Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1)=[O:4].[C:16](O)(=[O:21])[CH2:17][C:18](O)=[O:19].C(OC(=O)C)(=O)C>>[CH3:1][N:2]1[C:18](=[O:19])[CH2:17][C:16](=[O:21])[N:5]([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:13])([F:14])[F:15])[CH:7]=2)[C:3]1=[O:4]
Reactant: O=C(O)CC(=O)O
Reactant: CNC(=O)Nc1cccc(C(F)(F)F)c1
Solvent: CC(=O)OC(C)=O
Product: CN1C(=O)CC(=O)N(c2cccc(C(F)(F)F)c2)C1=O
Temperature: 80 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
1-Methyl-3-(3-(trifluoromethyl)phenyl)urea (available from Crescent Chemical Co., Inc.) (4.03 g) and malonic acid (2.11 g) were suspended into acetic anhydride (12 ml) and the resulting mixture was stirred at 80° C. for one hour. After the reaction solutions were concentrated under reduced pressure, to the residue was added saturated aqueous sodium hydrogen carbonate solution and the resulting mixture was washed with ethyl acetate. The aqueous layer was acidified with concentrated hydrochloric acid and the resulting mixture was extracted with ethyl acetate (50 ml×2). The organic layer was washed with saturated saline (50 ml), dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol) to afford 1-methyl-3-(3-(trifluoromethyl)phenyl)pyrimidin-2,4,6-(1H, 3H, 5H)-trione (2.75 g).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[S:5])#[N:2].[CH3:7][CH:8]([CH3:16])[CH2:9][C:10](=O)[CH2:11][C:12](=O)[CH3:13].C(N(CC)CC)C>CCO>[CH2:9]([C:10]1[CH:11]=[C:12]([CH3:13])[C:3]([C:1]#[N:2])=[C:4]([SH:5])[N:6]=1)[CH:8]([CH3:16])[CH3:7]
Reactant: N#CCC(N)=S
Reactant: CC(=O)CC(=O)CC(C)C
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(CC(C)C)nc(S)c1C#N
Temperature: 50 °C
Yield: 61.7 %

Procedure:
To a stirred solution of cyanothioacetamide (2.20 g, 22 mmol) and 6-methyl-2,4-heptanedione (3.12 g, 22 mmol) in anhydrous EtOH (40 mL) was added triethylamine (0.4 mL) and the reaction was heated at 50° C. for 1 h before it was allowed to cool to room temperature. Filtration and washing of the precipitates with EtOH gave 6-isobutyl-2-mercapto-4-methylnicotinonitrile as a yellow solid (2.8 g, 61%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][N:6]=[C:7]([O:9][CH2:10][CH3:11])[CH3:8].[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C1CCN2C(=NCCC2)CC1.[Cl-].[NH4+]>ClCCl>[N:12]1([CH2:2][CH2:3][CH2:4][O:5][N:6]=[C:7]([O:9][CH2:10][CH3:11])[CH3:8])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: C1CCNCC1
Reactant: CCOC(C)=NOCCCBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CCOC(C)=NOCCCN1CCCCC1
Temperature: 25 °C
Reaction time: 36 h
Yield: 32 %

Procedure:
A 500 mg (2.23 mmol) portion of ethyl N-(3-bromopropoxy)acetoimidate was dissolved in 6 ml of dichloromethane, and the solution was mixed with 0.22 ml (2.23 mmol) of piperidine and 0.33 ml (2.23 mmol) of 1,8-diazabicyclo[5.4,0]-7-undecene and stirred at room temperature for 36 hours. The reaction solution was mixed with a saturated ammonium chloride aqueous solution and extracted with chloroform. The chloroform layer was washed with saturated brine and dried with anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform/methanol=10/1) to obtain 166 mg (yield, 32%) of ethyl N-(3-piperidinopropoxy)acetoimidate.
Reaction SMILES: [NH2:1]CCCN1CCN(CCCN)CC1.[Cl:15][CH2:16][CH2:17][C:18]([N:20]=[C:21]=[O:22])=[O:19]>>[Cl:15][CH2:16][CH2:17][C:18]([NH:20][C:21]([NH2:1])=[O:22])=[O:19]
Reactant: O=C=NC(=O)CCCl
Reactant: NCCCN1CCN(CCCN)CC1
Product: NC(=O)NC(=O)CCCl
Yield: 318.8 %

Procedure:
In the same way as in Example 1, reaction of 10.0 g (50 mmols) of N,N'-bis(3-aminopropyl)piperazine with 14.3 g (106 mmols) of 3-chloropropionyl isocyanate gives 24.0 g of the 3-chloropropionylurea compound of the formula ##STR11##
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][CH:14]1[C:23]2[N:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:17][CH2:16][CH2:15]1)(=[O:12])=[O:11])([O-:3])=[O:2].[C:24]([O-:27])([O-])=O.[K+].[K+].[CH3:30][C:31]#[N:32]>C(OCC)(=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]([CH2:19][C:18]1[CH:23]=[CH:14][C:15]([C:24]([NH:32][C:31]2[CH:30]=[CH:6][CH:5]=[CH:4][N:1]=2)=[O:27])=[CH:16][CH:17]=1)[CH:14]1[C:23]2[N:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:17][CH2:16][CH2:15]1)(=[O:11])=[O:12])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NC1CCCc2cccnc21
Reactant: CC#N
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: O=C(Nc1ccccn1)c1ccc(CN(C2CCCc3cccnc32)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Yield: 92 %

Procedure:
8-[N-(2-nitrobenzenesulfonyl)]amino-5,6,7,8-tetrahydroquinoline (230 mg, 0.69 mmol), 4-Chloromethyl-N-pyridinyl-2-yl-benzamide (170 mg, 0.69 mmol), and K2CO3 (285 mg, 2.06 mmol) were heated to reflux in CH3CN (3 mL) for 24 hours under N2. The reaction mixture was diluted with 200 mL ethyl acetate, and washed with sat. NaHCO3, then brine and dried over Na2SO4. Evaporation of the solvent and purification of the residue by flash chromatography on silica gel using 6% ethyl acetate in CH2Cl2 afforded the title compound (344 mg, 92%) as white foam. 1H NMR (CDCl3) δ 1.61-1.65 (m, 1H), 1.74-1.86 (m, 2H), 2.33-2.37 (m, 1H), 2.59-2.65 (m, 2H), 3.92 (d, 1H, J=16.2), 4.87 (d, 1H, J=16.5 Hz), 5.32 (dd, 1H, J=5.8, 11.3 Hz), 7.04-7.11 (m, 2H), 7.31-7.37 (m, 3H), 7.49-7.67 (m, 3H), 7.73-7.80 (m, 3H), 8.15 (d, 1H, J=7.8 Hz), 8.22 (d, 1H, J=4.2 Hz), 8.31 (d, 1H, J=4.2 Hz), 8.35 (d, 1H, J=8.4 Hz), 8.45 (br, s, 1H); ES-MS m/z 544.1 (M+H).
Reaction SMILES: [Mg].[Si:2]([Cl:6])(Cl)([Cl:4])[Cl:3].[CH3:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Cl)=[CH:11][CH:10]=1>C(OCC)C>[CH3:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][Si:2]([Cl:6])([Cl:4])[Cl:3])=[CH:11][CH:10]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Cl[Si](Cl)(Cl)Cl
Agent: [Mg]
Solvent: CCOCC
Product: COc1ccc(C[Si](Cl)(Cl)Cl)cc1
Reaction time: 4 h
Yield: 26.9 %

Procedure:
In a 2-liter three-neck flask equipped with a stirrer, reflux condenser, dropping funnel, and thermometer were placed 30 g (1.2 gram atom) of magnesium powder, 170 g (1.00 mol) of silicon tetrachloride, and 500 ml of diethyl ether. The flask was cooled below 10° C. A mixture of 100.0 g (0.639 mol) of p-methoxybenzyl chloride and 200 ml of diethyl ether was added dropwise with stirring for the dropping funnel over 4 hours. After aging at room temperature for 1 hour, excess magnesium and magnesium chloride were removed by suction filtration. The filtrate was distilled to give 44.0 g (0.172 mol) of the desired product in a yield of 26.9%.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:7]=[CH:8][C:9]([OH:12])=[N:10][CH:11]=1.O>S(=O)(=O)(O)O>[F:5][C:6]1[CH:7]=[C:8]([N+:1]([O-:4])=[O:2])[C:9]([OH:12])=[N:10][CH:11]=1
Reactant: O=[N+]([O-])O
Reactant: Oc1ccc(F)cn1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1cc(F)cnc1O
Temperature: 85 °C
Yield: 60 %

Procedure:
A mixture of nitric acid (70%, 15 ml) and sulfuric acid (15 ml) was slowly added at 5° C.˜10° C. to a solution of 5-fluoro-2-hydroxypyridine (13.0 g, 115 mmol) prepared in Step 2 in sulfuric acid (31 ml). The reaction mixture was heated for 2 hours at 85° C. and then cooled to room temperature. Water was added to the reaction mixture, which was then filtered. The resulting yellow solid was dried to give 11 g of the titled compound as yellow solid. (Yield: 60%).
Reaction SMILES: Cl/[C:2](=[N:8]/[NH:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[O:17][CH2:18]/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)/[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(N(CC)CC)C.CCOC(C)=O>C1(C)C=CC=CC=1>[F:16][C:14]1[CH:13]=[CH:12][C:11]2[O:17][CH2:18][C@@H:19]3[C@H:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:8][N:9]3[C:10]=2[CH:15]=1
Reactant: CCOC(=O)/C(Cl)=N\Nc1cc(F)ccc1OC/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=NN2c3cc(F)ccc3OC[C@@H]2[C@@H]1c1ccccc1

Procedure:
Ethyl (2E)-chloro[(5-fluoro-2-{[(2E)-3-phenylprop-2-enyl]oxy}phenyl)hydrazono]ethanoate (5-3, 3.1 g, 8.23 mmol) was dissolved in anhydrous toluene (20 mL) and treated with triethylamine (11.5 mL, 83 mmol). The reaction was heated at reflux for 24 h, and cooled. EtOAc (100 mL) was added and the organic layer was washed with 5% NaHCO3. The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure. The crude was purified by flash column chromatography (120 g SiO2 Redisep, 0-30% EtOAc/hexanes gradient) to give pure trans-ethyl 8-fluoro-3-phenyl-3a,4-dihydro-3H-pyrazolo[5,1-c][1,4]benzoxazine-2-carboxylate (5-4). 1H NMR (300 MHz, CDCl3) δ 7.32 (m, 6H), 6.86 (dd, J=8.9, 5.0 Hz, 1H), 6.68 (app dt, J=7.9, 3.1 Hz, 1H), 4.34-4.12 (m, 5H), 3.62 (t, J=10.7 Hz, 1H), 1.23 (t, J=7.0 Hz, 2H); MS (M+H+, C19H17FN2O3) 340.1 found 340.4 required.
Reaction SMILES: [C:1]12([CH2:11][S:12]([OH:15])(=[O:14])=[O:13])[C:8]([CH3:10])([CH3:9])[CH:5]([CH2:6][CH2:7]1)[CH2:4][C:2]2=[O:3].O=[Al-:17]=O.[Na+]>>[C:1]12([CH2:11][S:12]([O-:15])(=[O:13])=[O:14])[C:8]([CH3:10])([CH3:9])[CH:5]([CH2:6][CH2:7]1)[CH2:4][C:2]2=[O:3].[Al+3:17].[C:1]12([CH2:11][S:12]([O-:15])(=[O:13])=[O:14])[C:8]([CH3:10])([CH3:9])[CH:5]([CH2:6][CH2:7]1)[CH2:4][C:2]2=[O:3].[C:1]12([CH2:11][S:12]([O-:15])(=[O:13])=[O:14])[C:8]([CH3:10])([CH3:9])[CH:5]([CH2:6][CH2:7]1)[CH2:4][C:2]2=[O:3]
Reactant: O=[Al-]=O
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: [Na+]
Product: CC1(C)C2CCC1(CS(=O)(=O)[O-])C(=O)C2
Product: [Al+3]

Procedure:
To the amine in the sodium aluminate example above, camphorsulfonic acid was added to bring the pH to the range of 7.5-9. The insoluble precipitate that formed was filtered before use. The control did not require any acid addition.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]#[N:24])[CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:25]([O:27]CC)=[O:26])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[OH-].[Li+]>O1CCOCC1.O>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]#[N:24])[CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:25]([OH:27])=[O:26])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCOC(=O)C1CC(c2ccc(CC)cc2)CN(C(=O)N2CCC(C#N)CC2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCC(C#N)CC3)C2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
650 mg (1.60 mmol) of ethyl 5-(4-ethylphenyl)-1-[(4-cyanopiperidin-1-yl)carbonyl]piperidine-3-carboxylate were dissolved in a mixture of 20 ml of dioxane and 10 ml of water, 153 mg (6.40 mmol) of lithium hydroxide were added and the mixture was stirred at RT for 15 min. For work-up, the reaction solution was concentrated under reduced pressure, water was then added and the mixture was acidified with 1N hydrochloric acid. The precipitate formed was filtered off and dried under reduced pressure. The residue was purified by preparative HPLC. Yield: 347 mg (59% of theory)
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([S:16][CH2:17][C@H:18]2[O:23]C(C)(C)[O:21][C@@H:20]([CH2:26][C:27]([O:29]C(C)(C)C)=O)[CH2:19]2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.C(#N)C.C(Cl)Cl>C(Cl)Cl>[C:12]([C:9]1[CH:8]=[C:7]([S:16][CH2:17][C@H:18]2[O:23][C:27](=[O:29])[CH2:26][C@H:20]([OH:21])[CH2:19]2)[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:14])([CH3:13])[CH3:15]
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CSc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)OC(C)(C)O1
Solvent: ClCCl
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1cc(SC[C@@H]2C[C@@H](O)CC(=O)O2)cc(C(C)(C)C)c1O
Yield: 80.3 %

Procedure:
In 6.5 ml of anhydrous methylene chloride was dissolved 0.647 g (1.346 mmol) of tert-butyl [(4R,6S)-6-[[(3,5-di-tert-butyl-4-hydroxyphenyl)thio]methyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate. Thereto was added dropwise 1.3 ml of trifluoroacetic acid with cooling with ice and stirred for a half hour at the same temperature, further stirred for 2 hours at room temperature. The reaction solution was distilled away under reduced pressure. To the residue was added toluene, and again the mixture was distilled away under reduced pressure. After repeating such procedure twice, the obtained residue was purified by subjecting to silica gel column chromatography [eluent: acetonitrile-methylene chloride (1:9 to 1:4)]to give 0.396 g of (4R,6S)-6-[[(3,5-di-tert-butyl-4-hydroxyphenyl)thio]methyl]-4-hydroxytetrahydropyrane-2-one as crystals (yield: 83%). The desired compound was recrystallized from hexane.
Reaction SMILES: C([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12](Cl)[CH:13]=2)[N:8]=[C:7]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])[CH:6]=1)C=C.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([NH:33][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][CH3:25])[CH:6]=[C:5]2[NH2:4])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NCc1ccccc1
Reactant: C=CCNc1cc(NCc2ccccc2OC)nc2ccc(Cl)cc12
Product: COc1ccccc1CNc1cc(N)c2cc(NCc3ccccc3)ccc2n1

Procedure:
The title compound, MS: m/e=385.3 (M+H+), was prepared in accordance with the general method of example 44 from N4-allyl-6-chloro-N2-(2-methoxy-benzyl)-quinoline-2,4-diamine and benzylamine
Reaction SMILES: Br[CH2:2][C:3]([OH:5])=[O:4].[CH2:6]([NH2:9])[CH2:7][CH3:8].[OH-].[Na+].[C:12](=O)([O:18]C(C)(C)C)[O:13][C:14]([CH3:17])([CH3:16])[CH3:15].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.C(O)C>[C:14]([O:13][C:12]([N:9]([CH2:2][C:3]([OH:5])=[O:4])[CH2:6][CH2:7][CH3:8])=[O:18])([CH3:17])([CH3:16])[CH3:15]
Reactant: CCCN
Reactant: O=C(O)CBr
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CCCN(CC(=O)O)C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 64.7 %

Procedure:
Ethanol (36 ml) was added to bromoacetic acid (5.00 g, 36.0 mmol), and the mixture was stirred under ice-cold water-cooling. Propylamine (14.8 ml, 180 mmol) was added to the mixture over one minute, and then the whole was stirred at an external temperature of 80° C. for 2.5 hours. A 4 N aqueous sodium hydroxide solution (27 ml) was added to the reaction mixture, the whole was concentrated under reduced pressure, then water (27 ml) and tetrahydrofuran (30 ml) were added to the concentrate, and the whole was stirred at room temperature. A solution of di-t-butyl carbonate (9.43 g, 43.2 mmol) in tetrahydrofuran (6 ml) was added thereto, and after 15 minutes, citric acid monohydrate was added thereto to weakly acidify the whole. The whole was extracted with ethyl acetate (150 ml). The organic layer was washed with water (100 ml) and saturated brine (50 ml) successively, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography to give 2-[N-(t-butoxycarbonyl)-N-propylamino]acetic acid (5.06 g, 65%) as a colorless solid.
Reaction SMILES: C[NH:2][CH2:3][CH2:4][NH:5][CH3:6].[CH2:7](N(CC)CC)C.[Br:14][C:15]1[CH:16]=[C:17]([S:21](Cl)(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1>C(Cl)(Cl)Cl>[Br:14][C:15]1[CH:16]=[C:17]([S:21]([NH:2][CH2:3][CH2:4][N:5]([CH3:6])[CH3:7])(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: CNCCNC
Reactant: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN(C)CCNS(=O)(=O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Under cooling in an ice bath, N,N′-dimethylethylenediamine (414 mg) and triethylamine (1.10 mL) were added to a chloroform (10 mL) solution of 3-bromobenzenesulfonyl chloride (1.00 g), and the obtained solution was then stirred at a room temperature for 45 minutes. The reaction solution was washed with water, and was then dried over anhydrous sodium sulfate, followed by vacuum concentration. The residue was purified by column chromatography (silica gel 60N, chloroform:methanol=98:2 to 96:4), so as to obtain the title compound (1.14 g) in the form of a colorless solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([N:17]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:18](=[O:21])[CH2:19][CH3:20])[CH2:9][CH2:8][N:7](CC2C=CC=CC=2)[CH2:6][CH2:5]1.[H][H]>[Pd].C(O)(=O)C>[CH3:1][O:2][CH2:3][C:4]1([N:17]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:18](=[O:21])[CH2:19][CH3:20])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1
Reactant: [H][H]
Reactant: CCC(=O)N(c1ccccc1)C1(COC)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCC(=O)N(c1ccccc1)C1(COC)CCNCC1

Procedure:
A mixture of 52 parts of N-[4-(methoxymethyl)-1-(phenylmethyl)-4-piperidinyl]-N-phenylpropanamide and 200 parts of acetic acid is hydrogenated at normal pressure and at room temperature with 3 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is taken up in water, cooled and alkalized with ammonium hydroxide. The product is extracted with trichloromethane. The extract is washed with water, dried, filtered and evaporated, yielding N-[4-(methoxymethyl)-4-piperidinyl]-N-phenylpropanamide as an oily residue.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:13]=[C:14]([NH2:17])[NH:15][N:16]=2)=[CH:4]1)[CH3:2].[N:18]1([CH2:23][CH2:24][CH2:25][C:26](O)=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19]1.C([O-])=O>>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:13]=[C:14]([NH:17][C:26](=[O:27])[CH2:25][CH2:24][CH2:23][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[NH:15][N:16]=2)=[CH:4]1)[CH3:2]
Reactant: O=C(O)CCCN1CCCC1
Reactant: CCn1cc(-c2cc(N)[nH]n2)c2ccccc21
Agent: O=C[O-]
Product: CCn1cc(-c2cc(NC(=O)CCCN3CCCC3)[nH]n2)c2ccccc21
Yield: 42.1 %

Procedure:
The product was prepared according to the general synthetic method for the synthesis of ω-amino-alkanoic acid (1H-pyrazol-3-yl-5-aryl)-amides via the amino acid route, starting from 5-(1-ethyl-1H-indol-3-yl)-2H-pyrazol-3-ylamine (99.0 mg, 0.5 mmol, 1.0 eq) and 4-pyrrolidin-1-yl-butyric acid (118 mg, 0.75 mmol). The crude product was purified via preparative HPLC; the title product (77.0 mg, 42% yield) was obtained as formate salt.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]1[CH2:11][C@@H:10]([C:12]([OH:14])=[O:13])[C:9]1([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[Cl:26][C:27]1[CH:35]=[C:34]([Cl:36])[CH:33]=[C:32]([Cl:37])[C:28]=1[C:29](Cl)=[O:30]>C1COCC1>[Cl:26][C:27]1[CH:35]=[C:34]([Cl:36])[CH:33]=[C:32]([Cl:37])[C:28]=1[C:29]([O:13][C:12]([C@@H:10]1[CH2:11][C@H:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:9]1([CH3:16])[CH3:15])=[O:14])=[O:30]
Reactant: CC(C)(C)OC(=O)[C@H]1C[C@@H](C(=O)O)C1(C)C
Reactant: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@H]1C[C@@H](C(=O)OC(=O)c2c(Cl)cc(Cl)cc2Cl)C1(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of (1R,3S)-3-(tert-butoxycarbonyl)-2,2-dimethylcyclobutanecarboxylic acid (about 0.450 g, 1.97 mmol) and DIPEA (about 1.01 ml, 5.92 mmol) in THF (about 4 ml) and 2,4,6-trichloro benzoyl chloride (0.35 ml, 2.17 mmol) were added at 0° C. and the reaction mixture was allowed to stir at room temperature for about 6 hours, after completion of the reaction (monitored by TLC), the solvent was evaporated and crude product proceeded as such for the next reaction.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][C:10]2[CH:24]=[CH:23][C:13]([CH2:14][N:15]3[CH2:18][CH:17]([C:19]([O:21][CH3:22])=[O:20])[CH2:16]3)=[CH:12][C:11]=2[F:25])=[N:6][CH:7]=1.[Br-].[CH2:27]([Zn+])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[CH2:27]([C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][C:10]2[CH:24]=[CH:23][C:13]([CH2:14][N:15]3[CH2:18][CH:17]([C:19]([O:21][CH2:22][C:10]4[CH:24]=[CH:23][CH:13]=[CH:12][CH:11]=4)=[O:20])[CH2:16]3)=[CH:12][C:11]=2[F:25])=[N:6][CH:7]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)C1CN(Cc2ccc(C#Cc3ccc(Br)cn3)c(F)c2)C1
Reactant: [Zn+]Cc1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)C1CN(Cc2ccc(C#Cc3ccc(Cc4ccccc4)cn3)c(F)c2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 1-(4-(2-(5-bromopyridin-2-yl)ethynyl)-3-fluorobenzyl)azetidine-3-carboxylate (340.0 mg, 843 μmol), PdCl2(P(t-Bu)2Ph)2 (37 mg, 59 μmol), and THF (4.0 mL) were combined under an argon atmosphere. Benzylzinc(II) bromide (0.5M in THF; 1.92 mL, 961 μmol) was added via syringe, and the resulting solution was stirred at 25° C. for 1 h. Additional benzylzinc(II) bromide (0.5M in THF; 1.92 mL) was then added, and the resulting solution was stirred for 1 h at 25° C. A third portion of benzylzinc(II) bromide (0.5M in THF; 1.92 mL) was then added, and the resulting solution was stirred for 1 h at 25° C. The mixture was subsequently partitioned between half-saturated aqueous NaHCO3 (50 mL) and EtOAc (100 mL). The organic layer was separated, washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-100% EtOAc/Hexanes) separately furnished benzyl 1-(4-(2-(5-benzylpyridin-2-yl)ethynyl)-3-fluorobenzyl)azetidine-3-carboxylate (MS (ESI) m/z: Calculated: 490.2; Observed: 490.8 (M++1)) and methyl 1-(4-(2-(5-benzylpyridin-2-yl)ethynyl)-3-fluorobenzyl)azetidine-3-carboxylate (MS (ESI) m/z: Calculated: 414.2; Observed: 414.8 (M++1)) as a yellow oils.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]2=[C:9]([C:19]3[CH:20]=[CH:21][C:22]4[C:26]([CH:27]=3)=[N:25][N:24]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:23]=4)[CH:10]=[C:11]([C:12]([CH:14]3[CH2:18][CH2:17][NH:16][CH2:15]3)=[O:13])[N:7]2[N:6]=[CH:5][N:4]=1.C(N(CC)CC)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>ClCCl>[NH2:2][C:3]1[C:8]2=[C:9]([C:19]3[CH:20]=[CH:21][C:22]4[C:26]([CH:27]=3)=[N:25][N:24]([CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:23]=4)[CH:10]=[C:11]([C:12]([CH:14]3[CH2:18][CH2:17][N:16]([S:43]([CH3:42])(=[O:45])=[O:44])[CH2:15]3)=[O:13])[N:7]2[N:6]=[CH:5][N:4]=1
Reactant: Nc1ncnn2c(C(=O)C3CCNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC(C(=O)c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Reaction time: 18 h
Yield: 24.5 %

Procedure:
[4-Amino-5-(2-benzyl-2H-indazol-6-yl)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-pyrrolidin-3-yl-methanone hydrochloride salt (89 mg, 0.19 mmol) was dissolved in dichloromethane (1 mL) and triethylamine (0.079 mL, 0.56 mmol) was added, followed by methanesulfonyl chloride (0.022 mL, 0.28 mmol). The mixture was stirred at it for 18 h and then at 50° C. overnight. The mixture was concentrated, diluted with MeOH, filtered and the filtrate purified by HPLC eluting with 20-95% gradient acetonitrile/water to afford 24 mg (25%) of the title compound. 1H-NMR (CD2Cl2-d2) 8.13-8.06 (m, 2 H), 7.81 (dt, 1H), 7.77-7.76 (m, 1 H), 7.43 (s, 1H), 7.42-7.33, (m, 5 H), 7.19 (dd, 1 H), 5.64 (s, 1 H), 4.61-4.53 (m, 1 H), 3.74-3.65 (m, 2 H), 3.54-3.44 (m, 1 H), 3.39-3.31 (m, 1 H), 2.89 (s, 1 H), 2.46-2.28 (m, 2 H); LC-MS [M+H]+=516.2, RT=2.88 min.
Reaction SMILES: Cl.[CH2:2]([NH:5][CH2:6][CH:7]=[CH2:8])[CH:3]=[CH2:4].[C:9](OC(=O)C)(=[O:11])[CH3:10].O>N1C=CC=CC=1>[C:9]([N:5]([CH2:6][CH:7]=[CH2:8])[CH2:2][CH:3]=[CH2:4])(=[O:11])[CH3:10]
Reactant: C=CCNCC=C
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: C=CCN(CC=C)C(C)=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 90.2 %

Procedure:
In 10 ml of pyridine was dissolved 0.5 g of diallylamine hydrochloride, and 1.0 g of acetic anhydride was added to the solution. The mixture was stirred at room temperature for 10 hours. Water was added to the mixture and the mixture was extracted with chloroform. The chloroform layer was washed with 0.01 N aqueous HCl solution, 1% aqueous sodium bicarbonate solution and finally with water, and concentrated to obtain 0.47 g of N-acetyldiallylamine [IR: 1640 cm-1, 1H-NMR δH 2.08 (3H), 3.94(4H), 5.16(4H), 5.76(2H)].