Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6]([NH:11][CH2:12][CH3:13])=[C:5](Cl)[N:4]=1)#[N:2].[C:15]1([OH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[K+].O>O1CCCC1>[C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6]([NH:11][CH2:12][CH3:13])=[C:5]([O:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:4]=1)#[N:2]
Reactant: Oc1ccccc1
Reactant: CCNc1nc(C#N)c(C#N)nc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCNc1nc(C#N)c(C#N)nc1Oc1ccccc1
Yield: 83.7 %

Procedure:
2,3-Dicyano-5-ethylamino-6-chloropyrazine (2.07 g; 0.01 mole) was dissolved in 40 ml of tetrahydrofuran. The solution was cooled to 0° to 5° C., and with stirring, a solution prepared from 0.94 g (0.01 mole) of phenol, 0.56 g (0.01 mole) of potassium hydroxide, 5 ml of water and 20 ml of tetrahydrofuran was added dropwise over the period of 10 minutes. Then, the mixture was stirred at 0° to 5° C. for 1 hour. After the reaction, the precipitate was separated by filtration. The filtrate was concentrated under reduced pressure, and the residue was poured into 80 ml of water. The precipitated crystals were collected by filtration, and recrystallized from benzene to afford 2.22 g (yield 84%) of 2,3-dicyano-5-ethylamino-6-phenoxypyrazine.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH2:27][C:28]4[CH:37]=[C:36]5[C:31]([CH2:32][CH2:33][NH:34][CH2:35]5)=[CH:30][CH:29]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[C:41]1(O[Si](C)(C)C)[CH2:43][CH2:42]1)C.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH2:27][C:28]4[CH:37]=[C:36]5[C:31]([CH2:32][CH2:33][N:34]([CH:41]6[CH2:43][CH2:42]6)[CH2:35]5)=[CH:30][CH:29]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncnn2c(Cc3ccc4c(c3)CNCC4)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1ncnn2c(Cc3ccc4c(c3)CN(C3CC3)CC4)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Yield: 49.8 %

Procedure:
5-(2-Benzyl-2H-indazol-6-yl)-7-(1,2,3,4-tetrahydro-isoquinolin-7-ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine (0.100 g, 0.21 mmol) was dissolved in MeOH (1 mL) and (1-ethoxy-cyclopropoxy)-trimethyl-silane (0.22 g, 1.24 mmol) was added followed by acetic acid (0.118 mL, 2.05 mmol) and sodium cyanoborohydride (0.058 g, 0.92 mmol). The resulting mixture was refluxed overnight and then allowed to cool. The mixture was filtered, concentrated and the residue was purified by preparative HPLC to give 55 mg (50%) of the title compound. 1H-NMR (CD3OD-d4) 8.36-8.23 (m, 1 H), 7.81 (s, 1 H), 7.78 (dd, 1H), 7.38-7.29 (m, 4 H), 7.19 (dd, 1 H), 7.10-6.99 (m, 2 H), 6.44 (s, 1 H), 5.63 (s, 2 H), 4.23 (s, 2 H), 3.72 (s, 2 H), 2.96-2.81 (m, 4 H), 1.86-1.79 (m, 1 H), 0.57-0.75 (m, 4 H); LC-MS [M+H]+=426.3, RT=2.32 min.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10].[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:34])[C:18]=1[NH:19][C:20]1[C:29]2[C:24](=[C:25]([OH:32])[C:26]([O:30][CH3:31])=[CH:27][CH:28]=2)[O:23][C:22](=[O:33])[CH:21]=1>>[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:34])[C:18]=1[NH:19][C:20]1[C:29]2[C:24](=[C:25]([O:32][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N+:9]([O-:11])=[O:10])[C:26]([O:30][CH3:31])=[CH:27][CH:28]=2)[O:23][C:22](=[O:33])[CH:21]=1
Reactant: O=[N+]([O-])c1ccccc1CBr
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1O
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCc1ccccc1[N+](=O)[O-]

Procedure:
The title compound was prepared from 1-(bromomethyl)-2-nitrobenzene and 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxy-2H-chromen-2-one (Example 29) following the procedure outlined in Example 25. 1H NMR (400 MHz, DMSO-d6): δ 9.55 (s, 1H), 8.81 (s, 2H), 8.12 (dd, 1H), 8.05 (d, 1H), 7.99 (d, 1H), 7.82 (td, 1H), 7.62 (td, 1H), 7.22 (d, 1H), 5.43 (s, 2H), 4.65 (s, 1H), (s, 3H); MS (ESI): 487.8.
Reaction SMILES: C1C=CC=CC=1.[CH3:7][O:8][C:9]1[CH:21]=[CH:20][C:12]([O:13][CH2:14][CH2:15][CH2:16][C:17](O)=[O:18])=[CH:11][CH:10]=1.S(Cl)([Cl:24])=O>O>[CH3:7][O:8][C:9]1[CH:21]=[CH:20][C:12]([O:13][CH2:14][CH2:15][CH2:16][C:17]([Cl:24])=[O:18])=[CH:11][CH:10]=1
Reactant: COc1ccc(OCCCC(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: O
Product: COc1ccc(OCCCC(=O)Cl)cc1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
Benzene (70.0 cc) and 14 0 grams of γ-(p-methoxyphenoxy)butyric acid were agitated with water cooling and 5.74 cc of thionyl chloride was added dropwise. Subsequently, the mixture was agitated for 10 minutes at an internal temperature of 60° C. After the reaction had been completed, the reaction mixture was cooled and transferred to a separate flask and the solvent and excess thionyl chloride were removed in a rotary evaporator. γ-(p-Methoxyphenoxy)butyric acid chloride was obtained as white crystals.
Reaction SMILES: [C:1](OC1C2C(=CC=CC=2)N(CCC)C1=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])[C:28](=[O:38])[C:27]2=[O:39]>>[C:1]([O:39][CH:27]1[C:26]2[C:30](=[CH:31][CH:32]=[C:24]([Cl:23])[CH:25]=2)[N:29]([CH2:33][CH2:34][CH:35]([CH3:36])[CH3:37])[C:28]1=[O:38])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCN1C(=O)C(OC(=O)c2ccccc2)c2ccccc21
Reactant: CC(C)CCN1C(=O)C(=O)c2cc(Cl)ccc21
Product: CC(C)CCN1C(=O)C(OC(=O)c2ccccc2)c2cc(Cl)ccc21

Procedure:
This compound was prepared in a similar way to 2-oxo-1-propylindolin-3-yl benzoate starting from 5-chloro-1-isopentylindoline-2,3-dione. 1H-NMR δ 8.11 (dd, 2H), 7.60 (dt, 1H), 7.47 (m, 2H) 7.45 (m, 3H), 7.33 (dd, 1H), 6.80 (d, 1H), 6.10 (d, 1H), 3.76 (m, 2H), 1.72 (m, 1H), 1.01 (dd, 6H).
Reaction SMILES: [CH3:1][Mg]Br.[CH:4]([C:6]1[C:14]2[O:13][CH2:12][CH:11]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:10]=2[C:9]([CH3:24])=[C:8]([NH:25][C:26](=[O:32])[CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:7]=1[CH3:33])=[O:5]>O>[OH:5][CH:4]([C:6]1[C:14]2[O:13][CH2:12][CH:11]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:10]=2[C:9]([CH3:24])=[C:8]([NH:25][C:26](=[O:32])[CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:7]=1[CH3:33])[CH3:1]
Reactant: Cc1c(C=O)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Reactant: C[Mg]Br
Solvent: O
Product: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1C(C)O)OCC2c1ccc(C(C)C)cc1
Reaction time: 1 h
Yield: 23.7 %

Procedure:
To methylmagnesium bromide (2.0 M THF solution, 5.0 mL, 10.0 mmol) was added N-(7-formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (1.0 g, 1.91 mmol) obtained in Example 20 at 0° C. and the reaction solution was stirred at the same temperature for 1 hour. The reaction solution was poured into water and the product was extracted with ethyl acetate. The organic layer was washed with water and 1 N hydrochloric acid, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain 192 mg (yield: 19%) of the title compound as a low polarity isomer. Melting point: 147-148° C. (ethyl acetate-hexane).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9](=O)[CH2:10][CH:11]([CH3:13])[CH3:12].[N:15]([O-])=O.[Na+].O.O.[Sn](Cl)Cl>O.Cl>[OH:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[NH:1][N:15]=[C:9]2[CH2:10][CH:11]([CH3:13])[CH3:12]
Reactant: O=N[O-]
Reactant: CC(C)CC(=O)c1cc(O)ccc1N
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: CC(C)Cc1n[nH]c2ccc(O)cc12
Yield: 41.1 %

Procedure:
In an analogous manner to the procedure of Example XIV, 783 mg (4.05 mmol) of 1-(2-amino-5-hydroxyphenyl)-3-methyl-1-butanone in 30 ml of half-conc. hydrochloric acid are reacted with 294 mg (4.25 mmol) of sodium nitrite in 15 ml of water and 914 mg (4.05 mmol) of tin(II) chloride dihydrate in 15 ml of conc. hydrochloric acid to give 317 mg (41%) of 5-hydroxy-3-isobutyl-1H-indazole.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][CH:8]([CH3:15])[CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)=[O:5].[N:21]([O-])=O.[Na+].[OH-].[Na+].C(O)(=O)C>O.Cl>[Cl:20][C:17]1[CH:18]=[CH:19][C:2]2[N:1]=[N:21][N:6]([CH2:7][CH:8]([CH3:15])[CH2:9][N:10]3[CH:14]=[CH:13][N:12]=[CH:11]3)[C:4](=[O:5])[C:3]=2[CH:16]=1
Reactant: O=N[O-]
Reactant: CC(CNC(=O)c1cc(Cl)ccc1N)Cn1ccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC(Cn1ccnc1)Cn1nnc2ccc(Cl)cc2c1=O

Procedure:
A solution of 5.86 g of 2-amino-5-chloro-N-[3-(1H-imidazol-1-yl)-2-methylpropyl]benzamide in 30 ml of water and 8.3 ml of concentrated hydrochloric acid was cooled in an ice bath and a solution of 1.42 g of sodium nitrite in 10 ml of water was added dropwise. The mixture was stirred, treated for 50 minutes with 10 ml of 10N sodium hydroxide, stirred for 50 minutes and acetic acid was added until a pH of 6-7 was reached. The product was extracted into methylene chloride and the organic layer was washed with water, dried over magnesium sulfate and concentrated. Treatment with ethyl ether resulted in crystals of the desired product, mp 100°-102° C. A sample was converted to the hydrochloride salt, mp 185°-188° C.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:21]=[CH:22][CH:23]=1)[C:7]([S:9][C:10]1[C:15]([F:16])=[C:14]([F:17])[C:13]([F:18])=[C:12]([F:19])[C:11]=1[F:20])=[O:8].[C:24](Cl)([Cl:26])=[S:25]>O.C(Cl)(Cl)Cl>[Cl:26][C:24]([O:3][C:4]1[CH:5]=[C:6]([CH:21]=[CH:22][CH:23]=1)[C:7]([S:9][C:10]1[C:11]([F:20])=[C:12]([F:19])[C:13]([F:18])=[C:14]([F:17])[C:15]=1[F:16])=[O:8])=[S:25]
Reactant: S=C(Cl)Cl
Reactant: O=C(Sc1c(F)c(F)c(F)c(F)c1F)c1cccc(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(Sc1c(F)c(F)c(F)c(F)c1F)c1cccc(OC(=S)Cl)c1

Procedure:
A solution of 187 mg of sodium hydroxide in 5 ml of water was added to a stirred suspension of S-(pentafluorophenyl) 3-(hydroxy)thiobenzoate (1.0 g) in chloroform (10 ml) at -10° C. Thiophosgene (0.36 ml) was added and the solution stirred whilst being allowed to reach room temperature. The chloroform layer was separated, dried over anhydrous calcium chloride and evaporated to leave a reside which was chromatographed on silica gel using ethyl acetate/hexane mixtures as eluant to give 0.61 g of the title compound.
Reaction SMILES: [O:1]([C:8]1[CH:28]=[CH:27][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:19]2[CH:24]=[CH:23][C:22]([CH2:25][NH2:26])=[CH:21][CH:20]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.CN1C[CH2:39][CH2:38][C:37]1=[O:41]>ClCCl>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:19]2[CH:24]=[CH:23][C:22]([CH2:25][NH:26][C:37](=[O:41])[CH2:38][CH3:39])=[CH:21][CH:20]=2)=[CH:27][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccc(-c2cnccc2Oc2ccc(Oc3ccccc3)cc2)cc1
Reactant: CN1CCCC1=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(=O)NCc1ccc(-c2cnccc2Oc2ccc(Oc3ccccc3)cc2)cc1
Yield: 43 %

Procedure:
N-(4-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)propionamide was prepared from (4-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)methanamine and pyridine instead of N, N-diethylethanamine, 1-methylpyrrolidin-2-one, dichloromethane using Method G (43% yield). HPLC: 99%, RT=4.032 min. MS: m/z=425 [M+H]+, RT=3.22 min.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[C:8]([N:15]([CH2:20][CH:21]=[CH2:22])[CH2:16][C:17]([OH:19])=[O:18])([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]>ClCCl.CO>[CH3:1][O:18][C:17](=[O:19])[CH2:16][N:15]([CH2:20][CH:21]=[CH2:22])[C:8]([O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[O:9]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: C=CCN(CC(=O)O)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CO
Product: C=CCN(CC(=O)OC)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trimethylsilyldiazomethane (2N, in hexane) (12 ml) was added dropwise to a solution of N-Boc-allylglycine (3.09 g) in dichloromethane/methanol (2/1) mixture (30 ml), and the resulting mixture was stirred at room temperature for 3 hours. After concentrating the reaction solution, the residue was purified by column chromatography (silica gel, eluent: cyclohexane/ethyl acetate=20/1-10/1) to obtain N-Boc-allylglycine methyl ester (3.11 g). NMR (H1, CDCl3): δ 2.43-2.55 (2H, m), 3.72 (3H, s), 4.34-4.39 (1H, brm), 5.02 (1H, brs), 5.09-5.13 (2H, m), 5.62-5.72 (1H, m)
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH2:6][CH:7]([CH2:13][CH3:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9].[F:20][C:21]([F:32])([F:31])[C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>CN(C)C=O>[CH3:19][O:18][C:17]1[CH:16]=[CH:15][C:5]([CH2:6][CH:7]([CH2:13][CH3:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][C:3]=1[CH2:2][NH:1][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][C:22]([C:21]([F:20])([F:31])[F:32])=[CH:23][CH:24]=1
Reactant: CCOC(=O)C(CC)Cc1ccc(OC)c(CN)c1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CC)Cc1ccc(OC)c(CNC(=O)c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.5 %

Procedure:
0.40 g of ethyl 2-[3-(aminomethyl)-4-methoxybenzyl]butanoate and 0.29 g of 4-(trifluoromethyl)benzoic acid were dissolved in 5 ml N,N-dimethylformamide, and 0.24 ml diethyl cyanophosphonate and 0.21 ml triethylamine were added under ice-cooling. After stirring the reaction mixture at room temperature for 16 hours, the mixture was poured into ice-water and extracted with ethyl acetate. The organic layer was successively washed with 1N hydrochloric acid and brine, dried over anhydrous magnesium sulfate and the solvent was evapoarated. The residue was subjected to silica gel column chromatography, and from fractions eluted with hexane-ethyl acetate (3:1), 0.59 g of ethyl 2-[4-methoxy-3-({[4-(trifluoromethyl)benzoyl]amino}methyl)benzyl]butanoate was obtained.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([CH3:12])[N:3]=1.C(N(CC)CC)C.[CH2:20]([NH:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH3:21]>C(O)C>[Cl:11][C:6]1[C:7]([N+:8]([O-:10])=[O:9])=[C:2]([N:22]([CH2:20][CH3:21])[CH2:23][CH2:24][CH2:25][CH3:26])[N:3]=[C:4]([CH3:12])[N:5]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Reactant: CCCCNCC
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCCN(CC)c1nc(C)nc(Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 92 %

Procedure:
Part A. A solution of 4,6-dichloro-2-methyl-5-nitropyrimidine (prepared using the methods of Albert, et al., J. Chem. Soc. 1954, p. 3832) (2.77 g, 13.3 mmol) in absolute ethanol (25 mL) was cooled to 0° C., and treated with triethylamine (2.00 mL, 14.3 mmol). Then, a solution of ethylbutylamine (1.80 mL, 13.2 mmol) in ethanol (3 mL) was added dropwise with stirring. The mixture was allowed to stir and warm to ambient temperature overnight, then was partitioned between water and ethyl acetate (100 mL each). The organic phase was seperated, washed with satd. aq. brine (100 mL), dried over anhydrous sodium sulfate, filtered and evaporated. The residue was separated by column chromatography (silica gel, dichloromethane) to afford 4-chloro-6-(ethylbutylamino)-2-methyl-5-nitropyrimidine as an oil (3.34 g, 12.2 mmol, 92%). Spectral data: TLC RF 0.59 (dichloromethane). 1H NMR (300 MHz, CDCl3): δ3.45 (2H, q, J=7.0 Hz), 3.38 (2H, t, J=7.7 Hz), 2.50 (3H, s), 1.62-1.52 (2H, m), 1.38-1.26 (2H, m), 1.20 (3H, t, J=7.0 Hz), 0.94 (3H, t, J=7.3 Hz). MS (NH3—CI): m/e 276 (4), 275 (40), 274 (16), 273 (100).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([C:21]3[C:32](=[O:33])[N:31]([CH3:34])[C:24]4[N:25]=[C:26](SC)[N:27]=[CH:28][C:23]=4[CH:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:35][NH2:36]>C1COCC1>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([C:21]3[C:32](=[O:33])[N:31]([CH3:34])[C:24]4[N:25]=[C:26]([NH:36][CH3:35])[N:27]=[CH:28][C:23]=4[CH:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1ncc2cc(-c3cc(NC(=O)Nc4cc(C(C)(C)C)on4)ccc3C)c(=O)n(C)c2n1
Reactant: CN
Solvent: C1CCOC1
Product: CNc1ncc2cc(-c3cc(NC(=O)Nc4cc(C(C)(C)C)on4)ccc3C)c(=O)n(C)c2n1
Yield: 32 %

Procedure:
Using general method B, the carbamate of 5-t-butylisoxazol-3-amine (108 mg, 0.480 mmol) and Example A44 (150 mg, 0.480 mmol) were combined to give the intermediate sulfide, 1-(5-tert-butylisoxazol-3-yl)-3-(4-methyl-3-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (35 mg, 15% yield). Using a procedure analogous to Example A1, 1-(5-tert-butylisoxazol-3-yl)-3-(4-methyl-3-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (158 mg, 0.330 mmol) and 2.0N solution of methylamine in THF (1.7 mL) were combined and purified by chromatography (Biotage Si-25 column, 60-100% ethyl acetate/Hex) to afford 1-(5-tert-butylisoxazol-3-yl)-3-(4-methyl-3-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (49 mg, 32% yield). 1H NMR (300 MHz, DMSO-d6): δ 1.26 (s, 9H), 2.06 (s, 3H), 2.90 (s, 3H), 3.53-3.60 (m, 3H), 6.46 (s, 1H), 7.14-7.16 (m, 1H), 7.26-7.28 (m, 1H), 7.32 (s, 1H), 7.67 (s, 1H), 7.65-7.80 (br m, 1H), 8.60-8.65 (m, 1H), 8.72 (s, 1H), 9.47 (s, 1H); MS (ESI) m/z: 462.0 (M+H+).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[C:7]([O:14][C:15]2[CH:16]=[N:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:49][O:50][C:51]1[CH:56]=[C:55]([NH2:57])[CH:54]=[CH:53][N:52]=1.C(N(CC)CC)C>ClCCl>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH:57][C:55]2[CH:54]=[CH:53][N:52]=[C:51]([O:50][CH3:49])[CH:56]=2)=[O:11])=[C:7]([O:14][C:15]2[CH:16]=[N:17][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:19][CH:20]=2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(C(=O)O)c(Oc2ccc(C(F)(F)F)nc2)c1
Reactant: COc1cc(N)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(NC(=O)c2ccc(C(C)(C)C)cc2Oc2ccc(C(F)(F)F)nc2)ccn1
Yield: 61.5 %

Procedure:
A solution of 4-(tert-butyl)-2((6-(trifluoromethyl)pyridin-3-yl)oxy)benzoic acid (169.7 mg, 0.5 mmol), HATU (190 mg, 0.5 mmol), 2-methoxypyridin-4-amine (62.1 mg, 0.5 mmol) and tri-ethyl amine (278.8 μL, 2 mmol) in dichloromethane (5 mL) was stirred at room temperature over 72 hours. The reaction was purified by silica gel chromatography using gradient of ethyl acetate in hexanes (0-40%) to yield 4-(tert-butyl)-N-(2-methoxypyridin-4-yl)-2-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzamide (137 mg, 60%). ESI-MS m/z calc. 445.16. found 446.3 (M+1)+; Retention time: 1.87 minutes (3 minutes run).
Reaction SMILES: [NH3:1].[Br:2][C:3]1[N:4]=[C:5]([CH:13]2[CH2:16][C:15]([CH3:18])([OH:17])[CH2:14]2)[N:6]2[CH:11]=[CH:10][N:9]=[C:8](Cl)[C:7]=12>CC(O)CC>[NH2:1][C:8]1[C:7]2[N:6]([C:5]([CH:13]3[CH2:16][C:15]([CH3:18])([OH:17])[CH2:14]3)=[N:4][C:3]=2[Br:2])[CH:11]=[CH:10][N:9]=1
Reactant: N
Reactant: CC1(O)CC(c2nc(Br)c3c(Cl)nccn23)C1
Solvent: CCC(C)O
Product: CC1(O)CC(c2nc(Br)c3c(N)nccn23)C1
Temperature: 90 °C

Procedure:
A 35% ammonia solution (132 ml, 2.9 moles) was added to a suspension of 3-(1-bromo-8-chloroimidazo[1,5-a]pyrazin-3-yl)-1-methylcyclobutanol (22.0 g, 0.06463 mol) in 2-butanol (81 ml). The mixture was heated at 90° C. in a pressure vessel for 15 hr then concentrated to −130 ml, cooled to room temperature and the solid collected by filtration. This material was washed with water (3×22 mL) and dried at 40° C. under vacuum. To afford the desired product. 1H NMR (DMSO-d6, 400 MHz): δ 7.5 (d, 1H), 7.0 (d, 1H), 6.6 (bs, 2H), 5.1 (s, 1H), 3.4 (pentet, 1H), 2.3-2.4 (m, 4H) and 1.4 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[CH:37][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]4[C@@H:18]([CH2:26][NH:27][CH:28]4[CH2:31][CH:30]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:29]4)[O:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.[C:43]([BH3-])#N.[Na+].C(O)(=O)C.C=O>CO>[CH3:1][O:2][C:3]1[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[CH:37][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:24])([CH3:25])[O:23][C@@H:19]4[C@@H:18]([CH2:26][N:27]([CH3:43])[CH:28]4[CH2:29][CH:30]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:31]4)[O:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1
Reactant: [BH3-]C#N
Reactant: COC(=O)CC1CC(NC[C@H]2O[C@@H](n3ccc4c(NCc5ccc(OC)cc5OC)ncnc43)[C@@H]3OC(C)(C)O[C@@H]32)C1
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)CC1CC(N(C)C[C@H]2O[C@@H](n3ccc4c(NCc5ccc(OC)cc5OC)ncnc43)[C@@H]3OC(C)(C)O[C@@H]32)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
A solution of methyl 2-(3-((((3aR,4R,6R,6aR)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)amino)cyclobutyl)acetate (267 mg, 0.459 mmol) in methanol (12 mL) was treated with sodium cyanoborohydride (380 mg, 6.1 mmol). The pH of the solution was adjusted to ˜6 by the dropwise addition of a 10% (v/v) solution of glacial acetic acid in methanol. The mixture was treated with 37% formaldehyde (0.57 mL, 7.6 mmol) dropwise and the mixture was stirred at room temperature for 1 h at which time, HPLC indicated the starting material was consumed. The reaction mixture was concentrated to remove the methanol. The aqueous solution that remained was diluted with 25 mL NaHCO3 and the aqueous phase was extracted with three 20 mL portions of CH2Cl2. The organic phase was washed with 20 mL sat NaHCO3, dried over Na2SO4, filtered and concentrated to yield the title compound (272 mg, 100%) as a colorless stiff foam which was found to be of sufficient purity for use in the next step: MS (ESI+) for C31H41N5O7 m/z 596.5 (M+H)+; HPLC purity >95% (ret. time, 2.89 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[O:5][CH:6]1[CH2:12][CH:11]2[N:13]([CH2:14][C:15]([NH2:17])=[S:16])[CH:8]([CH2:9][CH2:10]2)[CH2:7]1.Cl[CH2:23][CH:24]=O>C(O)(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[O:5][CH:6]1[CH2:12][CH:11]2[N:13]([CH2:14][C:15]3[S:16][CH:23]=[CH:24][N:17]=3)[CH:8]([CH2:9][CH2:10]2)[CH2:7]1
Reactant: O=CCCl
Reactant: NC(=S)CN1C2CCC1CC(Oc1ccc(Cl)c(Cl)c1)C2
Solvent: O
Solvent: CC(=O)O
Product: Clc1ccc(OC2CC3CCC(C2)N3Cc2nccs2)cc1Cl
Temperature: 25 °C

Procedure:
to 2-[3-(3,4-Dichloro-phenoxy)-8-aza-bicyclo[3.2.1]oct-8-yl]-thioacetamide (0.5 g) in 5 ml of acetic acid was added 0.13 g of 50% chloroacetaldehyde in water. The reaction mixture was stirred at reflux overnight and cooled to room temperature and poured into 50 ml of water. The mixture was extracted twice with dichloromethane. The organic phase was dried with magnesium sulphate and evaporated to and oil. The product was isolated by column chromatography with dichloromethane/methanol (9:1) with 1% ammonia as eluent, the product fractions was evaporated to dryness. Yield 0.1 g (19%). Mp. 123-124° C.