Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:36]([CH3:37])=[CH:35][C:13]2[N:14]=[C:15]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH:19]([C:24]4[CH:25]=[C:26]5[C:30](=[CH:31][CH:32]=4)[N:29]([CH3:33])[N:28]=[CH:27]5)[C:18]3=O)[S:16][C:12]=2[C:11]=1[C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[C:45](O[C@@H](C1C(C)=CC2N=C(N3CCNC(C4C=C5C(=CC=4)N(C)N=C5)C3)SC=2C=1C1C=CC(Cl)=CC=1)C(OCC)=O)(C)(C)[CH3:46]>>[C:1]([O:5][C@@H:6]([C:10]1[C:36]([CH3:37])=[CH:35][C:13]2[N:14]=[C:15]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH:19]([C:24]4[CH:25]=[C:26]5[C:30](=[CH:31][CH:32]=4)[N:29]([CH3:33])[N:28]=[CH:27]5)[CH2:18]3)[S:16][C:12]=2[C:11]=1[C:38]1[CH:39]=[CH:40][C:41]([Cl:44])=[CH:42][CH:43]=1)[C:7]([O:9][CH2:45][CH3:46])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(N3CCNC(c4ccc5c(cnn5C)c4)C3)sc2c1-c1ccc(Cl)cc1
Reactant: Cc1cc2nc(N3CCN(C)C(c4ccc5c(cnn5C)c4)C3=O)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(N3CCN(C)C(c4ccc5c(cnn5C)c4)C3)sc2c1-c1ccc(Cl)cc1

Procedure:
(2S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(4-methyl-3-(1-methyl-1H-indazol-5-yl)piperazin-1-yl)benzo[d]thiazol-6-yl)acetate (16 mg) was prepared in a similar manner as (2S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(4-methyl-3-(1-methyl-1H-indazol-5-yl)-2-oxopiperazin-1-yl)benzo[d]thiazol-6-yl)acetic acid except using (2S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(3-(1-methyl-1H-indazol-5-yl)piperazin-1-yl)benzo[d]thiazol-6-yl)acetate instead of (2S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(3-(1-methyl-1H-indazol-5-yl)-2-oxopiperazin-1-yl)benzo[d]thiazol-6-yl)acetic acid. LCMS-ESI+: calc'd for C35H41ClN5O3S: 646.2 (M+H+); Found: 646.3 (M+H+).
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[CH:16]=[C:15]([CH2:17][OH:18])[C:14]([C:19]([F:22])([F:21])[F:20])=[N:13]3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[OH:18][CH2:17][C:15]1[C:14]([C:19]([F:22])([F:21])[F:20])=[N:13][N:12]([CH2:11][C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[CH:2]([NH:1][S:31]([CH3:30])(=[O:33])=[O:32])[CH2:3][CH2:4]3)[CH:16]=1
Reactant: NC1CCc2cc(Cn3cc(CO)c(C(F)(F)F)n3)ccc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NC1CCc2cc(Cn3cc(CO)c(C(F)(F)F)n3)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (1-((1-amino-2,3-dihydro-1H-inden-5-yl)methyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)methanol (0.096 mmol, 30 mg) and triethylamine (0.193 mmol, 0.027 mL, 19.50 mg) in DCM (0.9 mL) was added methanesulfonyl chloride (0.096 mmol, 7.46 μL, 11.04 mg) and the whole stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure and the residue purified by RP-HPLC to give a clear film (2.2 mg 5.7 μmol, 5.9%). MS (ESI): m/z [M+H]+ 390.0
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][OH:15])[CH2:9]1.[CH:16](O)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl>[C:17]1([CH:16]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[O:15][CH2:14][CH:10]2[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OC(c1ccccc1)c1ccccc1
Reactant: OCC1CCCNC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(C(OCC2CCCNC2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.6 %

Procedure:
Trifluoroacetic acid (20 ml) was added cautiously to a vigorously stirred solution of piperidine-3-methanol (5.75 g, 50 mmol) in dichloromethane (20 ml) and the mixture treated with benzhydrol (9.2 g, 50 mmol) portionwise over 5 minutes, stirred at room temperature for 2 hours and evaporated. The residue was dissolved in dioxane (50 ml) and the solution treated with 4M aqueous sodium hydroxide solution (100 ml), stirred at room temperature for 2 hours, diluted with ether and water and the layers separated. The organic layer was washed with water and extracted into 2M hydrochloric acid. The acidic extract was washed with ether, basified with solid sodium carbonate, extracted into ether, washed with water, dried over magnesium sulphate and evaporated to give the title compound (4.31 g) as a pale yellow oil which was characterised by its 1H-NMR spectrum.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH2:7][C:8](=[O:23])[C:9]=1[N:10]2C(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH2:7][C:8](=[O:23])[C:9]=1[NH:10]2
Reactant: CC(C)(C)OC(=O)n1c2c(c3c(Cl)c(Cl)ccc31)CCCC2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CCCc2c1[nH]c1ccc(Cl)c(Cl)c21
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.8 %

Procedure:
tert-Butyl 5,6-dichloro-1-oxo-3,4-dihydro-1H-carbazole-9(2H)-carboxylate (intermediate 1b) (0.9 g, 2.5 mmol) was dissolved in DCM (15 mL), cooled to 0° C., and TFA (1.6 mL) was added. The reaction mixture was stirred at 0° C. for 1 h, neutralized with saturated NaHCO3 (20 mL) and extracted with DCM (2×20 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give the title compound as a white solid (450 mg, 70%) which was directly in the next step without further purification. 1H NMR (500 MHz, CDCl3, δ in ppm) 9.18 (bs, 1H), 7.38 (d, J=9.0 Hz, 1H), 7.28 (d, J=9.5 Hz, 1H), 3.37 (t, J=6.0 Hz, 2H), 2.67 (t, J=7.0 Hz, 2H), 2.30-2.25 (m, 2H).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.CC([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:24][CH2:25][C:26]1[N:30]([CH3:31])[N:29]=[N:28][C:27]=1[CH2:32][O:33][C:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37]2=[N:44][N:45]=[C:46]([C:47]3[CH:51]=[C:50]([CH3:52])[O:49][N:48]=3)[N:36]2[N:35]=1)(C)C.O>C1COCC1.CO>[CH3:31][N:30]1[C:26]([CH2:25][OH:24])=[C:27]([CH2:32][O:33][C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:37]3=[N:44][N:45]=[C:46]([C:47]4[CH:51]=[C:50]([CH3:52])[O:49][N:48]=4)[N:36]3[N:35]=2)[N:28]=[N:29]1
Reactant: Cc1cc(-c2nnc3c4ccccc4c(OCc4nnn(C)c4CO[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)nn23)no1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cc(-c2nnc3c4ccccc4c(OCc4nnn(C)c4CO)nn23)no1
Reaction time: 8 h
Yield: 51.9 %

Procedure:
A solution of tetrabutylammonium fluoride (3.3 mmol) in THF (1.0 M, 3.3 ml) was added to a stirred solution of 6-({[5-({[(1,1-dimethylethyl)(diphenyl)silyl]oxy}methyl)-1-methyl-1H-[1,2,3]triazol-4-yl]methyl}oxy)-3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[3,4-α]phthalazine (1.90 g, 3.3 mmol) in THF (50 ml) and MeOH (10 ml) at room temperature under N2 and the reaction mixture was stirred overnight. H2O (10 ml) was added and then the mixture was concentrated under reduced pressure to remove the organic solvents. The resulting solid was filtered off, washed with H2O (20 ml), then triturated with CH2Cl2 (100 ml), filtered and dried, to yield the desired hydroxymethyltriazole (672 mg, 56%). 1H NMR (400 MHz, d6-DMSO) δ 8.56 (1H, d, J=7.9 Hz), 8.17-8.04 (2H, m), 7.91 (1H, td, J=7.9, 0.9 Hz), 7.22 (1H, s), 5.71 (2H, s), 5.42 (1H, t, J=5.6 Hz), 4.72 (2H, d, J=5.6 Hz), 4.06 (3H, s), 2.59 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][C:7](=O)[C:6]=2[CH:11]=1.[CH2:12]([O:14][C:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16])[CH3:13]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH2:12]([O:14][C:15]([N:17]1[CH2:18][CH2:19][N:20]([C:7]2[C:6]3[CH:11]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[O:9][CH:8]=2)[CH2:21][CH2:22]1)=[O:16])[CH3:13]
Reactant: O=C1COc2ccc(F)cc21
Reactant: CCOC(=O)N1CCNCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)N1CCN(c2coc3ccc(F)cc23)CC1
Temperature: 25 °C

Procedure:
To a stirred solution of TiCl4 (1M solution in CH2Cl2, 7 ml) and 5-fluoro-benzofuran -3-one (Cagniant, et al., Comptus Rendus des Seances Acad. de Sci., Ser. C, 282:993 (1976), 3.0 g) (3.0 g, 19.7 mmol) in methylene chloride (200 ml) at −10° C., ethyl-1-piperizine carboxylate (commercially available) (3.9 g, 35 mmol) was slowly added. After the addition, the reaction mixture was warmed to room temperature and slowly refluxed for 24 hours. After cooling to room temperature, the reaction was quenched with 2 N aqueous HCl. The organic layer was separated and the aqueous layer was extracted with chloroform. The combined organic layers were washed well with water and dried over anhydrous MgSO4, then filtered and concentrated resulting in a brown oil. Yield: 3.5 g, (60%); MS (ESI) m/z 293 [M+−H]+.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH:36]=O.CCCCCC>O1CCCC1>[CH3:2][O:3]/[CH:4]=[CH:36]\[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][N:30]=1
Reactant: O=Cc1ccccn1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CO/C=C\c1ccccn1
Temperature: -78 °C
Reaction time: 0.83 h
Yield: 24 %

Procedure:
A stirred suspension of methoxymethyltriphenyl phosphonium chloride (12.48 g) in tetrahydrofuran (60 ml) under argon was cooled in an ice-bath. Potassium tert-butoxide (36.41 ml, 1M solution in tetrahydrofuran) was then added dropwise over 30 minutes to give a deep orange-red colour. Stirring was continued at 0-5° C. for 50 minutes then the mixture was cooled to −78° C. 2-Pyridinecarboxaldehyde was added dropwise and stirring continued at −78° C. for a further 2 h then allowed to warm to room temperature and stirred for 2 h. Hexane (100 ml) was added, the mixture filtered and the filtrate evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting, with 10% ethyl acetate in hexane to give the pure cis-2-(2-methoxyvinyl)pyridine (0.91 g, 24%):
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[CH:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[C:16]([F:25])[CH:15]=2)=[O:11])=[CH:6][CH:5]=[C:4]([C:26]([F:29])([F:28])[F:27])[N:3]=1.[CH3:30][O:31][CH2:32][CH2:33][NH2:34].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[F:25][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:13][NH:12][C:10](=[O:11])[CH:9]=[CH:8][C:7]1[C:2]([NH:34][CH2:33][CH2:32][O:31][CH3:30])=[N:3][C:4]([C:26]([F:29])([F:28])[F:27])=[CH:5][CH:6]=1
Reactant: COCCN
Reactant: CS(=O)(=O)Nc1ccc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCNc1nc(C(F)(F)F)ccc1C=CC(=O)NCc1ccc(NS(C)(=O)=O)c(F)c1
Temperature: 110 °C
Reaction time: 12 h
Yield: 26 %

Procedure:
To a suspension of 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonylamino-benzyl)-acrylamide (35 mg, 0.077 mmol) and methoxyethylamine (5 eq) in DMF (0.5 ml) was added K2CO3 (5 eq). The mixture was stirred for 12 hours at 110° C. The reaction mixture was diluted with EtOAc and then washed two times with 1N-HCl and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was column-chromatographed to yield the title compound (10 mg, 26%).
Reaction SMILES: [F:1][CH:2]([F:32])[C:3]1[CH:4]=[C:5]([N:9]2[C:14]3[CH2:15][CH2:16][C:17](=[O:18])[C:13]=3[CH:12]([C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][C:20]=3[S:27]([CH3:30])(=[O:29])=[O:28])[NH:11][C:10]2=[O:31])[CH:6]=[CH:7][CH:8]=1.[C:33](=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[F:32][CH:2]([F:1])[C:3]1[CH:4]=[C:5]([N:9]2[C:14]3[CH2:15][CH2:16][C:17](=[O:18])[C:13]=3[CH:12]([C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][C:20]=3[S:27]([CH3:30])(=[O:29])=[O:28])[N:11]([CH3:33])[C:10]2=[O:31])[CH:6]=[CH:7][CH:8]=1
Reactant: CS(=O)(=O)c1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)F)c2)C2=C1C(=O)CC2
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN1C(=O)N(c2cccc(C(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl idodide (15 μL, 0.24 mmol) is added to a solution of 4-(1-(3-(difluoromethyl)-phenyl)-2,5-dioxo-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]pyrimidin-4-yl)-3-(methyl-sulfonyl)benzonitrile (example 15.4, 69 mg, 0.15 mmol) and cesium carbonate (98 mg, 0.30 mmol) in N,N-dimethylformamide (1.0 mL). The mixture is stirred at room temperature for 1 h and purified by reversed phase HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 19 mg; ESI mass spectrum [M+H]+=472; Retention time HPLC: 0.97 min (Z018_S04).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH2:8][OH:9])[N:5]=[C:4]([CH2:10][CH3:11])[C:3]=1[CH2:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[CH:14]=1.N1C=CN=C1.[C:26]([Si:30]([CH3:33])([CH3:32])Cl)([CH3:29])([CH3:28])[CH3:27]>CN(C)C=O>[Si:30]([O:9][CH2:8][CH2:7][N:6]1[C:2]([NH2:1])=[C:3]([CH2:12][C:13]2[CH:14]=[C:15]([Cl:20])[CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:4]([CH2:10][CH3:11])=[N:5]1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:33])[CH3:32]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCc1nn(CCO)c(N)c1Cc1cc(Cl)cc(Cl)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCc1nn(CCO[Si](C)(C)C(C)(C)C)c(N)c1Cc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.2 %

Procedure:
To a solution of the pyrazole of Example 89 (3.0 g, 9.6 mmol) in dimethylformamide (20 ml) was added imidazole (850 mg, 12.5 mmol), followed by tert-butyldimethylchlorosilane (1.58 g, 10.6 mmol). The solution was stirred at room temperature for 20 hours. The reaction mixture was partitioned between diethyl ether and aqueous sodium carbonate and the aqueous phase was separated and further extracted with diethyl ether. The combined organic phases were washed with water, washed with brine, dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (95:5:0.5, by volume) to afford the title compound (4.0 g) as a colourless oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:25]=[O:26])[C:8]2[C:9](=[O:24])[N:10]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=3[CH2:22][OH:23])[N:11]=[CH:12][C:13]=2[CH:14]=1)([CH3:4])([CH3:3])[CH3:2].ClC(Cl)C.[BH4-].[Na+].Cl>CO>[C:1]([C:5]1[CH:14]=[C:13]2[C:8](=[C:7]([CH2:25][OH:26])[CH:6]=1)[C:9](=[O:24])[N:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[CH2:22][OH:23])[N:11]=[CH:12]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(C=O)c2c(=O)n(-c3cccc(Cl)c3CO)ncc2c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(Cl)Cl
Product: CC(C)(C)c1cc(CO)c2c(=O)n(-c3cccc(Cl)c3CO)ncc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 26.4 %

Procedure:
The above 7-tert-butyl-3-[3-chloro-2-(hydroxymethyl)phenyl]-4-oxo-3,4-dihydrophthalazine-5-carbaldehyde (147 mg, 0.396 mmol) was combined with dichloroethane (5 mL) and methanol (5 mL) to give a yellow solution. Sodium borohydride (27 mg, 0.714 mmol) was added and the mixture was stirred at room temperature for 4 hrs. The mixture was treated with 1N hydrochloric acid and extracted with dichloromethane. The organic layer was washed with brined and dried over sodium sulfate. After the evaporation of solvents, the residue was purified by flash column chromatography (silica gel 40 g, 0% to 40% ethyl acetate in heptane) to give 6-tert-butyl-2-[3-chloro-2-(hydroxymethyl)phenyl]-8-(hydroxymethyl)phthalazin-1(2H)-one as a light yellow solid (39 mg, 26.4%). LC/MS calcd for C20H21ClN2O3 (m/e) 372.12, obsd 371.1 (M−H, ES−).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CN1CCOCC1.[C:24]([O:28][C:29]([N:31]1[CH2:38][CH2:37][CH2:36][C@H:32]1[C:33](O)=[O:34])=[O:30])([CH3:27])([CH3:26])[CH3:25].C1C=CC2N(O)N=NC=2C=1>ClCCl.C(OCC)(=O)C.O>[CH2:2]([O:9][C:10](=[O:16])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:33](=[O:34])[C@@H:32]1[CH2:36][CH2:37][CH2:38][N:31]1[C:29]([O:28][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:30])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 89.1 %

Procedure:
To a suspension of L-proline benzyl ester hydrochloride (3.37 g) in dichloromethane (60 ml) were added N-methylmorpholine (1.54 ml), N-(t-butoxycarbonyl)-L-proline (3.00 g), HOBt (2.08 g) and water-soluble carbodiimide hydrochloride (2.95 g) in order, followed by stirring for 1 hour. After stirring at room temperature for 17 hours, the reaction mixture was poured into ethyl acetate, washed with 1N hydrochloric acid, a saturated aqueous solution of sodium bicarbonate and saturated brine in order, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluate; hexane-ethyl acetate) to give 5.00 g of the title compound.
Reaction SMILES: O=[S:2]1(=O)[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.C(OCC)C>[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3]1
Reactant: O=S1(=O)CCc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: c1ccc2c(c1)CCS2
Reaction time: 0.5 h
Yield: 58 %

Procedure:
A solution of 22.3 g (132 mmole) of the product of Part (ii) in 200 ml tetrahydrofuran was added dropwise with stirring to a mixture of 5.81 g (145 mmole) lithium aluminum hydride (95%) in 400 ml dry ethyl ether, at a rate sufficient to maintain gentle reflux. Refluxing was continued for 30 minutes. The mixture was cooled in ice and quenched by cautious addition of 6 ml water followed by 6 ml 15% (w/v) sodium hydroxide and 18 ml water. The resulting mixture was filtered, the organic phase washed with brine, dried (Na2SO4) and evaporated to provide a yellow oil which was distilled to yield 10.4 g (58%) product, b.p. 129°-131° C. The structure was verified by 1H-NMR spectroscopy.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=2)[C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)([O-])=O.[Sn](Cl)Cl>Cl>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]([C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=2)[C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(N(c2ccc([N+](=O)[O-])cc2)c2ccc([N+](=O)[O-])cc2)cc1
Agent: Cl
Agent: Cl[Sn]Cl
Product: Nc1ccc(N(c2ccc(N)cc2)c2ccc(N)cc2)cc1
Yield: 99.3 %

Procedure:
Tris(4-nitrophenyl)amine (1.9 g) was suspended in 6 N hydrochloric acid (80 ml), and then tin dichloride (31.3 g) was added at room temperature and the mixture was heated to reflux for one day. After cooling, the reaction solution was filtered, and 6 N sodium hydroxide (160 ml) was added to the filtrate while cooling on ice. The mixture was extracted twice with dichloromethane (200 mL). The organic layer was collected and dried over sodium sulfate, and then concentrated to obtain 1.44 g of the title compound as a brown powder (quantitative yield).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.[Li]CCCC.[Cl:16][C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1.CN([CH:26]=[O:27])C.[BH4-].[Na+]>C1COCC1>[Cl:16][C:17]1[C:22]([CH2:26][OH:27])=[N:21][CH:20]=[CH:19][N:18]=1
Reactant: CN(C)C=O
Reactant: Clc1cnccn1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [BH4-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OCc1nccnc1Cl
Temperature: 0 °C

Procedure:
To a solution of 2,2,6,6-tetramethylpiperidine (TMP) (43.8 mL, 36.4 g, 0.258 mol, 1.18 eq.) in anhydrous THF (600 mL), cooled to −78° C., 2.5 M n-BuLi in hexanes (110.9 mL, 0.277 mol, 1.27 eq.) was added directly. The solution was allowed to warm to 0° C. for 20 min, after which the reaction was again cooled to −78° C. A solution of chloropyrazine (19.2 mL, 25.0 g, 0.218 mol) in THF (50 mL) was added dropwise over 10 min; a color change from light yellow to dark brown was observed. The reaction was allowed to react at −78° C. to −70° C. for 10 min. A solution of DMF (42.0 mL, 39.9 g, 0.546 mol, 2.5 eq.) in THF (50 mL) was added slowly over 12 min. The temperature was maintained at −78° C. to −70° C. for 2 h. The reaction was quenched with MeOH (400 mL) at −78° C. and charged with NaBH4 (16.5 g, 0.437 mol, 2.0 eq.) at 0° C. for 2 h. The solvent was partially removed in vacuo and additional CH2Cl2 (200 mL) was added to the oil and the reaction mixture was quenched with 2N HCl (900 mL) to a neutral pH. The aqueous layer was extracted with CH2Cl2 (4×) and EtOAc (2×). The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo, giving a crude black liquid. The crude material was adsorbed onto silica gel (for dry loading) and purified by chromatography on silica gel [2 kg silica gel, eluting with MeCN:CH2Cl2 2%→5%→10%] affording the title compound, as a dark brown oil; 1H NMR (400 MHz,CDCl3) δ 4.86 (2H, s), 8.36 (1H, d, J=4.35 Hz), 8.51 (1H, d, J=2.56 Hz); MS (ES+): m/z 144.93 (100) [MH+]; HPLC: tR=1.60 min (OpenLynx, polar—7 min).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH:7]([O:10][CH3:11])[N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:4].[CH2:19]([Si](C)(C)C)[CH:20]=C.B(F)(F)F.CCOCC>C(Cl)Cl.C(OCC)(=O)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH:7]([O:10][CH2:11][CH:19]=[CH2:20])[N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:4]
Reactant: C=CC[Si](C)(C)C
Reactant: COC(=O)C1CCC(OC)N1C(=O)OC(C)(C)C
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: C=CCOC1CCC(C(=O)OC)N1C(=O)OC(C)(C)C
Yield: 61 %

Procedure:
To a solution of 5-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester, 3, (9.86 g, 38.0 mmol) and allyltrimethylsilane (13.0 g, 114 mmol) in CH2Cl2 (200 mL) at −78° C. is added dropwise boron trifluoride etherate (4.82 mL, 38.0 mmol). Once consumption of the starting material is complete, water is cautiously added to quench the reaction. The resulting solution is taken up in ethyl acetate (200 mL) washed with water (1×250 mL), brine (1×250 mL), and dried with Na2SO4. The organics are concentrated in vacuo. The resulting residue is purified over silica (hexanes/ethyl acetate 85:15) to afford 6.2 g (61% yield) of the desired product as a light yellow oil. 1H-NMR (300 MHz, CDCl3): δ 5.85–5.70 (m, 1H), 5.09–5.00 (m, 2H), 4.31–4.16 (m, 1H), 3.95–3.76 (br m, 1H), 3.71–3.69 (m, 3H), 2.72–2.57 (br m, 1H), 2.24–1.69 (m, 5H), 1.45–1.38 (m, 9H); MS (ESI): m/e=270.11 (M+H).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]=[C:9]([C:11]3[C:12]([C:20]4[CH:25]=[CH:24][N:23]=[C:22](F)[CH:21]=4)=[N:13][N:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=34)[CH:8]=[CH:7][N:6]=2)[CH2:3][CH2:2]1.[CH:27]([NH2:30])([CH3:29])[CH3:28]>>[CH:1]1([NH:4][C:5]2[N:10]=[C:9]([C:11]3[C:12]([C:20]4[CH:25]=[CH:24][N:23]=[C:22]([NH:30][CH:27]([CH3:29])[CH3:28])[CH:21]=4)=[N:13][N:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=34)[CH:8]=[CH:7][N:6]=2)[CH2:3][CH2:2]1
Reactant: Fc1cc(-c2nn3ccccc3c2-c2ccnc(NC3CC3)n2)ccn1
Reactant: CC(C)N
Product: CC(C)Nc1cc(-c2nn3ccccc3c2-c2ccnc(NC3CC3)n2)ccn1
Yield: 80.7 %

Procedure:
A solution of N-cyclopropyl-4-[2-(2-fluoro-4-pyridinyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine (206 mg, 0.595 mmol) in isopropylamine (3 mL, 35.2 mmol) was heated at 150° C. in a steel bomb for 16 hours. The excess isopropylamine was removed under a stream of nitrogen. The crude material was triturated with ether to provide N-cyclopropyl-4-{2-[2-(isopropylamino)-4-pyridinyl]pyrazolo[1,5-a]pyridin-3-yl}-2-pyrimidinamine (185 mg, 80%) as a tan solid. 1H NMR (CDCl3) δ 8.60 (d, 1H), 8.51 (d, 1H), 8.14 (m, 2H), 7.32 (t, 1H), 6.93 (t, 1H), 6.80 (d, 1H), 6.62 (s, 1H), 6.55 (d, 1H), 5.62 (br, 1H), 4.60 (d, 1H), 3.87 (m, 1H), 2.85 (m, 1H), 1.29 (d, 3H), 1.22 (d, 3H), 0.86 (m, 2H), 0.63 (m, 2H); MS m/z 386 (M+1).