Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN([CH:9]=[O:10])C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O.[CH:16]1[C:33]2[C:20](=[CH:21][C:22]3[C:31]([CH:32]=2)=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=3)[CH:19]=[CH:18][CH:17]=1>ClC1C=CC=CC=1Cl>[CH:19]1[C:20]2[C:33](=[C:32]([CH:9]=[O:10])[C:31]3[C:22]([CH:21]=2)=[CH:23][C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:30]=3)[CH:16]=[CH:17][CH:18]=1
Reactant: CN(C=O)c1ccccc1
Reactant: c1ccc2cc3cc4ccccc4cc3cc2c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: O=Cc1c2ccccc2cc2cc3ccccc3cc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 31 %

Procedure:
To a 3-necked RB flask equipped with overhead mechanical stirrer, condenser, addition funnel and N2 inlet line with bubbler was added N-methylformanilide (Aldrich, 89.21 g, 0.66 mol, 81 mL) and o-dichlorobenzene (Aldrich, 200 mL). The mixture was cooled to 10° with an ice bath. Phosphorus oxychloride (Aldrich, 101.21 g, 0.66 mol, 60 mL) was then added dropwise to the solution not allowing the reaction temperature to rise above 10°. The reaction mixture was then allowed to warm to RT. Solid naphthacene (Cambridge Chemical, Inc., 50 g, 0.22 mol) was then added in five portions over 5 min. The reaction mixture was warmed slowly to 80° (the mixture turned from purple to an almost black color). The reaction was stirred at 80° for 12 h, cooled, poured into ice water (2 L) and stirred an additional 12 h at RT. The mixture was then filtered. The organic layer in the filtrate was dried (Na2SO4) and applied to a plug of SiO2 (500 g) and eluted first with PhCH3 followed by CH2Cl2. The appropriate fractions were combined and the solvent removed by rotary evaporation. Recrystallization (CH2Cl2 /EtOAc) gave 17.5 g (31.1% yield) of naphthacene-5-carbaldehyde, mp 163°-164° (lit. 164°, N. P. Buu-Hoi et al., Recueil 76, 674 (1957)), (C,H). The solid from the filtration of the crude reaction mixture was washed with a large volume of CH3OH (5×200 mL), dissolved in THF (4 L) and passed through a plug of SiO2 (500 g) using an additional 2 L of THF as eluting solvent. The solvent was reduced to a volume of 300 mL and then diluted to 800 mL with EtOAc. The solvent volume was reduced to 250 mL. After filtration and drying, 10.90 g (17.4% yield) of naphthacene-5,11-dicarbaldehyde, mp 247°-250°, (C,H) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:9][S:10](O)(=[O:12])=[O:11]>>[NH2:8][C:5]1[C:4]([S:10]([Cl:9])(=[O:12])=[O:11])=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1
Reactant: Nc1ccc(Br)cn1
Reactant: O=S(=O)(O)Cl
Product: Nc1ncc(Br)cc1S(=O)(=O)Cl
Temperature: 25 °C

Procedure:
5-Bromo-pyridin-2-ylamine (10 g, 57.8 mmol) was added to chlorosulfonic acid (40 mL, 602 mmol) while stirring at 25° C. The mixture was heated at 160° C. while stirring for 3 h. Upon cooling to 25° C., the brown solution was carefully poured over ice (˜500 g). The resulting precipitate was collected by vacuum filtration and rinsed with water to afford the intermediate, 2-amino-5-bromo-pyridine-3-sulfonyl chloride, as a beige solid. The solid was suspended in a 15% aqueous ammonium hydroxide solution. The reaction mixture stirred for 45 min. Everything was completely dissolved at this point. The mixture was cooled to 0° C. and the pH was adjusted to ˜8 by the careful addition of 12.0 M aqueous hydrochloric acid solution. A solid precipitated and was collected by vacuum filtration, rinsed with water (2×50 mL) and dried in vacuo to afford the desired product, 2-amino-5-bromo-pyridine-3-sulfonic acid amide (7.48 g, 29.7 mmol, 51%), as a light beige solid. 1H NMR (400 MHz, DMSO-d6) δ: 6.69 (2H, bs), 7.54 (2H, bs), 7.91 (1H, d, J=2.5 Hz), 8.22 (1H, d, J=2.3 Hz).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[N:13][CH:14]=[N:15][C:16](Cl)=[C:11]2[C:10]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C>O1CCOCC1.[H][H].[OH-].[OH-].[Pd+2]>[CH2:1]([N:8]1[C:12]2=[N:13][CH:14]=[N:15][CH:16]=[C:11]2[C:10]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ncnc2c1c(-c1ccco1)nn2Cc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: c1ccc(Cn2nc(-c3ccco3)c3cncnc32)cc1

Procedure:
5.81g of 1-benzyl-4-chloro-3-(2-furyl)pyrazolo[3,4-d]pyrimidine are dissolved in 450 ml of dioxane and hydrogenated in the Parr apparatus at a hydrogen pressure of 3 bar for 5 h using 4 g of 20% Pd(OH)2 on carbon after addition of 2.61 ml of triethylamine. After filtration through kieselguhr, evaporation and chromatography, 2.26 g of yellowish crystals are obtained (m.p.=106° C., Rf=0.2 toluene/ethyl acetate=4:1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].CN(C)CCN(C)CCN(C)C.C([Li])CCC.C[O:28]B(OC)OC.C(O)(=O)C.OO>O.O1CCCC1>[F:1][C:2]1[C:3]([O:8][CH3:9])=[CH:4][CH:5]=[CH:6][C:7]=1[OH:28]
Reactant: COc1ccccc1F
Reactant: COB(OC)OC
Agent: CN(C)CCN(C)CCN(C)C
Agent: OO
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1cccc(O)c1F
Temperature: -78 °C
Yield: 73.2 %

Procedure:
A mixture of 2-fluoroanisole (1.8 ml, 15.85 mmol), pentamethyldiethyenetriamine (3.6 mL, 17.45 mmol) and tetrahydrofuran (10 mL) is stirred at −78° C. A 2.5 M solution of n-butyllithium in hexanes (7 ml, 17.45 mmol) is added dropwise and the resulting solution is stirred at −78° C. 2 hr. Trimethylborate (2 mL, 17.45 mmol) is added and the reaction is warmed to room temperature and stirred 1 hr. Acetic acid (1.4 ml, 23.8 mmol) is added followed by an aqueous 30% solution of hydrogen peroxide (1.8 mL, 17.45 mmol) and the resulting mixture is stirred rapidly 18 hr at room temperature. The reaction mixture is diluted with water and extracted with ethyl acetate (3×50 mL). The combined extracts are dried over magnesium sulfate, filtered and concentrated to about 10 mL volume. The resulting mixture is purified via silica chromatography eluting with hexanes to 8:1 hexanes:ethyl acetate to give the title compound (1.65 g, 73%) as a colorless oil. MS ES 141 M−1.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([N:16]2[CH:20]=[C:19]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[N:18]=[CH:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[F:50][C:51]1[CH:52]=[C:53]([CH:61]=[C:62]([C:64]([F:67])([F:66])[F:65])[CH:63]=1)[O:54][CH:55]1[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]1>CN(C=O)C.O>[F:50][C:51]1[CH:52]=[C:53]([CH:61]=[C:62]([C:64]([F:66])([F:65])[F:67])[CH:63]=1)[O:54][CH:55]1[CH2:56][CH2:57][N:58]([C:25](=[O:27])[CH2:24][NH:23][C:21]([C:19]2[N:18]=[CH:17][N:16]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:20]=2)=[O:22])[CH2:59][CH2:60]1
Reactant: Fc1cc(OC2CCNCC2)cc(C(F)(F)F)c1
Reactant: O=C(O)CNC(=O)c1cn(-c2ccccc2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=O)N1CCC(Oc2cc(F)cc(C(F)(F)F)c2)CC1)c1cn(-c2ccccc2)cn1
Reaction time: 0.03 h
Yield: 54 %

Procedure:
DIPEA (97 mg, 0.75 mmol) was added to a stirred solution of [(1-phenyl-1H-imidazole-4-carbonyl)-amino]-acetic acid (prepared from Intermediate 68 by means of Step 3 of the General Scheme) (61 mg, 0.25 mmol) in DMF (2 mL) followed by HOBt (35 mg, 0.26 mmol) and EDCI (50 mg, 0.26 mmol). After 2 minutes of stirring, 4-(3-fluoro-5-trifluoromethyl-phenoxy)-piperidine hydrochloride (prepared by the method used for the synthesis of Intermediate 15) (75 mg, 0.25 mmol) was added and the resulting mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with cold water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated under reduced pressure The residue obtained was purified by column chromatography (using silica gel 60-120 and 40% EtOAc in hexane as eluent) to afford 66 mg (54% Yield) of 1-phenyl-1H-imidazole-4-carboxylic acid {2-[4-(3-fluoro-5-trifluoromethyl-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 491, 96%. 1H NMR (300 MHz, DMSO-d6): δ 8.4 (m, 1H), 8.3 (m, 1H), 8.03 (m, 1H), 7.78 (m, 2H), 7.58 (m, 2H), 7.4 (m, 1H), 7.3 (m, 1H), 7.2 (m, 2H), 4.8 (m, 1H), 4.2 (m, 2H), 3.9 (m, 1H), 3.7 (m, 1H), 3.4 (m, 2H), 2.0 (m, 2H), 1.6 (m, 2H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:14]([C@H:15]2[CH2:20][CH2:19][C@H:18]([CH2:21][C:22]#[N:23])[CH2:17][CH2:16]2)[C:6]2=[C:7]3[S:13][CH:12]=[CH:11][C:8]3=[N:9][CH:10]=[C:5]2[N:4]=1.[CH3:24][S:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])(=[O:27])=[O:26].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:22]([CH2:21][C@H:18]1[CH2:19][CH2:20][C@H:15]([N:14]2[C:6]3=[C:7]4[S:13][CH:12]=[CH:11][C:8]4=[N:9][CH:10]=[C:5]3[N:4]=[C:3]2[CH2:2][N:28]([S:25]([CH3:24])(=[O:26])=[O:27])[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:16][CH2:17]1)#[N:23]
Reactant: N#CC[C@H]1CC[C@H](n2c(CCl)nc3cnc4ccsc4c32)CC1
Reactant: CC(C)(C)OC(=O)NS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N(Cc1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CC#N)CC1)S(C)(=O)=O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of {trans-4-[2-(chloromethyl)-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl]cyclohexyl}acetonitrile (from example 17, 22.2 mg, 0.0644 mmol) dissolved in N,N-dimethylformamide (0.2 mL) was added tert-butyl (methylsulfonyl)carbamate (19 mg, 0.096 mmol) and potassium carbonate (18 mg, 0.13 mmol). The reaction was stirred at 50° C. overnight. The mixture was diluted with water, extracted with EtOAc. The combined organic layers were dried over MgSO4 and concentrated to give tert-butyl ({1-[trans-4-(cyanomethyl)cyclohexyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}methyl)(methylsulfonyl)carbamate. LCMS calculated for C23H30N5O4S2 (M+H)+: m/z=504.2. Found: 504.1. This crude intermediate was treated with trifluoroacetic acid (0.1 mL, 1 mmol) in methylene chloride (0.1 mL) at room temperature for 30 min, and then the solvent was removed in vacuo. The residue was then dissolved in MeOH and purified on prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (9.5 mg, 36%). LCMS calculated for C18H22N5O2S2 (M+H)+: m/z=404.1. Found: 404.0.
Reaction SMILES: [C:1]([C:4]1[N:9]=[N:8][C:7]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[NH:17]C(=O)OC(C)(C)C)=[CH:6][C:5]=1[NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([OH:35])([CH3:34])[CH3:33])[N:27]=1)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:17][C@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]1[NH:10][C:7]1[N:8]=[N:9][C:4]([C:1]([NH2:2])=[O:3])=[C:5]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([OH:35])([CH3:33])[CH3:34])[N:27]=2)[CH:6]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cc(Nc2cccc(C(C)(C)O)n2)c(C(N)=O)nn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(O)c1cccc(Nc2cc(N[C@@H]3CCCC[C@@H]3N)nnc2C(N)=O)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.2 %

Procedure:
To a solution of tert-butyl (1S,2R)-2-(6-carbamoyl-5-(6-(2-hydroxypropan-2-yl)pyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate (179 mg, 369 μmol) in CH2Cl2 (3.00 mL) was added TFA (1.48 g, 1.00 mL, 13.0 mmol) and mixture stirred to room temperature for 18 h. The solvent was evaporated and the residue purified by flash chromatography (spherical silica 20-45 μM, 23 g, Versaflash Supelco) eluting with 0 to 5% over 20 min (MeOH containing 10% NH4OH)/CH2Cl2 to give 6-((1R,2S)-2-aminocyclohexylamino)-4-(6-(2-hydroxypropan-2-yl)pyridin-2-ylamino)pyridazine-3-carboxamide (80 mg, 56.3% yield) as an off-white foam. 1H NMR (DMSO-d6) δ: 11.76 (s, 1H), 8.38 (br. s., 1H), 7.90 (s, 1H), 7.60-7.78 (m, 2H), 7.23 (d, J=7.6 Hz, 1H), 6.70-6.83 (m, 2H), 5.18 (s, 1H), 3.70 (br. s., 1H), 3.09 (br. s., 1H), 1.21-1.77 (m, 16H); LC-MS 386.1 [M+H]+.
Reaction SMILES: [N:1]12CCCN=[C:7]1CCCC[CH2:2]2.S(C[N+]#[C-])(C1C=CC(C)=CC=1)(=O)=O.[O:25]1[CH2:30][CH2:29][CH:28]=[CH:27][C:26]1=[O:31]>O1CCCC1>[CH:2]1[NH:1][CH:7]=[C:27]2[C:26](=[O:31])[O:25][CH2:30][CH2:29][C:28]=12
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=C1C=CCCO1
Agent: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Solvent: C1CCOC1
Product: O=C1OCCc2c[nH]cc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU, 8.39 mL, 56.1 mmol) was added to a stirred mixture of tosylmethyl isocyanide (10.95 g, 56.1 mmol) in tetrahydrofuran (THF, 56 mL) at 0° C. After 15 minutes, to the mixture was added 5,6-dihydro-2H-pyran-2-one (5 g, 51 mmol). The mixture was then stirred at room temperature for 2 hours. The reaction was quenched with brine and extracted with THF several times. The combined extracts were dried (sodium sulfate), filter and concentrated to give 6,7-dihydro-2H-pyrano[3,4-c]pyrrol-4-one.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([O:7][Si](C)(C)C)[CH2:3][CH2:2]1.C[Si](C)(C)[O:14][C:15]([CH3:17])=[CH2:16].C(=O)(O)[O-].[Na+].O>C(#N)C>[O:14]=[C:15]([CH3:17])[CH2:16][CH:3]1[C:4](=[O:7])[CH2:5][CH2:6][O:1][CH2:2]1
Reactant: C=C(C)O[Si](C)(C)C
Reactant: C[Si](C)(C)OC1=CCOCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(=O)CC1COCCC1=O
Yield: 46.4 %

Procedure:
(3,6-dihydro-2H-pyran-4-yloxy)trimethylsilane (1.0 g, 5.80 mmol) and trimethyl(prop-1-en-2-yloxy)silane (7.56 g, 58.0 mmol) were added dropwise to a vigorously stirred suspension of ceric ammonium nitrate (6.36 g, 11.61 mmol) and sodium bicarbonate (1.950 g, 23.22 mmol) in dry acetonitrile (40 ml). The resulting mixture was stirred until the orange color disappeared and a thick white precipitate formed. The reaction mixture was then poured into water and extracted with EtOAc. The combined extracts were washed by brine, and dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by column chromatography on silica gel, using EtOAc/Hex 10-50% to give the product (0.42 g, 46.3% yield). 1H NMR (400 MHz, CDCl3) δ (ppm) 4.30-4.25 (m, 1H), 4.21-4.16 (m, 1H), 3.68-3.62 (m, 1H), 3.37-3.31 (m, 1H), 3.19-3.15 (m, 1H), 2.91-2.85 (m, 1H), 2.75-2.66 (m, 1H), 2.39-2.34 (m, 1H), 2.21-2.15 (m, 4H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][O:20][CH3:21])=[N:11][C:10]=1[C:22](O)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.ClC(OCC(C)C)=O.Cl.[CH2:41]([O:48][C:49](=[O:52])[CH2:50][NH2:51])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C(Cl)Cl>[CH2:41]([O:48][C:49](=[O:52])[CH2:50][NH:51][C:22]([C:10]1[N:11]=[C:12]([CH2:19][O:20][CH3:21])[C:13]2[C:18]([C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:23])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: COCc1nc(C(=O)O)c(OCc2ccccc2)c2ccccc12
Reactant: NCC(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCc1nc(C(=O)NCC(=O)OCc2ccccc2)c(OCc2ccccc2)c2ccccc12
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 81 %

Procedure:
To a mixture of 4-benzyloxy-1-methoxymethyl-isoquinoline-3-carboxylic acid (120 mg, 0.37 mmol), NEt3 (109 μl, 0.78 mmol), and CH2Cl2 (7 ml) cooled with an ice bath was added ClCO2iBu (52 μl, 0.39 mmol) with stirring. After stirring for 15 min glycine benzyl ester hydrochloride (79 mg, 0.39 mmol) was added and the mixture was stirred for another 15 min before the ice bath was removed. Stirring was then continued at ambient temperature for additional 1.5 h. Subsequently the mixture was concentrated in vacuo. To the residue was added water (10 ml) and a few drops of aqueous 6N HCl. The mixture was extracted with EtOAc (15 ml). The organic phase was dried over MgSO4 and concentrated in vacuo to give a yellowish gum. Purification by flash column chromatography on silica gel using hexanes:EtOAc=7:3 as the eluent gave the title compound as a yellow oil (141 mg); MS-(+)-ion: M+1=471.1.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[CH:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1C=CC=CC=1.[Cl:25]CCCl>>[C:2](=[O:3])([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[O:18][CH:11]([Cl:25])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ClCCCl
Reactant: O=Cc1ccccc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Product: O=C(Oc1ccccc1)OC(Cl)c1ccccc1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
Phenyl chloroformate (3.0 g, 19.2 mmol) and benzaldehyde (2.4 g, 23.0 mmol) were dissolved in 1,2-dichloroethane (15 ml) and pyridine (0.09 g, 1.14 mmol) was added dropwise to the stirred solution. Stirred at 80° C. for two days and at 100° C. for one day. Washed with water (25 ml), the aqueous phase was back-extracted with dichloromethane (25 ml). The combined organic phases were dried (MgSO4) and concentrated. Purified by flash chromatography (Silikagel 60, petroleum ether/ethyl acetate 95 5). Yield: 1.5 g. 1H-NMR (CDCl3): delta=7.34 (CH); 7.20-7.61 ppm (phenyl). GC/MS: 262.1 (M+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:7]1([C:10]([Cl:12])=[O:11])[CH2:9][CH2:8]1>C(O)(=O)C>[ClH:12].[CH:7]1([C:10]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[O:11])[CH2:9][CH2:8]1
Reactant: O=C(Cl)C1CC1
Reactant: C1CNCCN1
Solvent: CC(=O)O
Product: Cl
Product: O=C(C1CC1)N1CCNCC1
Temperature: 40 °C

Procedure:
Acetic acid (700 ml) was treated with piperazine (50.00 g, 0.581 mol) portionwise over 15 minutes with stirring under nitrogen The reaction mixture was warmed to 40° C. and maintained at this temperature until a complete solution was obtained. Cyclopropanecarbonyl chloride 59.2 ml, 0.638 mol) was added over 15 minutes. The reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered and the filtrate distilled under reduced pressure until 430 ml of distillates had been collected. Toluene (550 ml) was charged to the reaction mixture and reduced pressure distillation continued until a further 400 ml of distillates were collected. A further charge of toluene (550 ml) was added and reduced pressure distillation continued until 350 ml of distillates were collected. The resulting slurry was diluted with toluene (200 ml) and stirred overnight. Further toluene (500 ml) was added in order to mobilise the slurry. The slurry was filtered, washed with toluene (100 ml) and dried in vacuo at 40° C. to give the title compound as an off white solid (86.78 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:5]2[N:15]=[C:16]([C:18]3[C:27]([CH3:28])=[N:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)[CH:17]=[C:4]2[N:3]=1.Cl.[F:30][C@@H:31]1[CH2:35][CH2:34][NH:33][CH2:32]1.C(N(C(C)C)CC)(C)C.O>CN1CCCC1=O>[F:30][C@@H:31]1[CH2:35][CH2:34][N:33]([C:2]2[CH:7]=[C:6]([NH:8][CH:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)[N:5]3[N:15]=[C:16]([C:18]4[C:27]([CH3:28])=[N:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[CH:17]=[C:4]3[N:3]=2)[CH2:32]1
Reactant: F[C@@H]1CCNC1
Reactant: Cc1nc2ccccc2nc1-c1cc2nc(Cl)cc(NC3CCOCC3)n2n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1nc2ccccc2nc1-c1cc2nc(N3CC[C@@H](F)C3)cc(NC3CCOCC3)n2n1
Temperature: 80 °C

Procedure:
To a suspension of 5-chloro-2-(3-methylquinoxalin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine (Example 1.001 (g)) (4.26 g, 10.8 mmol), (R)-3-fluoropyrrolidine hydrochloride (13.7 g, 108 mmol), and diisopropylethylamine (20.7 g, 160 mmol) in N-methyl-2-pyrrolidinone (108 mL) was heated 80° C. for 3 days. After being cooled to ambient temperature, the reaction mixture was poured into water. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over sodium sulfate, filtrate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (silica gel 800 g, hexane:ethyl acetate=1:1 to ethyl acetate) to give 5-[(3R)-3-fluoropyrrolidin-1-yl]-2-(3-methylquinoxalin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine. MS (APCI): m/z 448 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][C:5]([O:10][CH2:11][CH2:12][O:13][CH:14]([CH3:16])[CH3:15])=[C:6]([CH:9]=1)[C:7]#[N:8].[B:18]1([OH:28])[C:22]2[CH:23]=[CH:24][C:25]([OH:27])=[CH:26][C:21]=2[CH2:20][O:19]1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[Cl:1][C:2]1[C:3]([O:27][C:25]2[CH:24]=[CH:23][C:22]3[B:18]([OH:28])[O:19][CH2:20][C:21]=3[CH:26]=2)=[N:4][C:5]([O:10][CH2:11][CH2:12][O:13][CH:14]([CH3:16])[CH3:15])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: CC(C)OCCOc1nc(Cl)c(Cl)cc1C#N
Reactant: OB1OCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC(C)OCCOc1nc(Oc2ccc3c(c2)COB3O)c(Cl)cc1C#N
Temperature: 40 °C
Reaction time: 2 h

Procedure:
Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen were placed a solution of 5,6-dichloro-2-(2-isopropoxyethoxy)nicotinonitrile (1.13 g, 4.12 mmol, 1.00 equiv) in DMSO (80 mL), benzo[c][1,2]oxaborole-1,5(3H)-diol (650 mg, 4.33 mmol, 1.00 equiv) and Cs2CO3 (1.6 g, 4.91 mmol, 1.20 equiv). The resulting mixture was stirred for 2 h at 40° C., then quenched by the addition of 50 mL of water. The resulting solution was extracted with 3×30 mL of ethyl acetate. The organic layers were combined, washed with 2×50 mL of water, then dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 5-chloro-6-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)-2-(2-isopropoxyethoxy)nicotinonitrile (1.3 g, 80%) as a white solid. LC-MS (ES, m/z): 389 [M+H]+. 1H-NMR (300 MHz, DMSO-d6) δ (ppm) 9.260 (1H, s), 8.596 (1H, s), 7.817-7.791 (1H, d, J=7.8 Hz), 7.337 (1H, s), 7.268-7.235 (1H, m), 5.007 (2H, s), 4.105-4.072 (2H, t), 3.495-3.435 (2H, m), 3.415-3.395 (1H, t), 1.016-0.995 (6H, d, J=6.3 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](S)=[N:7][C:6]=2[CH:11]=1.O=P(Cl)(Cl)[Cl:14].P(Cl)(Cl)(Cl)(Cl)Cl>C(Cl)Cl>[Cl:14][C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:11][C:6]=2[N:7]=1
Reactant: Cc1ccc2oc(S)nc2c1
Reactant: O=P(Cl)(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc2oc(Cl)nc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 107.6 %

Procedure:
To a suspension of 5-methylbenzo[d]oxazole-2-thiol (1.0 g, 6.1 mmol.) in POCl3 (11.7 g, 76.4 mmol.) at room temperature was added PCl5 (1.9 g, 9.15 mmol.) along with CH2Cl2 (10 mL). After 4 h of stirring at room temperature, the reaction mixture was concentrated to remove excess POCl3, and the residue was treated with Na2CO3 solution until ˜pH 8 was reached. The aqueous phase was extracted with CH2Cl2. The combined organic extracts were dried over Na2SO4, filtered and concentrated to afford 2-chloro-5-methylbenzo[d]oxazole (1.1 g crude product) which was used without further purification. MS (ESI) m/e (M+H+) 168.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13]([CH:15]2[CH2:17][CH:16]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:14])[CH:3]=1.[NH:24]1[CH2:29][CH2:28][CH:27]([CH2:30][CH2:31][OH:32])[CH2:26][CH2:25]1>CN1C(=O)CCC1.CS(C)=O.CO>[OH:32][CH2:31][CH2:30][CH:27]1[CH2:28][CH2:29][N:24]([C:2]2[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13]([CH:15]3[CH2:17][CH:16]3[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:14])[CH:3]=2)[CH2:25][CH2:26]1
Reactant: Cc1cc2nc(NC(=O)C3CC3c3ccccc3)cc(Cl)n2n1
Reactant: OCCC1CCNCC1
Solvent: CN1CCCC1=O
Solvent: CO
Solvent: CS(C)=O
Product: Cc1cc2nc(NC(=O)C3CC3c3ccccc3)cc(N3CCC(CCO)CC3)n2n1
Temperature: 25 °C
Yield: 3.5 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-2-phenylcyclopropanecarboxamide (8C, 200 mg, 0.612 mmol) and 2-(piperidin-4-yl)ethanol (158 mg, 1.2 mmol) in NMP (1.85 mL) was stirred at 100° 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, 40-50% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (9 mg, 4%). 1H NMR (METHANOL-d4) δ: 7.25-7.31 (m, 2H), 7.14-7.23 (m, 4H), 6.07 (s, 1H), 4.41 (d, J=12.1 Hz, 2H), 3.67 (t, J=6.6 Hz, 2H), 2.98 (td, J=12.4, 2.4 Hz, 2H), 2.51 (ddd, J=9.2, 6.4, 4.3 Hz, 1H), 2.40 (s, 3H), 2.15-2.23 (m, 1H), 1.85 (br. s., 2H), 1.29-1.69 (m, 7H). ESI-MS: m/z 420.0 (M+H)+.