Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[N:12]=[CH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[C:16]([N:21]1[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]1)[CH:15]=2)=[O:10].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[N:12]=[CH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[C:16]([N:21]1[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]1)[CH:15]=2)=[O:10]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3cc(C(=O)Nc4ccccc4N)ncc3c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccccc1NC(=O)c1cc2ccc(N3CCNCC3)cc2cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
To a solution of tert-butyl 4-(3-(2-aminophenylcarbamoyl)isoquinolin-7-yl)piperazine-1-carboxylate (100 mg, 0.22 mmol) in DCM (3 mL) was added TFA (1.5 mL). The resulting mixture was stirred at r.t. for 1 h. The mixture was concentrated to a residue, which was purified by Pre-HPLC to afford the desired compound, N-(2-aminophenyl)-7-(piperazin-1-yl)isoquinoline-3-carboxamide (75 mg, 70%) as a light yellow solid. 1H NMR (500 MHz, DMSO) δ 10.12 (s, 1H), 9.18 (s, 1H), 8.48 (s, 1H), 8.03 (d, J=9.1 Hz, 1H), 7.73 (d, J=7.0 Hz, 1H), 7.61 (d, J=7.9 Hz, 1H), 7.45 (s, 1H), 6.95 (t, J=7.6 Hz, 1H), 6.85 (d, J=7.8 Hz, 1H), 6.68 (t, J=7.5 Hz, 1H), 4.89 (s, 2H), 3.33-3.12 (m, 4H), 2.93-2.84 (m, 4H). LCMS: 1.69 min, m/z=348 (M+H)+
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24][Br:25])[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].ClC1C=CC=C(C(OO)=[O:36])C=1.O>ClCCl>[O:36]=[S:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]([CH2:21][CH2:22][CH2:23][CH2:24][Br:25])([C:5](=[O:6])[NH:4][CH2:3][C:2]([F:1])([F:26])[F:27])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]1=2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2Sc2ccccc21
Solvent: ClCCl
Solvent: O
Product: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2S(=O)c2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
The compound (46 mg) prepared in step (d) of Example 133 was dissolved in dichloromethane (1 ml). m-Chloroperbenzoic acid (19 mg) was added to the solution at 0° C., and the mixture was stirred at 0° C. for one hr. Water was added to the reaction solution, and the mixture was extracted with chloroform. The extract was dried over anhydrous MgSO4, and the solvent was then removed by distillation under the reduced pressure. The residue was purified by preparative TLC (n-hexane:ethyl acetate=1:4) to give 4-[10-oxo-9-(2,2,2-trifluoroethylcarbamoyl)-9,10-dihydro-10λ4-thioxanthen-9-yl]butyl bromide (38 mg).
Reaction SMILES: [OH:1][C@@H:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[CH3:3].[C:14]1(O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.O>[O:1]([C@H:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[CH3:3])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Oc1ccccc1
Reactant: COC(=O)c1ccc([C@@H](C)O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc([C@H](C)Oc2ccccc2)cc1
Temperature: 20 °C
Reaction time: 12 h
Yield: 54.6 %

Procedure:
To a solution of (R)-methyl 4-(1-hydroxyethyl)benzoate (0.9 g, 5 mmol), phenol (525 mg, 5.6 mmol), triphenylphosphine (2198 mg, 8.4 mmol) in tetrahydrofuran (30 mL) was added diisopropyl azodicarboxylate (1695 mg, 8.4 mmol) at 0° C. The mixture was stirred at 20° C. for 12 hours. Water (15 mL) was added to the mixture and then extracted with ethyl acetate (35 mL×3). The combined organic phase was dried by sodium sulfate, and then filtered. The filtrate was concentrated in vacuo and purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1) to give (S)-methyl 4-(1-phenoxyethyl)benzoate (700 mg, 54%). 1H NMR (300 MHz, d6-DMSO): δ 8.02-7.98 (m, 2H), 7.46-7.43 (m, 2H), 7.23-7.16 (m, 2H), 6.91-6.80 (m, 3H), 5.36 (q, J=6.0 Hz, 1H), 3.90 (s, 3H), 1.64 (d, J=6.6 Hz, 3H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11](Cl)=[O:12])=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.Cl.[CH3:15][NH:16][O:17][CH3:18].N1C=CC=CC=1>C(Cl)Cl>[CH3:18][O:17][N:16]([CH3:15])[C:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[N:4]2)=[O:12]
Reactant: O=C(Cl)c1ccc2nccnc2c1
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CON(C)C(=O)c1ccc2nccnc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of intermediate from step B (484 mg, 2.51 mmol) in 17 mL anhydrous methylene chloride cooled to 0° C. was added N,O-dimethylhydroxylamine hydrochloride (368 mg, 3.77 mmol) followed by pyridine (0.61 mL, 7.54 mmol). The reaction was warmed to room temperature and stirred overnight after which it was quenched with water. The aqueous layer was extracted with methylene chloride (2×) and the combined organic layers were dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography using 40% EtOAc/Hexanes to give the product as a colorless oil. 1H NMR (CDCl3, 500 MHz): 3.45 (d, J=2.5 Hz, 3H), 3.59 (d, J=2.5 Hz, 3H), 8.05 (m, 1H), 8.15 (dd, J=8.7, 3.2 Hz, 1H), 8.46 (d, J=1.8 Hz, 1H), 8.91 (d, J=2.5, 2H). LC-MS: 1.11 min. (M+H)=111.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:7])[C:3]([CH3:6])([OH:5])[CH3:4].F[C:9]1[C:10]([C:19]#[C:20][Si](C)(C)C)=[C:11]([C:17]#[N:18])[C:12](=[CH:15][CH:16]=1)[C:13]#[N:14].C([O-])([O-])=O.[K+].[K+].CN1C(=O)CCC1>O>[OH:5][C:3]([CH3:6])([CH3:4])[C@@H:2]([N:1]1[C:9]2[C:10](=[C:11]([C:17]#[N:18])[C:12]([C:13]#[N:14])=[CH:15][CH:16]=2)[CH:19]=[CH:20]1)[CH3:7]
Reactant: C[C@H](N)C(C)(C)O
Reactant: C[Si](C)(C)C#Cc1c(F)ccc(C#N)c1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: C[C@H](n1ccc2c(C#N)c(C#N)ccc21)C(C)(C)O
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 50.2 %

Procedure:
An oven-dried vial was charged with (S)-3-amino-2-methylbutan-2-ol (Example 21G) (0.064 g, 0.622 mmol), 4-fluoro-3-((trimethylsilyl)ethynyl)phthalonitrile (0.126 g, 0.518 mmol), and K2CO3 (0.143 g, 1.036 mmol) and sealed with a rubber septum. Anhyd NMP (3 mL) was added via syringe and the mixture was stirred in a heating block at 60° C. under N2. After 30 min, the vial was sealed with a PTFE-faced crimp top and the mixture was subjected to microwave heating (140° C.) for 15 min. The mixture was poured into water and extracted with EtOAc (×3). Combined organics were washed (water, brine), dried over Na2SO4 and concentrated in vacuo. The residue was purified by low pressure liquid chromatography (silica gel, EtOAc/hexanes, gradient elution) affording (S)-1-(3-hydroxy-3-methylbutan-2-yl)-1H-indole-4,5-dicarbonitrile (0.0659 g, 50% yield) as a tan solid: 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J=8.7 Hz, 1H), 7.69 (d, J=3.3 Hz, 1H), 7.51 (d, J=8.7 Hz, 1H), 6.84 (d, J=3.2 Hz, 1H), 4.47 (q, J=7.0 Hz, 1H), 1.63 (d, J=7.0 Hz, 3H), 1.53 (s, 1H), 1.34 (s, 3H), 1.11 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:19]=1.N1CCCCC1>C(O)C>[C:14]([C:11]1[CH:10]=[C:7]([CH:8]=[C:24]([C:20]2[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=2)[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:12]=1[OH:13])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: CCOC(=O)Cc1cccnc1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)C(=Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)c1cccnc1
Temperature: 25 °C
Yield: 46.6 %

Procedure:
Here, 3,5-di-t-butyl-4-hydroxybenzaldehyde (223 g, 0.952 mol), Ethyl 3-pyridylacetate (157.2 g, 0.952 mol), piperidine (81 g, 0.952 mol) and p-tolunesulfonic acid (0.5 g) are combined in ethanol (2,400 ml) and heated at reflux for 48 hours. The reaction mixture is allowed to cool to room temperature and then stirred on an ice bath, whereupon the product begins to crystallize. The mixture is stored in the freezer overnight, filtered and rinsed with cold ethanol-water (1:1). The product is dried, giving ethyl 3-(3,5-di-t-butyl-4-hydroxyphenyl)-2-(3-pyridyl)propenoate (169.1 g) Mp 119.5°-120.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH:13]([OH:15])[CH3:14])=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[C:16]1(=O)[CH2:20][CH2:19][C:18](=[O:21])[CH2:17]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]([CH:13]([O:15][C:16]3[CH2:20][CH2:19][C:18](=[O:21])[CH:17]=3)[CH3:14])=[CH:11][N:12]=2)=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)C1
Reactant: CC(O)c1cnc(-c2ccc(Cl)cc2)s1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(OC1=CC(=O)CC1)c1cnc(-c2ccc(Cl)cc2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.9 %

Procedure:
To a solution of 1-[2-(4-Chloro-phenyl)-thiazol-5-yl]-ethanol (4.1 g, 17.1 mmol) in anhydrous THF (100 ml), at 0° C. under an atmosphere of nitrogen was added cyclopentane-1,3-dione (2.18 g, 22.23 mmol), followed by triphenylphosphine (5.83 g, 22.23 mmol). Diisopropylazodicarboxylate (4.31 ml, 22.23 mmol) was then added dropwise over a period of 5 minutes and the reaction allowed to warm to room temperature and stirred for 2 hours. The crude reaction mixture was dry loaded onto silica and purified by flash chromatography to give 3-{1-[2-(4-Chloro-phenyl)-thiazol-5-yl]-ethoxy}-cyclopent-2-enone (2.29 g).
Reaction SMILES: C(OCCOC1C=CC([C:15]2[CH:16]=[CH:17][C:18]3[N:24](CCCOCC)[CH2:23][CH2:22][C:21]([C:31](O)=[O:32])=[CH:20][C:19]=3[CH:34]=2)=CC=1)CCC.S(Cl)(Cl)=O.C[N:40](C=O)C>C1COCC1>[NH:24]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:34][C:19]=2[CH:20]=[C:21]([C:31]([NH2:40])=[O:32])[CH2:22][CH2:23]1
Reactant: CN(C)C=O
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CCCOCC)cc1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: NC(=O)C1=Cc2ccccc2NCC1
Reaction time: 1.5 h

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-(3-ethoxypropyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (250 mg) in THF (10 ml) were added thionyl chloride (0.078 ml) and DMF (one droplet) at room temperature, and the mixture was stirred for 1.5 hours. The solvent was evaporated under reduced pressure, and the resulting residue was dissolved in THF (20 ml), which was added dropwise to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (128 mg) and triethylamine (0.44 ml) in THF (3 ml) at 0° C. The mixture was stirred at room temperature for 64 hours, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried with magnesium sulfate. After concentration under reduced pressure, the residue was purified with column chromatography (ethanol:ethyl acetate=1:4), and the resulting crystals were purified by recrystallization (hexane-ethyl acetate) to give 7-[4-(2-butoxyethoxy)phenyl]-1-(3-ethoxypropyl)-N-[4-[N-methyl-N-tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 106) (224 mg) as yellow crystals.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[O:29][NH2:30].ON1C2C=CC=CC=2N=N1>C(Cl)Cl>[C:1]1([CH2:7][N:8]2[CH2:9][CH2:10][N:11]([C:14]3[CH:15]=[CH:16][C:17]([C:18]([NH:30][O:29][CH:24]4[CH2:25][CH2:26][CH2:27][CH2:28][O:23]4)=[O:19])=[CH:21][CH:22]=3)[CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Reactant: NOC1CCCCO1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(NOC1CCCCO1)c1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Yield: 95.9 %

Procedure:
A mixture of 4-[4-(phenylmethyl)-1-piperazinyl]-benzoic acid (0.0145 mol), O-(tetrahydro-2H-pyran-2-yl)-hydroxylamine (0.029 mol), N,N′-methanetetrayl-biscyclohexanamine (0.0145 mol) and 1-hydroxy-1H-benzotriazole (0.021 mol) in DCM p.a. (200 ml) was stirred at room temperature over the weekend. The reaction mixture was washed with water, dried (MgSO4), filtered and the solvent was evaporated. The residue was crystallized from EtOAc, filtered off and dried, yielding 3.5 g and another crop: 2.0 g, total yielding 5.5 g (95%) of 4-[4-(phenylmethyl)-1-piperazinyl]-N—[(tetrahydro-2H-pyran-2-yl)oxy]-benzamide (interm. 8).
Reaction SMILES: Br[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3]1.[N-:12]=[N+:13]=[N-:14].[Na+]>CN(C=O)C>[N:12]([CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3]1)=[N+:13]=[N-:14]
Reactant: O=C1CC(Br)c2ccccc21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC1CC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86 %

Procedure:
To a stirring solution of 3-Bromo indan-1-one (400 mg, 1.90 mmol) in DMF (5 ml) was added sodium azide (1.98 g, 0.03 mol). The reaction was allowed to stir at room temperature for 15 mins. The product was partitioned between water (10 ml) and ether (10 ml). The ether layers were combined and the crude reaction mixture was passed through a plug of flash silica, eluting with petroleum ether:ethyl acetate (9:1). The product was isolated as an orange oil (283 mg, 86%).
Reaction SMILES: [OH:1][C:2]([CH3:27])([CH3:26])[C@H:3]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14](Br)[N:15]=2)[N:10]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:7])[CH3:4].[Cl:28][C:29]1[CH:37]=[C:36]2[C:32]([C:33]([Sn](CCCC)(CCCC)CCCC)=[N:34][N:35]2[CH3:38])=[CH:31][CH:30]=1>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[OH:1][C:2]([CH3:27])([CH3:26])[C@H:3]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:33]3[C:32]4[C:36](=[CH:37][C:29]([Cl:28])=[CH:30][CH:31]=4)[N:35]([CH3:38])[N:34]=3)[N:15]=2)[N:10]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:7])[CH3:4]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(C)(C)O
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2cc(Cl)ccc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)C(C)(C)O
Temperature: 90 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
In a round-bottomed flask, 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-2-hydroxy-1,2-dimethyl-propyl)-amide (120 mg, 0.26 mmol) and 6-chloro-1-methyl-3-tributylstannyl-1H-indazole (319 mg, 0.42 mmol) were dissolved in DMF (2.5 ml). The flask was evacuated and backfilled with argon then tetrakis(triphenylphosphine)palladium(0) (16 mg, 0.014 mmol) and copper(I) iodide (10 mg, 0.053 mmol) were added. The reaction mixture was stirred at 90° C. in an oil bath overnight then cooled to room temperature, quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with MeOH/CH2Cl2/0.5% NH4OH (gradient 0-2% MeOH) to afford 122 mg (86%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-2-hydroxy-1,2-dimethyl-propyl)-amide as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:18][CH3:19])[C:4]2[C:9]([C:10](=[O:16])[C:11]=1[C:12]([NH:14][CH3:15])=[O:13])=[CH:8][CH:7]=[C:6](Cl)[N:5]=2.[CH2:20]([NH:23][C:24](=[O:27])[O:25][CH3:26])[C:21]#[CH:22]>CN(C=O)C.CCN(CC)CC.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[NH2:1][C:2]1[N:3]([CH2:18][CH3:19])[C:4]2[N:5]=[C:6]([C:22]#[C:21][CH2:20][NH:23][C:24](=[O:27])[O:25][CH3:26])[CH:7]=[CH:8][C:9]=2[C:10](=[O:16])[C:11]=1[C:12](=[O:13])[NH:14][CH3:15]
Reactant: C#CCNC(=O)OC
Reactant: CCn1c(N)c(C(=O)NC)c(=O)c2ccc(Cl)nc21
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCn1c(N)c(C(=O)NC)c(=O)c2ccc(C#CCNC(=O)OC)nc21

Procedure:
A suspension of 0.8 g (2.85 mmol) of 2-amino-7-chloro-1-ethyl-N-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide in 22 ml of a DMF/Et3N (v/v; 2.2/1) mixture is placed in a 10 ml microwave tube. Argon is sparged into this suspension for 10 minutes and then 0.98 g of methyl (prop-2-yn-1-yl)carbamate (8.66 mmol), 0.076 g of CuI (0.40 mmol) and 0.139 g of bis(triphenylphosphine)palladium(II)dichloride (0.20 mmol) are successively added.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.[C:27]([O-])(=[O:29])C.[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]([C:14]2[CH:15]=[CH:16][C:17]([CH:27]=[O:29])=[CH:18][CH:19]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)[O-]
Reactant: Brc1ccc(CN(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=Cc1ccc(N(Cc2ccc(Br)cc2)c2ccccc2)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
In an argon atmosphere, N-(4-bromobenzyl)diphenylamine (169 mg, 0.500 mmol) obtained in Example 64 was dissolved in dimethylformamide (1.5 mL), and phosphorus oxychloride (0.116 mL, 1.25 mmol) was added thereto, followed by stirring at 100° C. for 30 minutes. The reaction liquid was cooled to room temperature, poured into saturated sodium acetate aqueous solution, and was extracted with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:hexane/ethyl acetate=4/1) to give 4-[N-(4-bromobenzyl)-N-phenylamino]-benzaldehyde (159 mg, 87%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:25][CH:26]1[CH:31]2[CH2:32][CH2:33][N:28]([CH2:29][CH2:30]2)[CH2:27]1>>[N:28]12[CH2:33][CH2:32][CH:31]([CH2:30][CH2:29]1)[CH:26]([NH:25][C:10]([C:8]1[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=1)=[O:12])[CH2:27]2
Reactant: NC1CN2CCC1CC2
Reactant: O=C(O)c1ccc2c(c1)OCO2
Agent: O=C(n1ccnc1)n1ccnc1
Product: O=C(NC1CN2CCC1CC2)c1ccc2c(c1)OCO2

Procedure:
Following the procedure of Example 22, 1,3-benzodioxole-5-carboxylic acid, 1,1'-carbonyldiimidazole and 3-aminoquinuclidine are reacted to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]=[C:4]([C:11]([OH:13])=[O:12])[CH:3]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[O:17]1[CH2:18][CH2:19][N:14]([C:2]2[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]=[C:4]([C:11]([OH:13])=[O:12])[CH:3]=2)[CH2:15][CH2:16]1
Reactant: C1COCCN1
Reactant: O=C(O)c1cc(Cl)cc(C(=O)O)n1
Product: O=C(O)c1cc(N2CCOCC2)cc(C(=O)O)n1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
4-chloro-pyridine-2,6-dicarboxylic acid (0.025 mol, 5.0 g) is slowly added under stirring to a solution of morpholine (0.250 mol, 21.6 g) at room temperature. Care is taken to avoid a too-fast addition leading to local temperature increase. Precipitation of a solid is observed. The reaction mixture is heated at 120° C. for 2 hr. By gradually heating the reaction mixture becomes solid. After cooling at 60° C., H20 (80 ml) is added and the mixture is stirred for 30 min. until the solid is completely dissolved. The solution is then acidified with 2M HCl until pH=1. The formed precipitate is filtered, washed twice H2O and dried overnight at 70° C. (70%)
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[N:11]([N:16]=[CH:17][C:18]=2[C:19](OC)=[O:20])[CH:12]=[C:13]([Cl:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([N:16]=[CH:17][C:18]=2[CH2:19][OH:20])[CH:12]=[C:13]([Cl:15])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cnn2cc(Cl)cc(OCc3ccccc3)c12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cnn2cc(Cl)cc(OCc3ccccc3)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 4-(benzyloxy)-6-chloropyrazolo[1,5-a]pyridine-3-carboxylate (220 mg, 0.692 mmol) in THF (3.0 mL) at 0° C. was added lithium aluminum hydride (0.783 mL, 0.783 mmol, 1M solution in THF). The reaction was warmed to room temperature and was stirred for 30 minutes. The reaction was quenched by the addition of a saturated aqueous solution of KHSO4 and was then diluted with EtOAc. The layers were separated and the aqueous layer was washed with EtOAc several times until no longer cloudy. Combined organics were washed with brine, dried (MgSO4), filtered and concentrated to afford (4-(benzyloxy)-6-chloropyrazolo[1,5-a]pyridin-3-yl)methanol which was used directly in the next reaction. LCMS-ESI+ (m/z): [M+H]+ calcd for C15H13ClN2O2: 289.1; found 289.0.
Reaction SMILES: F[C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][C:9]2[S:13][C:12]([NH:14][C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=3)=[N:11][C:10]=2[C:25]([NH2:27])=[O:26])=[O:7])=[CH:4][CH:3]=1.[NH2:30][CH2:31][CH2:32][OH:33]>CN1C(=O)CCC1.O>[OH:33][CH2:32][CH2:31][NH:30][C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][C:9]2[S:13][C:12]([NH:14][C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=3)=[N:11][C:10]=2[C:25]([NH2:27])=[O:26])=[O:7])=[CH:4][CH:3]=1
Reactant: NCCO
Reactant: NC(=O)c1nc(Nc2ccc3ccccc3c2)sc1NC(=O)c1ccc(F)cc1
Solvent: O
Solvent: CN1CCCC1=O
Product: NC(=O)c1nc(Nc2ccc3ccccc3c2)sc1NC(=O)c1ccc(NCCO)cc1
Yield: 31.3 %

Procedure:
A solution of 5-(4-fluorobenzamido)-2-(naphthalen-2-ylamino)thiazole-4-carboxamide (0.10 g, 0.25 mmol) and 2-aminoethanol (0.15 g, 2.46 mmol) in NMP (1 mL) was treated using a microwave synthesizer for 1 hr (CEM Corp., 180° C.). The, reaction mixture was diluted with water (3 mL), and the resulting solids were collected by filtration. The solids were washed with water, and dried to give 0.035 g (31% yield) of the titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]3[N:16]=[C:15](O)[O:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.O=P(Cl)(Cl)[Cl:26]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]3[N:16]=[C:15]([Cl:26])[O:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nc(C2(c3ccc(Br)cc3)CCC2)no1
Solvent: c1ccncc1
Product: Clc1nc(C2(c3ccc(Br)cc3)CCC2)no1
Temperature: 90 °C
Reaction time: 18 h
Yield: 59.5 %

Procedure:
To a solution of R109 (500 mg, 1.694 mmol) in pyridine (1.618 mL, 20 mmol) is added POCl3 (1.551 mL, 16.94 mmol) in a pressure flask. The reaction mixture is stirred at 90° C. for 18 hours. After this time, the reaction mixture is poured into ice water and extracted with EA twice. The organics are combined and washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude is purified by flash chromatography (SiO2, 5-40% EA/Heptane) to afford the title compound (316 mg); no ionization.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].S(=O)(=O)(O)O.[CH2:10]([OH:13])[CH2:11]C>>[CH:11]1([NH:1][C:2]([NH2:4])=[O:3])[NH:4][C:2](=[O:3])[NH:1][C:10]1=[O:13]
Reactant: NC(N)=O
Reactant: CCCO
Agent: O=S(=O)(O)O
Product: NC(=O)NC1NC(=O)NC1=O
Temperature: 25 °C

Procedure:
A mixture of 26.4 g of glyoxylic acid propyl ester propyl hemiacetal (0.15 mol), 30.0 g of urea (0.5 mol), 600 g of propanol and 7.5 g of 8% strength propanolic sulfuric acid was heated under reflux for 4 hours. Thereafter, the reaction had ended and the reaction mixture was cooled to room temperature, whereupon a colorless precipitate separated out, which was filtered off, washed with methanol and dried in vacuo at 50° C. 13.6 g, that is to say 42% of theory, of crystalline allantoin acid propyl ester were obtained by this reaction.