Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:21]([O:25][C:26]([N:28]1[CH2:33][CH:32]2C[CH:29]1[CH2:30][N:31]2[C:35]1[CH:36]=[N:37][C:38]([NH2:41])=[CH:39][CH:40]=1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:35]2[CH:36]=[N:37][C:38]([NH:41][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:20])[CH3:1])[N:14]([CH:15]5[CH2:19][CH2:18][CH2:17][CH2:16]5)[C:8]=4[N:9]=3)=[CH:39][CH:40]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CC2CC1CN2c1ccc(N)nc1
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n1C1CCCC1
Yield: 95.8 %

Procedure:
Using General Buchwald method 1, 2-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (200 mg, 0.683 mmol, 1.0 eq) was combined with 5-(6-Amino-pyridin-3-yl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (218 mg, 0.751 mmol, 1.1 eq) to give 4-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (350 mg, 94% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.32 (s, 6H) 1.39 (s, 6H) 1.62 (br. s., 3H) 1.94 (br. s., 8H) 2.41 (br. s., 3H) 2.92-3.02 (m, 2H) 3.05 (br. s., 7H) 3.26 (d, J=11.12 Hz, 3H) 3.34 (br. s., 3H) 3.51-3.64 (m, 1H) 4.39 (s, 1H) 4.45 (br. s., 1H) 4.55 (br. s., 1H) 4.72 (t, J=8.59 Hz, 1H) 6.58 (s, 1H) 7.12 (dd, J=9.09, 3.03 Hz, 1H) 7.74 (d, J=2.53 Hz, 1H) 8.02 (t, J=8.08 Hz, 1H) 8.72 (s, 1H) 9.15 (s, 1H); MS m/z 547.1 (M+H)+.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C([Sn](CCCC)(CCCC)[C:12]1[S:13][CH:14]=[CH:15][N:16]=1)CCC>C1(C)C=CC=CC=1>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[C:12]1[S:13][CH:14]=[CH:15][N:16]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: Brc1nccs1
Solvent: Cc1ccccc1
Product: c1csc(-c2nccs2)n1
Temperature: 125 °C
Yield: 93.3 %

Procedure:
A solution of 2-bromothiazole (2.85 g, 17.4 mmol), 2-(tributylstannyl)thiazole (5.00 g, 13.4 mmol) and tetrakistriphenylphosphine palladium (0.77 g, 0.67 mmol) in toluene (120 mL) was degassed under vacuum for several minutes, backfilled with nitrogen and heated in a sealed pressure vessel at 125° C. for 48 h. The crude reaction mixture was concentrated and the residue was purified by column chromatography (0 to 30% ethyl acetate/hexanes) to yield 2,2′-bithiazole (2.21 g, 12.5 mmol, 93% yield) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[CH2:12][C@H:11]2[C:13]([OH:15])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].ClC(OCC)=O.[CH2:22]([NH2:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:22]([NH:30][C:13]([C@@H:11]1[CH2:12][C@H:10]1[C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)=[O:15])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccc([N+](=O)[O-])cc1
Reactant: CCCCCCCCN
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCNC(=O)[C@@H]1C[C@H]1c1ccc([N+](=O)[O-])cc1
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
To a stirred slurry of 4.1 g. of trans-2-(4-nitrophenyl)cyclopropanecarboxylic acid in 50 ml. of chloroform was added 2.2 g. of triethylamine. The clear solution thus obtained was cooled to ca. 5° C., and a solution of 2.4 g. of ethyl chloroformate in 15 ml. of chloroform was added dropwise with stirring during 15 minutes. Stirring was continued for 20 minutes, and then a solution of 2.8 g. of octylamine in 15 ml. of chloroform was added dropwise with stirring, at 0°-5° C., during 10-15 minutes. The cooling bath was removed, and stirring was continued for 1 hour. At this point, the solvent was removed by evaporation in vacuo, and the residue was triturated under a mixture of 70 ml. of water and 15 ml. of ethanol. The solid which remained out of solution was recovered by filtration, washed with water, and dried, to give 6.2 g. of the title compound as a white solid, m.p. 126°- 129° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[CH3:14])[CH:7]=1.CC([O-])=O.[K+].[Cl:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C([O-])([O-])=O.[Na+].[Na+].Cl.CCO>O1CCOCC1.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[ClH:20].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([CH2:8][N:9]3[CH:13]=[CH:12][N:11]=[C:10]3[CH3:14])[CH:7]=2)=[CH:23][CH:22]=1
Reactant: Cc1nccn1Cc1cncc(Br)c1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: Cc1nccn1Cc1cncc(-c2ccc(Cl)cc2)c1
Temperature: 100 °C
Yield: 1224.2 %

Procedure:
A mixture of 3-bromo-5-(2-methyl-imidazol-1-ylmethyl)-pyridine (120 mg, 0.48 mmol), bis(triphenylphosphine)palladium (II) choride (10 mg, 0.01 mmol) and KOAc (140 mg, 0.14 mmol) were stirred in dioxane (10 ml) for 1 h at 20° C. 4-Chlorophenyl boronic acid (78 mg, 0.05 mmol) and 2N Na2CO3 solution (1.2 ml) were then added and the mixture heated to 100° C. for 7-24 h under an argon atmosphere. After cooling, the solvent was evaporated and 2N NaOH (5 ml) and AcOEt were added. The mixture was shaken and the aqueous phase separated and further extracted with AcOEt, the combined organic extracts were washed with brine then dried over Na2SO4, filtered and evaporated. The residue was chromatographed [silica, elution with CH2Cl2/(2M NH3 in MeOH)=97:3)]. The product was dissolved in MeOH, cooled to 4° C. with stirring and treated with HCl/EtOH (1.46 M 1.1 eq) for 45 min. Evaporation of the solvent and drying under high vacuum at 50° C. for 2 h afforded the title compound (98 mg, 64%) as a light brown solid. MS: m/e=284.2 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([O:11][CH3:12])=[O:10])[CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[Br:19][CH2:20][CH2:21]Br>CC(C)=O>[Br:19][CH2:20][CH2:21][N:7]1[C:6]([C:9]([O:11][CH3:12])=[O:10])=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[N:8]1
Reactant: COC(=O)c1cc([N+](=O)[O-])[nH]n1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc([N+](=O)[O-])nn1CCBr
Temperature: 0 °C
Yield: 63.4 %

Procedure:
To a solution of methyl 5-nitro-1H-pyrazole-3-carboxylate (1 g, 5.84 mmol) in acetone (30 mL) was added potassium carbonate (4.04 g, 29.2 mmol) and 1,2-dibromoethane (3.29 g, 1.51 mL, 17.5 mmol) and the resulting solution heated to reflux for 2 h. The resulting mixture was cooled to 0° C. filtered and concentrated and the residue purified by flash chromatography (silica gel, 60 g, 20% to 40% ethyl acetate in hexanes) to give methyl 1-(2-bromoethyl)-3-nitro-1H-pyrazole-5-carboxylate (1.03 g, 63%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH2:11])[C:5]([OH:7])=[O:6].C(O)(=O)C.[N:16]([O-])=O.[Na+]>O>[C:5]([C:4]1[CH:8]=[CH:9][C:10]2[NH:11][N:16]=[N:1][C:2]=2[CH:3]=1)([OH:7])=[O:6]
Reactant: Nc1ccc(C(=O)O)cc1N
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1ccc2[nH]nnc2c1
Yield: 717.2 %

Procedure:
15.2 g (0.01 mol) of 3,4-diaminobenzoic acid was dissolved in a mixed solvent composed of 100 ml of acetic acid and 50 ml of water. The solution was cooled to less than 5° C., and a solution prepared by dissolving 10 g (0.14 mol) of sodium nitrite in 30 ml of water was added dropwise with stirring. After the mixture was stirred at a room temperature for 2 hours, the precipitated crystal was filtered off. It was recrystallized from methanol to obtain 5-carboxybenzotriazole 11.7 g (72% yield). Melting point 300° C. (decomposition).
Reaction SMILES: [OH:1][C@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[S:4][C@H:3]1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.C(OCC)(=O)C.[CH3:28][N:29]([CH2:31][CH2:32]Cl)[CH3:30].C([O-])([O-])=O.[K+].[K+]>O>[CH3:28][N:29]([CH3:30])[CH2:31][CH2:32][N:7]1[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[S:4][C@@H:3]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C@@H:2]([OH:1])[C:8]1=[O:9]
Reactant: COc1ccc([C@@H]2Sc3ccccc3NC(=O)[C@@H]2O)cc1
Reactant: CN(C)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Temperature: 25 °C
Yield: 69.6 %

Procedure:
A 5-L three-necked flask equipped with a heating mantle, a mechanical stirrer and a condenser was charged with 162 g (0.54 mol) of (+)-(2S,3S)-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one and then 1 L of ethyl acetate. After stirring to dissolve the solution, 100 g (0.694 mol) of dimethylaminoethyl chloride.HC1 was added in one portion followed by 300 g (2.16 mol) of finely ground K2CO3 and 5 mL of H2O. (The 5 ml. of water was essential to cause a reaction between the phases, while addition of much more water would have resulted in gummy mixture that was difficult to filter.) This heterogeneous mixture was rapidly stirred at reflux for 5 hours. By thin layer chromatography (8:1, CH2C12 -MeOH, short wave UV), reaction was complete and therefore the mixture was allowed to cool to room temperature, filtered through a sintered glass funnel and washed with 100 mL 1:1 hexanes-ethyl acetate. The solvent was evaporated and on standing the oil crystallized. Recrystallization from ether gave 140 g (70%) of colorless crystalline (+)-(2S,3S)-5-[2-(dimethylamino)ethyl]-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one, m.p. 79-81° C., [α]D20=+ 156.4°(C=1.0; CHC13).
Reaction SMILES: F[C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([F:11])=[CH:4][N:3]=1.Cl.[F:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[CH2:21][CH2:22][O:23][CH2:24][C:25]([NH2:27])=[NH:26]>>[F:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[CH2:21][CH2:22][O:23][CH2:24][C:25]1[NH:27][C:8](=[O:10])[C:7]2[CH:6]=[C:5]([F:11])[CH:4]=[N:3][C:2]=2[N:26]=1
Reactant: O=C(O)c1cc(F)cnc1F
Reactant: N=C(N)COCCc1cc(F)ccc1F
Agent: Cl
Product: O=c1[nH]c(COCCc2cc(F)ccc2F)nc2ncc(F)cc12

Procedure:
The title compound was prepared in analogy to example 85 from 2,5-difluoropyridine-3-carboxylic acid and 2-[2-(2,5-difluoro-phenyl)-ethoxy]-acetamidine hydrochloride (example 78.2). Light brown solid. MS: m/e=336.3 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH2:15][CH3:16])[CH3:14])=[CH:9][CH:8]=1)=[O:5].[F:21][C:22]([F:36])([F:35])[C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]=O)=[CH:28][C:27]=1[I:34])=[O:24]>CCO>[CH:13]([C:10]1[CH:11]=[CH:12][C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:1]=[C:32]2[C:29]2[CH:30]=[CH:31][C:26]([NH:25][C:23](=[O:24])[C:22]([F:35])([F:21])[F:36])=[C:27]([I:34])[CH:28]=2)=[CH:8][CH:9]=1)([CH2:15][CH3:16])[CH3:14]
Reactant: O=Cc1ccc(NC(=O)C(F)(F)F)c(I)c1
Reactant: CCC(C)c1ccc(NC(=O)c2ccccc2N)cc1
Solvent: CCO
Product: CCC(C)c1ccc(-n2c(-c3ccc(NC(=O)C(F)(F)F)c(I)c3)nc3ccccc3c2=O)cc1
Yield: 66 %

Procedure:
2-amino-N-(4-sec-butylphenyl)benzamide (0.275 g, 1.00 mmol) and anhydrous CuCl2 (0.275 g, 2.00 mmol) were added to a solution of 2,2,2-trifluoro-N-(4-formyl-2-iodophenyl)acetamide in anhydrous EtOH (15 mL) and heated to reflux temperature for 3 hours. After concentrating in vacuo, the residue was dissolved in EtOAc, washed with H2O, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 10% to 60% EtOAc in heptane, afforded N-(4-(3-(4-sec-butylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)-2-iodophenyl)-2,2,2-trifluoroacetamide (0.390 g, 66%).
Reaction SMILES: [CH3:1][C:2](C)([CH2:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[C:3](O)=O.C1(P([N:27]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C.[OH-].[K+].Cl>C(O)(C)(C)C.O.C(O)CO>[CH3:1][C:2]([CH3:3])([NH2:27])[CH2:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(C)(Cc1cccs1)C(=O)O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(N)Cc1cccs1

Procedure:
A solution of 2,2-dimethyl-3-(2-thienyl)propanoic acid (Va; 11.2 g., 0.06 mole), diphenylphosphorylazide (16.7 g., 0.06 mole) (Aldrich Chemical Company), and triethylamine (6.14 g., 0.06 mole) in tert.-butanol (100 ml.) was heated at reflux for 5 hr. The solution was poured into water (300 ml.) and the crude material extracted with Et2O. The combined extracts were washed with brine, dried over MgSO4 and finally evaporated to get 11.9 g. of crude intermediate. This oil was added to a mixture of ethylene glycol (50 ml.), H2O (20 drops) and KOH (10 g.). The mixture was heated at reflux for 5 hr., cooled to 25°, diluted with H2O (300 ml.) and acidified to pH 1 with conc. HCl. A wash with Et2O removed the acid insoluble material which was discarded. The aqueous solution was made basic with 50% NaOH and the product was extracted with Et2O. The ether extracts were washed with brine, dried over a MgSO4 and evaporated to give 6.9 g. (74%) of product. the NMR spectrum is consistent with the assigned structure.
Reaction SMILES: [C:1]([CH2:4][C:5]([OH:15])([CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])[C:6]([OH:8])=[O:7])([OH:3])=[O:2].[CH:16](O)=O.C(OCC)(=O)C.O>CO>[CH3:16][O:2][C:1]([CH2:4][C:5]1([C:6]([OH:8])=[O:7])[CH2:9][CH2:10][CH2:11][C:12]([CH3:13])([CH3:14])[O:15]1)=[O:3]
Reactant: O=CO
Reactant: CC(C)=CCCC(O)(CC(=O)O)C(=O)O
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: COC(=O)CC1(C(=O)O)CCCC(C)(C)O1
Temperature: 25 °C

Procedure:
The solution obtained from the previous stage and containing 5 kg of 2-carboxymethyl-2-hydroxy-6-methyl-5-heptenoic acid 100% is charged into an enameled reactor. This residue is then cooled to 20-30° C. and 15 kg of formic acid 99% are added. The mixture is then heated to 70-75° C. and kept under stirring at that temperature for at least 4 hours. It is then cooled to 50-60° C. and the water is removed by vacuum distillation until an oily residue is obtained. The oily residue is cooled to 30-35° C. and 15 kg of ethyl acetate and 5 kg of demineralised water are added. The mixture obtained is stirred always at 30-35° C. and left under rest until the phases separate, eliminating the aqueous phase, while the solvent is removed from the organic phase by vacuum distillation until an oily residue is obtained. This residue is then cooled and 10.0 kg of methanol are added.
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:13]=[C:12]2[CH2:25][C:26]([NH2:28])=[O:27])C.[OH-].[Na+].Cl>CCO.C1COCC1>[NH2:28][C:26](=[O:27])[CH2:25][C:12]1[C:11]2[C:15](=[CH:16][CH:17]=[C:9]([O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:29])=[O:3])[CH:10]=2)[N:14]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:13]=1
Reactant: CCOC(=O)CCCOc1ccc2c(c1)c(CC(N)=O)cn2Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: NC(=O)Cc1cn(Cc2ccccc2)c2ccc(OCCCC(=O)O)cc12
Yield: 45.5 %

Procedure:
4-[[3-(2-Amino-2-oxoethyl)-1-(phenylmethyl)-1H-indol-5-yl]oxy]butanoic acid ethyl ester (260 mg, 0.66 mmol) was stirred with 2 mL of 2N NaOH in 25 mL of EtOH and 5 mL of THF for 18 hours. The mixture was acidified with 5N HCl, extracted with EtOAc, the EtOAc solution washed with saturated NaCl solution and dried (Na2SO4). After concentrating, the residue was crystallized from methylene chloride/ethanol to give 110 mg (46% yield) of 4-[[3-(2-amino-2-oxoethyl)-1-(phenylmethyl)-1H-indol-5-yl]oxy]butanoic acid, mp, 160-163° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:21][CH:20]=[CH:19][N:5]2[C:6](=[O:18])[C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1.[CH:22]1([CH2:25][O:26][C:27]2[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[CH:31][C:28]=2[CH:29]=O)[CH2:24][CH2:23]1.[O-]CC.[Na+]>C(O)C>[CH:22]1([CH2:25][O:26][C:27]2[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[CH:31][C:28]=2/[CH:29]=[CH:1]/[C:2]2[N:3]=[C:4]3[S:21][CH:20]=[CH:19][N:5]3[C:6](=[O:18])[C:7]=2[C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)[CH2:23][CH2:24]1
Reactant: COc1cccc(C=O)c1OCC1CC1
Reactant: Cc1nc2sccn2c(=O)c1-c1cccc(C(F)(F)F)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(/C=C/c2nc3sccn3c(=O)c2-c2cccc(C(F)(F)F)c2)c1OCC1CC1
Yield: 41.1 %

Procedure:
The title compound was prepared by condensation of Intermediate 6 (175 mg, 0.561 mmol) with 2-cyclopropylmethoxy-3-methoxybenzaldehyde (150 mg, 0.783 mmol) in presence of sodium ethoxide (76 mg, 1.118 mmol) in ethanol (10 ml) according to the procedure of Example 24 afforded 115 mg of the desired product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.24 (d, J=4.2 Hz, 2H), 0.48 (d, J=5.7 Hz, 2H), 0.93-0.99 (m, 1H), 3.67 (d, J=6.6 Hz, 2H), 3.77 (s, 3H), 6.85-7.01 (m, 4H), 7.53 (d, J=4.8 Hz, 1H), 7.66-7.76 (m, 4H), 8.00 (d, J=4.8 Hz, 1H), 8.16 (d, J=15.3 Hz, 1H); ESI-MS (m/z) 499.13 (M+H)+.
Reaction SMILES: FC(F)(F)S([O:6][Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])(=O)=O.[F:19][C:20]1[CH:21]=[CH:22][C:23]2[N:24]([C:26]([N:29]3[CH2:33][CH2:32][C@@H:31](O)[CH2:30]3)=[N:27][N:28]=2)[CH:25]=1.CCN(CC)CC.N>CO.C(Cl)Cl.CN(C=O)C>[F:19][C:20]1[CH:21]=[CH:22][C:23]2[N:24]([C:26]([N:29]3[CH2:33][CH2:32][C@@H:31]([O:6][Si:7]([CH:8]([CH3:9])[CH3:10])([CH:11]([CH3:12])[CH3:13])[CH:14]([CH3:15])[CH3:16])[CH2:30]3)=[N:27][N:28]=2)[CH:25]=1
Reactant: O[C@@H]1CCN(c2nnc3ccc(F)cn23)C1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Agent: N
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)[Si](O[C@@H]1CCN(c2nnc3ccc(F)cn23)C1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
Triisopropylsilyl trifluoromethanesulfonate (280 mg, 0.919 mmol) was added to a solution of Intermediate 38a (170 mg, 0.766 mmol) and Et3N (116 mg, 1.14 mmol) in a DMF (3 mL) and the mixture stirred at RT for 1 h. The reaction mixture was applied to an SCX-2 cartridge (10 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 0-10% [2M NH3 in MeOH] in DCM, gave the title compound (260 mg, 90%). LCMS (Method 3): Rt 4.26 min, m/z 379 [MH+].
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([CH2:24][CH:25]=O)=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=2)[N:4]=1)[CH3:2].[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([CH2:24][CH2:25][N:39]4[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]4)=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=2)[N:4]=1)[CH3:2]
Reactant: CN1CCNCC1
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(CC=O)ccn34)c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(CCN5CCN(C)CC5)ccn34)c12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The crude N-(3-Ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-oxoethyl)imidazo[1,2-a]pyridine-3-carboxamide (112 mg, 0.248 mmol), and N-methylpiperazine (25 mg, 0.25 mmol) were dissolved in DCM (5 mL), and treated with 10 equivalents of sodium triacetoxyborohydride, followed by 2 drops of glacial acetic acid. The reaction mixture was stirred at ambient temperature for 48 hours. The reaction mixture was concentrated, and resuspended in saturated aqueous sodium carbonate. The mixture was extracted with DCM and EtOAc, the combined organic layers were dried over anhydrous sodium sulfate, then filtered and concentrated. Purification of the crude material by preparative thin-layer chromatography on silica with 7N NH3-MeOH/MeOH/DCM, 2/8/98 as eluent afforded 83.5 mg of a foamy, white solid. MS (ES+APCI) m/z=537 (M+H) detected.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:23]=[CH:22][C:7]2[CH:8]=[C:9]([C:11]([NH:13][C@@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)=[O:12])[S:10][C:6]=2[CH:5]=1.C(N(CC)CC)C.[F:31][C:32]([F:44])([F:43])[O:33][C:34]1[CH:35]=[C:36]([N:40]=[C:41]=[O:42])[CH:37]=[CH:38][CH:39]=1>C1COCC1.CN(C=O)C>[ClH:1].[N:16]12[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17]1)[C@@H:14]([NH:13][C:11]([C:9]1[S:10][C:6]3[CH:5]=[C:4]([NH:3][C:41]([NH:40][C:36]4[CH:37]=[CH:38][CH:39]=[C:34]([O:33][C:32]([F:31])([F:43])[F:44])[CH:35]=4)=[O:42])[CH:23]=[CH:22][C:7]=3[CH:8]=1)=[O:12])[CH2:15]2
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Reactant: O=C=Nc1cccc(OC(F)(F)F)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(OC(F)(F)F)c1)Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Reaction time: 18 h

Procedure:
A solution of 40 mg (0.11 mmol) of 6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride in 2 ml of THF and 0.2 ml of DMF is mixed with 29.8 μl (0.21 mmol) of triethylamine and 43.4 mg (0.21 mmol) of 3-trifluoromethoxyphenyl isocyanate. After 18 h at room temperature, the product is purified by preparative HPLC. The concentrated product fraction is dissolved in a mixture of methanol and 1 N hydrochloric acid (2:1), again concentrated and dried under high vacuum. 8.5 mg (14.7% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:9])[CH:5]=[C:6]([CH3:8])[N:7]=1.Br[CH2:11][CH2:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1>>[CH3:1][C:2]1[N:3]([CH2:11][CH2:12][O:13][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=2)[C:4](=[O:9])[CH:5]=[C:6]([CH3:8])[N:7]=1
Reactant: Cc1cc(=O)[nH]c(C)n1
Reactant: O=Cc1ccc(OCCBr)cc1
Product: Cc1cc(=O)n(CCOc2ccc(C=O)cc2)c(C)n1
Yield: 28 %

Procedure:
The title compound (0.8 g, 30%) was prepared from 2,4-dimethyl-1,6-dihydro-6-pyrimidone (1.3 g, 10.48 mmol) and 4-[2-bromoethoxy]benzaldehyde (2.4 g, 10.48 mmol) in the presence of a base K2C3 (2.89 g, 20.96 mmol) by a similar procedure as described in preparation 1.
Reaction SMILES: C[O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[CH:17]=3)=[C:11]([CH3:28])[N:10]=2)=[CH:7][N:6]=[C:5]([NH:29][CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[N:4]=1.Br.CCOC(C)=O>C(O)(=O)C>[CH3:28][C:11]1[N:10]=[C:9]([C:8]2[C:3](=[O:2])[NH:4][C:5]([NH:29][CH2:30][C:31]([CH3:34])([CH3:32])[CH3:33])=[N:6][CH:7]=2)[CH:14]=[CH:13][C:12]=1[O:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]2[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=2)[CH:17]=1
Reactant: COc1nc(NCC(C)(C)C)ncc1-c1ccc(Oc2ccnc(-c3cnn(C)c3)c2)c(C)n1
Agent: Br
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1nc(-c2cnc(NCC(C)(C)C)[nH]c2=O)ccc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 56.1 %

Procedure:
A solution of 4-methoxy-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-N-neopentylpyrimidin-2-amine (0.081 g, 0.176 mmol) in acetic acid (2 mL) was treated with HBr (48% aq, 0.080 mL, 0.705 mmol), heated at 80° C. for 6 h, then cooled to RT overnight. The mixture was treated with ice and EtOAc, neutralized with satd. NaHCO3, extracted with EtOAc (3×) and the combined organics were washed with brine, dried over MgSO4 and concentrated to dryness. The material was suspended in MeCN, heated to near-reflux and allowed to stand at RT for 3 h. The resulting solid was collected via filtration to afford 5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-(neopentylamino)pyrimidin-4(3H)-one (44 mg, 56%). 1H NMR (400 MHz, DMSO-d6): δ 10.84 (s, 1H), 8.68 (s, 1H), 8.35 (d, J=6.6 Hz, 1H), 8.28-8.23 (m, 2H), 7.96 (s, 1H), 7.52 (d, J=8.6 Hz, 1H), 7.22 (d, J=3.0 Hz, 1H), 6.73 (br s, 1H), 6.60 (dd, J=5.1, 2.3 Hz, 1H), 3.86 (s, 3H), 3.22 (d, J=6.2 Hz, 2H), 2.34 (s, 3H), 0.91 (s, 9H); MS (ESI) m/z: 446.2 (M+H+).