Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@H:11]3[C@@H:15]([CH2:16][CH3:17])[CH2:14][N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:12]3)=[C:8]([C:25](=[O:27])[NH2:26])[CH:7]=[N:6][N:5]2[CH:28]=1.[CH:29](NC(C)C)(C)[CH3:30].C([Si](C)(C)C)#C.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:25]([C:8]1[CH:7]=[N:6][N:5]2[CH:28]=[C:2]([C:29]#[CH:30])[CH:3]=[C:4]2[C:9]=1[NH:10][C@H:11]1[C@@H:15]([CH2:16][CH3:17])[CH2:14][N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])[CH2:12]1)(=[O:27])[NH2:26]
Reactant: CC[C@H]1CN(C(=O)OC(C)(C)C)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Reactant: CC(C)NC(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#C[Si](C)(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C#Cc1cc2c(N[C@@H]3CN(C(=O)OC(C)(C)C)C[C@@H]3CC)c(C(N)=O)cnn2c1
Temperature: 25 °C
Yield: 57.9 %

Procedure:
A mixture of (3S,4S)-tert-butyl 3-((6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)-4-ethylpyrrolidine-1-carboxylate (330 mg, 0.730 mmol), bis(triphenylphosphine)-palladium(II) chloride (154 mg, 0.219 mmol) and copper(I) iodide (41.7 mg, 0.219 mmol) in DMF (4 mL) was stirred and degassed by bubbling nitrogen through for 15 minutes. While maintaining positive nitrogen pressure, bis(isopropyl)amine (2.58 mL, 18.24 mmol) and ethynyltrimethylsilane (0.515 mL, 3.65 mmol) were added. The flask was immediately placed in a hot oil bath at 90° C. After stirring overnight at 90° C., the reaction was complete. The reaction was then cooled to room temperature and diluted with ethyl acetate (50 mL). This mixture was filtered through Celite, and was concentrated to an oil. This crude material was suspended in MeOH (5 mL) and potassium carbonate (121 mg, 0.876 mmol) was added. After stirring the mixture at room temperature for 1 h, the insoluble solids were removed by filtration, and the resulting solution was concentrated to an oil. This crude material was purified by flash chromatography, eluting with 0-100% EtOAc in hexanes. Concentration of the pure fractions afforded a brown solid as the title compound (168 mg, 56.7% yield). 1H NMR (400 MHz, DMSO-d6) δ 11.14 (t, J=9.0 Hz, 1H), 8.27 (s, 1H), 7.96 (d, J=1.3 Hz, 1H), 7.06 (s, 1H), 4.85-4.65 (m, 1H), 4.10 (d, J=1.8 Hz, 1H), 3.73-3.54 (m, 2H), 3.43-3.24 (m, 1H), 3.08-2.92 (m, 1H), 2.44-2.26 (m, 1H), 1.55-1.43 (m, 2H), 1.36 (d, J=15.4 Hz, 9H), 0.86 (t, J=7.4 Hz, 3H). MS (ES+) m/z: 398.2 (M+H); LC retention time: 2.993 min (analytical HPLC Method O).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Cl:11][C:12]1[CH:33]=[C:32]([O:34][CH2:35][CH:36]=[C:37]([Cl:39])[Cl:38])[CH:31]=[C:30]([Cl:40])[C:13]=1[O:14][CH2:15][CH:16]([OH:29])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1.C(N(CC)CC)C>ClCCl.O>[Cl:11][C:12]1[CH:33]=[C:32]([O:34][CH2:35][CH:36]=[C:37]([Cl:38])[Cl:39])[CH:31]=[C:30]([Cl:40])[C:13]=1[O:14][CH2:15][C:16](=[O:29])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1
Reactant: OC(COc1ccc(C(F)(F)F)cc1)COc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C(COc1ccc(C(F)(F)F)cc1)COc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
1.15 ml of dimethyl sulfoxide are added at −60° C. in the course of 5 minutes to 0.63 ml of oxalyl chloride in 50 ml of dichloromethane. After 40 minutes, a solution of 3.4 g of 1-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-3-(4-trifluoromethyl-phenoxy)-propan-2-ol in 30 ml of dichloromethane is added dropwise in the course of 10 minutes. After 40 minutes, 4.5 ml of triethylamine are added and the reaction mixture is slowly heated to room temperature. The reaction mixture is then poured into water and extracted with dichloromethane. After concentration of the organic phase and crystallisation from diethyl ether/hexane, 1-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-3-(4-trifluoromethyl-phenoxy)-propan-2-one is obtained. 1H-NMR (CDCl3) 300 MHz: 4.61 (d, 2H), 4.74 (s, 2H), 5.21 (s, 2H), 6.12 (t, 1H), 6.90 (s, 2H), 7.11 (d, 2H), 7.59 (d, 2H)
Reaction SMILES: [N+:1]([CH2:4][C:5]1([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH:10]2[CH:6]1[CH:7]=[CH:8][CH2:9]2)([O-])=O.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:1][CH2:4][C:5]1([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH:10]2[CH:6]1[CH:7]=[CH:8][CH2:9]2
Reactant: CC(C)(C)OC(=O)CC1(C[N+](=O)[O-])CC2CC=CC21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)CC1(CN)CC2CC=CC21
Reaction time: 4.5 h

Procedure:
Tert-butyl [6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-ylacetate] (1.98 g, 7.41 mmol) was dissolved in ethanol (20 mL) and water (10 mL). To the solution, iron powder (2.07 g, 37.0 mmol) and ammonium chloride (392.7 mg, 7.41 mmol) were added, and the mixture was stirred for 4.5 hours under heating to reflux. The mixture was allowed to cool, then diluted with saturated saline, a saturated aqueous solution of sodium bicarbonate, and ethyl acetate, and filtered through Celite to remove insoluble matter. The filtrate was separated into organic and aqueous layers. The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure to obtain the compound of interest as a pale yellow solid (1.99 g, this compound was used directly in the next reaction without being purified).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]([OH:15])=[O:14])=[CH:6]2.O[CH2:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([NH:24][C:25]([C:27]2[CH:28]=[CH:29][C:30]3[S:35][CH2:34][C:33](=[O:36])[NH:32][C:31]=3[CH:37]=2)=[O:26])[CH2:20][CH2:19]1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.CN(C)C1C=CN=CC=1>[O:36]=[C:33]1[NH:32][C:31]2[CH:37]=[C:27]([C:25]([NH:24][C@H:21]3[CH2:22][CH2:23][C@H:18]([CH2:17][O:14][C:13]([C:7]4[CH:8]=[N:9][C:10]5[C:5]([CH:6]=4)=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=5)=[O:15])[CH2:19][CH2:20]3)=[O:26])[CH:28]=[CH:29][C:30]=2[S:35][CH2:34]1
Reactant: O=C1CSc2ccc(C(=O)N[C@H]3CC[C@H](CO)CC3)cc2N1
Reactant: COc1ccc2ncc(C(=O)O)cc2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: COc1ccc2ncc(C(=O)OC[C@H]3CC[C@H](NC(=O)c4ccc5c(c4)NC(=O)CS5)CC3)cc2c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
6-Methoxy-quinoline-3-carboxylic acid (27 mg, 0.13 mmol, 1.0 eq) is added at room temperature to a stirred solution of 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid (trans-4-hydroxymethyl-cyclohexyl)-amide (47 mg, 0.13 mmol, 1.0 eq) in N,N-dimethylformamide (2 mL), followed by N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (28 mg, 0.15 mmol, 1.10 eq) and 4-(dimethylamino)pyridine (24 mg, 0.20 mmol, 1.50 eq). After 15 hours stirring at room temperature, solvent is evaporated and the residue is extracted with dichloromethane (3×10 mL) and water (10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by preparative HPLC to afford 6-methoxy-quinoline-3-carboxylic acid trans-4-[(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl)-amino]-cyclohexylmethyl ester as a white solid (7 mg, 10% yield).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8]2[N:28]=[C:11]3[CH:12]=[C:13]([NH:16][C:17]([C:19]4[N:23]([CH3:24])[N:22]=[CH:21][C:20]=4[C:25]([OH:27])=O)=[O:18])[CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[F:1][C:2]1[N:7]=[C:6]([C:8]2[N:28]=[C:11]3[CH:12]=[C:13]([NH:16][C:17]([C:19]4[N:23]([CH3:24])[N:22]=[CH:21][C:20]=4[C:25]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[O:27])=[O:18])[CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3cccc(F)n3)nc2c1
Reactant: C1COCCN1
Product: Cn1ncc(C(=O)N2CCOCC2)c1C(=O)Nc1ccn2nc(-c3cccc(F)n3)nc2c1
Yield: 77.6 %

Procedure:
The product was prepared in the same manner as described in example 3 using 5-(2-(6-fluoropyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (60 mg, 157 μmol) and morpholine (41.1 mg, 472 μmol) as starting materials. The reaction affords 2-methyl-4-(morpholine-4-carbonyl)-2H-pyrazole-3-carboxylic acid [2-(6-fluoro-pyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-amide (54.9 mg, 77.5%) as white solid. MS: m/z=451.0 (M+H+).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1)=[O:3].[CH:13](=O)[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[Na+]>C(O)C>[N+:10]([C:6]1[CH:5]=[C:4]([C:2](=[O:3])[CH:1]=[CH:13][CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=[CH:8][CH:7]=1)([O-:12])=[O:11]
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1
Reactant: O=CC=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(C=CC=Cc1ccccc1)c1cccc([N+](=O)[O-])c1
Yield: 68.6 %

Procedure:
Using a procedure similar to that described in Example D, 33 g of 3-nitroacetophenone and 26.2 g of cinnamaldehyde in 200 ml of ethanol were condensed in the presence of 10 ml of a 5% strength NaOH solution to give 38 g (71% of theory) of 1-(3-nitrophenyl)-5-phenyl-2,4-pentadien-1-one of melting point 127°-129° C.
Reaction SMILES: O[C:2]1([C:38]2[CH:43]=[CH:42][C:41]3[O:44][CH2:45][O:46][C:40]=3[CH:39]=2)[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:12][CH2:13][CH3:14])=[CH:8][CH:9]=2)[C:4]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2[O:23][CH2:24][CH2:25][O:26]CC2C=CC=CC=2)=[C:3]1[C:34]([O:36]C)=[O:35].C(O)C>C(OC(=O)C)C>[OH:26][CH2:25][CH2:24][O:23][C:16]1[CH:17]=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:15]=1[C@@H:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH3:14])[CH:6]=2)[C@H:2]([C:38]2[CH:43]=[CH:42][C:41]3[O:44][CH2:45][O:46][C:40]=3[CH:39]=2)[C@H:3]1[C:34]([OH:36])=[O:35]
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCCOCc1ccccc1)=C(C(=O)OC)C2(O)c1ccc2c(c1)OCO2
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCOc1ccc2c(c1)[C@@H](c1ccc(OC)cc1OCCO)[C@H](C(=O)O)[C@H]2c1ccc2c(c1)OCO2
Reaction time: 48 h
Yield: 83.3 %

Procedure:
A mixture of methyl (1SR)-1hydroxy-3-[2-(2-benzyloxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxy phenyl)-5-propoxyindene-2-carboxylate (88 g, 0.141 moles) 10% palladium on carbon (21 g), 0.65L of absolute ethanol and 0.65L of ethylacetate was hydrogenated at 50 psi, 55° C. for 48 hrs. The catalyst was filtered off, and the filtrate concentrated in vacuo to give an amorphous glass. Crystallization from 350 mL of absolute ethanol gave 59.5 g (81%) of white solid; m.p. 165°-168° C.
Reaction SMILES: [N:1]([O-])=O.[Na+].Cl.[F:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][NH2:14])=[CH:9][CH:8]=1>O.Cl.C(OCC)C>[N:13]([C:10]1[CH:11]=[CH:12][C:7]([F:6])=[CH:8][CH:9]=1)=[N+:14]=[N-:1]
Reactant: NNc1ccc(F)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: [N-]=[N+]=Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 194 %

Procedure:
A solution of 262 mg of sodium nitrite dissolved in 2.0 ml of water was dropped into a solution of 3.09 g of 4-fluorophenylhydrazine hydrochloride in 20 ml of concentrated hydrochloric acid and 10 ml of diethyl ether under cooling with ice. Temperature of the reaction solution was raised to room temperature followed by stirring for 3 hours. The reaction solution was diluted with diethyl ether, washed with water and then with a saturated saline solution and dried over sodium sulfate. The solvent was evaporated in vacuo to give 1.01 g of the crude title compound as a brown oily substance.
Reaction SMILES: [F:1][C:2]1[C:20](F)=[CH:19][C:5]2=[N:6][C:7]3[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.[F:22][C:23]1[CH:24]=[C:25]([CH:29]2[CH2:34][NH:33][CH2:32][CH2:31][NH:30]2)[CH:26]=[CH:27][CH:28]=1>>[F:1][C:2]1[C:20]([N:33]2[CH2:32][CH2:31][NH:30][CH:29]([C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([F:22])[CH:24]=3)[CH2:34]2)=[CH:19][C:5]2=[N:6][C:7]3[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1
Reactant: Fc1cccc(C2CNCCN2)c1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(F)cc3nc21
Product: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCNC(c5cccc(F)c5)C4)cc3nc21
Yield: 86.2 %

Procedure:
The reaction is performed under the conditions of Example 16, but starting with 7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]-naphthyridine-3-carboxylic acid (1.3 g) and (RS)-2-(3-fluorophenyl)piperazine (1.8 g). After 1 recrystallization in dimethylformamide (50 cc) containing ethanol (50%), (RS)-7-fluoro-8-[3-(3-fluorophenyl)-1-piperazinyl]-1-methyl-4-oxo -1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (1.74 g) is obtained in the form of a yellow solid, m.p. 254° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[CH2:10]([O:13][CH2:14][CH2:15]Br)[CH2:11][CH3:12].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>O.CN(C=O)C>[CH2:10]([O:13][CH2:14][CH2:15][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1)[CH2:11][CH3:12]
Reactant: OCc1ccc(O)cc1
Reactant: CCCOCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOCCOc1ccc(CO)cc1
Temperature: 90 °C
Reaction time: 72 h

Procedure:
A mixture of 4-hydroxybenzyl alcohol (3.00 g), 2-bromoethyl propyl ether (4.0 ml), sodium iodide (4.75 g), potassium carbonate (6.68 g) and DMF (30 ml) was stirred at 90° C. for 3 days. The reaction mixture was mixed with water, and was extracted with ethyl acetate. The organic layer was washed with water and an aqueous saturated solution of sodium chloride, and was dried with magnesium sulfate. After concentration under reduced pressure, the residue was subjected to separation and purification using column chromatography (ethyl acetate:hexane 1:2→1:1) to obtain 4-(2-propoxyethoxy)benzyl alcohol (2.27 g) as a light yellow, oily substance.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[NH:8].O.[OH-].[Na+].[CH3:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=1[N:20]=[C:21]=[O:22]>C1C=CC=CC=1>[CH3:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH3:12])[C:14]=1[NH:20][C:21]([N:8]=[C:4]1[CH2:5][CH2:6][CH2:7][N:3]1[CH3:2])=[O:22]
Reactant: CN1CCCC1=N
Reactant: Cc1cccc(C)c1N=C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: Cc1cccc(C)c1NC(=O)N=C1CCCN1C

Procedure:
To a stirring solution of 6.73 g. (0.05 mole) of 1-methyl-2-iminopyrrolidine hydrochloride in about 2 ml. of water is added about 50 ml. of benzene followed by 10 ml. of 50% NaOH. After stirring 1 min. the benzene layer is decanted onto anhydrous potassium carbonate. The extraction is repeated twice. The combined benzene extracts are filtered from a drying agent (dicalite pad) and rinsed well with dry benzene. To the filtrate is added in one portion with stirring 7.36 g. (0.05 mole) of 2,6-dimethylphenylisocyanate. The reaction mixture is stirred overnight. Solvent removel and recrystallization from ethyl acetate-ether gives the product, 1-(2,6-dimethylphenyl)-3-(1-methyl-2-pyrrolidylidene)urea, as white crystals, m.p. = 119°-120° C.
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:22][C:3]=1[C:4]([NH:6][C:7]1[NH:8][N:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:11]=1)=[O:5].N1C=CC=CC=1.[CH3:38][N:39]([CH2:51][CH2:52][N:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1)[C:40]([C:42]1[CH:43]=[C:44]([CH:48]=[CH:49][CH:50]=1)[C:45](Cl)=[O:46])=[O:41]>ClCCl.C(OCC)(=O)C>[CH3:38][N:39]([CH2:51][CH2:52][N:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1)[C:40](=[O:41])[C:42]1[CH:50]=[CH:49][CH:48]=[C:44]([C:45]([NH:1][C:2]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:22][C:3]=2[C:4](=[O:5])[NH:6][C:7]2[NH:8][N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=3)[N:11]=2)=[O:46])[CH:43]=1
Reactant: Nc1ccc(N2CCCCC2)cc1C(=O)Nc1nc(-c2cccc(C(F)(F)F)c2)n[nH]1
Reactant: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)Cl)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2nc(-c3cccc(C(F)(F)F)c3)n[nH]2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 14.2 %

Procedure:
To a solution of 2-amino-5-(piperidin-1-yl)-N-(5-(3-(trifluoromethyl)phenyl)-2H-1,2,4-triazol-3-yl)benzamide (50 mg, 0.12 mmol, 1.00 equiv) in dichloromethane (3 mL) was added pyridine (73 mg, 0.92 mmol, 8.00 equiv) followed by the dropwise addition of a solution of 3-(methyl(2-morpholinoethyl)carbamoyl)benzoyl chloride (54 mg, 0.17 mmol, 1.50 equiv) in dichloromethane (2 mL) and the resulting solution was stirred for 30 min at room temperature. The mixture was diluted with 50 mL of ethyl acetate, washed with 2×20 mL of NH4Cl and 2×20 mL of brine, dried over anhydrous sodium sulfate and then concentrated under vacuum. The crude product (50 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 12 mg (10%) of a yellow solid. 1H-NMR (300 MHz, CD3OD, ppm): δ 8.34(m, 3H), 8.17(t, J=7.8 Hz, 2H), 7.73(m, 5H), 7.42 (m, 1H), 3.98(s, 2H), 3.55(m, 3H), 3.40(m, 5H), 3.29(m, 1H), 3.09(m, 3H), 1.86(d, J=4.8 Hz, 4H), 1.71(t, J=5.1 Hz, 2H). MS (ES, m/z): 705 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:14]([C:15]([OH:17])=O)[CH2:13][CH2:12][CH:11]2[CH:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:19][C:20]1([C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)[CH2:22][CH2:21]1>>[CH3:30][O:29][C:27]([C:26]1[CH:31]=[CH:32][C:23]([C:20]2([NH:19][C:15]([C@H:14]3[CH2:13][CH2:12][CH:11]4[CH:9]([CH2:10]4)[N:8]3[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:17])[CH2:21][CH2:22]2)=[CH:24][CH:25]=1)=[O:28]
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Reactant: CC(C)(C)OC(=O)N1C2CC2CC[C@@H]1C(=O)O
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)[C@H]3CCC4CC4N3C(=O)OC(C)(C)C)CC2)cc1
Yield: 16.3 %

Procedure:
The title compound (D70) (28 mg) was prepared according to the general procedure for amides preparation (Method C) starting from (3R)-2-(tert-butoxycarbonyl)-2-azabicyclo[4.1.0]heptane-3-carboxylic acid (D22) (100 mg) and methyl 4-(1-aminocyclopropyl)benzoate hydrochloride (103 mg). Reaction time: 1 h
Reaction SMILES: II.O[PH2]=O.[N:6]1[CH:7]=[CH:8][N:9]2[CH:14]=[C:13]([CH:15]([C:17]3[N:21]4[N:22]=[C:23]([C:26]5[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=5)[CH:24]=[CH:25][C:20]4=[N:19][CH:18]=3)O)[CH:12]=[CH:11][C:10]=12>C(O)(=O)C.O>[N:6]1[CH:7]=[CH:8][N:9]2[CH:14]=[C:13]([CH2:15][C:17]3[N:21]4[N:22]=[C:23]([C:26]5[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=5)[CH:24]=[CH:25][C:20]4=[N:19][CH:18]=3)[CH:12]=[CH:11][C:10]=12
Reactant: Cn1cc(-c2ccc3ncc(C(O)c4ccc5nccn5c4)n3n2)cn1
Agent: II
Agent: O=[PH2]O
Solvent: CC(=O)O
Solvent: O
Product: Cn1cc(-c2ccc3ncc(Cc4ccc5nccn5c4)n3n2)cn1
Temperature: 150 °C

Procedure:
Iodine (50.8 mg, 0.2 mmol) and H3PO2 (0.11 mL of a 50% aqueous solution, 1.0 mmol) were added to a solution of (rac)-Imidazo[1,2-a]pyridin-6-yl-[6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-3-yl]-methanol (Example 9, 34.5 mg, 0.1 mmol) in acetic acid (0.5 mL). The RM was heated at 150° C. for 1 h. The RM was diluted with water and extracted with EtOAc. The organic layer was separated and washed with 10% Na2CO3-sol then dried on Na2SO4, filtered and concentrated. Combined aqueous layers were completely neutralized and again extracted with DCM containing little MeOH. Organic layers were evaporated and both crudes from the two extractions were purified together by flash chromatography (CombiFlash® Companion System®, with RediSep® silica gel column, DCM/MeOH=95:5->80:20). The fractions containing the product were evaporated and the residue taken in EtOAc and pentane, filtered and dried under high vacuum to afford the title compound as beige crystals (tR 2.70 min (conditions 3), MH+=330.2, 1H-NMR in DMSO-d6: 8.58 (s, 1H); 8.44 (s, 1H); 8.12 (s, 1H); 8.08 (d, 1H); 7.90 (s, 1H); 7.62 (s, 1H); 7.54-7.44 (m, 3H); 7.22 (d, 1H); 4.31 (s, 2H); 3.90 (s, 3H)).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1I.[OH:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:33]1[CH:34]=[CH:35][C:30]([OH:29])=[CH:31][CH:32]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3I)n(-c3ccccc3)c(=O)c12
Reactant: OB(O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3ccc(O)cc3)n(-c3ccccc3)c(=O)c12
Yield: 7.4 %

Procedure:
(S)-2-(1-((6-Amino-5-iodopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.10 mol) was treated with (4-hydroxyphenyl)boronic acid (21 mg, 0.15 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (14 mg, 0.02 mol) and sodium carbonate (2M, 231 μl, 0.46 mol) according to the method described in Example 3 to give 5 mg (11% yield) of the title compound as a white solid. Purity 100%.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:14][CH2:13][C@@H:12]([CH2:15][OH:16])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1.[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-]>[C:21]1([CH2:20][CH2:19][CH2:18][O:16][CH2:15][C@@H:12]2[CH2:13][CH2:14][N:10]([C:8]([O:7][C:3]([CH3:6])([CH3:5])[CH3:4])=[O:9])[CH2:11]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCCCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CO)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](COCCCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.9 %

Procedure:
NaH (170 mg, 7.1 mmol, 2.0 equiv.) was added to a solution of 1-(tert-butoxycarbonyl)-3(R)-pyrrolidinylmethanol (500 mg, 2.49 mmol) in anhydrous THF (40 mL) with ice cooling under N2. The solution was stirred for 2 h at room temperature. (3-Bromopropyl)benzene (590 mg, 2.96 mmol, 1.2 equiv.) and n-Bu4NBr (80 mg, 0.25 mmol, 0.10 equiv.) were added, and the mixture was stirred overnight at 25° C. The reaction was then quenched with water. After concentration under vacuum, the solution was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was applied onto a silica gel column, which was eluted with EtOAc/petroleum ether 1:10 to afford the product (500 mg, 63%) as a yellowish oil. 1H NMR (CDCl3, 300 MHz) δ 7.33-7.19 (m, 5H), δ 3.55-3.31 (m, 7H), δ 3.11 (dd, 1H, J=10.8, 6.9 Hz), 2.71 (t, 2H) 2.48 (m, 1H), 1.87-2.01 (m, 3H), 1.71-1.64 (m, 1H), 1.48 (s, 9H). LC-MS (ESI) m/z 320 (M+H+).
Reaction SMILES: [C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:25]=[C:26]1[O:30][C:28](=[O:29])[CH2:27]1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[C:28]([O:11][CH2:10][CH2:9][CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)(=[O:29])[CH2:27][C:26]([CH3:25])=[O:30]
Reactant: OCCCC(c1ccccc1)c1ccccc1
Reactant: C=C1CC(=O)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)OCCCC(c1ccccc1)c1ccccc1
Temperature: 80 °C

Procedure:
825 mg (3.65 mmol) of 4,4-diphenylbutane-1-ol, 0.1 ml (0.72 mmol) of triethylamine and 0.40 ml (5.19 mmol) of diketene were stirred in 30 ml of toluene under heating at 80° C. for 4 hours. After the addition of saturated aqueous sodium hydrogencarbonate solution at room temperature followed by the extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound.