Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([N:13]([CH2:24][C:25]3[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=3)[C:14]3[N:18]([CH3:19])[C:17]4[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=4[N:15]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.O.[NH:35]1[C:39]([NH2:40])=[N:38][N:37]=[N:36]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.Cl>CN(C=O)C.CCOC(C)=O>[C:1]1([C:7]2[CH:12]=[CH:11][C:10]([N:13]([CH2:24][C:25]3[CH:33]=[CH:32][C:28]([C:29]([NH:40][C:39]4[NH:38][N:37]=[N:36][N:35]=4)=[O:30])=[CH:27][CH:26]=3)[C:14]3[N:18]([CH3:19])[C:17]4[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=4[N:15]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: Cn1c(N(Cc2ccc(C(=O)O)cc2)c2ccc(C3=CCCCC3)cc2)nc2ccccc21
Reactant: Nc1nnn[nH]1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cn1c(N(Cc2ccc(C(=O)Nc3nnn[nH]3)cc2)c2ccc(C3=CCCCC3)cc2)nc2ccccc21
Reaction time: 8 h

Procedure:
To a solution of the title compound of Example 221 Step F (0.11 mmol, 50 mg), 1H-tetraazol-5-amine monohydrate (0.23 mmol, 24 mg), HOBt (0.29 mmol, 43 mg) and EDC (0.46 mmol, 88 mg) in 1 mL of DMF was added DIEA (0.57 mmol, 100 μL). The reaction mixture was allowed to stand at ambient temperature overnight, then poured into a mixture of dilute pH 7 buffer/EtOAc, which was acidified with 2 N HCl until two clear layers formed after agitation. The organic phase was concentrated under reduced pressure and the residue was purified by reverse-phase chromatography (Condition B) and lyophilized, affording a white solid. 1H NMR (500 MHz, DMSO) δ 8.06 (d, 2H), 7.68 (d, 2H), 7.55 (m, 2H), 7.42 (d, 2H), 7.34 (m, 2H), 7.20 (d, 2H), 6.18 (m, 1H), 5.38 (s, 2H), 3.31 (s, 3H), 2.35 (m, 2H), 2.18 (m, 2H), 1.73 (m, 2H), 1.60 (m, 2H). MS (ESI): m/z 505 (M+H). HPLC A: 1.99 min.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.[NH2:35][C:36]1([CH3:49])[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]1.O>CN(C=O)C.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:35][C:36]5([CH3:49])[CH2:37][CH2:38][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:40][CH2:41]5)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(F)cc21
Reactant: CC1(N)CCN(C(=O)OC(C)(C)C)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC4(C)CCN(C(=O)OC(C)(C)C)CC4)c3n2)c2ccc(F)cc21
Reaction time: 16 h
Yield: 61.6 %

Procedure:
To a stirred solution of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 0.32 mmol) in 10 mL of DMF were added EDCI (122 mg, 0.64 mmol), tert-butyl 4-amino-4-methylpiperidine-1-carboxylate (103 mg, 0.48 mmol) and DMAP (78 mg, 0.64 mmol) in one portion at room temperature. Then the reaction mixture was stirred for 16 hours, then was poured into 50 mL of water and filtered. The filter cake was washed with water (10 mL) and passed through a pad of silica gel (200-300 mesh, eluting with a mixture of petroleum ether and ethyl acetate (1:2, v/v) to give tert-butyl 4-(2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamido)-4-methylpiperidine-1-carboxylate (100 mg, 61.6%) as a white solid which was used for the next step without further purification. MS: (M+H)+=508.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=2)[CH:15]=[C:14]([C:25]([OH:27])=O)[CH:13]=1.Cl.[O:29]1[CH2:34][CH2:33][N:32]([CH2:35][C@@H:36]([NH2:38])[CH3:37])[CH2:31][CH2:30]1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CN(C)C=O>>[CH3:37][C@@H:36]([NH:38][C:25]([C:14]1[CH:13]=[C:12]([C:3]2[C:4]([C:8]([F:9])([F:10])[F:11])=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=2)[CH:15]=1)=[O:27])[CH2:35][N:32]1[CH2:33][CH2:34][O:29][CH2:30][CH2:31]1
Reactant: C[C@H](N)CN1CCOCC1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(-c3c(F)cccc3C(F)(F)F)c2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C(=O)N[C@H](C)CN3CCOCC3)cc(-c3c(F)cccc3C(F)(F)F)c2)nc1
Temperature: 25 °C

Procedure:
A round bottom flask was charged with 2′-fluoro-5-(5-methylpyridin-2-yl)-6′-(trifluoromethyl)biphenyl-3-carboxylic acid (100.00 mg, 0.26644 mmol), (S)-1-morpholinopropan-2-amine hydrochloride (112.10 mg, 0.62047 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.49150 g, 1.2926 mmol), N,N-diisopropylethylamine (0.36025 mL, 2.0682 mmol), N,N-dimethylformamide (0.882 mL, 11.4 mmol) and the reaction stirred over night at room temperature. The solvent was removed under reduced pressure and the residue purified by prep HPLC to get the compound as white solid.
Reaction SMILES: C[O:2][C:3](=[O:31])[C@@H:4]([O:28][CH2:29][CH3:30])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[O:17][C:18]=2[CH3:19])=[CH:8][C:7]=1[CH3:27].[Li+].[OH-]>>[CH2:29]([O:28][C@@H:4]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[O:17][C:18]=2[CH3:19])=[CH:8][C:7]=1[CH3:27])[C:3]([OH:31])=[O:2])[CH3:30]
Reactant: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccccc3F)oc2C)cc1C)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccccc3F)oc2C)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 1 g], (S)-2-ethoxy-3-{4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionic acid methyl ester was treated with LiOH to obtain (S)-2-ethoxy-3-{4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionic acid as colorless solid, which was crystalized from hexane/dichloromethane to afford colorless crystals. According to chiral HPLC of the corresponding methyl ester (Chiralcel-ODH), the enantiomeric excess amounts to 99.4%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][CH:3]=1.[NH2:17][C:18]1[C:22]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[CH:21][NH:20][N:19]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:19]3[N:20]=[CH:21][C:22]([C:23]4[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=4)=[C:18]3[N:17]=2)=[CH:4][CH:3]=1
Reactant: Nc1n[nH]cc1-c1ccncc1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(Cl)cc1
Product: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc2c(-c3ccncc3)cnn12
Yield: 72 %

Procedure:
Reaction of 1-(4-chloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (125 mg, 0.5 mmol), prepared from commercially available 4-chloro-acetophenone according to general procedure A, and 3-amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9; prepared from 4-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (80 mg, 9.5 mmol) according to general procedure B yielded the title compound as a yellow solid (135 mg, 72%). MS (ISP) 375.3 [(M+H)+]; mp 274° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.C([Li])CCC.F[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>C(OCC)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:3][CH:4]=1
Reactant: Fc1ccccn1
Reactant: Brc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: Brc1ccc(-c2ccccn2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 57.7 %

Procedure:
1,4-Dibromobenzene (5.90 g, 25.0 mmol) was dissolved in anhydrous diethyl ether (40 mL) and flushed with argon before the solution was cooled to −78° C. and n-butyl lithium (2.5M in hexanes, 10.2 mL, 25.6 mmol) was added dropwise at a rate that maintained the temperature below −70° C. The reaction mixture was stirred at this temperature for 30 minutes then 2-fluoropyridine (1.72 mL, 20.0 mmol) was added dropwise and stirring continued at −78° C. for 1 h then the reaction mixture was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was poured onto water (50 mL) and extracted with diethyl ether (3×50 mL). The combined organic layers were washed with 5% HCl (3×200 mL) then the pH of the aqueous phase was adjusted to 10 by the addition of potassium hydroxide and the aqueous phase was extracted with diethyl ether (3×200 mL). The combined organic phase was dried over sodium sulfate, filtered and evaporated to afford the title compound (2.7 g, 58%). 1H NMR (CDCl3, 300 MHz): 8.71-8.66 (m, 1H), 7.91-7.85 (m, 2H), 7.79-7.67 (m, 2H), 7.64-7.57 (m, 2H), 7.28-7.22 (m, 1H).
Reaction SMILES: Cl[C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[C:5]2[N:16]=[CH:17][CH:18]=[CH:19][C:4]=2[N:3]=1.[CH2:20]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][NH2:25])[CH3:21]>C(O)C>[CH2:20]([N:22]([CH2:23][CH2:24][NH:25][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[C:5]2[N:16]=[CH:17][CH:18]=[CH:19][C:4]=2[N:3]=1)[CH2:26][CH3:27])[CH3:21]
Reactant: CCN(CC)CCN
Reactant: Cc1ccc(-n2c(=O)c(Cl)nc3cccnc32)cc1
Solvent: CCO
Product: CCN(CC)CCNc1nc2cccnc2n(-c2ccc(C)cc2)c1=O

Procedure:
Preparation as in Example 39 but using 2-chloro-3,4-dihydro-4-(4-methylphenyl)-3-oxopyrido[2,3-b]pyrazine and N,N-diethylethylene diamine in refluxing ethanol gave the title compound mp 131°-132° C.
Reaction SMILES: [CH:1]1([C:4]2[C:9]([CH2:10]O)=[CH:8][CH:7]=[C:6]([C:12]([F:15])([F:14])[F:13])[N:5]=2)[CH2:3][CH2:2]1.S(Cl)([Cl:18])=O>ClCCl.CN(C=O)C.CCOC(C)=O>[Cl:18][CH2:10][C:9]1[C:4]([CH:1]2[CH2:3][CH2:2]2)=[N:5][C:6]([C:12]([F:15])([F:14])[F:13])=[CH:7][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(C(F)(F)F)nc1C1CC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(CCl)c(C2CC2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 93.2 %

Procedure:
To a stirring solution of (2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)methanol (890 mg, 4.1 mmol) in dichloromethane (10 mL) at room temperature under argon was added thionyl chloride (730 mg, 6.1 mmol) followed by 3 drops of DMF. The reaction mixture was stirred at room temperature for 15 h. The reaction mixture was then concentrated under vacuum to obtain a light brown oil. This oil was diluted with EtOAc (20 mL) and washed with 10% aqueous Na2CO3 solution (20 mL). The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated to obtain 900 mg of the title compound as a light brown oil. HPLC/MS: retention time=3.66 min, [M+H]+=236.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[S:12]([N:15]([C:19]1[CH:23]=[CH:22][S:21][C:20]=1[C:24]([O:26][CH3:27])=[O:25])COC)(=[O:14])=[O:13].Cl>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:9])([CH3:10])[CH3:11])[CH:5]=[CH:4][C:3]=1[S:12]([NH:15][C:19]1[CH:23]=[CH:22][S:21][C:20]=1[C:24]([O:26][CH3:27])=[O:25])(=[O:13])=[O:14]
Reactant: COCN(c1ccsc1C(=O)OC)S(=O)(=O)c1ccc(C(C)(C)C)cc1Cl
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)c1sccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1Cl
Temperature: 75 °C
Yield: 68.2 %

Procedure:
To a solution of 21 (292.0 mg; 0.68 mmol) in tetrahydrofuran (5 mL) was added aqueous hydrochloric acid (3.38 mL; 6.76 mol; 2N). The reaction mixture was heated at 75° C. for 4 hours, and then additional aqueous hydrochloric acid (3.0 mL; 6N) was added and the reaction mixture further heated at reflux for 4-5 hours. The reaction mixture was allowed to cool to room temperature and then extracted with ethyl acetate (15 mL). The organic layer was separated, dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield a white solid which was purified by automated silica gel chromatography (Biotage®) eluting with ethyl acetate/hexanes (0 to 25% v/v over 400 mL gradient elution) to yield the title as an off-white solid (180 mg).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([O:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10])=[O:2].[OH-].[Na+].Cl.CCOCC>C(O)C>[CH:1]([C:3]1[CH:4]=[C:5]([O:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10])=[O:2]
Reactant: CCOC(=O)CCCOc1ccc([N+](=O)[O-])c(C=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: O=Cc1cc(OCCCC(=O)O)ccc1[N+](=O)[O-]
Yield: 94 %

Procedure:
To a solution of ethyl 4-(3-formyl-4-nitrophenyl)oxybutyrate (65 g) in ethanol (400 ml) was added 3N NaOH (100 ml) in small portions. After 30 minutes at room temperature the reaction mixture was acidified with concentrated HCl and the ethanol evaporated. The aqueous residue was extracted with ethyl acetate (4×200 ml). The combined organic layers were washed with brine (2×200 ml), dried over Na2SO4, filtered and evaporated to give a light yellow solid. Trituration with ether afforded 4-(3-formyl-4-nitrophenyl)oxybutyric acid (55 g), m.p. 109°-110° C.
Reaction SMILES: Cl.[F:2][C:3]([F:12])([F:11])[C:4]1[CH:10]=[CH:9][C:7](N)=[CH:6][CH:5]=1.N([O-])=O.[Na+].[C:17]1(=[O:23])[NH:21][C:20](=[O:22])[CH:19]=[CH:18]1.C([O-])(=O)C.[Na+]>O.CC(C)=O.[Cu](Cl)Cl>[F:2][C:3]([F:12])([F:11])[C:4]1[CH:10]=[CH:9][C:7]([C:19]2[C:20](=[O:22])[NH:21][C:17](=[O:23])[CH:18]=2)=[CH:6][CH:5]=1
Reactant: O=C1C=CC(=O)N1
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: Cl[Cu]Cl
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: O=C1C=C(c2ccc(C(F)(F)F)cc2)C(=O)N1

Procedure:
A mixture of hydrochloric acid (37%, 285 mL) and water (190 mL) was added to 4-(trifluoromethyl)aniline (150 g, 116 mL) at room temperature with vigorous stirring and the formed precipitate was allowed to stir for further 30 minutes. Temperature was reduced to 0° C. and sodium nitrite (70.6 g) in 180 mL of water was added dropwise to the stirred suspension. At the end of diazotisation, a clear yellow solution was obtained. Maleimide (180 g) in acetone (1.1 l) was added dropwise at 0° C. and then the pH of the solution was adjusted to 3-3.5 by adding sodium acetate. Copper (II) chloride (18.8 g) was added to the vigorously stirred mixture. After a few minutes a gas started to develop (conspicuous foaming). The reaction mixture was allowed to stir at 0° C. for 1 h and overnight at room temperature.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:21]2[CH:22]=[N:23][N:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=23)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[C:12](F)=[CH:11][C:10]=2[O:19][CH3:20])=[N:6][CH:7]=1.[CH3:30][NH:31][CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.CCN(C(C)C)C(C)C>CC(N(C)C)=O.CO>[Cl:1][C:2]1[C:3]([C:21]2[CH:22]=[N:23][N:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=23)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[C:12]([N:31]([CH3:30])[CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:11][C:10]=2[O:19][CH3:20])=[N:6][CH:7]=1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Reactant: CNCCN1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: CO
Product: COc1cc(N(C)CCN2CCOCC2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Temperature: 140 °C
Yield: 106.1 %

Procedure:
5-Chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine (Intermediate 20, 311 mg, 0.75 mmol), N-methyl-2-morpholinoethanamine (130 mg, 0.90 mmol) and DIPEA (0.157 mL, 0.90 mmol) were dissolved in DMA (3 mL) and sealed into a microwave tube. The mixture was heated to 140° C. for 0.75 h in the microwave then cooled to r.t. The mixture was then diluted with CH3OH and purified by ion exchange chromatography, using an SCX column and eluting with 1:1 7N methanolic ammonia in CH2Cl2. Appropriate fractions were combined and concentrated in vacuo to give the title compound (429 mg, 106%) as an orange solid which was used without further purification; 1H NMR: 2.36 (4H, s), 2.54 (2H, m), 2.89 (3H, s), 3.34 (2H, m), 3.49 (4H, m), 3.91 (3H, s), 6.81 (1H, s), 7.15 (1H, m), 7.35 (1H, t), 8.16 (1H, s), 8.45 (2H, m), 8.76 (1H, s), 8.86 (1H, d), 8.96 (1H, s); m/z: ES+ MH+ 539.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:13])[C@H:5]([CH2:7][C:8]1[N:12]=[CH:11][NH:10][CH:9]=1)[NH2:6].[CH2:14]([N:21]=[C:22]=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:14]([NH:21][C:22]([NH2:6])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:2][O:3][C:4](=[O:13])[C@H:5]([CH2:7][C:8]1[N:12]=[CH:11][NH:10][CH:9]=1)[NH2:6]
Reactant: O=C=NCc1ccccc1
Agent: COC(=O)[C@@H](N)Cc1c[nH]cn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of histidine methyl ester hydrochloride (2.0 g, 4.3 mmol) in methylene chloride, at 0° C., was added benzyl isocyanate (0.58 mL, 0.63 g, 4.7 nmol) and triethylamine (1.32 mL, 9.5 mmol), and the solution was stirred overnight at room temperature. The solution was concentrated and the residue taken up in ethyl acetate. The solution was washed with water, saturated NaHCO3, brine, dried over MgSO4, and concentrated. The product was obtained as a white foam (1.09 g, 84%).
Reaction SMILES: [CH:1]1([C:6]([N:8]2[CH2:13][CH2:12][CH:11]([O:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]4[C:23]5[CH:31]=[C:30](F)[N:29]=[CH:28][C:24]=5[N:25]=[CH:26][N:27]=4)=[CH:17][C:16]=3[CH3:33])[CH2:10][CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1.CCN(CC)CC>CS(C)=O>[CH:1]1([C:6]([N:8]2[CH2:13][CH2:12][CH:11]([O:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]4[C:23]5[CH:31]=[C:30]([N:34]6[CH2:38][CH2:37][CH2:36][CH2:35]6)[N:29]=[CH:28][C:24]=5[N:25]=[CH:26][N:27]=4)=[CH:17][C:16]=3[CH3:33])[CH2:10][CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(Nc2ncnc3cnc(F)cc23)ccc1OC1CCN(C(=O)C2CCCC2)CC1
Reactant: C1CCNC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1cc(Nc2ncnc3cnc(N4CCCC4)cc23)ccc1OC1CCN(C(=O)C2CCCC2)CC1
Yield: 39.9 %

Procedure:
A solution of Cyclopentyl-{4-[4-(6-fluoro-pyrido[3,4-d]pyrimidin-4-ylamino)-2-methyl-phenoxy]-piperidin-1-yl}-methanone (50 mg, 0.11 mmol), pyrrolodine (15.8 mg, 0.222 mmol), and NEt3 (33.7 mg, 0.333 mmol) in DMSO (1 mL) was heated to 120° C. for 12 h. The reaction was concentrated and purified by preparative HPLC to give the title compound as a yellow solid (22 mg, 40%). MS: 501.4 (MH+); 1H NMR (DMSO-d6, 400 MHz): δ 8.84 (s, 1H), δ 8.30 (s, 1H), δ 7.50-7.54 (m, 2H), δ 7.24 (s, 1H), δ 6.08 (d, J=8.72 Hz, 1H), δ 6.55 (s, 1H), δ 4.52 (m, 1H), δ 3.70 (m, 3H), δ 3.48-3.65 (m, 4H) δ 2.86-2.94 (m, 1H), δ 2.22 (s, 3H), 1.53-2.00 (m, 17H)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[N+:23]([C:26]1[CH:27]=[C:28]([CH2:32][S:33](Cl)(=[O:35])=[O:34])[CH:29]=[CH:30][CH:31]=1)([O-:25])=[O:24]>O1CCCC1>[N+:23]([C:26]1[CH:27]=[C:28]([CH:29]=[CH:30][CH:31]=1)[CH2:32][S:33]([NH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH:5]=[CH:6][CH:7]=1)(=[O:35])=[O:34])([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1cccc(CS(=O)(=O)Cl)c1
Reactant: CC(C)(C)OC(=O)Nc1cccc(N)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1cccc(NS(=O)(=O)Cc2cccc([N+](=O)[O-])c2)c1
Yield: 99.2 %

Procedure:
Into a 1-neck round-bottom flask was added tert-butyl (3-aminophenyl)carbamate (1.0 g, 4.8 mmol) and tetrahydrofuran (20 mL) and triethylamine (1.0 mL, 7.2 mmol). The mixture was cooled in an ice bath and (3-nitrophenyl)methanesulfonyl chloride (1.1 g, 4.8 mmol) was slowly added. The resultant mixture was warmed to rt. The solvent was removed under vacuum and EtOAc and water added. The aqueous phase was extracted again with EtOAc. The organic layers were combined, dried over Na2SO4 and the solvent removed under vacuum to give the desired product (1.94 g, 99%). LCMS for C18H21N3O6S (M-Boc+H)+: m/z=308.0. 1H NMR (400 MHz, DMSO-d6): δ 9.84 (s, 1H), 9.37 (s, 1H), 8.98 (s, 1H), 8.19 (ddd, J=8.1, 2.3, 1.1 Hz, 1H), 8.11 (t, J=1.9 Hz, 1H), 7.71 (dt, J=7.7, 1.3 Hz, 1H), 7.63 (t, J=7.9 Hz, 1H), 7.44 (t, J=2.0 Hz, 1H), 7.15 (t, J=8.0 Hz, 1H), 7.10 (m, 1H), 6.81 (t, J=8.0 Hz, 1H), 6.78 (br, 1H), 6.75 (ddd, J=7.4, 2.2, 1.6 Hz, 1H), 1.46 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH:3]=1.[CH3:24][CH:25]1[O:30][CH:29]([CH3:31])[CH2:28][NH:27][CH2:26]1>CN1C(=O)CCC1.CS(C)=O.CO>[CH3:31][CH:29]1[CH2:28][N:27]([C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[CH:3]=2)[CH2:26][CH:25]([CH3:24])[O:30]1
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(Cl)n3nccc3n2)cc1
Reactant: CC1CNCC(C)O1
Solvent: CO
Solvent: CS(C)=O
Solvent: CN1CCCC1=O
Product: CC1CN(c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3ccnn23)CC(C)O1
Temperature: 25 °C
Yield: 66.3 %

Procedure:
A solution of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 50 mg, 0.151 mmol) and 2,6-dimethylmorpholine (35 mg, 0.302 mmol) in NMP (0.950 mL) was stirred at 85° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC, 35-65% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (41 mg, 66%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.19 (d, J=6.06 Hz, 6 H) 1.46 (s, 6 H) 2.68 (t, J=11.24 Hz, 2 H) 3.80-3.91 (m, 2 H) 4.38 (d, J=11.62 Hz, 2 H) 6.37 (d, J=2.27 Hz, 1 H) 7.40 (s, 1 H) 7.60 (d, J=8.34 Hz, 2 H) 8.00 (d, J=8.59 Hz, 2 H) 8.10 (d, J=2.27 Hz, 1 H) 10.91 (s, 1 H). ESI-MS: m/z 410.3 (M+H)+.
Reaction SMILES: N[C:2]1[O:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.N([O-])=O.[Na+].[I-:29].[K+].C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C.O>[I:29][C:2]1[O:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1
Reactant: [I-]
Reactant: CCOC(=O)c1coc(N)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: O=N[O-]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1coc(I)n1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
2.00 g (12.81 mmol) of ethyl 2-amino-1,3-oxazole-4-carboxylate are added to a solution of 8.00 g (38.43 mmol) of p-toluenesulfonic acid dihydrate in 48 ml of acetonitrile. The suspension is cooled to 0° C., and a solution of 1.77 g (25.62 mmol) sodium nitrite and 5.32 g (32.02 mmol) potassium iodide in 7.2 ml of water is then added. The mixture is stirred at 0° C. for 10 min and, after warming to RT, further overnight. The mixture is then diluted with 200 ml of water. By addition of 1 M aqueous sodium bicarbonate solution, the pH is adjusted to 9. 24 ml of 2 M sodium thiosulfate solution are then added. The aqueous phase is extracted three times with in each case 30 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate. After filtration, the solvent is removed on a rotary evaporator. The residue is purified by column chromatography on silica gel 60 (mobile phase gradient: cyclohexane/ethyl acetate 300:1→2:1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7](O)[CH2:6][CH2:5]2.[Br:12][Si](C)(C)C>C(Cl)(Cl)Cl>[Br:12][CH:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: OC1CCc2cc(Br)ccc21
Reactant: C[Si](C)(C)Br
Solvent: ClC(Cl)Cl
Product: Brc1ccc2c(c1)CCC2Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound obtained in Step A (70.19 mmol) is brought into solution in 420 ml of CHCl3, and bromotrimethylsilane (13.90 ml, 105.28 mmol, 1.5 eq.) is added at room temperature. The reaction mixture is stirred overnight at room temperature. The solvent and excess bromotrimethylsilane are removed by evaporation under reduced pressure. The oil is taken up in 150 ml of CHCl3, washed with 2×80 ml of water and 3×100 ml of saturated NaCl and dried over Na2SO4. The organic phase is then concentrated under reduced pressure to yield the title compound in the form of a brown oil.