Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH3:1].[C:2]1([S:8]([C:11]2[C:12]([S:29][CH3:30])=[N:13][N:14]3[C:19](Cl)=[CH:18][C:17]([CH2:21][N:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)=[N:16][C:15]=23)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.CN(C=O)C>[C:2]1([S:8]([C:11]2[C:12]([S:29][CH3:30])=[N:13][N:14]3[C:19]([NH2:1])=[CH:18][C:17]([CH2:21][N:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)=[N:16][C:15]=23)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSc1nn2c(Cl)cc(CN3CCN(C)CC3)nc2c1S(=O)(=O)c1ccccc1
Reactant: N
Solvent: CO
Solvent: CN(C)C=O
Product: CSc1nn2c(N)cc(CN3CCN(C)CC3)nc2c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
10 ml of a 50% solution of NH3 in MeOH were added to a solution of 0.8 g (1.77 mmol) of 3-benzenesulphonyl-7-chloro-5-(4-methyl-piperazin-1-ylmethyl)-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine in 20 ml of DMF and stirred at RT for 4 hrs. The reaction solution was evaporated and the residue was partitioned between 2N NaOH and CH2Cl2. The aqueous phase was extracted three times with CH2Cl2, and the combined organic phases were dried (MgSO4), filtered and evaporated. Subsequent chromatography (SiO2, CH2Cl2/MeOH/NH40H 90:10:1) yielded 0.59 g (77%) of 3-benzenesulphonyl-5-(4-methyl-piperazin-1-ylmethyl)-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-ylamine as colorless crystals, m.p. 203-205°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[H-].[Na+].Cl[CH2:25][CH2:26][S:27](Cl)(=[O:29])=[O:28].O>C1COCC1.CCCCCC>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:13][CH:14]=2)[C:5]2[N:6]([CH:7]=1)[CH2:25][CH2:26][S:27](=[O:29])(=[O:28])[N:8]=2
Reactant: Nc1ncc(F)cc1-c1ccc(Oc2ccccc2)cc1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=S1(=O)CCN2C=C(F)C=C(c3ccc(Oc4ccccc4)cc3)C2=N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-fluoro-3-(4-phenoxyphenyl)pyridin-2-amine (124 mg) in THF (dry) (5 mL) was added to a suspension of NaH (60%, 88.0 mg) and 2-chloroethanesulfonyl chloride (0.139 mL) in THF (dry) (5 mL) at 0° C. The mixture was stirred at room temperature overnight. Water and hexane were added to give a white precipitate. The precipitate was collected by filtration and washed with water and EtOAc, then recrystallized from EtOAc-EtOH to give the title compound (29.0 mg) as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([NH2:8])[S:6][CH:7]=1)[CH3:2].[Br:9]Br>S(=O)(=O)(O)O>[Br:9][C:7]1[S:6][C:5]([NH2:8])=[N:4][C:3]=1[CH2:1][CH3:2]
Reactant: BrBr
Reactant: CCc1csc(N)n1
Agent: O=S(=O)(O)O
Product: CCc1nc(N)sc1Br
Temperature: 0 °C

Procedure:
The above prepared 4-ethyl-thiazol-2-ylamine (1.125 g, 8.77 mmol) was dissolved in 4.5 mL of 20% aq. sulfuric acid, cooled to 0° C., and treated with Br2 (0.494 mL, 1.1 eq.). After 10 Min., the reaction mixture was carefully poured onto crashed ice/Na2CO3, twofold extracted with ethyl acetate, washed with water, dried over sodium sulfate, and evaporated to dryness. Thereby, 1.306 g of the title compound was obtained as light brown viscous oil, sufficiently pure to be used for the next step.
Reaction SMILES: [O:1]1[CH2:6]C[CH2:4][O:3][CH:2]1[C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[Cl:22])[CH:14]=2)=[N:11][CH:12]=1.BrC1C=CC(C2OCCO2)=CN=1>>[O:1]1[CH2:6][CH2:4][O:3][CH:2]1[C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[Cl:22])[CH:14]=2)=[N:11][CH:12]=1
Reactant: Clc1ccnc2cc(-c3ccc(C4OCCCO4)cn3)sc12
Agent: Brc1ccc(C2OCCO2)cn1
Product: Clc1ccnc2cc(-c3ccc(C4OCCO4)cn3)sc12
Yield: 79 %

Procedure:
Following the procedure described above for the synthesis of compound 29 (Scheme 8) but substituting compound 28 for compound 35, title compound 36 was obtained in 79% yield. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.70 (d, J=1.8 Hz, 1H), 8.67 (d, J=5.1 Hz, 1H), 8.48 (s, 1H), 8.35 (d, J=8.4 Hz, 1H), 8.00 (dd, J=8.2, 2.1 Hz, 1H), 7.61 (d, J=5.1 Hz, 1H), 5.90 (s, 1H), 4.13-4.07 (m, 2H), 4.05-3.99 (m, 2H). MS (m/z): 319.2 (M+H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.[Si:22]([O:29][C@@H:30]([CH3:65])[C@@H:31]([NH:54][C:55]1[CH:60]=[CH:59][C:58]([C:61]#[N:62])=[C:57]([Cl:63])[C:56]=1[CH3:64])[C:32]([NH:34][NH:35][C:36](=[O:53])[C:37]1[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=2)=[CH:39][CH:38]=1)=O)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>C(Cl)Cl>[Si:22]([O:29][C@@H:30]([CH3:65])[C@@H:31]([NH:54][C:55]1[CH:60]=[CH:59][C:58]([C:61]#[N:62])=[C:57]([Cl:63])[C:56]=1[CH3:64])[C:32]1[O:53][C:36]([C:37]2[CH:38]=[CH:39][C:40]([O:43][CH2:44][C:45]3[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=3)=[CH:41][CH:42]=2)=[N:35][N:34]=1)([C:25]([CH3:26])([CH3:28])[CH3:27])([CH3:24])[CH3:23]
Reactant: COc1ccc(COc2ccc(C(=O)NNC(=O)[C@H](Nc3ccc(C#N)c(Cl)c3C)[C@H](C)O[Si](C)(C)C(C)(C)C)cc2)cc1
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(COc2ccc(-c3nnc([C@H](Nc4ccc(C#N)c(Cl)c4C)[C@H](C)O[Si](C)(C)C(C)(C)C)o3)cc2)cc1
Temperature: 25 °C
Yield: 87.2 %

Procedure:
Polymer supported Triphenylphosphine (3 g, 8.38 mmol) was dissolved in 250 mL of DCM followed by addition of I2 (2.13 g, 8.38 mmol) and TEA (3.11 mL, 22.36 mmol) at 0° C. N′-((2R,3S)-3-(tert-butyldimethylsilyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino)butanoyl)-4-(4-methoxybenzyloxy)benzohydrazide (3.56 g, 5.59 mmol) in 200 ml DCM was added to the pre-cooled solution mixture of PPh3/I2/TEA system and stirred. The temperature was allowed to warm to room temperature and stirred for additional 10 minutes. The reaction was quenched with 50 ml saturated sodium thiosulfate and the biphasic mixture was separated. The aqueous layer was extracted with EtOAc (3×80 mL) and the combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The resulting crude oil was purified by flash chromatography (SiO2) to provide the title compound (3.02 g, 87%). 1H NMR (400 MHz, Acetone d6, δ in ppm): 7.93 (d, J=9 Hz, 2H), 7.48 (d, J=9 Hz, 1H), 7.43 (d, J=9 Hz, 2H), 7.18 (d, J=9 Hz, 2H), 6.96 (d, J=9 Hz, 2H), 6.83 (d, J=9 Hz, 1H) 5.52 (d, J=9 Hz, 1H), 5.21 (dd, J=2 and 9 Hz, 1H), 5.13 (s, 2H), 4.73 (m, 1H), 3.80 (s, 3H), 2.41 (s, 3H), 1.47 (d, J=6 Hz, 3H), 0.86 (s, 9H), 0.11 (s, 3H), 0.01 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([C:13](=O)[CH2:14][CH3:15])[CH:10]=[CH:9][C:8]=2[C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:27][O:28][CH3:29].Cl.N1C=CC=CC=1>CCO>[CH3:29][O:28][N:27]=[C:13]([C:11]1[CH:10]=[CH:9][C:8]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:19][CH:18]=2)=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:12]=1)[CH2:14][CH3:15]
Reactant: CCC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)c(-c2ccccc2)n1
Reactant: CON
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CCC(=NOC)c1ccc(-c2ccc(C(F)(F)F)cc2)c(-c2ccccc2)n1

Procedure:
Following General Procedure P, 1-[6-phenyl-5-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-propan-1-one (Compound 78), (24 mg, 0.07 mmol), NH2OMe—HCl (23 mg, 0.25 mmol) and pyridine (21 mg, 0.28 mmol) in EtOH (2 ml) were reacted to give title compound as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:9]=[CH:8][N:7]([CH3:10])[C:6]=1[C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][NH2:13])=O.CC(C)([O-])C.[Na+]>CN(C)C=O>[CH3:17][O:16][C:14]([C:11]1[C:6]2[N:7]([CH3:10])[CH:8]=[CH:9][C:5]=2[C:3](=[O:2])[NH:13][CH:12]=1)=[O:15]
Reactant: COC(=O)C(=CN)c1c(C(=O)OC)ccn1C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1c[nH]c(=O)c2ccn(C)c12
Reaction time: 0.17 h
Yield: 39.2 %

Procedure:
A mixture of 2-(2-amino-1-methoxycarbonyl-vinyl)-1-methyl-1H-pyrrole-3-carboxylic acid methyl ester (3.3 g), sodium tert-butoxide (0.267 g) and dimethylformamide (22 ml) was split equally between 2×20 ml sealed vessels and irradiated with microwaves at 160° C. for 5 minutes. The cooled solutions were combined and added slowly to ice water and stirred for 10 minutes. A precipitate formed which was filtered off and dried to yield the title compound as a white solid (1.12 g). The aqueous filtrate was extracted three times with ethyl acetate and the combined organics were washed with saturated brine solution. The dried (Na2SO4) organic layer was evaporated to yield a yellow oil which was triturated with warm isopropyl alcohol to yield the title compound as a white solid (0.66 g). Total product weight (1.78 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[C:6]#[N:7].[CH3:21][NH:22][CH2:23][CH2:24][C:25]1[CH:26]=[C:27]([CH:33]=[CH:34][CH:35]=1)[C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[C:6]([C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:3][CH2:2][N:22]([CH3:21])[CH2:23][CH2:24][C:25]1[CH:26]=[C:27]([CH:33]=[CH:34][CH:35]=1)[C:28]([O:30][CH2:31][CH3:32])=[O:29])#[N:7]
Reactant: COc1ccc(C(C#N)(CCCBr)C(C)C)cc1OC
Reactant: CCOC(=O)c1cccc(CCNC)c1
Product: CCOC(=O)c1cccc(CCN(C)CCCC(C#N)(c2ccc(OC)c(OC)c2)C(C)C)c1

Procedure:
Reaction of 1f with 2e produced 3z. MS found M+H=467. The oxalate salt of 3z was recrystallized from ethyl acetate; mp 128-129° C.
Reaction SMILES: [CH:1]1([C:4]2[C:9]3[O:10][CH:11]([CH3:15])[C:12](=[O:14])[NH:13][C:8]=3[CH:7]=[C:6]([CH:16]=O)[CH:5]=2)[CH2:3][CH2:2]1.[N:18]1([C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[CH:1]1([C:4]2[C:9]3[O:10][CH:11]([CH3:15])[C:12](=[O:14])[NH:13][C:8]=3[CH:7]=[C:6]([CH2:16][N:21]3[CH2:20][CH2:19][N:18]([C:24]4[CH:25]=[CH:26][C:27]([C:28]#[N:29])=[CH:30][CH:31]=4)[CH2:23][CH2:22]3)[CH:5]=2)[CH2:2][CH2:3]1
Reactant: CC1Oc2c(cc(C=O)cc2C2CC2)NC1=O
Reactant: N#Cc1ccc(N2CCNCC2)cc1
Product: CC1Oc2c(cc(CN3CCN(c4ccc(C#N)cc4)CC3)cc2C2CC2)NC1=O

Procedure:
Using 346A and 4-(piperazin-1-yl)benzonitrile in the general procedure for reductive aminations, the title compound was obtained as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 0.58-0.71 (m, 2H) 0.85-0.96 (m, 2H) 1.42 (d, J=6.82 Hz, 3H) 2.05-2.12 (m, 1H) 2.38-2.48 (m, 4H) 3.27-3.32 (m, 4H) 3.36 (s, 2H) 4.64 (q, J=6.74 Hz, 1H) 6.41 (d, J=1.52 Hz, 1H) 6.68 (d, J=1.77 Hz, 1H) 7.00 (m, J=9.09 Hz, 2H) 7.57 (m, 2H) 10.56 (br. s., 1H). ESI-MS: m/z 403.4 (M+H)+. mp=194.3-195.5° C.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=2)[CH:10]=[N:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH:24]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH:33]([CH3:35])[CH3:34])[C:28]=1[N:36]=[C:37]=[O:38])([CH3:26])[CH3:25]>>[CH:24]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH:33]([CH3:34])[CH3:35])[C:28]=1[NH:36][C:37](=[O:38])[N:14]([CH2:13][C:11]1[CH:10]=[N:9][N:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH:12]=1)[C:15]1[CH:20]=[CH:19][C:18]([CH:21]([CH3:22])[CH3:23])=[CH:17][CH:16]=1)([CH3:25])[CH3:26]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CCCCCCCn1cc(CNc2ccc(C(C)C)cc2)cn1
Product: CCCCCCCn1cc(CN(C(=O)Nc2c(C(C)C)cccc2C(C)C)c2ccc(C(C)C)cc2)cn1

Procedure:
By the reaction and treatment in the same manner as in Example 62 using [(1-heptylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (1.1 g) and 2,6-diisopropylphenyl isocyanate (1.13 mL) as starting materials, N′-(2,6-diisopropylphenyl)-N-[(1-heptylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)urea (1.35 g) was obtained.
Reaction SMILES: [F:1][C:2]1([F:13])[O:6][C:5]2[CH:7]=[C:8](I)[C:9]([F:11])=[CH:10][C:4]=2[O:3]1.C(O[B:18]1[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]1)(C)C>O1CCCC1>[CH3:25][C:20]1([CH3:26])[C:21]([CH3:24])([CH3:23])[O:22][B:18]([C:8]2[C:9]([F:11])=[CH:10][C:4]3[O:3][C:2]([F:13])([F:1])[O:6][C:5]=3[CH:7]=2)[O:19]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Fc1cc2c(cc1I)OC(F)(F)O2
Solvent: C1CCOC1
Product: CC1(C)OB(c2cc3c(cc2F)OC(F)(F)O3)OC1(C)C
Temperature: 5 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
2,2,5-Trifluoro-6-iodobenzo[d][1,3]dioxole (1.0 g, 3.3 mmol) was dissolved in dry tetrahydrofuran (10 mL), cooled to 5° C. and treated with isopropylmagnesiumchloride-lithium chloride complex solution (1.3 M; 2.7 mL, 3.5 mmol). The mixture was stirred for 1 h at 5-15° C., treated with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (720 μL, 660 mg, 3.5 mmol) and stirred for 20 min. The reaction was quenched by addition of saturated ammonium chloride (NH4Cl; 5 mL) and mixed with ethyl acetate (20 mL) and saturated NaCl (10 mL). The separated organic phase was washed with saturated NaCl (10 mL), dried (Na2SO4) and evaporated to give the title compound as a white solid (1.0 g, 100%): 1H NMR (400 MHz, CDCl3) δ 7.37 (d, J=4.3 Hz, 1H), 6.81 (d, J=7.7 Hz, 1H), 1.35 (s, 12H); 19F NMR (376 MHz, CDCl3) δ −49.96 (s), −104.21 (s)); EIMS m/z 302.
Reaction SMILES: [CH2:1]([S:4][C:5]1[C:6]([S:14]([NH:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:16])=[O:15])=[C:7]([C:10]([O:12][CH3:13])=[O:11])[S:8][CH:9]=1)[CH2:2][CH3:3].ClC1C=C(C=CC=1)C(OO)=[O:27]>C(Cl)Cl>[CH2:1]([S:4]([C:5]1[C:6]([S:14]([NH:17][C:18]([CH3:20])([CH3:19])[CH3:21])(=[O:16])=[O:15])=[C:7]([C:10]([O:12][CH3:13])=[O:11])[S:8][CH:9]=1)=[O:27])[CH2:2][CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCSc1csc(C(=O)OC)c1S(=O)(=O)NC(C)(C)C
Solvent: ClCCl
Product: CCCS(=O)c1csc(C(=O)OC)c1S(=O)(=O)NC(C)(C)C
Temperature: -80 °C
Reaction time: 0.33 h

Procedure:
A solution of 2.32 g 4-propylthio-3-(N-(1,1-dimethylethyl)aminosulfonyl)-2-thiophenecarboxylic acid, methyl ester in 75 mL methylene chloride was cooled to -80° C. and 1.39 g of 80-85% m-chloroperoxybenzoic acid was added in one portion. After stirring at -80° C. for 20 minutes and warming to 20° C. the solution was diluted with more methylene chloride and washed with aqueous sodium bicarbonate, sodium bisulfite, sodium bicarbonate and water, dried and concentrated to 2.2 g of colorless oil in sufficiently pure form for the purposes of this invention.
Reaction SMILES: CCN(C(C)C)C(C)C.[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[N:15]=[C:16]=[O:17].FC(F)(F)C(O)=O.[Cl:25][C:26]1[CH:27]=[C:28]2[CH:34]=[C:33]([C:35]([NH:37][NH2:38])=[O:36])[NH:32][C:29]2=[CH:30][N:31]=1>C1(C)C=CC=CC=1.O1CCOCC1>[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[NH:15][C:16]([NH:38][NH:37][C:35]([C:33]1[NH:32][C:29]2=[CH:30][N:31]=[C:26]([Cl:25])[CH:27]=[C:28]2[CH:34]=1)=[O:36])=[O:17]
Reactant: O=C=Nc1cccs1
Reactant: NNC(=O)c1cc2cc(Cl)ncc2[nH]1
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NNC(=O)c1cc2cc(Cl)ncc2[nH]1)Nc1cccs1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
DIPEA (53 μL, 0.31 mmol) and thienyl isocyanate (40 μL, 0.32 mmol) were added to a suspension of 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid hydrazide trifluoroacetic acid salt (Preparation 10—route 1, 101 mg, 0.31 mmol) in a mixture of toluene and 1,4-dioxane (10 mL, 1:1). After stirring the mixture at 100° C. for 12 h, the reaction was allowed to cool to rt and the solvent was removed. The remaining oily residue was purified by flash chromatography on silica gel (toluene/acetone:2/1) to give the title compound. δH (CDCl3): 6.60 (1H, d), 6.78 (1H, m), 6.84 (1H, d), 7.26 (1H, d), 7.82 (1H, s), 8.61 (2H, m), 9.97 (1H, s); m/z (ES+)=336 [M+H]+; RT=2.97 min.
Reaction SMILES: [Br:1][C:2]1[C:7]2[N:8]([CH:14]3[CH2:16][CH2:15]3)[C:9]([C@@H:11]([NH2:13])[CH3:12])=[N:10][C:6]=2[CH:5]=[CH:4][C:3]=1[F:17].[NH2:18][C:19]1[C:24]([C:25]#[N:26])=[C:23](Cl)[N:22]=[CH:21][N:20]=1.CCN(C(C)C)C(C)C>CC(O)C.CO>[NH2:18][C:19]1[C:24]([C:25]#[N:26])=[C:23]([NH:13][C@H:11]([C:9]2[N:8]([CH:14]3[CH2:15][CH2:16]3)[C:7]3[C:2]([Br:1])=[C:3]([F:17])[CH:4]=[CH:5][C:6]=3[N:10]=2)[CH3:12])[N:22]=[CH:21][N:20]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: C[C@H](N)c1nc2ccc(F)c(Br)c2n1C1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CC(C)O
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(Br)c2n1C1CC1
Temperature: 90 °C
Yield: 76.5 %

Procedure:
A mixture of (S)-1-(7-bromo-1-cyclopropyl-6-fluoro-1H-benzoimidazol-2-yl)ethylamine (80 mg, 0.27 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (41 mg, 0.27 mmol) and DIPEA (140 μL, 0.80 mmol) in IPA (1 mL) was heated at 90° C. in a sealed vial for 16 h. After cooling to RT, the reaction mixture was diluted with MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-100% EtOAc in cyclohexane) to afford 395 as a white solid (86 mg, 77%). LCMS (Method K): RT 4.10 min [M+H]+ 415.95. 1H NMR (CDCl3, 400 MHz): δ 8.20 (1H, s), 7.56 (1H, dd, J=8.73, 4.57 Hz), 7.10-7.04 (1H, m), 6.27 (1H, d, J=7.81 Hz), 6.06-5.98 (1H, m), 5.32 (2H, s), 3.52-3.46 (1H, m), 1.68 (3H, d, J=6.75 Hz), 1.45-1.33 (3H, m), 1.20-1.14 (1H, m)
Reaction SMILES: [F:1][CH:2]([F:19])[C:3]#[C:4][C:5]1([OH:18])[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1>C1COCC1.[Pd]>[F:19][CH:2]([F:1])[CH2:3][CH2:4][C:5]1([OH:18])[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:7][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(C#CC(F)F)CC1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(CCC(F)F)CC1
Temperature: 25 °C
Yield: 82.4 %

Procedure:
A solution of tert-butyl 4-(3,3-difluoroprop-1-yn-1-yl)-4-hydroxypiperidine-1-carboxylate (350 mg, 1.273 mmol) in 30 mL of anhydrous THF was stirred with Pd/C (200 mg) under H2 atmosphere at 15 psi at 48° C. for 8 h. The reaction mixture was cooled to r.t. and filtered, and the resulting mixture was concentrated in vacuo to afford 293 mg of title compound. 1H NMR (CHLOROFORM-d) δ: 5.89 (tt, J=56.9, 4.3 Hz, 1H), 3.84 (dd, J=9.8, 3.5 Hz, 2H), 3.24-3.10 (m, 2H), 2.05-1.89 (m, 2H), 1.67-1.60 (m, 2H), 1.55 (m, 4H), 1.47 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:16]=[CH:15][C:8]2[N:9]([CH2:12][CH2:13]Cl)[CH:10]=[N:11][C:7]=2[CH:6]=1)=[O:4].[N-:17]=[N+:18]=[N-:19].[Na+]>CS(C)=O>[CH3:1][O:2][C:3]([C:5]1[CH:16]=[CH:15][C:8]2[N:9]([CH2:12][CH2:13][N:17]=[N+:18]=[N-:19])[CH:10]=[N:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1ccc2c(c1)ncn2CCCl
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc2c(c1)ncn2CCN=[N+]=[N-]
Temperature: 75 °C
Reaction time: 15 h
Yield: 91.2 %

Procedure:
To a solution of 1-(2-chloroethyl)-1H-benzimidazole-5-carboxylic acid methyl ester (9.9 g, 0.0416 mol) in dry DMSO (90 mL) was added with stirring NaN3 (5.4 g, 0.0832 mol) and the mixture was stirred for 15 h at 75° C. The reaction mixture was cooled to ambient temperature and diluted with ice water (500 mL) and the solid precipitated was filtered, washed with water and dried under vacuum affording 9.3 g (91%) of 1-(2-azidoethyl)-1H-benzimidazole-5-carboxylic acid methyl ester as a solid. MS-ESI m/z 246 (M+1); 1H NMR (300 MHz, DMSO-d6) δ 3.8 (t, 2H), 3.9 (s, 3H), 4.5 (t, 2H), 7.8 (d, 1H), 7.9 (dd, 1H), 8.25 (s, 1H), 8.4 (s, 1H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:28])[NH:8][C:9](=[O:27])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][C:13]=1[F:26])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39].CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:28])[N:8]([CH2:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])[C:9](=[O:27])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][C:13]=1[F:26])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Reactant: CC(C)(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(C)n(CC(=O)C(C)(C)C)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Temperature: 90 °C
Reaction time: 2 h
Yield: 55.9 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]-3′-fluorobiphenyl-2-carbonitrile (1.22 g), cesium carbonate (1.73 g), 1-bromo-3,3-dimethylbutan-2-one (0.71 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.86 g, 34%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]2[S:12][C:11]([C:13]3[C:14]([NH:27][C@@H:28]4[CH2:33][CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29]4)=[N:15][C:16]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:17][C:18]=3[O:19]C)=[N:10][C:9]=2[CH:41]=1)([CH3:4])([CH3:3])[CH3:2]>Cl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]2[S:12][C:11]([C:13]3[C:18](=[O:19])[NH:17][C:16]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)=[N:15][C:14]=3[NH:27][C@@H:28]3[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]3)=[N:10][C:9]=2[CH:41]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1nc(N2CCOCC2)nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1-c1nc2cc(C(C)(C)C)ccc2s1
Agent: Cl
Product: CC(C)(C)c1ccc2sc(-c3c(N[C@@H]4CCCNC4)nc(N4CCOCC4)[nH]c3=O)nc2c1
Reaction time: 0.12 h

Procedure:
Following the same procedure as in step 4 of Example 337 using tert-butyl (3R)-3-[[5-(5-tert-butyl-1,3-benzothiazol-2-yl)-6-methoxy-2-(morpholin-4-yl)pyrimidin-4-yl]amino]piperidine-1-carboxylate (101.6 mg, 0.17 mmol, 1.00 equiv) and hydrochloric acid (10 mL, 6M). The crude product was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm,; mobile phase, water with 0.05% TFA and CH3CN (30.0% CH3CN up to 44.0% in 7 min, up to 100.0% in 5 min, down to 30.0% in 1 min); Detector, Waters 2489 254&220 nm to afford the title compound as the corresponding FTA salt as a white solid. 1H-NMR(400 MHz, DMSO-d6): □δ ppm 1.239 (s, 1H), 1.375 (s, 9H), 1.837(d, J=9.2 Hz, 2H), 2.0(d, J=6 Hz, 1H), 2.126 (s, 1H), 2.936-3.01 (m, 2H), 3.272(d, J=11.2 Hz, 1H), 3.489(d, J=9.6 Hz, 1H), 3.706-3.726(m, 8H), 4.375(d, J=5.2 Hz, 1H), 7.349(t, J=1.6 Hz, J=8.4 Hz, 1H), 7.752(d, J=1.6 Hz, 1H), 7.849(d, J=8.4 Hz, 1H), 8.733(br, 1H), 8.866 (br, 1H), 10.768(d, J=6.8 Hz, 1H), 11.133 (s, 1H); 19F-NMR (400 MHz, DMSO-d6): δ ppm −74.25; MS m/z [M+H]+ (ESI): 469. IRAK4 IC50=1300 nM
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH:12]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:11][CH2:10]2)(=O)=O.[CH3:23][N:24]1CCCC1=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[C:23]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH:12]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:11][CH2:10]2)#[N:24]
Reactant: CN1CCCC1=O
Reactant: COC(=O)CC1CCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COC(=O)CC1CCc2cc(C#N)ccc21
Temperature: 100 °C
Reaction time: 16 h

Procedure:
To a solution methyl (R/S)-(5-trifluoromethylsulfonyloxy-indan-1-yl)acetate (2.63 g, 7.80 mmol, from Step D) in N-methylpyrrolidinone (20 mL) under argon, zinc cyanide (733 mg, 6.24 mmol), Pd2 dba3 (36 mg, 39.0 μmol) and dppf (52.0 mg, 93.6 μmol) were added, and the reaction mixture was heated to 100° C. After 16 hr, the reaction mixture was concentrated iji vacuo and partitioned between EtOAc and H2O. The layers were separated and the organic layer was washed with H2O, brine and dried over MgSO4. The mixture was filtered, the filtrate concentrated in vacuo, and the residue purified by flash chromatography (5, 10% EtOAc/hexanes) on SiO2 to give 1.40 g of the title compound as a white solid: 1H NMR (CDCl3) δ 1.80-1.84 (m, 1H), 2.43-2.48 (m, 1H), 2.52 (dd, 1H, J=8.5, 15.8 Hz), 2.77 (dd, 1H, J=6.0, 15.8 Hz), 2.92-3.00 (m, 2H), 3.62-3.66 (m, 1H), 3.74 (s, 3H), 7.27 (d, 1H, J=5.5 Hz), 7.47 (d, 1H, J=7.8 Hz), 7.51 (s, 1H).