C=NCC>C(Cl)Cl.O>[ClH:47].[ClH:47].[F:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:26]([C@@H:25]([NH2:24])[CH3:29])[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:4]=2[C:3]=1[CH3:16]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1c(F)ccc(N)c1Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1c(F)ccc2nc([C@H](C)N)n(-c3ccccc3)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4-fluoro-3-methyl-N2-phenylbenzene-1,2-diamine (600 mg, 2.77 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (577 mg, 3.05 mmol), HOAt (415 mg, 3.05 mmol), 4-methylmorpholine (0.67 mL, 6.1 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (586 mg, 3.05 mmol) in DCM (10 mL) was stirred at RT for 1 h. The reaction mixture was diluted with water and extracted with DCM (×3). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17][CH2:16][CH2:15][C@H:14]4C)[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][O:22][C:23]1[N:28]=[CH:27][C:26](B(O)O)=[CH:25][N:24]=1.N1C=C(B(O)O)C=NC=1>>[CH3:21][O:22][C:23]1[N:28]=[CH:27][C:26]([C:2]2[CH:20]=[CH:19][C:5]3[N:6]=[C:7]([C@H:9]4[CH2:12][C@H:11]([N:13]5[CH2:14][CH2:15][CH2:16][CH2:17]5)[CH2:10]4)[S:8][C:4]=3[CH:3]=2)=[CH:25][N:24]=1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Reactant: COc1ncc(B(O)O)cn1
Agent: OB(O)c1cncnc1
Product: COc1ncc(-c2ccc3nc([C@H]4C[C@H](N5CCCC5)C4)sc3c2)cn1

Procedure:
The title compound was prepared according to the procedure described in Example 1F, substituting the product of Example 62A for the product of Example 1E and substituting 2-methoxypyrimidine-5-boronic acid for pyrimidine-5-boronic acid. 1H NMR (300 MHz, CDCl3) δ ppm 8.78 (s, 1H) 8.07 (d, J=8.48 Hz, 1H) 7.98 (d, J=1.70 Hz, 1H) 7.60 (dd, J=8.48, 2.03 Hz, 1H) 4.08 (s, 3H) 3.93-4.07 (m, 1H) 3.26-3.45 (m, 1H) 2.50-2.80 (m, 6H) 1.78-1.96 (m, 4H) 1.59 (m, 2H). MS: (M+H)+=367.
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH3:4].[CH3:6][C:7]([C:10]1[C:15]([OH:16])=[C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])[N:13]=[C:12]([NH:21][C:22]([NH2:24])=[S:23])[N:11]=1)([CH3:9])[CH3:8].O.C([O-])(O)=O.[Na+]>C(O)C>[CH3:9][C:7]([C:10]1[C:15]([OH:16])=[C:14]([C:17]([CH3:18])([CH3:20])[CH3:19])[N:13]=[C:12]([NH:21][C:22]2[S:23][CH:2]=[C:3]([CH3:4])[N:24]=2)[N:11]=1)([CH3:6])[CH3:8]
Reactant: CC(C)(C)c1nc(NC(N)=S)nc(C(C)(C)C)c1O
Reactant: CC(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1csc(Nc2nc(C(C)(C)C)c(O)c(C(C)(C)C)n2)n1
Yield: 45 %

Procedure:
Chloroacetone (0.17 g, 1.9 mmol) is added to a solution of N-[4,6-bis(1,1-dimethylethyl)-5-hydroxy-2-pyrimidinyl]thiourea in 25 mL of ethanol. The reaction mixture is warmed to reflux for 18 hours. The solution is poured into 100 mL of water and the pH is adjusted to 4 with saturated NaHCO3. The resulting precipitate is collected by filtration. Recrystallization from hexane gives 0.26 g (45%) of 4,6-bis(1,1-dimethylethyl)-2-[(4-methyl-2-thiazolyl)amino]-5-pyrimidinol; mp 171°-173° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[N:9]=[CH:10][S:11][CH:12]=2)[CH2:3][CH2:2]1.[C:13](=[O:15])=[O:14].C([Li:20])CCC>C(OCC)C>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[N:9]=[C:10]([C:13]([O-:15])=[O:14])[S:11][CH:12]=2)[CH2:3][CH2:2]1.[Li+:20]
Reactant: O=C=O
Reactant: [Li]CCCC
Reactant: c1nc(CN2CCOCC2)cs1
Solvent: CCOCC
Product: O=C([O-])c1nc(CN2CCOCC2)cs1
Product: [Li+]
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
4-(Morpholinomethyl)thiazole (640 mg) was dissolved in diethyl ether (5 ml) in an argon atmosphere, and n-butyllithium (1.54N hexane solution, 2.50 ml) was added dropwise at −78° C. The reaction mixture was stirred for 10 minutes under ice cooling, and cooled again to −78° C. After blowing carbon dioxide into the reaction mixture for 20 minutes, it was heated to room temperature. The reaction mixture was concentrated under reduced pressure to obtain the title compound (873 mg) as crude yellow powder.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[F:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:29]=[C:28]3[CH2:30][NH:31][CH2:32][CH2:33][C:27]3=[N:26][C:25]=2[NH:34][CH:35]([CH3:37])[CH3:36])[CH2:20][CH2:19]1)[C:12]#[N:13].C(N(CC)CC)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>C(Cl)Cl>[F:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH:18]1[CH2:19][CH2:20][N:21]([C:24]2[N:29]=[C:28]3[CH2:30][N:31]([S:46]([CH3:45])(=[O:48])=[O:47])[CH2:32][CH2:33][C:27]3=[N:26][C:25]=2[NH:34][CH:35]([CH3:37])[CH3:36])[CH2:22][CH2:23]1)[C:12]#[N:13].[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(C#N)cc3F)CC1)CNCC2
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(C#N)cc3F)CC1)CN(S(C)(=O)=O)CC2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-fluoro-4-((1-(2-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)oxy)benzonitrile TFA salt (98.6 mg, 0.094 mmol) and triethylamine (0.039 mL, 0.283 mmol) in DCM (1.0 mL) was added methanesulfonyl chloride (10.9 μL, 0.141 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min and then concentrated via rotary evaporation. The crude material was diluted with DMSO, filtered, rinsed with DMSO, and purified by HPLC Method B, with the exception that a Waters XSelect® CSH C18, 5 μm, ID 4.6×50 mm was used, using an ACN gradient of 30% to 70% to give the title compound as a TFA salt (3.5 mg, 6.2%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.18 (d, J=6.3 Hz, 6H), 1.88-1.96 (m, 2H), 2.09-2.16 (m, 2H), 2.76 (t, J=5.9 Hz, 2H), 2.89-2.96 (m, 2H), 2.97 (s, 3H), 3.24-3.30 (m, 2H), 3.45 (t, J=5.9 Hz, 2H), 4.10-4.16 (m, 3H), 4.81-4.85 (m, 1H), 5.66 (d, J=8.3 Hz, 1H), 7.50 (t, J=8.7 Hz, 1H), 7.68 (ddd, J=8.6, 2.0, 1.3 Hz, 1H), 7.86 (dd, J=11.4, 2.0 Hz, 1H); ESI-MS m/z [M+H]+ 489.5.
Reaction SMILES: [CH2:1]([CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]2=[N:13][CH:14]=[C:15]([C:18]#[N:19])[C:16](=[O:17])[N:5]2[CH2:4]1)[CH3:2]>[Pd].CC1C=CC(C(C)C)=CC=1.C(Cl)Cl>[CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]2=[N:13][CH:14]=[C:15]([C:18]#[N:19])[C:16](=[O:17])[N:5]2[CH:4]=1)[CH3:2]
Reactant: CCC1Cn2c(ncc(C#N)c2=O)-c2ccccc21
Agent: [Pd]
Solvent: Cc1ccc(C(C)C)cc1
Solvent: ClCCl
Product: CCc1cn2c(=O)c(C#N)cnc2c2ccccc12
Yield: 46 %

Procedure:
A stirred mixture of (±)-7-ethyl-6,7-dihydro-4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carbonitrile (3.5 g.) and 10% palladium on carbon (1.5 g.) in p-cymene (50 ml.) was refluxed for 18 hours. The mixture was diluted with methylene chloride and filtered to remove the catalyst. The solvents were removed on a rotary evaporator and the residue crystallized from ethanol to give 1.6 g. (46% yield) of the title compound, m.p. 208°-211°. Successive recrystallizations from toluene and ethanol provided the analytical sample, m.p. 218°-219°.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([NH:6]C(=O)OC(C)(C)C)[CH2:5][CH2:4]1.[F:14][C:15]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:16]=1[CH2:17][O:18][C:19]1[N:24]2[N:25]=[C:26]([CH3:31])[C:27]([C:28](O)=[O:29])=[C:23]2[CH:22]=[C:21]([CH3:32])[CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C.ClCCl>[NH2:6][C:3]1([CH2:2][NH:1][C:28]([C:27]2[C:26]([CH3:31])=[N:25][N:24]3[C:19]([O:18][CH2:17][C:16]4[C:33]([F:37])=[CH:34][CH:35]=[CH:36][C:15]=4[F:14])=[CH:20][C:21]([CH3:32])=[CH:22][C:23]=23)=[O:29])[CH2:4][CH2:5]1
Reactant: Cc1cc(OCc2c(F)cccc2F)n2nc(C)c(C(=O)O)c2c1
Reactant: CC(C)(C)OC(=O)NC1(CN)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1cc(OCc2c(F)cccc2F)n2nc(C)c(C(=O)NCC3(N)CC3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
20.5 mg (0.11 mmol) of tert-butyl [1-(aminomethyl)cyclopropyl]carbamate were initially charged in a 96-well deep well multititre plate. A solution of 33.2 mg (0.1 mmol) of 7-[(2,6-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylic acid from Example 4A in 0.4 ml of DMF/dichloromethane (1:1, v/v) and a solution of 49.4 mg (0.13 mol) of HATU in 0.4 ml of DMF/dichloromethane (1:1, v/v) were added successively. After adding 20.2 mg (0.20 mmol) of 4-methylmorpholine, the mixture was shaken at RT overnight. Subsequently, the mixture was heated to 60° C. and shaken at this temperature for 7 h. Then the solvent was evaporated off completely. The residue was admixed with 0.6 ml of TFA and shaken at room temperature overnight. Then the mixture was concentrated fully, the residue was dissolved in 0.8 ml of DMF and filtered, and the target compound was isolated from the filtrate by preparative LC-MS (Method 9). The product-containing fractions were concentrated under reduced pressure using a centrifugal dryer. The residue of each product fraction was dissolved in 0.6 ml of DMSO. These were combined and finally freed of the solvent in a centrifugal dryer. 0.5 mg (1.3% of theory) of the title compound were obtained.
Reaction SMILES: [I:1]Cl.[N:3]1[C:4](=[O:12])[N:5]=[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=12>C(O)(=O)C>[I:1][C:10]1[CH:9]=[CH:8][C:7]2=[N:3][C:4](=[O:12])[N:5]=[C:6]2[CH:11]=1
Reactant: O=C1N=c2ccccc2=N1
Reactant: ClI
Solvent: CC(=O)O
Product: O=C1N=c2ccc(I)cc2=N1
Temperature: 80 °C

Procedure:
A mixture of iodine monochioride and 2H-benzimidazole-2-one (0.67 g) (Method 59) in glacial acetic acid (8 ml) was heated to 80° C. for 1 hour then cooled. The mixture was partitioned between saturated aqueous sodium sulphite solution and DCM. The organic layer was evaporated to dryness then redissolved in ethyl acetate. The aqueous layer was extracted with ethyl acetate then all ethyl acetate extracts were combined and washed with saturated aqueous sodium hydrogen carbonate solution, water and brine. The organic extracts were passed through a Varian Chem Elut column and washed through with ethyl acetate. Volatile material was removed by evaporation to give the title compound (0.36 g) as a solid which was used without further purification. MS (ESP+): 261 (M+H)+.
Reaction SMILES: P(Br)(Br)[Br:2].O[CH2:6][CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1>CCOCC>[Br:2][CH2:6][CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1
Reactant: BrP(Br)Br
Reactant: OCCCc1c[nH]c2ccccc12
Solvent: CCOCC
Product: BrCCCc1c[nH]c2ccccc12
Temperature: 23 °C
Yield: 14.8 %

Procedure:
Phosphorus tribromide (17.4 g) in Et2O (30 mL) was added dropwise to a Et20 solution (100 mL) containing 3-(3-hydroxypropyl)indole (VI; 7.5 g) at 0° C. with stirring and under N2 atmosphere. After the addition was complete, the reaction was allowed to warm to 23° C. and continuously stirred for 16 h. At the end of this time, the reaction was cooled to 0° C. and ice (ca. 25 mL) added portionwise and stirred an additional 2 h. The organic phase was separated from the aqueous phase and the aqueous layer extracted with Et2O. The combined organic phases were washed with sat. NaCl solution, dried with MgSO4. filtered and concentrated under reduced pressure to afford 3-(3-bromopropyl)indole (V; 1.51 g; 15%).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][C:5]([CH3:12])=[CH:4][C:3]=1[N:13]1[N:17]=[C:16]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:15]2=[N:14]1.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:35]Br>C(Cl)(Cl)(Cl)Cl>[OH:1][C:2]1[C:7]([C:8]([CH3:9])([CH3:11])[CH3:10])=[CH:6][C:5]([CH2:12][Br:35])=[CH:4][C:3]=1[N:13]1[N:17]=[C:16]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:15]2=[N:14]1
Reactant: BrBr
Reactant: Cc1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)C)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1cc(CBr)cc(-n2nc3ccc(Cl)cc3n2)c1O
Temperature: 25 °C

Procedure:
2-(2′-Hydroxy-3′-tert-butyl-5′-bromomethylphenyl)-5-chlorobenzotriazole was prepared from the bromination of 2-(2′-Hydroxy-3′-tert-butyl-5′-methylphenyl)-5-chlorobenzotriazole using azobis isobutyronitrile (AIBN) as an initiator. In a 500 ml three-necked round bottomed flask, 7.042 g (0.0223 mole) 2-(2′-Hydroxy-3′-tert-butyl-5′-methylphenyl)-5-chlorobenzotriazole and 100 mg of AIBN were taken and dissolved in 150 ml of dry carbon tetrachloride. In a separate conical flask 4.18 g (1.5 ml, 0.03 mole) of bromine was dissolved in 75 ml of dry carbon tetrachloride and solution was transferred to a cylindrical funnel with pressure equalizing tube. Three-necked round-bottomed flask containing solution of 2-(2′-Hydroxy-3′-tert-butyl-5′-methylphenyl)-5-chlorobenzotriazole was kept in oil-bath with temperature 50° C. Nitrogen was bubbled through the solution for creating inert atmosphere Cylindrical funnel containing bromine solution was mounted on the three-necked round-bottomed flask. Solution in the flask was continuously stirred with the help of magnetic stirrer. Bromine solution was added, drop-by-drop, from funnel to the flask for a span of 4-5 hours till all the solution was poured out. After that heating was stopped and the final reaction mixture was allowed to cool at room temperature Product was separated by solvent evaporation. Finally the product was purified by recrystallization from acetone. The yield of 2-(2′-Hydroxy-3′-tert-butyl-5′-bromomethylphenyl)-5-chlorobenzotriazole was 7.2 g (81%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-])=O)[C:5]([O:7][CH3:8])=[O:6].[H][H].O.[C:18](OC(=O)C)(=[O:20])[CH3:19]>C1COCC1.[Pd]>[C:18]([NH:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[OH:1])(=[O:20])[CH3:19]
Reactant: [H][H]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(O)c1
Agent: [Pd]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NC(C)=O)c(O)c1
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
A solution of methyl 3-hydroxy-4-nitrobenzoate (0.78 g, 3.96 mmol) in THF (40 ml) with Pd on charcoal (10%, 0.15 g) was stirred in the atmosphere of hydrogen at atmospheric pressure overnight. The mixture was filtered through celite. The solvent was removed in vacuo. The residue was taken into water (20 ml), and acetic anhydride (0.5 ml, 5.29 mmol) was added. The mixture was vigorously stirred at 65° C. for 30 min. After cooling to room temperature, the precipitate was collected by filtration, washed with water, and dried. White powder (0.64 g, 77%).
Reaction SMILES: [CH2:1]([NH:6][CH2:7][C:8]1[NH:9][C:10](=[O:18])[C:11]2[CH2:17][O:16][CH2:15][CH2:14][C:12]=2[N:13]=1)[C:2]([CH3:5])([CH3:4])[CH3:3].[F:19][C:20]1[CH:37]=[CH:36][C:23]([C:24]([CH:26]2[CH2:31][CH2:30][N:29]([CH2:32][C:33](O)=[O:34])[CH2:28][CH2:27]2)=[O:25])=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([CH:26]2[CH2:27][CH2:28][N:29]([CH2:32][C:33]([N:6]([CH2:1][C:2]([CH3:5])([CH3:4])[CH3:3])[CH2:7][C:8]3[NH:9][C:10](=[O:18])[C:11]4[CH2:17][O:16][CH2:15][CH2:14][C:12]=4[N:13]=3)=[O:34])[CH2:30][CH2:31]2)=[O:25])=[CH:36][CH:37]=1
Reactant: CC(C)(C)CNCc1nc2c(c(=O)[nH]1)COCC2
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Product: CC(C)(C)CN(Cc1nc2c(c(=O)[nH]1)COCC2)C(=O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Yield: 17 %

Procedure:
The title compound (17 mg) was prepared following the general procedure of Example 1 from 2-((neopentylamino)methyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one (50 mg, 0.20 mmol) and 2-(4-(4-fluorobenzoyl)piperidin-1-yl)acetic acid (62 mg, 0.20 mmol). 1H NMR (400 MHz, CDC3) δ 7.98 (dd, J=9.0, 5.5 Hz, 2H), 7.07-7.21 (m, 2H), 4.61 (s, 2H), 4.49 (br. s., 2H), 3.86-4.05 (m, 2H), 3.30-3.50 (m, 3H), 3.13-3.29 (m, 2H), 2.90-3.13 (m, 2H), 2.52-2.76 (m, 4H), 2.01-2.27 (m, 3H), 1.88 (d, J=3.0 Hz, 1H), 1.02 (s, 3H), 0.96 (s, 7H). HRMS calculated for C27H35FN4O4 499.2721. found (ESI, [M+H]+), 499.2738. MS m/z 499.3 (M+1), retention time=3.32 min.