Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:6][C@@:5]([CH3:12])([C:7](OCC)=[O:8])[CH2:4][O:3]1.[H-].C([Al+]CC(C)C)C(C)C.CO.O>CCOCC>[CH:7]([C@@:5]1([CH3:12])[CH2:4][O:3][C:2]([CH3:13])([CH3:1])[O:6]1)=[O:8]
Reactant: CCOC(=O)[C@@]1(C)COC(C)(C)O1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CO
Solvent: O
Solvent: CCOCC
Product: CC1(C)OC[C@](C)(C=O)O1
Reaction time: 0.5 h

Procedure:
To a solution of 5 g of ethyl (R)-2,2,4-trimethyl-1,3-dioxolan-4-carboxylate in 30 ml of anhydrous ether, cooled down to -78°, were added dropwise while stirring for about 30 minutes, 4.55 g of diisobutylaluminium hydride in 25 ml of anhydrous ether. The temperature was held at -78° during the entire addition. The stirring was continued at -70° for a further 5 hours in order to complete the reaction. Excess reagent was then decomposed by cautious addition of a mixture of 2 ml of methanol and 2 ml of water, the cooling bath was removed and the reaction mixture was slowly brought to room temperature. While vigorously stirring under ice-cooling, 5 ml of 1-M sodium bicarbonate were added thereto. The addition of a total of 3 g of solid sodium bicarbonate in small portions led to the precipitation of aluminium hydroxide. After further vigorous stirring at 0° for 30 minutes, the precipitate was filtered off and washed three times with 30 ml of ether. The combined ether phases were dried over magnesium sulfate and the solvent was distilled off under normal pressure at about 65° bath temperature. The residue was distilled at about 80° bath temperature and 12 mmHg and there were thus obtained 3.2 g of (R)-4-formyl-2,2,4-trimethyl-1,3-dioxolan.
Reaction SMILES: [NH:1]([C:3](=[O:16])[CH2:4][CH:5]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6]1)[NH2:2].[Br:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[C:20]([F:27])[CH:19]=1>ClCCl>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:2][NH:1][C:3](=[O:16])[CH2:4][CH:5]2[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH2:6]2)=[O:26])=[C:20]([F:27])[CH:19]=1
Reactant: O=C=Nc1ccc(Br)cc1F
Reactant: CC(C)(C)OC(=O)N1CC(CC(=O)NN)C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(CC(=O)NNC(=O)Nc2ccc(Br)cc2F)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a round bottom flask under nitrogen, a solution of 1,1-dimethylethyl 3-(2-hydrazino-2-oxoethyl)-1-azetidinecarboxylate (15.18 mmol) in dichloromethane (20 mL) at 0° C. was treated with 4-bromo-2-fluorophenylisocyanate (15.18 mmol). The cooling bath was removed and the clear yellow solution was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo to afford the crude title compound as a white foamy solid. This material was used directly without further purification. MS(ES)+ m/e 445.2, 447.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]2[C:3]=1[CH2:4][CH:5]([CH3:14])[CH2:6][C:7]2=[O:13].C([Sn](CCCC)(CCCC)[C:20]1[S:21][CH:22]=[CH:23][N:24]=1)CCC>O1CCOCC1.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>[OH:12][C:9]1[CH:10]=[CH:11][C:2]([C:20]2[S:21][CH:22]=[CH:23][N:24]=2)=[C:3]2[C:8]=1[C:7](=[O:13])[CH2:6][CH:5]([CH3:14])[CH2:4]2
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: CC1CC(=O)c2c(O)ccc(Br)c2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC1CC(=O)c2c(O)ccc(-c3nccs3)c2C1
Yield: 61.1 %

Procedure:
A solution of 5-bromo-8-hydroxy-3-methyl-1,2,3,4-tetrahydronaphthalen-1-one (3.0 g, 0.012 mol) and 2-(tri-n-butylstannyl)thiazole (6.4 g, 0.17 mol) in dioxan (100 mL) was degassed with nitrogen for 30 min. Tetrakis(triphenylphosphine)palladium(0) (1 g) was added and the mixture heated at reflux for 48 h. The solvent was evaporated and the residue chromatographed on silica gel, eluting with EtOAc:hexane (1:4). The title compound (1.9 g, 62%) was isolated as a yellow oil. 1H NMR (360 MHz, CDCl3) δ 1.13 (3H, d, J=6.5 Hz), 2.20-2.34 (1H, m), 2.39-2.47 (1H, m), 2.73-2.83 (2H, m), 3.34-3.49 (1H, m), 6.90 (1H, d, J=8.8 Hz), 7.40 (1H, d, J=3.3 Hz), 7.73 (1H, d, J=8.8 Hz), 7.89 (1H, d, J=3.3 Hz), 12.93 (1H, s). MS (ES+) 260 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:6]=[CH:5][C:4]=1[C:18]1[N:23]=[N:22][C:21]([N:24]([CH3:35])[CH:25]2[CH2:30][C:29]([CH3:32])([CH3:31])[NH:28][C:27]([CH3:34])([CH3:33])[CH2:26]2)=[CH:20][CH:19]=1.Br[C:37]1[NH:38][CH:39]=[CH:40][N:41]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>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.O.CCO>[NH:41]1[CH:40]=[CH:39][N:38]=[C:37]1[C:7]1[CH:6]=[CH:5][C:4]([C:18]2[N:23]=[N:22][C:21]([N:24]([CH3:35])[CH:25]3[CH2:26][C:27]([CH3:33])([CH3:34])[NH:28][C:29]([CH3:31])([CH3:32])[CH2:30]3)=[CH:20][CH:19]=2)=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: Brc1ncc[nH]1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: COc1cc(-c2ncc[nH]2)ccc1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Temperature: 150 °C
Yield: 45.3 %

Procedure:
To a microwave vial was added 6-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (Intermediate 9-3, 100 mg, 0.21 mmol), 2-bromo-1H-imidazole (61.2 mg, 0.42 mmol), Na2CO3 (44 mg, 0.42 mmol), and Pd(PPh3)2Cl2 (14 mg, 0.02 mmol), followed by DME (1 mL)/EtOH 0.25 mL)/(H2O (0.25 mL). The vial was purged with N2 for 10 min and the reaction mixture was heated at 150° C. in a microwave reactor for 20 min. The reaction mixture was filtered through celite and the filter cake was washed with EtOAc. The filtrate was concentrated in vacuo to give the crude product which was purified by silica gel chromotography (5%-15% MeOH/DCM) to afford 6-(4-(1H-imidazol-2-yl)-2-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (40 mg, MS: 421.3 [M+H+]).
Reaction SMILES: [Na].[Cl-].NC(N)=[NH2+].[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][C:16]=1[Cl:17])[CH:13]([CH2:18][C:19]([O:21]CC)=[O:20])[N:12]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:11]2=[O:28]>C(O)C>[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][C:16]=1[Cl:17])[CH:13]([CH2:18][C:19]([OH:21])=[O:20])[N:12]([CH2:24][CH:25]([CH3:26])[CH3:27])[C:11]2=[O:28]
Reactant: CCOC(=O)CC1c2cc(Cl)c(Cl)cc2C(=O)N1CC(C)C
Agent: NC(N)=[NH2+]
Agent: [Cl-]
Agent: [Na]
Solvent: CCO
Product: CC(C)CN1C(=O)c2cc(Cl)c(Cl)cc2C1CC(=O)O
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 42.1 %

Procedure:
0.09 g of sodium is added to 5 cm3 of absolute ethanol under an inert atmosphere. After the sodium has totally disappeared, 0.04 g of guanidinium chloride is added. The reaction mixture is stirred under an inert atmosphere at a temperature in the region of 20° C. for 1.5 hours, followed by addition of a solution of 0.93 g of ethyl (5,6-dichloro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate in 10 cm3 of absolute ethanol. The reaction mixture is stirred at a temperature in the region of 20° C. for 18 hours and is then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is taken up in a mixture of 5 cm3 of water and 15 cm3 of diethyl ether and is then stirred at a temperature in the region of 20° C. for 1 hour. The mixture is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is taken up in a mixture of dichloromethane and ethyl acetate and then filtered. The filtrate is purified by chromatography under argon pressure (80 kPa), on a cartridge of silica gel (particle size 32-63 μm), eluting with a mixture of dichloromethane/methanol (95/5 by volume). The fractions comprising the expected product are combined and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is taken up in diethyl ether, triturated and then filtered. The solid is dried in a desiccator under reduced pressure (2 Pa) at a temperature in the region of 35° C. and then redissolved in 70 cm3 of ethyl acetate and treated with 50 cm3 of aqueous 1N sodium hydroxide solution. After separation of the phases by settling, the organic phase is washed with 50 cm3 of aqueous 1N sodium hydroxide solution. The aqueous extracts are combined and then treated with aqueous 5N hydrochloric acid solution to pH 1. After extraction with 3 times 50 cm3 of ethyl acetate, the organic extracts are combined, washed with 100 cm3 of saturated brine, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 0.36 g of (5,6-dichloro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetic acid is thus obtained in the form of a yellow solid. (Rf=0.33, thin layer chromatography on silica gel, eluent: dichloromethane/methanol (90/10 by volume)).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][C:13]2[N:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:7][C:6]=1[CH3:19])=O.[NH2:20][C:21]([NH2:23])=[S:22]>CCO>[CH3:19][C:6]1[CH:7]=[C:8]([O:12][C:13]2[N:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:9]=[C:10]([CH3:11])[C:5]=1[C:3]1[N:20]=[C:21]([NH2:23])[S:22][CH:2]=1
Reactant: NC(N)=S
Reactant: Cc1cc(Oc2ncccn2)cc(C)c1C(=O)CBr
Solvent: CCO
Product: Cc1cc(Oc2ncccn2)cc(C)c1-c1csc(N)n1
Yield: 16.1 %

Procedure:
A mixture of 2-bromo-1-(2,6-dimethyl-4-(pyrimidin-2-yloxy)phenyl)ethanone (6-2, 1.54 g, 4.79 mmol) and thiourea (0.370 g, 4.86 mmol) in 95% EtOH (6.9 mL) was heated at reflux for 60 min. The solution was concentrated and added with water and saturated aqueous Na2CO3 (1.0 mL). The resultant precipitate was filtered and recrystallized in toluene. The solids were filtered and dried under vacuum to give 4-(2,6-dimethyl-4-(pyrimidin-2-yloxy)phenyl)thiazol-2-amine (6-3, 0.23 g) as brown solids in 9.1% yield: 1H NMR (500 MHz, DMSO-d6) δ 8.64 (d, J=4.5 Hz, 2 H), 7.25 (m, 1 H), 6.99 (bs, 2 H), 6.89 (s, 2 H), 6.41 (s, 1 H), 2.11 (s, 6 H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C@@H:19]([NH2:21])[CH3:20])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.[NH2:22][C:23]1[C:28]([C:29]#[N:30])=[C:27](Cl)[N:26]=[CH:25][N:24]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:22][C:23]1[C:28]([C:29]#[N:30])=[C:27]([NH:21][C@H:19]([C:7]2[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)=[N:9][C:10]3[C:5]([CH:6]=2)=[CH:4][CH:3]=[C:2]([F:1])[CH:11]=3)[CH3:20])[N:26]=[CH:25][N:24]=1
Reactant: C[C@H](N)c1cc2ccc(F)cc2nc1-c1cccc(F)c1
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc(N)c1C#N)c1cc2ccc(F)cc2nc1-c1cccc(F)c1
Temperature: 100 °C
Yield: 16 %

Procedure:
To a solution of 2-((S)-1-(7-fluoro-2-(3-fluorophenyl)quinolin-3-yl)ethyl)-isoindoline-1,3-dione (60.0 mg, 145 μmol) in EtOH (2 mL) was added NH2NH2 (1.0 mL, 1.45 mmol, 10 eq) and the resulting solution was heated to 80° C. for 2 h. A precipitate was filtered away and the filtrate was removed under reduce pressure to afford (1S)-1-(7-fluoro-2-(3-fluorophenyl)quinolin-3-yl)ethanamine. To the crude residue of (1S)-1-(7-fluoro-2-(3-fluorophenyl)quinolin-3-yl)-ethanamine in DMF (2 mL) was added 4-amino-6-chloropyrimidine-5-carbonitrile (22 mg, 145 μmol) and DIEA (0.06 mL, 319 μmol). The resulting mixture was heated to 100° C. overnight. Solvent was removed under reduce pressure and purified via preparatory HPLC using 15-60% MeCN/H2O w/0.01% TFA to afford a white solid of 4-amino-6-((S)-1-(7-fluoro-2-(3-fluorophenyl)-quinolin-3-yl)ethylamino)pyrimidine-5-carbonitrile (9.3 mg, 16%). 1H NMR (500 MHz, CD3OD) δ ppm 1.63 (d, J=6.85 Hz, 3H) 5.70 (q, J=7.01 Hz, 1H) 7.25-7.34 (m, 1H) 7.44-7.54 (m, 2H) 7.55-7.63 (m, 2H) 7.74 (dd, J=9.78, 2.45 Hz, 1H) 8.05 (s, 1H) 8.18 (dd, J=9.05, 5.87 Hz, 1H) 8.72 (s, 1H). Mass Spectrum (ESI) m/e=403 (M+1).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:11]2=[O:28])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:29]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)([OH:31])=[O:30].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:36]4[CH:35]=[CH:34][CH:33]=[C:32]([C:29]([OH:31])=[O:30])[CH:37]=4)=[CH:17][CH:16]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:11]2=[O:28])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: O=C1N(c2ccccc2)C(c2ccc(Br)cc2)CN1S(=O)(=O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cccc(-c2ccc(C3CN(S(=O)(=O)c4ccccc4)C(=O)N3c3ccccc3)cc2)c1

Procedure:
In analogy to example 1, step 3,1-benzenesulfonyl-4-(4-bromo-phenyl)-3-phenyl-imidazolidin-2-one (example 1, step 2) was reacted with 3-carboxyphenylboronic acid in the presence of dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethane adduct and sodium carbonate in dioxane/water to give 4′-(1-benzenesulfonyl-2-oxo-3-phenyl-imidazolidin-4-yl)-biphenyl-3-carboxylic acid as an off-white solid. MS: 497.1 ([M−H]−)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[Br:28]N1C(=O)CCC1=O>C1COCC1.O>[Br:28][CH:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)Cc1cccnc1
Reactant: O=C1CCC(=O)N1Br
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(Br)c1cccnc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
Ethyl 3-pyridylacetate (1.0 g, 1.0 eq) was dissolved in THF (50 mL) and cooled to −78° C. Lithium bis (trimethylsilyl) amide (6.66 mL, 1.1 eq) was added to the reaction and stirred for 20 minutes. Chlorotrimethylsilane (1.44 mL, 1.875 eq) was added at −78° C. and stirred for 20 minutes. N-bromosuccinimide (1.09 g, 1.01 eq) was added to the reaction mixture. The reaction mixture was allowed to stir and warm to room temperature overnight. The reaction mixture was diluted with H2O. The organic layer was extracted with ethyl acetate. The organic phase was dried over sodium sulfate and the solvent was evaporated to give a yellow oil. The resulting oil was chromatographed on silica gel using hexanes and ethyl acetate (1:1) to give ethyl 2-bromo-2(3-pyridyl)acetate.
Reaction SMILES: [C:1]1([CH2:7][S:8](Cl)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:12][O:13][CH2:14][CH2:15][NH2:16]>C1COCC1>[CH3:12][O:13][CH2:14][CH2:15][NH:16][S:8]([CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:10])=[O:9]
Reactant: COCCN
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: C1CCOC1
Product: COCCNS(=O)(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 99.4 %

Procedure:
Phenylmethanesulfonyl chloride (3.0 g, 15.7 mmol) was dissolved in dry THF (15 mL) and it was added dropwise to a solution of 2-methoxyethylamine (2.36 g, 31.5 mmol) in dry THF (50 mL) at 0° C. After addition the ice-bath was removed and the reaction was stirred at rt for 2.5 h. The solvent was removed in vacuo and the residue was dissolved in DCM. The mixture was washed with one portion of 5% aqueous HCl, several portions of water, dried through a phase separator and evaporated to give the title compound (3.58 g, 94%); 1H NMR (400 MHz, CDCl3): δ 7.43-7.35 (m, 5H), 4.52 (br s, 1H), 4.26 (s, 2H), 3.40 (t, 2H), 3.32 (s, 3H), 3.14-3.09 (m, 2H); Mass Spectrum: M−H+ 228.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].[CH2:7]([O:18][CH2:19]Cl)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[C:21]([O-:29])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Na+]>CCCCCC>[C:21]([O-:29])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[OH:5][CH2:4][CH2:3][N+:2]([CH3:6])([CH3:1])[CH2:19][O:18][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CN(C)CCO
Reactant: CCCCCCCCCCCOCCl
Agent: O=C([O-])c1ccccc1
Agent: [Na+]
Solvent: CCCCCC
Product: CCCCCCCCCCCOC[N+](C)(C)CCO
Reaction time: 0.25 h
Yield: 80 %

Procedure:
2-(dimethylamino)ethanol (0.05 mol) was dissolved in anhydrous hexane (20 mL) and a solution of chloromethyl undecyl ether (0.05 mol) was added dropwise at room temperature. The reaction mixture was stirred for 15 minutes. The obtained precipitate was washed with dry hexane (40 mL). The material was used in the next step, without further purification. The prepared ammonium chloride was dissolved in water and an aqueous solution of sodium benzoate (0.07 mol) was added. The solution was stirring for 15 min. After 10 h, the reaction mixture was concentrated using a rotary evaporator. To a dry crude product, anhydrous acetone (30 mL) was added. The solid product was filtered and acetone was removed. The product was dried for 10 h at 50° C. in vacuum to obtain (2-hydroxyethyl)dimethylundecyloxymethylammonium benzoate as a grease in 80% yield. Thermogravimetric analysis: Tonset=127° C. 1H and 13C NMR (DMSO) were obtained.
Reaction SMILES: C([NH:4][C:5]1([CH2:22][CH3:23])[C:17]2[N:16]3[CH:18]=[CH:19][N:20]=[C:15]3[C:14](=[O:21])[NH:13][C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=2)(=O)C.[ClH:24]>C(O)C>[ClH:24].[NH2:4][C:5]1([CH2:22][CH3:23])[C:17]2[N:16]3[CH:18]=[CH:19][N:20]=[C:15]3[C:14](=[O:21])[NH:13][C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=2.[ClH:24].[ClH:24].[NH2:4][C:5]1([CH2:22][CH3:23])[C:17]2[N:16]3[CH:18]=[CH:19][N:20]=[C:15]3[C:14](=[O:21])[NH:13][C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=2
Reactant: CCC1(NC(C)=O)c2ccccc2-c2[nH]c(=O)c3nccn3c21
Agent: Cl
Solvent: CCO
Product: CCC1(N)c2ccccc2-c2[nH]c(=O)c3nccn3c21
Reaction time: 1 h

Procedure:
0.46 g of 10-acetamido-10-ethyl-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one is dissolved in 25 ml of boiling 2N hydrochloric acid and the solution is stirred for 1 hours at boiling, cooled and concentrated to dryness under reduced pressure (15 mmHg; 2 kPa) at 60° C. The product obtained is suspended in 15 ml of ethanol and the insoluble product is isolated by filtration, washed twice with 10 ml in total of ethanol and dried under reduced pressure (1 mmHg; 0.13 kPa) at 100° C. 0.28 g of 10-amino-10-ethyl-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one sesquihydrochloride is thus obtained, decomposing without melting above 250° C. (Analysis, % calculated C: 56.13, H: 4.87, Cl: 16.57, N: 17.45, O: 4.98, % found C: 56.2, H: 4.5, Cl: 16.5, N: 17.2).
Reaction SMILES: [N:1]([CH2:4][CH:5]([C:7]1[CH:12]=[C:11]([S:13](=[O:16])(=[O:15])[NH2:14])[CH:10]=[CH:9][C:8]=1[O:17][CH3:18])[OH:6])=[N+]=[N-]>[Pd].C(O)C>[NH2:1][CH2:4][CH:5]([C:7]1[CH:12]=[C:11]([S:13](=[O:15])(=[O:16])[NH2:14])[CH:10]=[CH:9][C:8]=1[O:17][CH3:18])[OH:6]
Reactant: COc1ccc(S(N)(=O)=O)cc1C(O)CN=[N+]=[N-]
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(S(N)(=O)=O)cc1C(O)CN
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.4 %

Procedure:
11 g (0.040 mol) of (−)-α-azidomethyl-2-methoxy-5-sulphamoylbenzenemethanol, 500 ml of ethanol and 2.2 g of 10% palladium on charcoal are introduced into a 1-liter reactor. The reactor is closed and purged with nitrogen, and the mixture is stirred under 400 kPa of hydrogen at room temperature for 3 hours. The reaction mixture is then filtered through Whatman paper, the recovered catalyst is suspended in 200 ml of methanol and the mixture is heated to boiling for 30 minutes. It is then filtered through Whatman paper, the filtrates are combined and concentrated and the residue is dried in a desiccator under vacuum over phosphorus pentoxide. 9.4 g of (−)-α-aminomethyl-2-methoxy-5-sulphamoylbenzenemethanol are obtained.
Reaction SMILES: [CH2:1]([C@:4]1([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:9][CH2:8][N:7]([C@H:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH3:11])[C:6](=[O:16])[NH:5]1)[CH:2]=C.[O:24]=[O+][O-].[BH4-].[Na+]>C(Cl)Cl>[CH3:13][C:12]([CH3:15])([CH3:14])[C@@H:10]([N:7]1[CH2:8][CH2:9][C@@:4]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)([CH2:1][CH2:2][OH:24])[NH:5][C:6]1=[O:16])[CH3:11]
Reactant: O=[O+][O-]
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)C(C)(C)C)C(=O)N1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H](N1CC[C@](CCO)(c2ccc(F)cc2)NC1=O)C(C)(C)C
Temperature: 25 °C
Yield: 42 %

Procedure:
A solution of (R)-4-allyl-1-((S)-3,3-dimethylbutan-2-yl)-4-(4-fluorophenyl)tetrahydropyrimidin-2(1H)-one (285 mg, 0.90 mmol) in CH2Cl2 (5 mL) was treated with O3 till the mixture was turned blue. Then NaBH4 was added and the mixture was stirred at rt till the reaction was over. The reaction was quenched with H2O, and the mixture was extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by preparative TLC to afford (S)-1-((S)-3,3-dimethylbutan-2-yl)-4-(4-fluorophenyl)-4-(2-hydroxyethyl)tetrahydropyrimidin-2(1H)-one (120 mg, 42%). LC-MS Method 1 tR=1.021, min, m/z=323.1; 1H NMR (CDCl3): 0.72 (s, 9H), 0.99 (d, 3H), 1.35-1.98 (m, 2H), 2.03-2.14 (m, 3H), 2.51 (m, 1H), 3.04 (m, 1H), 3.31 (m, 1H), 3.64 (m, 1H), 4.47 (m, 1H), 6.66 (s, 1H), 6.96-7.01 (m, 2H), 7.24-7.28 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]2[O:14][CH2:15][C@H:16]([CH3:17])[N:7]3[C:8]=2[C:3]=1[C:4](=[O:23])[C:5]([C:18]1[NH:22][N:21]=[N:20][N:19]=1)=[CH:6]3.[N:24]1([CH2:29][CH2:30][CH2:31][NH2:32])[CH:28]=[CH:27][N:26]=[CH:25]1>CS(C)=O>[N:24]1([CH2:29][CH2:30][CH2:31][NH:32][C:10]2[C:9]3[O:14][CH2:15][C@H:16]([CH3:17])[N:7]4[C:8]=3[C:3]([C:4](=[O:23])[C:5]([C:18]3[NH:22][N:21]=[N:20][N:19]=3)=[CH:6]4)=[C:2]([NH2:1])[C:11]=2[F:12])[CH:28]=[CH:27][N:26]=[CH:25]1
Reactant: C[C@H]1COc2c(F)c(F)c(N)c3c(=O)c(-c4nnn[nH]4)cn1c23
Reactant: NCCCn1ccnc1
Solvent: CS(C)=O
Product: C[C@H]1COc2c(NCCCn3ccnc3)c(F)c(N)c3c(=O)c(-c4nnn[nH]4)cn1c23
Temperature: 120 °C

Procedure:
To a solution of 13 (250 mg, 0.78 mmol) in 5 ml of DMSO were added 132 μl (1.17 mmol) of 3-(1H-imidazol-1-yl)propan-1-amine. The reaction mixture was heated to 120° C. for 1 h. Upon completion of the reaction the DMSO was removed and the remaining solid was purified by preparative HPLC. To the combined HPLC fractions containing the product were added several drops of 1 N HCl before they were dried down to generate the HCl salt of the compound. The title compound was obtained as a yellow solid (118 mg, 37% yield).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25]([OH:27])=O)[CH:4]=[N:3]1.[CH3:28][NH:29][CH2:30][C:31]1[CH:32]=[N:33][C:34]([CH3:37])=[CH:35][CH:36]=1.C(N(C(C)C)CC)(C)C.CCCP(=O)=O>O1CCCC1>[CH3:28][N:29]([CH2:30][C:31]1[CH:32]=[N:33][C:34]([CH3:37])=[CH:35][CH:36]=1)[C:25]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[C:7]([NH:8][C:9]1[CH:14]=[CH:13][N:12]2[N:15]=[C:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:17]=[C:11]2[CH:10]=1)=[O:24])=[O:27]
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Reactant: CNCc1ccc(C)nc1
Agent: CCCP(=O)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(CN(C)C(=O)c2cnn(C)c2C(=O)Nc2ccn3nc(-c4ccccc4)nc3c2)cn1
Temperature: 70 °C
Reaction time: 20 h
Yield: 93.5 %

Procedure:
A mixture of 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (100 mg, 276 μmol), N-methyl-1-(6-methylpyridin-3-yl)methanamine (50 mg, 367 μmol), diisopropylethylamine (145 μl, 828 μmol) and propylphosphonic anhydride (50% in ethyl acetate, 407 μl, 690 μmol) in tetrahydrofurane (7.00 ml) is stirred for 20 hours at 70° C. under nitrogen atmosphere. The solvent is evaporated and to the residue is added sat. aqueous sodium hydrogencarbonate solution. The mixture is stirred for 20 minutes while a white solid precipitates. The solid is collected by filtration, washed with diethylether and dried affording N4,1-dimethyl-N4-((6-methylpyridin-3-yl)methyl)-N5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-4,5-dicarboxamide (124 mg, 93.5%) as a white solid. mp.: 110-150° C. MS: m/z=481.4 (M+H+).