Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[B-](F)(F)F.[N:6]1([O+]=C(N(C)C)N(C)C)[C:10]2C=CC=CC=2N=N1.CN.[NH2:25][C:26]1[N:31]=[CH:30][C:29]([C:32]2[CH:33]=[N:34][N:35]([C@H:37]3[CH2:41][N:40]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C@H:39]([C:49](O)=[O:50])[CH2:38]3)[CH:36]=2)=[CH:28][C:27]=1[C:52]1[O:53][C:54]2[CH:60]=[CH:59][CH:58]=[CH:57][C:55]=2[N:56]=1.C(N(CC)CC)C>CN(C=O)C>[NH2:25][C:26]1[N:31]=[CH:30][C:29]([C:32]2[CH:33]=[N:34][N:35]([C@H:37]3[CH2:41][N:40]([C:42]([O:44][C:45]([CH3:47])([CH3:48])[CH3:46])=[O:43])[C@H:39]([C:49](=[O:50])[NH:6][CH3:10])[CH2:38]3)[CH:36]=2)=[CH:28][C:27]=1[C:52]1[O:53][C:54]2[CH:60]=[CH:59][CH:58]=[CH:57][C:55]=2[N:56]=1
Reactant: CN(C)C(=[O+]n1nnc2ccccc21)N(C)C
Reactant: CC(C)(C)OC(=O)N1C[C@H](n2cc(-c3cnc(N)c(-c4nc5ccccc5o4)c3)cn2)C[C@H]1C(=O)O
Agent: CN
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)[C@@H]1C[C@@H](n2cc(-c3cnc(N)c(-c4nc5ccccc5o4)c3)cn2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.4 %

Procedure:
A slurry of benzotriazol-1-yl-[bis(dimethylamino)methylene]oxonium tetrafluoroborate (149 mg) was added to methylamine (0.892 ml, 2M in methanol) and (2S,4R)-4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]pyrazol-1-yl]-1-tert-butoxycarbonyl-pyrrolidine-2-carboxylic acid (175 mg) and triethylamine (0.883 ml) dissolved in DMF (8 ml) over a period of 10 minutes. The resulting solution was stirred at 25° C. overnight. The mixture was evaporated and a saturated solution of NaHCO3 (50 ml) was added to the mixture, extracted with methylene chloride (50 ml×2), dried over Magnesium sulphate, filtered and evaporated in reduce pressure. The reaction mixture was purified by preparative HPLC using a Waters X-Terra reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 ml/minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford (2S,4R)-tert-butyl 4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]pyrazol-1-yl]-2-(methylcarbamoyl)pyrrolidine-1-carboxylate (60 mg) as a solid. Retention time: 3.44 min Mass spectrum: M+H+ 504
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:26]=[CH:25][C:9]2[N:10]=[C:11]([NH:14][CH:15]3[C:19]4[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:18]=4[O:17][CH2:16]3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[F:24][C:22]1[CH:21]=[CH:20][C:19]2[CH:15]([NH:14][C:11]3[O:12][CH2:13][C:8]4[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:31]5[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]5)[CH:26]=[CH:25][C:9]=4[N:10]=3)[CH2:16][O:17][C:18]=2[CH:23]=1
Reactant: CN1CCNCC1
Reactant: O=C(CCl)Nc1ccc2c(c1)COC(NC1COc3cc(F)ccc31)=N2
Product: CN1CCN(CC(=O)Nc2ccc3c(c2)COC(NC2COc4cc(F)ccc42)=N3)CC1
Yield: 99.2 %

Procedure:
Prepared from rac-2-chloro-N-[2-(6-fluoro-2,3-dihydro-benzofuran-3-ylamino)-4H-benzo[d][1,3]oxazin-6-yl]-acetamide (Example 42 step A) (50 mg, 0.133 mmol, HPLC 1.056 min) and 1-methylpiperazine (300 ul, 2.66 mmol) according to the procedure described for Example 3 step B. Obtained the title compound as a white solid (58 mg, 99%, HPLC 0.468 min 100%), MS (ISP) m/e=440.3 [(M+H)+].
Reaction SMILES: Cl[NH:2][C:3]1[N:8]=[C:7]([NH:9]Cl)[N:6]=[C:5]([NH:11]Cl)[N:4]=1.[Cl:13][CH2:14][CH2:15][C:16](Cl)=[O:17]>C(Cl)(Cl)(Cl)Cl.CCCCCC>[Cl:13][CH2:14][CH2:15][C:16]([NH:2][C:3]1[N:8]=[C:7]([NH:9][C:16](=[O:17])[CH2:15][CH2:14][Cl:13])[N:6]=[C:5]([NH:11][C:16](=[O:17])[CH2:15][CH2:14][Cl:13])[N:4]=1)=[O:17]
Reactant: O=C(Cl)CCCl
Reactant: ClNc1nc(NCl)nc(NCl)n1
Solvent: CCCCCC
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(CCCl)Nc1nc(NC(=O)CCCl)nc(NC(=O)CCCl)n1
Yield: 98 %

Procedure:
To a stirring suspension of 2.3 g trichloromelamine in 40 ml CCl4 was added 7.62 g 3-chloropropionyl chloride under Argon. The reaction mixture was heated in an oil bath at 65°-70° C. for 6 hours. The reaction mixture was cooled and then diluted with 50 ml hexane. The precipitates were filtered, washed with hexane and dried under reduced pressure (3.9 g; 98% yield). The product thus obtained was characterized to be N'N',N"-tris (3-chloropropionyl) melamine by 1H NMR, 13C NMR, IR, and mass spectroscopy.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]([N+:16]([O-:18])=[O:17])[C:10]=1Cl)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[OH2:22]>>[C:1]([NH:5][S:6]([C:9]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]([N+:16]([O-:18])=[O:17])[C:10]=1[OH:22])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O
Reactant: CC(C)(C)NS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)NS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1O

Procedure:
Following the general hydrolysis procedure outlined in example 15, N-(tert-butyl)-2,6-dichloro-3-nitrobenzenesulfonamide (1.67 g, 5.1 mmol), 60% NaH (612 mg, 15.3 mmol) and water (92 μL, 5l mmol) were reacted to form the crude product (1.54 g), which was carried on to the next step without purification. 1H NMR (MeOD-d4): δ 8.00 (d, 1H), 7.08 (d, 1H), 1.24 (s, 9H).
Reaction SMILES: [CH3:1][C@@H:2]1[C@@H:7]([O:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:6][CH2:5][NH:4][CH2:3]1.[CH3:15][C@@H:16]1[CH2:18][O:17]1>C(O)C>[OH:17][C@H:16]([CH3:18])[CH2:15][N:4]1[CH2:5][CH2:6][C@H:7]([O:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[C@@H:2]([CH3:1])[CH2:3]1
Reactant: C[C@H]1CNCC[C@@H]1OC(=O)C(C)(C)C
Reactant: C[C@@H]1CO1
Solvent: CCO
Product: C[C@@H](O)CN1CC[C@H](OC(=O)C(C)(C)C)[C@@H](C)C1

Procedure:
A solution of piperidine 17 (2 g, 10.8 mmol) and (R)-2-Methyl-oxirane (3.78 ml, 54 mmol) in 2 ml of ethanol is stirred for 24 hours in a closed flask. The solvent is evaporated and the residue distilled in a Kugelrohr apparatus (0.08 mbar, 75-90 C).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].C([O-])([O-])=O.[K+].[K+].[CH2:20](Br)[CH2:21][CH:22]([CH3:24])[CH3:23]>CN(C=O)C>[CH2:20]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([O:7][CH2:2][CH2:3][CH:4]([CH3:8])[CH3:5])=[O:6])[CH2:21][CH:22]([CH3:24])[CH3:23]
Reactant: CC(C)CCBr
Reactant: O=C(O)c1cc(O)cc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)CCOC(=O)c1cc(OCCC(C)C)cc([N+](=O)[O-])c1
Temperature: 90 °C
Yield: 113.8 %

Procedure:
5.15 g (28 mmol) 8 were dissolved in 15 mL DMF (anhydrous, Aldrich) and added to a suspension of 15.5 g (112 mmol, 4 eq.) K2CO3 in 25 mL DMF under nitrogen atmosphere. 13.4 mL (112 mmol, 4 eq.) iso-pentyl bromide were added. The thick, canary-yellow reaction mixture was heated to 90° C. and became stirrable again. It was left at this temperature for at least 8 h. Product formation could be followed by TLC (hexanes/ethyl acetate 9:1, Rf (product)=0.85). After cooling to r.t., DMF was removed with a vacuum rotovap, then ethyl acetate and water were added. After phase separation, the water layer was extracted with ethyl acetate two more times, the organics were pooled, washed with brine, dried with MgSO4, concentrated and put under vacuum overnight. The crude product was purified by column chromatography (hexanes/ethyl acetate 9:1), yielding 5.15 g (80%) of a yellow liquid. 1H NMR (CDCl3) δ 8.42 (dd, J1=1.5 Hz, J2=2.4 Hz, 1H), 7.90 (t, J1=2.4 Hz, J2=2.4 Hz, 1H),7.87 (dd, J1=1.5 Hz, J2=2.4 Hz, 1H), 4.40 (t, J=6.7 Hz, 2H, PhOCH2CH2CH(CH3)2), 4.11 (t, J=6.6 Hz, 2H, PhOCH2CH2CH(CH3)2), 1.93-1.65 (m, 6H), 0.99 (d, J=6.6 Hz, 12H, 2×CH(CH3)2); 13C NMR (CDCl3) 164.38, 159.51, 148.94, 132.69, 121.46, 116.10, 112.87, 67.40, 64.42, 37.38, 37.08, 24.97, 24.77, 22.29; ESI-MS m/z 360 [M+K−2]+, 408 [M+2Na+K], 669 [M2+Na]+.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[CH2:2][CH3:3].Cl[CH2:12][CH:13]1[O:15][CH2:14]1.C(O)C.[OH-].[K+]>O>[O:15]1[CH:13]([CH2:12][O:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:1][CH2:2][CH3:3])[CH2:14]1
Reactant: CCCc1ccccc1O
Reactant: ClCC1CO1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCc1ccccc1OCC1CO1

Procedure:
To a solution of 27.2 parts of 2-propylphenol and 56 parts of 1-chloro-2,3-epoxypropane in 30 parts of ethyl alcohol, heated under reflux, was added a solution of 13.2 parts of potassium hydroxide in 50 parts of ethyl alcohol and 6 parts of water over 15 minutes and the mixture obtained was heated under reflux for a further 2 hours. The mixture was poured into 1,000 parts of water and extracted with ethyl acetate. The organic phase was separated, washed with water, dried over magnesium sulphate, filtered and evaporated to yield a yellow oil. The oil was distilled at the water pump to yield 31.0 parts of 1,2-epoxy-3-(2-propylphenoxy)propane, boiling point 155°-158° at 15 mm.
Reaction SMILES: [CH3:1][NH:2][NH2:3].C([O-])([O-])=O.[K+].[K+].C(O[CH:13]=[C:14]([C:20]([CH:22]([F:24])[F:23])=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])C>O.C1(C)C=CC=CC=1>[F:23][CH:22]([F:24])[C:20]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][N:2]([CH3:1])[N:3]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)C(F)F
Reactant: CNN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(C)nc1C(F)F
Temperature: -5 °C
Reaction time: 1.5 h
Yield: 82.6 %

Procedure:
40% Methylhydrazine (565 g, 4.91 moles) in aqueous solution and K2CO3 (237 g, 1.72 moles) are dissolved in water (2134 g) and mixed to make a clear solution. Toluene (2292 g) is added to make a two phase system, and then cooled to −10-0° C. Crude ethyl 2-ethoxymethylenedifluoroacetoacetate (Formula VI) (˜1010 g, ˜4.91 moles) in toluene (1500 g) is then added dropwise with effective agitation while maintaining at the same temperature. The agitation is kept constant for 1-2 hours until GC shows the content of ethyl 2-ethoxymethylenedifluoroacetoacetate <0.2%. Two phases are separated and the organic phase is concentrated until GC shows toluene content <5%. A mixture of toluene (757 g) and petroleum ether (3028 g) (bp. 60-90° C.) is added in and then heated up to 50-60° C. to make a solution. The yellowish solid precipitated after the solution is slowly cooled down to 10-15° C. The solid is collected by filtration and dried in a vacuum oven to give a yellowish solid (828 g, Yield=82.5%). The product only contains 0.01% of the positional isomer of formula XI and 0.01% of the des-difluoro-impurity of Formula XII.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][CH2:12][CH2:13][CH2:14][P:15](=[O:22])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])[C:6]=2[C:5](=[O:23])[NH:4][C:3]1=[O:24].[CH3:25][CH:26]([CH2:29][CH3:30])[CH2:27]Cl>>[CH3:25][CH:26]([CH3:27])[CH2:29][CH2:30][N:4]1[C:5](=[O:23])[C:6]2[N:7]([CH2:11][CH2:12][CH2:13][CH2:14][P:15](=[O:22])([O:16][CH2:17][CH3:18])[O:19][CH2:20][CH3:21])[CH:8]=[N:9][C:10]=2[N:2]([CH3:1])[C:3]1=[O:24]
Reactant: CCOP(=O)(CCCCn1cnc2c1c(=O)[nH]c(=O)n2C)OCC
Reactant: CCC(C)CCl
Product: CCOP(=O)(CCCCn1cnc2c1c(=O)n(CCC(C)C)c(=O)n2C)OCC

Procedure:
The title substance was prepared from diethyl [4-(3-methylxanthin-7-yl)-butyl]phosphonate and 2-methylbutyl chloride analogously to Example 1 and chromatographed on silica gel (eluent: dichloromethane/methanol 10:1)
Reaction SMILES: [CH2:1]([N:13]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[S:14]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([OH:27])=[C:19]([N:28]=NC2C=CC(OC)=CC=2)[CH:18]=1)(=[O:16])=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:50]([NH:53][C:54]1[C:63]2[C:58](=[CH:59][CH:60]=[C:61]([N:65]=[N:66][C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][C:68]=3[O:73][CH3:74])[C:62]=2[OH:64])[C:57]([S:75](Cl)(=[O:77])=[O:76])=[CH:56][CH:55]=1)(=[O:52])[CH3:51]>O1CCCC1>[C:50]([NH:53][C:54]1[C:63]2[C:58](=[CH:59][CH:60]=[C:61]([N:65]=[N:66][C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][C:68]=3[O:73][CH3:74])[C:62]=2[OH:64])[C:57]([S:75]([NH:28][C:19]2[CH:18]=[C:17]([S:14](=[O:16])(=[O:15])[N:13]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[OH:27])(=[O:77])=[O:76])=[CH:56][CH:55]=1)(=[O:52])[CH3:51]
Reactant: CCCCCCCCCCCCN(CCCCCCCCCCCC)S(=O)(=O)c1cc(N=Nc2ccc(OC)cc2)c(O)c2ccccc12
Reactant: COc1ccccc1N=Nc1ccc2c(S(=O)(=O)Cl)ccc(NC(C)=O)c2c1O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCN(CCCCCCCCCCCC)S(=O)(=O)c1cc(NS(=O)(=O)c2ccc(NC(C)=O)c3c(O)c(N=Nc4ccccc4OC)ccc23)c(O)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3.47 g (0.0050 mole) 4-(N,N-didodecylsulfamyl)-2-(p-methoxyphenylazo)-1-naphthol in 50 ml tetrahydrofuran containing 0.5 g 5% palladium/carbon catalyst was hydrogenated at low pressure and room temperature for 2 hr. The mixture was filtered and poured into water, then extracted with ether. The extract was concentrated to a gum which was dissolved in 50 ml pyridine. The solution was cooled in an ice bath, and 2.17 g (0.005 mole) 4-acetamido-5-hydroxy-6-(o-methoxyphenylazo)naphthalene-1-sulfonyl chloride was added. The mixture was stirred overnight at room temperature, then poured into ice-water containing 50 ml concentrated hydrochloric acid. The purple solid was recrystallized from dichloroethane and ethyl acetate to give, after drying under vacuum, an amorphous solid (Compound No. 14), m.p. 200°-202° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([C:9]([F:12])([F:11])[F:10])(O)[CH2:4][CH:5]=[CH:6]C.OS(O)(=O)=O>>[F:1][C:2]([F:13])([F:14])[C:3]([C:9]([F:10])([F:11])[F:12])=[CH:4][CH:5]=[CH2:6]
Reactant: CC=CCC(O)(C(F)(F)F)C(F)(F)F
Agent: O=S(=O)(O)O
Product: C=CC=C(C(F)(F)F)C(F)(F)F
Temperature: 95 °C
Yield: 33.8 %

Procedure:
The crude 1,1-bis(trifluoromethyl)-3-penten-1-ol (54 grams) can be placed in a 250 mL three-neck flask and 125 mL of concentrate H2SO4 added to form a mixture which can be stirred and heated slowly to 95° C. (separating compounds having lower boiling points from the mixture between 34° C. and 55° C.). The 1,1,1-trifluoro-2-trifluoromethyl-2,4-pentadiene (15.6 grams, 45.5% yield) produced can be separate from the mixture as a gas between 70° C. and 74° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C@@H:14]([CH3:31])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:38][O:39][C:40](=[O:47])[C:41]([CH3:46])([CH3:45])[CH2:42][CH2:43]Br>CN(C=O)C>[CH3:38][O:39][C:40](=[O:47])[C:41]([CH3:46])([CH3:45])[CH2:42][CH2:43][O:29][C:26]1[CH:25]=[CH:24][C:23]([C:22]([N:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@H:12]([N:8]([C:9](=[O:11])[CH3:10])[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH2:13][C@@H:14]2[CH3:31])=[O:30])=[CH:28][CH:27]=1
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(O)cc2)c2ccccc21
Reactant: COC(=O)C(C)(C)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)CCOc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Temperature: 80 °C
Yield: 77 %

Procedure:
(2S,4R)-N-(4-Chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide (0.126 g, 0.242 mmol) was dissolved in 3 ml DMF at room temperature and K2CO3 (0.267 g, 1.94 mmol) was added. 4-Bromo-2,2-dimethyl-butyric acid methyl ester (0.202 g, 0.969 mmol, prepared according to the procedure from Tetrahedron 1994, 50(32), 9825-30) was added and the reaction was allowed to heat to 80° C. overnight. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO4, filtered and concentrated down. The crude residue was purified by silica gel chromatography (50% EtOAc/50% Hexane) to afford the (2S,4R)-4-(4-{4-[acetyl(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-2,2-dimethyl-butyric acid methyl ester (0.105 g, 77%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=2)=[N:6][CH:7]=1.[NH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28])=[O:22])=[CH:18][N:17]=2)=[N:6][CH:7]=1
Reactant: CC(C)(N)CO
Reactant: Cn1nnc(-c2ccc(F)cn2)c1COc1ccc(C(=O)O)cn1
Product: Cn1nnc(-c2ccc(F)cn2)c1COc1ccc(C(=O)NC(C)(C)CO)cn1
Yield: 97 %

Procedure:
As described for example 35b, 6-[5-(5-fluoro-pyridin-2-yl)-3-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-nicotinic acid (80 mg, 0.24 mmol) was converted, using 2-amino-2-methyl-1-propanol instead of 4-aminotetrahydropyran, to the title compound (94 mg, 97%) which was obtained as a white solid. MS: m/e=401.3 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[CH2:17][CH2:18][CH2:19][CH2:20][CH:21]1[CH2:25][CH2:24][O:23][C:22]1=[O:26].CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]1[CH2:25][CH2:24][O:23][C:22]1=[O:26])(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C1OCCC1CCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1OCCC1CCCCOS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 22.6 %

Procedure:
Trifluoromethanesulfonic anhydride (0.64 mL, 3.8 mmol) was added dropwise to a 0° C. solution of 3-(4-hydroxybutyl)-dihydrofuran-2(3H)-one (0.50 g, 3.2 mmol) and DIEA (0.94 mL, 5.4 mmol) in CH2Cl2 (15 mL). After stirring at 0° C. for 1.5 hours, the reaction was diluted with CH2Cl2 and washed sequentially with water, 1 M HCl, and water. The organics were dried over MgSO4 and concentrated under reduced pressure. The crude product was chromatographed (1:2 EtOAc/hexanes) to afford the product as a colorless oil (0.21 g, 23%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:17]([CH2:32][CH2:33][OH:34])[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=4)[N:20]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>ClCCl>[NH2:1][C:2]1[N:3]=[CH:4][N:5]=[C:6]([N:10]2[CH2:11][CH2:12][CH:13]([C:16]3[N:17]([CH2:32][CH2:33][O:34][S:43]([CH3:42])(=[O:45])=[O:44])[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=4)[N:20]=3)[CH2:14][CH2:15]2)[C:7]=1[C:8]#[N:9]
Reactant: N#Cc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C#N)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-hydroxy-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile (22.8 mg; 0.47 mmol; 1.00 eq) was dissolved in dichloromethane (10.00 mL) and chilled to −78° C. The solution was charged with triethylamine (0.20 mL; 1.41 mmol; 3.00 eq) and methanesulfonyl chloride (0.05 mL; 0.70 mmol; 1.50 eq). The reaction was stirred, cold, for 1 hour, then allowed to warm to ambient temperature. The reaction mixture was quenched by dropwise addition of sodium bicarbonate (saturated aq; 10 mL). The organic layer was separated, dried over sodium sulphate, filtered and concentrated to yield methanesulfonic acid 2-[2-[1-(6-amino-5-cyano-pyrimidin-4-yl)-piperidin-4-yl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-imidazol-1-yl]-ethyl ester (259 mg; 0.47 mmol; 99.8%). LC-MS: (M+1=554, obsd.=554).
Reaction SMILES: [CH2:1]([C:3]1[C:14]([CH:15]([CH3:18])[CH2:16][NH2:17])=[C:6]2[C:7]3[CH2:13][CH2:12][O:11][C:8]=3[CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2].C(N(CC)CC)C.[C:26](Cl)(=[O:28])[CH3:27].C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:1]([C:3]1[C:14]([CH:15]([CH3:18])[CH2:16][NH:17][C:26](=[O:28])[CH3:27])=[C:6]2[C:7]3[CH2:13][CH2:12][O:11][C:8]=3[CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nn2ccc3c(c2c1C(C)CN)CCO3
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCc1nn2ccc3c(c2c1C(C)CNC(C)=O)CCO3
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96.2 %

Procedure:
To a solution of 2-(2-ethyl-8,9-dihydrofuro[3,2-c]pyrazolo[1,5-a]pyridin-1-yl)propan-1-amine (118 mg, 0.481 mmol) and triethylamine (134 μL, 0.961 mmol) in tetrahydrofuran (5 mL) was added acetyl chloride (90.9 μL, 0.962 mmol) under ice-cooling, and the mixture was stirred at room temperature for 10 min. A saturated aqueous sodium hydrogen carbonate solution (100 μL) was added and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→5/95) to give the title compound (133 mg, yield 96%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[NH3:10]>CO>[NH2:1][C:2]1[N:7]=[C:6]([NH2:10])[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1cc(Cl)nc(N)n1
Reactant: N
Solvent: CO
Product: Cc1cc(N)nc(N)n1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
A mixture of 50.0 grams (0.348 mole) of 2-amino-4-chloro-6-methylpyrimidine (commercially available) and 100 mL of aqueous 30% ammonia in 400 mL of methanol was placed in a high pressure vessel and heated to 130°-165° C. under a pressure of 140°-250 psig, where it was stirred for 13 hours. After this time, the reaction mixture was allowed to cool to ambient temperature. The reaction vessel was then opened and the reaction mixture was removed. The reaction vessel was washed with 200 mL of methanol, and the wash was combined with the reaction mixture. The combination was concentrated under reduced pressure to a residual solid. The solid was then stirred for 2 hours at ambient temperature with 100 mL of aqueous 30% ammonia. The mixture was cooled to 0° C., and the solid was collected by filtration. The solid was dried, yielding 40.8 grams of 2,4-diamino-6-methylpyrimidine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].Br[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:4]([CH:3]([C:2](=[O:7])[CH3:1])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:6])[CH3:5]
Reactant: CC(=O)CC(C)=O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CC(C(C)=O)C(C)=O
Reaction time: 18 h
Yield: 56.9 %

Procedure:
A solution of 28.2 ml (0.275 moles) of 2,4-pentanedione and 27.7 ml (0.25 moles) of ethyl bromoacetate in 50 ml of acetone was stirred under nitrogen while 38.0 g (0.275 moles) of dry potassium carbonate, predried at 100° C. under vacuum for 18 hours, was added. The mixture was heated to reflux for 4.5 hours. After cooling, the mixture was separated by filtration and the solid was washed with two portions of 50 ml of acetone. The filtrate was concentrated to dryness, dissolved in methylene chloride, filtered through Fluorosil, concentrated under vacuum to dryness, leaving a residual oil which was distilled. The fraction distilling at 48°-52° C. at 0.05 mm pressure was collected and 26.5 g of ethyl 3-acetyl-4-oxopentanoate were obtained.