Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]3[N:13]([CH2:16][C@@H:17]4[CH2:22][N:21]([C:23]5[N:28]=[CH:27][C:26]([C:29]6[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][OH:37])[CH2:31][CH:30]=6)=[CH:25][N:24]=5)[CH2:20][CH2:19][O:18]4)[N:14]=[N:15][C:10]3=[N:9][CH:8]=2)[CH:4]=[N:3]1>CO.C(Cl)Cl.[Pt]=O>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]3[N:13]([CH2:16][C@@H:17]4[CH2:22][N:21]([C:23]5[N:24]=[CH:25][C:26]([CH:29]6[CH2:30][CH2:31][N:32]([CH2:35][CH2:36][OH:37])[CH2:33][CH2:34]6)=[CH:27][N:28]=5)[CH2:20][CH2:19][O:18]4)[N:14]=[N:15][C:10]3=[N:9][CH:8]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(C6=CCN(CCO)CC6)cn5)CCO4)c3n2)cn1
Agent: O=[Pt]
Solvent: CO
Solvent: ClCCl
Product: Cn1cc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(C6CCN(CCO)CC6)cn5)CCO4)c3n2)cn1
Yield: 13.8 %

Procedure:
(S)-2-(4-(2-(2-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)-5,6-dihydropyridin-1(2H)-yl)ethanol 54 mg (0.11 mmol) was dissolved in methanol 3 ml and methylene chloride 2 ml, and an excess of platinum oxide was added. The mixture was degassed, and a hydrogen balloon was connected, followed by reaction at room temperature for 1 day. After the reaction, the platinum oxide was removed using a celite filter, and separation by PLC (methylene chloride:methanol=5:1) gave a yellow solid 7.7 mg (14%).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[I:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.C(OCC)(=O)C>CN(C)C=O>[I:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(I)cc2)CC1

Procedure:
10.67 g (57.3 mmol) of t-butyl piperazine-1-carboxylate was dissolved in 180 ml of dimethylformamide. 10 ml (57.3 mmol) of diisopropylethylamine and a solution of 17.3 g (57.3 mmol) of 4-iodobenzenesulfonyl chloride in 20 ml of dimethylformamide were added to the solution at 0° C., and the resultant mixture was stirred for 5 hours. After the treatment with ethyl acetate as the extractant in an ordinary manner, crude t-butyl 4-(4-iodobenzenesulfonyl)piperazine-1-carboxylate was obtained. This crude product was dissolved in 150 ml of dimethylformamide. 750 mg (3.5 mmol) of palladium (II) acetate, 55 ml (1.39 mol) of methanol and 19 ml (139 mmol) of triethylamine were added to the solution, and the resultant mixture was stirred under heating at 90° C. in the presence of carbon monoxide for 23 hours. After the treatment with ethyl acetate as the extractant in an ordinary manner, the crude title compound was obtained. This product was then purified by the silica gel column chromatography.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>C(O)(=O)C>[NH:1]([C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1)[C:15]([CH3:16])=[O:17]
Reactant: Nc1ccc(C(=O)O)c2c1OCCO2
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(C(=O)O)c2c1OCCO2
Yield: 84 %

Procedure:
43 g of 8-amino-1,4-benzodioxane-5-carboxylic acid and 72 ml of acetic acid were introduced into a balloon flask and then 24.5 ml of acetic anhydride were added in portions. The mixture was heated to 60°-70° C. and then cooled. The precipitate was dried off, washed with acetic acid and water and dried. 44 g of 8-acetamino-1,4-benzodioxane-5-carboxylic acid were obtained (M.P.: 233° C.; yield: 84%).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:10](=O)[NH:9][C:8]=2[N:7]=[C:6]1[N:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]1)[C:2]#[C:3][CH3:4].P(Cl)(Cl)([Cl:39])=O>>[CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:10]([Cl:39])=[N:9][C:8]=2[N:7]=[C:6]1[N:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]1)[C:2]#[C:3][CH3:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2[nH]c(=O)n(CCc3ccccc3)c(=O)c21
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2nc(Cl)n(CCc3ccccc3)c(=O)c21
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A mixture consisting of 290 mg of t-butyl 4-[7-(2-butynyl)-2,6-dioxo-1-(2-phenylethyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylate and 4 ml of phosphorus oxychloride was heated and stirred in an oil bath at 120° C. for 8 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 5 ml of tetrahydrofuran. This solution was added dropwise to a mixture consisting of 250 mg of di-t-butyl dicarbonate, 10 ml of a saturated sodium bicarbonate solution, and 10 ml of tetrahydrofuran while the mixture was being stirred and cooled with ice. The mixture was incubated at room temperature for 4 hours, and then extracted with ethyl acetate. The organic layer was washed with water then with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduce pressure. The residue was purified by silica gel column chromatography using 30 to 50% ethyl acetate/hexane. Then, the material was further purified by reverse-phase column chromatography using 50 to 100% methanol/water to give 60 mg of the title compound.
Reaction SMILES: [Mg].Br[CH:3]([CH2:5][CH3:6])[CH3:4].[CH3:7][C:8](=[CH:11][CH2:12][CH3:13])[CH:9]=[O:10]>CCOCC>[CH3:7][C:8]([CH:9]([OH:10])[CH:3]([CH3:4])[CH2:5][CH3:6])=[CH:11][CH2:12][CH3:13]
Reactant: CCC(C)Br
Reactant: CCC=C(C)C=O
Agent: [Mg]
Solvent: CCOCC
Product: CCC=C(C)C(O)C(C)CC

Procedure:
The Grignard reagent obtained by reacting 18.7 g (0.77 g-atom) of magnesium in 100 ml of ether with 105.4 g (0.77 mol) of 2-bromobutane in 300 ml of ether is reacted with 62.72 g (0.64 mol) of 2-methyl-2-pentenal in 200 ml of ether. The fractional distillation of the crude product (98.8 g) over a 20 cm Widmer column gives 68.4 g (68.5%) of olfactorily good 4,6-dimethyl-3-octen-5-ol of boiling point 83° C./12 Torr.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].Cl>CN(C=O)C.[I-].[K+]>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(NC(=O)OCc1ccccc1)C(=O)OCC
Reactant: CC(C)(C)OC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC(=O)OC(C)(C)C)(NC(=O)OCc1ccccc1)C(=O)OCC
Temperature: 50 °C
Reaction time: 1 h
Yield: 100.8 %

Procedure:
A suspension of diethyl 2-benzyloxycarbonylaminomalonate (5.0 g), potassium carbonate (2.7 g), potassium iodide (0.27 g), and t-butyl 2-bromoacetate (4.1 g) in DMF (50 mL) was stirred at 50° C. for 1 hour. The reaction mixture was cooled, and then poured into diluted hydrochloric acid, the mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography, and then purification was performed with n-hexane/ethyl acetate (5:1), to obtain the title compound (6.9 g, yield: 99%) as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[N:20]2[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]2)=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl>O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3cc(C(=O)c4cccc(Cl)c4)cnc23)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(c1cccc(Cl)c1)c1cnc2c(N3CCNCC3)cccc2c1
Yield: 193.9 %

Procedure:
A stirred solution of 1,1 dimethylethyl 4-{3-[(3-chlorophenyl)carbonyl]-8-quinolinyl}-1-piperazinecarboxylate (D6) (0.15 g, 0.33 mmol) in 1,4-dioxan (3 ml) and aqueous 4 M hydrochloric acid (3 ml) was heated at 80° C. for 1.5 h under argon. The reaction mixture was concentrated in vacuo and the residue was stirred with acetone/diethyl ether (2:1)(10 ml) to afford the title compound (E2) as a yellow solid (0.126 g, 0.32 mmol, 98%).
Reaction SMILES: C(O)C.C(=O)(O)O.[NH2:8][C:9]([NH2:11])=[NH:10].[C:12](OCC)(=[O:17])[CH2:13][C:14]([CH3:16])=O>CCCCCC>[CH3:16][C:14]1[NH:8][C:9]([NH2:11])=[N:10][C:12](=[O:17])[CH:13]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: CCO
Solvent: CCCCCC
Product: Cc1cc(=O)nc(N)[nH]1
Reaction time: 8 h
Yield: 186.9 %

Procedure:
Into a 1 liter flask 600 ml of dried Ethanol and 91.89 g (0.51 mol) of Guanidine Carbonate and 146.1 g (1.11 mol) of ethyl acetoacetate were added. The reaction solution was gradually heated to reflux temperature and stirred overnight. 300 ml of Ethanol was evaporated and reaction solution was heated under reflux for two hours. After cooling, 300 ml of Hexane was added. Deposit was filtered, washed and dried. 119.3 g of 6-methylisocytosine was obtained.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][CH2:9][C:10]([NH2:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C>ClCCl>[C:1]1([CH:7]=[CH:8][CH2:9][CH2:10][NH2:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)CC=Cc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: NCCC=Cc1ccccc1
Temperature: 0 °C
Reaction time: 96 h
Yield: 79.3 %

Procedure:
A suspension of 4-phenyl-but-3-enoic acid amide (5.0 g, 31 mmol) in 250 mL dichloromethane was cooled to 0° C. Diisobutylaluminum hydride (1 M in dichloromethane, 250 mL) was added and the resulting homogeneous mixture was allowed to slowly warm to rt. The reaction was stirred for 4 days then quenched by carefully pouring the mixture onto 200 mL of 1:1 water/methanol at 0° C. The aluminum salts were removed by filtration and washed with methanol. The combined filtrate was collected and the volatile material was removed by a rotary evaporator to give of 4-phenyl-but-3-enylamine (3.62 g, 79%) as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]1.C(=O)(O)[O-].[Na+].Cl[CH2:25][CH2:26][CH2:27][C:28]1([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)OCC[O:29]1>CN(C)C=O.O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][N:15]([CH2:25][CH2:26][CH2:27][C:28]([C:33]2[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=2)=[O:29])[CH2:14]1
Reactant: Fc1ccc(C2(CCCCl)OCCO2)cc1
Reactant: COc1ccc2[nH]cc(CC3CCCNC3)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc2[nH]cc(CC3CCCN(CCCC(=O)c4ccc(F)cc4)C3)c2c1

Procedure:
A mixture of compound of Description 6 [5-methoxy-3-(piperidin-3-ylmethyl)-1H-indole] (2 g; 0.0082 mol), sodium bicarbonate (0.68 g; 0.0082 mol), KI (0.087 g; 0.00053 mol) and 2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxolane [2.2 g (1,8 ml); 0.009 mol] in dry dimethylformamide (25 ml) and tetrahydrofuran (25 ml), was heated under reflux for 5 hours. After evaporation under vacuum, the residue was flash chromatographed on silica gel using as eluent methylene chloride/methanol/ammonia (95/5/0.5) and the desired compound was obtained. A solution of the compound in ethanol was saturated with gaseous hydrogen chloride, a solid was precipitated. The title compound hydrochloride was collected by filtration.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[S:33]1[CH2:37][CH2:36][NH:35][CH2:34]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18](=[O:20])[N:35]3[CH2:36][CH2:37][S:33][CH2:34]3)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: C1CSCN1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(Cn1c(-c2ccc(Cl)cc2)nc2cccnc21)N1CCSC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 49.3 %

Procedure:
A suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0174 mole), 1,1'-carbonyldiimidazole (2.82 g, 0.0174 mole) and dry tetrahydrofuran (100 ml) was stirred at room temperature for 3.5 hours while nitrogen was bubbled through it. Solid thiazolidine (2.33 g, 0.0261 mole) was added and the reaction mixture was stirred at 55° C., under nitrogen overnight. The solvent was removed under reduced pressure. The resulting white solid was triturated with water (100 ml), filtered, rinsed with water, twice with 5% potassium hydroxide solution and twice more with water. The resulting solid was heated in boiling isopropyl alcohol and filtered hot. Upon cooling to room temperature, a white solid precipitated. The solid was collected by filtration and dried under high vacuum to give 3.08 g (49.4%) of title compound, mp. 215°-218° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[Br:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[CH3:20])[NH2:16]>>[Br:12][C:13]1[CH:14]=[C:15]([NH:16][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])[CH:17]=[CH:18][C:19]=1[CH3:20]
Reactant: Cc1ccc(N)cc1Br
Reactant: O=C(O)Cc1ccccc1Br
Product: Cc1ccc(Nc2ccccc2CC(=O)O)cc1Br

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 3-bromo-4-methylaniline to yield 2-[(3-bromo-4-methylphenyl)amino]phenylacetic acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.[I-:10].[K+].II>N.O>[Br:1][C:2]1[CH:7]=[C:6]([I:10])[C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1
Reactant: Oc1ccc(Br)cc1Cl
Reactant: [I-]
Agent: II
Agent: N
Agent: [K+]
Solvent: O
Product: Oc1c(Cl)cc(Br)cc1I
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.1 %

Procedure:
To a solution of 4-bromo-2-chlorophenol (10 g, 48.2 mmol) in 25% aqueous ammonia solution (140 mL) was added a solution of potassium iodide (24 g, 144.6 mmol) and iodine (12.2 g, 48.2 mmol) in water (125 mL). The reaction mixture was stirred at ambient temperature for 4 h and quenched with 100 mL of water. The reaction was acidified by addition of concentrated HCl (150 mL) and extracted with ethyl acetate (3×40 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give the crude product which was purified by column chromatography (SiO2, 9:1 hexanes/ethyl acetate) providing 4-bromo-2-chloro-6-iodophenol (14 g, 89%) as an off-white solid: 1H NMR (CDCl3, 400 MHz) δ 7.74 (d, J=2.0 Hz, 1H), 7.47 (d, J=2.0 Hz, 1H), 5.93 (s, 1H).
Reaction SMILES: C([Mg]Cl)(C)C.I[C:7]1[CH:8]=[C:9]([CH3:14])[C:10]([CH3:13])=[N:11][CH:12]=1.CON(C)[C:18]([C:20]1[C:29](=[O:30])[C:28]2[C:23](=[N:24][C:25]([CH3:31])=[CH:26][CH:27]=2)[N:22]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Br:39])[N:34]=2)[CH:21]=1)=[O:19].O>O1CCCC1>[Br:39][C:35]1[N:34]=[C:33]([CH2:32][N:22]2[C:23]3[C:28](=[CH:27][CH:26]=[C:25]([CH3:31])[N:24]=3)[C:29](=[O:30])[C:20]([C:18]([C:7]3[CH:12]=[N:11][C:10]([CH3:13])=[C:9]([CH3:14])[CH:8]=3)=[O:19])=[CH:21]2)[CH:38]=[CH:37][CH:36]=1
Reactant: Cc1cc(I)cnc1C
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2nc(C)ccc2c1=O
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc2c(=O)c(C(=O)c3cnc(C)c(C)c3)cn(Cc3cccc(Br)n3)c2n1
Reaction time: 1 h
Yield: 39.6 %

Procedure:
0.23 mL (0.469 mmol, 2M in THF) isopropylmagnesium chloride was added to a solution of 104.4 mg (0.448 mmol) of 5-iodo-2,3-dimethyl-pyridine in 1 mL of tetrahydrofuran. After the reaction was stirred for 40 min at room temperature 85 mg (0.204 mmol) of 1-(6-Bromo-pyridin-2-ylmethyl)-7-methyl-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid methoxy-methyl-amide in 0.6 mL of tetrahydrofuran was added and the reaction stirred for 1 h. Water was added and was extracted with dichloromethane (3×10 mL). The combined organic layers were dried over magnesium sulfate, filtered and dried in vacuo. The crude product was purified by flash column chromatography using 20-100% ethyl acetate in hexane to yield 37.4 mg of 1-(6-Bromo-pyridin-2-ylmethyl)-3-(5,6-dimethyl-pyridine-3-carbonyl)-7-methyl-1H-[1,8]naphthyridin-4-one. LC-MSD, m/z for C23H19BrN4O2 [M+H]: 463.07 LC retention time on HPLC, C18 column gradient 20-95% acetonitrile with 0.1% TFA in 4 minutes: 1.7 min
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5]2.C(N(CC)CC)C.[CH3:31][C:32]([CH3:38])([CH3:37])[CH2:33][C:34](Cl)=[O:35].O>ClCCl>[CH3:31][C:32]([CH3:38])([CH3:37])[CH2:33][C:34]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5]2)=[O:35]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: CCOC(=O)c1cc2cc(N)ccc2n1Cc1ccccc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1cc2cc(NC(=O)CC(C)(C)C)ccc2n1Cc1ccccc1F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
23.2 g (74.28 mmol) of ethyl 5-amino-1-(2-fluorobenzyl)-1H-indole-2-carboxylate from Example XXXVI and 15.03 g (20.71 ml, 148.56 mmol) of triethylamine are added to 300 ml of dichloromethane. The mixture is cooled to 0° C., and a solution of 11 g (11.35 ml, 81.71 mmol) of 3,3-dimethylbutyryl chloride in 300 ml of dichloromethane is added. The mixture is stirred at RT overnight and, for work-up, poured into water. The pH is adjusted to 7 and the mixture is extracted 3 times with ethyl acetate. The combined organic phases are dried over sodium sulphate, filtered and concentrated under reduced pressure.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]12[CH2:13][CH2:12][C:9]([NH:14][CH2:15][C:16]([N:18]3[CH2:22][C@@H:21]([F:23])[CH2:20][C@H:19]3[C:24]([NH2:26])=O)=[O:17])([CH2:10][CH2:11]1)[CH2:8][CH2:7]2)=[O:5])[CH3:2].FC(F)(F)C(O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]12[CH2:13][CH2:12][C:9]([NH:14][CH2:15][C:16]([N:18]3[CH2:22][C@@H:21]([F:23])[CH2:20][C@H:19]3[C:24]#[N:26])=[O:17])([CH2:10][CH2:11]1)[CH2:8][CH2:7]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C(N)=O)(CC1)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C#N)(CC1)CC2
Temperature: 0 °C
Yield: 80.7 %

Procedure:
(2S,4S)-1-[2-[(4-Ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carboxamide (3.70 g) was dissolved in N,N-dimethylformamide (18.5 mL), and while stirring under ice-cooling, trifluoroacetic acid (0.78 mL) was added thereto at an inner temperature of 10° C. or lower. After stirring at an inner temperature of from 0 to 10° C. for 10 minutes, trifluoroacetic anhydride (1.46 mL) was added dropwise thereto, followed by stirring at the same temperature for 1 hour. The reaction solution was poured into ice-water (92.5 mL), potassium carbonate (2.80 g) was added thereto in small portions at an inner temperature of 10° C. or lower and then, after gradually increasing the temperature, potassium carbonate (1.50 g) was further added thereto at an inner temperature of from 35 to 40° C. This was stirred at the same temperature for 10 minutes and then ice-cooled and stirred for 1 hour. The precipitate were collected by filtration, washed with water (37.0 mL) and then dried at 60° C. under reduced pressure, thereby obtaining a white powder of (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (obtained amount: 2.84 g, yield: 81%).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[CH:23]=[N:22][C:21]([C:24](F)(F)F)=[N:20]1)=[O:11].CC1C=CC(N2C=NC(C)=N2)=C(C=1)C(O)=O>>[NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[CH:23]=[N:22][C:21]([CH3:24])=[N:20]1)=[O:11]
Reactant: Cc1ccc(-n2cnc(C(F)(F)F)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Agent: Cc1ccc(-n2cnc(C)n2)c(C(=O)O)c1
Product: Cc1ccc(-n2cnc(C)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1

Procedure:
The title compound was synthesized following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)phenyl)methanone in Example A51, starting from 5-methyl-2-(3-methyl-1H-1,2,4-triazol-1-yl)benzoic acid. ESI-MS (m/z): 328 [M+1]+.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:11][CH3:12])[CH2:4][NH:5][C:6](=[O:10])[O:7][CH2:8][CH3:9].[OH-].[K+].[Cl:15][C:16](=[CH2:19])[CH2:17]I>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.C1(C)C=CC=CC=1>[Cl:15][C:16](=[CH2:17])[CH2:19][N:5]([CH2:4][CH:3]([O:2][CH3:1])[O:11][CH3:12])[C:6](=[O:10])[O:7][CH2:8][CH3:9]
Reactant: C=C(Cl)CI
Reactant: CCOC(=O)NCC(OC)OC
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C=C(Cl)CN(CC(OC)OC)C(=O)OCC
Reaction time: 8 h

Procedure:
115 g (0.65 mol) of ethyl N-(2,2-dimethoxyethyl)-carbamate, 130 g of powdered potassium hydroxide and 2 g of triethylbenzylammonium chloride are initially introduced into 650 ml of toluene and 142 g (0.7 mol) of 2chloroallyl iodide are added dropwise at room temperature. After stirring overnight, a gas chromatogram showed incomplete conversion, hence 65 g of powdered potassium hydroxide and 1 g of triethylbenzylammonium chloride were added again and a further 71 g (0.35 mol) of 2-chloroallyl iodide were added dropwise. After stirring overnight at room temperature, the salts were filtered off with suction, the filtrate was washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated, and the residue was distilled.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][C:10]([C:14]([N:16]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH2:19][CH3:20])=[O:15])=[N:9]2)=[C:4]([C:25]([N:27]2[C@H:36]([CH2:37][OH:38])[CH2:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:28]2)=[O:26])[CH:3]=1.[Si:39](Cl)([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40].N1C=CN=C1>C(Cl)Cl.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][C:10]([C:14]([N:16]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH2:19][CH3:20])=[O:15])=[N:9]2)=[C:4]([C:25]([N:27]2[C@H:36]([CH2:37][O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[CH2:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:28]2)=[O:26])[CH:3]=1
Reactant: CCCCN(CCCC)C(=O)c1cc(C)n(-c2ccc(Br)cc2C(=O)N2Cc3ccccc3C[C@H]2CO)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CCCCN(CCCC)C(=O)c1cc(C)n(-c2ccc(Br)cc2C(=O)N2Cc3ccccc3C[C@H]2CO[Si](C)(C)C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.9 %

Procedure:
To a solution of (S)-1-(4-bromo-2-(3-(hydroxymethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N,N-dibutyl-5-methyl-1H-pyrazole-3-carboxamide (3.0 g, 5.2 mmol) in DCM (30 mL) were added TBDMS-chloride (0.93 g, 6.2 mmol), imidazole (0.70 g, 10.3 mmol) followed by stirring at RT for 5 h. The reaction mixture was diluted with water, extracted with EtOAc (100 mL×2), twice. The combined organic layers were washed with water (100 mL), brine (50 mL), dried over sodium sulphate and concentrated invacuo. The residue was purified on silica gel (100-200 mesh) to afford the title compound as a liquid 3.0 g (83%). Rf=0.66 (50% EtOAc in hexane); 1H NMR (400 MHz, DMSO-d6): δ 8.00-7.40 (m, 3H), 7.30-6.60 (m, 4H), 6.55-6.20 (m, 1H), 5.00-4.10 (m, 2H), 4.10-2.40 (m, 6H), 2.40-2.00 (m, 6H), 1.60-0.50 (m, 23H), 0.20-−0.40 (m, 6H); LC-MS: m/z 695.3 (M+H).