Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[NH2:6].Cl[C:13]([O:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=[O:14].CN1CCOCC1>ClCCl>[CH3:8][C:7]([CH3:10])([CH3:9])[C@H:5]([NH:6][C:13]([O:15][C:16]1[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=1)=[O:14])[C:4]([O:3][CH3:2])=[O:11]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)[C@@H](N)C(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)[C@@H](NC(=O)Oc1ccc([N+](=O)[O-])cc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 64 h
Yield: 109.8 %

Procedure:
A solution of L-tert-leucine methyl ester hydrochloride (0.300 g, 1.65 mmol) in dichloromethane (4 mL) at 0° C. was treated with 4-nitrophenyl chloroformate (0.366, 1.82 mmol) and N-methyl morpholine (0.380 mL, 3.46 mmol), and the mixture was stirred at 25° C. for 64 hours. The reaction was partitioned between dichloromethane and saturated NaHCO3, and the organic phase was washed with brine and dried over MgSO4, filtered and concentrated to give the title compound (0.562 g, quantitative), which was used without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][CH2:13][CH:14]([C:25]1[N:34]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:33](=[O:41])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=1)[NH:15][C:16]1[N:24]=[CH:23][N:22]=[C:21]2[C:17]=1[N:18]=[CH:19][NH:20]2)(C)(C)C>ClCCl>[OH:12][CH2:13][CH:14]([C:25]1[N:34]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:33](=[O:41])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=1)[NH:15][C:16]1[N:24]=[CH:23][N:22]=[C:21]2[C:17]=1[N:18]=[CH:19][NH:20]2
Reactant: CC(C)(C)OCC(Nc1ncnc2[nH]cnc12)c1nc2ccccc2c(=O)n1-c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1c2ccccc2nc(C(CO)Nc2ncnc3[nH]cnc23)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Compound 92 was prepared by adding trifluoroacetic acid to a solution of 2-[2-tert-butoxy-1-(9H-purin-6-ylamino)-ethyl]-3-phenyl-3H-quinazolin-4-one in dichloromethane. The reaction was stirred at ambient temperature for 18 hours, then concentrated in vacuo. Purification by LC provided the product as a white solid. MS (ES): m/z 400 (M H), 382, 200, 136. Compound 92 is shown below.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]3[CH:19]=[N:20][C:21]([NH:24][S:25]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)(=[O:27])=[O:26])=[CH:22][CH:23]=3)[CH:12]=2)=[O:9])[CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.CN(C)C=O.I[CH2:50][C:51]([NH2:53])=[O:52]>C(=O)([O-])O.[Na+]>[NH2:53][C:51](=[O:52])[CH2:50][N:20]1[C:21](=[N:24][S:25]([C:28]2[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=2)(=[O:27])=[O:26])[CH:22]=[CH:23][C:18]([O:17][C:13]2[CH:12]=[C:11]([NH:10][C:8]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=3)=[O:9])[CH:16]=[CH:15][CH:14]=2)=[CH:19]1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3cccc(NC(=O)c4cccc(C)n4)c3)cn2)cc1
Reactant: NC(=O)CI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)N=c2ccc(Oc3cccc(NC(=O)c4cccc(C)n4)c3)cn2CC(N)=O)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 88 %

Procedure:
A mixture of 6-methyl-N-{3-[(6-{[(4-methylphenyl)sulfonyl]amino}pyridin-3-yl)oxy]phenyl}pyridine-2-carboxamide (14.8 g, 31.2 mmol), N,N-diisopropylethylamine (7.10 mL, 40.7 mmol) and N,N-dimethylformamide (100 mL) was stirred at room temperature for 20 min. After stirring, iodoacetamide (7.51 g, 40.6 mmol) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (0%→100% ethyl acetate-hexane→10% methanol-ethyl acetate) to give the title compound (14.6 g, 88%) as a pale-yellow oil.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5](Br)[C:6]2[O:10][CH:9]=[CH:8][C:7]=2[CH:11]=1.CO[Sn](CCCC)(CCCC)CCCC.C([O:33][C:34](=[CH:36][CH3:37])[CH3:35])(=O)C>C1(C)C=CC=CC=1>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH:36]([CH3:37])[C:34](=[O:33])[CH3:35])[C:6]2[O:10][CH:9]=[CH:8][C:7]=2[CH:11]=1
Reactant: CC=C(C)OC(C)=O
Reactant: FC(F)(F)c1cc(Br)c2occc2c1
Agent: CCCC[Sn](CCCC)(CCCC)OC
Solvent: Cc1ccccc1
Product: CC(=O)C(C)c1cc(C(F)(F)F)cc2ccoc12
Temperature: 100 °C
Yield: 34.1 %

Procedure:
A mixture of 0.27 gm (1.03 mMol) 5-trifluoromethyl-7-bromobenzofuran, 0.50 gm (1.55 mMol) methoxy(tri-n-butyl)tin, 0.18 gm (1.55 mMol) 2-acetoxy-2-butene, and 0.08 gm (0.10 mmol) bis[tri-o-tolylphosphine]palladium(II) chloride in 2.5 mL toluene was heated at 100° C. for 1 hour. The reaction mixture was cooled to room temperature and filtered through a pad of celite. The filtrate was concentrated under reduced pressure and the residue subjected to silica gel chromatography, eluting with 10% ethyl acetate in hexane. Fractions containing product were combined and concentrated under reduced pressure to provide 0.090 gm (34%) of the desired compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][CH3:15])[C@H:10]([CH2:16][N:17]([CH:34]([CH3:36])[CH3:35])[C:18](=[O:33])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32])[CH:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:37]1([C:40](Cl)=[O:41])[CH2:39][CH2:38]1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@@H:10]([CH2:16][N:17]([CH:34]([CH3:36])[CH3:35])[C:18](=[O:33])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32])[CH:20]=2)[C@H:11]([CH2:13][N:14]([C:40]([CH:37]2[CH2:39][CH2:38]2)=[O:41])[CH3:15])[CH2:12]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CNC[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CN(C(=O)c1ccc(OC)c(OCCCOC)c1)C(C)C
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CN(C)C(=O)C2CC2)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3R*,4R*)-3-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-4-methylaminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (134 mg, 0.264 mmol) in CH2Cl2 (2 mL), cyclopropanecarbonyl chloride (29 μL, 0.317 mmol) and triethylamine (44 μL, 0.317 mmol) are added under N2 atmosphere. The mixture is stirred overnight at RT, diluted with CH2Cl2 and poured into an aqueous saturated solution of NaHCO3. The organic layer is separated, and the aqueous one is extracted twice with CH2Cl2. The combined organic extracts are dried over Na2SO4, filtered and concentrated. The crude product is used in the next step without purification. TLC, Rf (CH2Cl2/MeOH 95:5)=0.2. MS (LC-MS): 476.1 [M+H-Boc]+. tR (HPLC, Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 ml/min): 5.42 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[C:20](=[O:21])[N:19]([CH3:22])[C:12]3[N:13]=[C:14](SC)[N:15]=[CH:16][C:11]=3[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]>CCO.[Ni].O>[NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[C:20](=[O:21])[N:19]([CH3:22])[C:12]3[N:13]=[CH:14][N:15]=[CH:16][C:11]=3[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CSc1ncc2cc(-c3ccc(F)c(N)c3)c(=O)n(C)c2n1
Agent: [Ni]
Solvent: O
Solvent: CCO
Product: Cn1c(=O)c(-c2ccc(F)c(N)c2)cc2cncnc21
Yield: 46.8 %

Procedure:
A solution of Example A3 (2.5 g, 7.9 mmol) in EtOH (30 ml) was treated with Raney Nickel® (50% slurry in water, 10 g, 85 mmol) and the mixture was refluxed for 3 h. The cooled reaction was filtered and the filtrate was concentrated to give the crude product, which was washed with cold MeOH (2 mL) to give 6-(3-amino-4-fluoro-phenyl)-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.0 g, 47% yield). 1H NMR (300 MHz, DMSO-d6)δ 9.10 (s, H), 9.07 (s, 1 H), 8.06 (s, 1 H), 7.14 (dd, J=8.7, 2.1 Hz, 1 H), 7.05 (dd, J=11.4, 8.4 Hz, 1 H), 6.82 (m, 1 H), 5.22 (s, 2 H), 3.68 (s, 3 H); MS (ESI) m/z: 271.3 (M+H+).
Reaction SMILES: [P:1]([O:5][CH2:6][C@@H:7]([OH:16])[C@@H:8]([OH:15])[C@H:9]([OH:14])[C@@H:10]([OH:13])[CH:11]=[O:12])([O-:4])([O-:3])=[O:2].[Ba+2].[OH-].[Na+].[BH4-].[Na+]>O>[CH2:6]([O:5][P:1]([OH:3])([OH:4])=[O:2])[C@H:7]1[O:16][C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([OH:14])[C@@H:8]1[OH:15]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)COP(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Ba+2]
Agent: [Na+]
Solvent: O
Product: O=P(O)(O)OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 45 °C
Reaction time: 24 h

Procedure:
To 10 ml of the aminated gel obtained in Preparation Example 2 were added, first 10 ml of water, next 1 g of barium glucose-6-phosphate, to which 0.5 ml of 2M NaOH was further added and the mixture was maintained at 45° C. for 1 hour. After 0.1 g of NaBH4 was added thereto, the mixture was allowed to stand at room temperature for 24 hours. After the reaction was completed, the gel was filtered off from the reaction mixture and washed with water to give a cellulose gel with immobilized glucose-6-phosphate. The amount of the introduced anionic functional group derived from the immobilized glucose-6-phosphate was 10 μmol to 1 ml of the adsorbent.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][O:10][C:11]1[C:12]([NH2:29])=[CH:13][C:14]2[CH:20]([CH3:21])[CH2:19][N:18]([C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])[CH2:17][CH2:16][C:15]=2[N:28]=1>C(Cl)Cl>[Br:8][C:13]1[C:14]2[CH:20]([CH3:21])[CH2:19][N:18]([C:22](=[O:27])[C:23]([F:26])([F:24])[F:25])[CH2:17][CH2:16][C:15]=2[N:28]=[C:11]([O:10][CH3:9])[C:12]=1[NH2:29]
Reactant: COc1nc2c(cc1N)C(C)CN(C(=O)C(F)(F)F)CC2
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COc1nc2c(c(Br)c1N)C(C)CN(C(=O)C(F)(F)F)CC2
Yield: 37 %

Procedure:
A solution of NBS (1.16 g, 6.50 mmol) in DCM (40 ml) was added dropwise to a stirred and cooled (0-5° C.) solution of 2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine (1.97 g, 6.50 mmol) in DCM (40 ml) over a period of 20 min. After 30 minutes of stirring, the reaction was quenched with sat. aq. NaHCO3 and extracted with DCM. The organic layer was dried, concentrated in vacuo and purified by column chromatography to provide 920 mg (37%) of 4-bromo-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine. 1H-NMR (CDCl3) δ 4.36 (0.5H), 4.18 (2H), 4.00 (0.5H), 3.95 (3H), 3.79 (1H), 3.74 (1H), 3.70 (1H), 3.38 (1H), 3.23 (1H), 3.07 (1H), 1.19 (3H) ppm. 4-Bromo-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine (57.0 mg, 0.15 mmol) of was deprotected using K2CO3 (62 mg, 0.45 mmol), MeOH (2.3 ml) and H2O (0.5 ml) at 55-60° C. for 30 minutes. After carefully removing MeOH under reduced pressure, the mixture was diluted with aq. NaHCO3 and extracted with DCM. The organic layer was dried over Na2SO4 and concentrated in vacuo to give 37.0 mg (86%) of 4-bromo-2-methoxy-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine. 1H-NMR (CDCl3) δ 3.96 (s, 3H), 3.54 (m, 1H), 3.26 (dd, 2H), 3.18 (dd, 1H), 3.02 (d, 1H), 2.94 (dd, 1H), 2.78 (dd, 1H), 1.32 (d, 3H) ppm.
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:26]3[CH:31]=[CH:30][C:29]([CH2:32][OH:33])=[CH:28][CH:27]=3)[CH:24]=2)[NH:19][CH:18]=1)=O)C1C=CC=CC=1.C(Cl)(=O)C>C(O)C>[OH:33][CH2:32][C:29]1[CH:28]=[CH:27][C:26]([C:23]2[CH:24]=[C:25]3[C:20](=[CH:21][CH:22]=2)[NH:19][CH:18]=[C:17]3[CH2:16][C@H:12]2[CH2:13][CH2:14][CH2:15][NH:11]2)=[CH:31][CH:30]=1
Reactant: O=C(OCc1ccccc1)N1CCC[C@@H]1Cc1c[nH]c2ccc(-c3ccc(CO)cc3)cc12
Solvent: CCO
Solvent: CC(=O)Cl
Product: OCc1ccc(-c2ccc3[nH]cc(C[C@H]4CCCN4)c3c2)cc1

Procedure:
3-(1-Benzyloxycarbonylpyrrolidin-2(R)-ylmethyl)-5-(4-hydroxymethylphenyl)-1H-indole (450 mg, 0.973 mmol) (see Preparation 39) in ethanol was reduced using catalytic hydrogenation as described in Example 35 except that no acetyl chloride was used in the reaction. This gave the title compound as an off-white powder, m.pt. 65°-69° C. (210 mg). Found: C,76.15; H,7.43; N,8.66; C20H22N2O.1/2H2O requires: C,76.16; H,7.35; N,8.88%.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[BH4-].[Na+].Cl>C(O)C>[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(C=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CN(C)c1ccc(CO)cc1
Temperature: 25 °C

Procedure:
Mix 4-dimethylaminobenzaldehyde (3.3 g, 22 mmol), sodium borohydride (830 mg, 22 mmol) and absolute ethanol (25 mL). Stir at room temperature until the reaction is complete, pour onto dilute hydrochloric acid and extract into ethyl acetate. Separate the organic phase and extract the aqueous phase with ethyl acetate (2×). Combine the organic phases and dry (MgSO4). Evaporate the solvent in vacuo and purify by silica gel chromatography to give 4-(dimethylamino)benzyl alcohol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][CH:10]([OH:12])[CH3:11])[CH:5]=[CH:4][N:3]=1.[I-].[NH2:14][N+:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([CH:10]([OH:12])[CH3:11])=[N:14][N:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=23)[CH:5]=[CH:4][N:3]=1
Reactant: CC(O)C#Cc1ccnc(F)c1
Reactant: N[n+]1ccccc1
Agent: [I-]
Solvent: CC#N
Product: CC(O)c1nn2ccccc2c1-c1ccnc(F)c1
Temperature: 25 °C
Yield: 45.7 %

Procedure:
A solution of 4-(2-fluoro-4-pyridinyl)-3-butyn-2-ol (1.4 g, 8.5 mmol), aminopyridinium iodide (2.2 g, 9.8 mmol), 1,8-diazobicyclo[5.4.0]undec-7-ene (1.9 mL, 12.7 mmol), and acetonitrile (20 mL) were allowed to stir for 12–16 hours at room temperature. When judged to be complete, the mixture was partitioned between ethyl acetate and water, the organics were washed with brine, dried over magnesium sulfate, filtered and suspended onto silica gel. The crude material was purified by flash chromatography (1:1 hexanes:ethyl acetate) to provide 1-[3-(2-fluoro-4-pyridinyl)pyrazolo[1,5-a]pyridin-2-yl]ethanol (1.0 g, 460%) as a beige solid. 1H NMR (DMSO-d6): δ 8.79 (d, 1H), 8.30 (d, 1H), 7.87 (d, 1H), 7.67 (d, 1H), 7.50 (s, 1H), 7.41 (m, 1H), 7.04 (m, 1H), 5.57 (m, 1H), 5.03 (m, 1H), 1.56 (d, 3H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:27][CH3:28])=[C:10]([CH2:19][NH:20][C:21](=[O:26])[CH2:22][C:23](O)=[O:24])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[Br:29][C:30]1[CH:31]=[C:32]([CH2:37][NH2:38])[CH:33]=[CH:34][C:35]=1[Cl:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl>[Br:29][C:30]1[CH:31]=[C:32]([CH2:37][NH:38][C:23](=[O:24])[CH2:22][C:21]([NH:20][CH2:19][C:10]2[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]3[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]3=[N:8][C:9]=2[CH2:27][CH3:28])=[O:26])[CH:33]=[CH:34][C:35]=1[Cl:36]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)O
Reactant: NCc1ccc(Cl)c(Br)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)NCc1ccc(Cl)c(Br)c1

Procedure:
A solution of 3-({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-3-oxopropanoic acid (600 mg, 1.541 mmol), 1-(3-bromo-4-chlorophenyl)methanamine (397 mg, 1.8 mmol), HATU (760 mg, 2.0 mmol), and triethylamine (0.488 ml, 3.5 mmol) in 25 mL of DCM was stirred at room temperature overnight. The reaction mixture was diluted with DCM, washed with saturated NaHCO3, water and saturated NaCl. The organic layer was dried over Na2SO4 and evaporated to a pale amber residue. This was purified on 80 g. Combi-Flash column with DCM [0-8% MeOH] to give N-[(3-bromo-4-chlorophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}propanediamide. LC-MS m/z 591.2 (M+H)+, 0.84 min (ret time).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[S:9][CH:8]=[N:7][C:6]=1[CH3:10].[C:11]([C:14]1[S:15][C:16]([CH2:20][CH2:21][O:22][CH3:23])=[C:17]([CH3:19])[N:18]=1)(=[O:13])[CH3:12]>>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[S:9][C:8]([C:11]([C:14]2[S:15][C:16]([CH2:20][CH2:21][O:22][CH3:23])=[C:17]([CH3:19])[N:18]=2)([OH:13])[CH3:12])=[N:7][C:6]=1[CH3:10]
Reactant: COCCc1scnc1C
Reactant: COCCc1sc(C(C)=O)nc1C
Product: COCCc1sc(C(C)(O)c2nc(C)c(CCOC)s2)nc1C

Procedure:
From 5-(2-methoxyethyl)-4-methylthiazole and 2-acetyl-5-(2-methoxyethyl)-4-methylthiazole.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([C:18]3[C:19]([C:27]4[CH:28]=[C:29]([NH:33]C(=O)C(F)(F)F)[CH:30]=[CH:31][CH:32]=4)=[N:20][N:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=34)[CH:15]=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1.[NH:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1>>[NH2:33][C:29]1[CH:28]=[C:27]([C:19]2[C:18]([C:16]3[CH:15]=[CH:14][N:13]=[C:12]([NH:11][C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH2:3][CH2:2][N:40]5[CH2:44][CH2:43][CH2:42][CH2:41]5)[CH:6]=4)[N:17]=3)=[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][N:21]3[N:20]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: C1CCNC1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(OCCCl)c3)n2)c1)C(F)(F)F
Product: Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(OCCN4CCCC4)c3)n2)c1
Temperature: 50 °C
Yield: 74 %

Procedure:
N-(3-{3-[2-({3-[(2-Chloroethyl)oxy]phenyl}amino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenyl)-2,2,2-trifluoroacetamide (0.500 g, 0.850 mmol) was dissolved in pyrrolidine and heated to 50° C. for 18 h. The reaction was cooled upon completion and absorbed directly onto silica gel. The crude product was purified via column chromatography using a 0-20% gradient of EtOAC/MeOH w/NH4OH to afford the desired product (310 mg, 74% yield) as a yellow solid. ES-LCMS m/z 492 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=2)[N:3]=1.[Br:24]N1C(=O)CCC1=O>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][C:10]([Br:24])=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=2)[N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(CNc2nc(N)nc(-c3ccco3)c2C#N)nc1
Solvent: CN(C)C=O
Product: Cc1ccc(CNc2nc(N)nc(-c3ccc(Br)o3)c2C#N)nc1

Procedure:
From 2-amino-4-furan-2-yl-6-[(5-methyl-pyridin-2-ylmethyl)-amino]-pyrimidine-5-carbonitrile and N-bromosuccinimide in DMF. ES-MS m/e (%): 387 (M{81Br}+H+, 100), 385 (M{79Br}+H+, 85).
Reaction SMILES: [N:1]1([C:10]2[S:11][C:12](/[CH:18]=[CH:19]/[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.O1CCCC1.[H][H]>[C].[Pd].C(O)C>[N:1]1([C:10]2[S:11][C:12]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CCOC(=O)/C=C/c1sc(-n2cnc3ccccc32)nc1C(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CCc1sc(-n2cnc3ccccc32)nc1C(C)C
Yield: 99.4 %

Procedure:
A mixture of ethyl (2E)-3-[2-(1H-benzimidazol-1-yl)-4-isopropyl-5-thiazolyl]propenoate (1.50 g), 5% palladium-carbon (1.0 g), tetrahydrofuran (20 mL) and ethanol (20 mL) was stirred at room temperature under an atmospheric pressure of hydrogen for 14 hrs. The catalyst was removed by filtration, and the organic layer was concentrated to give ethyl 3-[2-(1H-benzimidazol-1-yl)-4-isopropyl-5-thiazolyl]propionate (1.50 g, 99%) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([CH2:8][OH:9])=[O:7])([CH3:4])[CH3:3].[H-].[Na+].[Br:12][C:13]1[C:14](Cl)=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=1>C1COCC1>[C:2]([O:5][C:6](=[O:7])[CH2:8][O:9][C:14]1[C:13]([Br:12])=[CH:18][C:17]([Cl:19])=[CH:16][N:15]=1)([CH3:4])([CH3:3])[CH3:1]
Reactant: Clc1cnc(Cl)c(Br)c1
Reactant: CC(C)(C)OC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)COc1ncc(Cl)cc1Br
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 2-tert-butyl glycolate (437 mg; 3.31 mmol) in anhydrous THF (5 mL) was treated with NaH (159 mg; 3.97 mmol) and stirred at RT for 10 minutes before treating with a solution of 3-bromo-2,5-dichloropyridine (Matrix; 500 mg; 2.20 mmol) in anhydrous THF (5 mL). The resulting reaction mixture was stirred for 22 hours. The reaction mixture was treated with a solution of 2-tert-butyl glycolate (437 mg; 3.31 mmol) in THF (2 ml), then with NaH (159 mg; 3.97 mmol) and the reaction mixture was stirred for 16 h. The reaction was quenched with tBuOH, the solvent removed under reduced pressure affording a brown solid, which was purified by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc, affording the title compound as a yellow sticky solid.
Reaction SMILES: [Br:1][C@@H:2]1[C@@H:8]2[CH2:9][C@@H:5]([C:6](=[O:10])[O:7]2)[CH2:4][CH2:3]1.C(OCC)(=O)C.[CH3:17][NH:18][CH3:19].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O>[OH:7][C@@H:8]1[C@@H:2]([Br:1])[CH2:3][CH2:4][C@H:5]([C:6]([N:18]([CH3:19])[CH3:17])=[O:10])[CH2:9]1
Reactant: CNC
Reactant: O=C1O[C@H]2C[C@@H]1CC[C@@H]2Br
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: CN(C)C(=O)[C@H]1CC[C@H](Br)[C@@H](O)C1
Temperature: 5 °C
Reaction time: 14 h

Procedure:
(1S,4S,5S)-4-Bromo-6-oxabicyclo[3.2.1]octan-7-one (200 g) was added to ethyl acetate (1000 ml), and the obtained solution was then cooled to 5° C. Thereafter, a 50% dimethylamine aqueous solution (305.7 ml) was added to the reaction solution, and the obtained mixture was then stirred for 14 hours. Thereafter, a mixed solution of citric acid (131.17 g), common salt (92.00 g) and water (324 ml) was added to the reaction solution, and the obtained mixture was then heated to 30° C. The reaction solution was stirred for 30 minutes, and thereafter, it was left at rest, so that the organic layer was separated. Further, the aqueous layer was extracted with ethyl acetate (800 ml) again. The organic layers were gathered, and the gathered organic layer was then concentrated to 1000 ml. Water (400 ml) was added to the concentrated solution, and the thus mixed solution was concentrated again to obtain an aqueous solution (500 ml) of (1S,3S,4S)-3-hydroxy-4-bromo-N,N-dimethylcyclohexanecarboxamide. To this aqueous solution (500 ml), a 28% ammonia aqueous solution (1247 ml) and a 25% sodium hydroxide aqueous solution (123 ml) were added, and the obtained solution was then heated to 40° C., followed by stirring the reaction solution for 6 hours. Thereafter, the reaction solution was concentrated to 1000 ml to obtain an aqueous solution containing the title compound (147.52 g, yield: 81%).
Reaction SMILES: [C:1]([C:4]1[CH2:5][CH2:6][CH2:7][O:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].[BrH:11]>C(O)(=O)C>[Br:11][CH2:7][CH2:6][CH2:5][CH:4]([C:9](=[O:8])[CH3:10])[C:1](=[O:3])[CH3:2]
Reactant: Br
Reactant: CC(=O)C1=C(C)OCCC1
Solvent: CC(=O)O
Product: CC(=O)C(CCCBr)C(C)=O

Procedure:
35.0 g. (0.25 mole) of 5-acetyl-6-methyl -3,4-dihydro-2H-pyrane prepared according to Example 21 are added dropwise into 250 ml. of a 33% solution of of hydrogen bromide in acetic acid, at room temperature, under stirring. The mixture is refluxed for 4 hours, with stirring. After cooling it is poured into 1 kg. of ice water and is then extracted with three 100-ml. portions of chloroform. The combined chloroform solution is washed subsequently with three 50-ml. portions of water, three 50-ml. portions of a 5% aqueous sodium bicarbonate solution and two 50-ml. portions of water, dried over solid anhydrous magnesium sulfate, decoloured with activated carbon and evaporated. The product obtained is purified by fractionated distillation on a short Wigreux column, in vacuum.