Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[C:3]=1[C:16]#[N:17].C(O[CH:21](OCC)[N:22]([CH3:24])[CH3:23])C>C1(C)C=CC=CC=1>[C:16]([C:3]1[C:4]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)=[N:5][NH:6][C:2]=1[N:1]=[CH:21][N:22]([CH3:24])[CH3:23])#[N:17]
Reactant: CCOC(OCC)N(C)C
Reactant: COc1ccc(Nc2n[nH]c(N)c2C#N)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(Nc2n[nH]c(N=CN(C)C)c2C#N)cc1
Temperature: 25 °C

Procedure:
A suspension of 5.41 g (23.6 mmol) of 5-amino-4-cyano-3-(4-methoxy-phenylamino)-pyrazole [for preparation see: J. Heterocyclic Chem. 27, 775 (1990)] in 4.8 ml (27.2 mmol) of N,N-dimethylformamide diethyl acetal (97%) and 100 ml of toluene is heated under reflux for 5 hours. The reaction mixture is then cooled to room temperature and filtered and the filter residue is washed with toluene. Recrystallization of the crude product from methanol/water yields the title compound; m.p. 232-234° C. (decomp.).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[Cl:5][C:6]1[N:11]=[C:10](Cl)[CH:9]=[CH:8][N:7]=1.[NH4+].[Cl-]>C1COCC1>[Cl:5][C:6]1[N:11]=[C:10]([CH2:1][CH3:2])[CH:9]=[CH:8][N:7]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCc1ccnc(Cl)n1
Reaction time: 1 h
Yield: 27.9 %

Procedure:
Ethylmagnesium bromide (1.0 M in THF, 71.4 mL, 71.4 mmol) was added dropwise to a −78° C. solution of 2,4-dichloropyrimidine (10 g, 67.1 mmol) in THF (125 mL). After stirring for 1 h, saturated aqueous NH4Cl was added at −78° C. and the reaction was allowed to come to room temperature with stirring. Then, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous NaHCO3, then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with ethyl acetate and hexanes to provide 2-chloro-4-ethylpyrimidine (5.031 g, 18.70 mmol, 27.9%) as a 53:47 regioisomeric mixture.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:25])[C:7]=1[NH:8][C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:11]=1.P(Cl)(Cl)(Cl)=O.[CH2:31]([NH2:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C)C1C=CC=CC=1>[CH2:31]([NH:38][C:9](=[N:8][C:7]1[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=1[Cl:25])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:11]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)cc1OC1CCCC1
Reactant: NCc1ccccc1
Solvent: CN(C)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(C(=Nc2c(Cl)cncc2Cl)NCc2ccccc2)cc1OC1CCCC1
Temperature: 25 °C
Yield: 50.6 %

Procedure:
A solution of N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzamide (1 gram, 2.62 mmol) in phosphoryl chloride (15 milliliters, 161 mmol) and N, N-dimethylaniline (0.75 milliliters) was refluxed under nitrogen for 20 hours. The mixture was cooled to room temperature, volatiles removed in-vacuo, and the brown residue azeotroped with toluene (3×20 milliliters). The crude imino chloride was dissolved in toluene (15 milliliters), an excess of benzylamine (2.57 milliliters, 23.58 mmol) was added in one portion and the mixture refluxed, under nitrogen, for 4 hours. The mixture was cooled to room temperature, volatiles removed in-vacuo, and the residue dissolved in chloroform (100 milliliters) and washed with water (2×50 milliliters). The combined organics were dried (Na2SO4) and volatiles removed in-vacuo to yield a white solid. The mixture was purified by flash chromatography (SiO2 ; ethyl acetate : hexane (1:9), followed by ethyl acetate : hexane (1:4)) to yield the title compound (624 milligrams, 50%) as a white crystalline solid, m.p. 129-133° C.
Reaction SMILES: [C:1]12([CH2:11][CH2:12][O:13][C:14]3[CH:15]=[C:16]([CH2:20][C@H:21]([NH:23][CH2:24][C@@H:25]([C:27]4[CH:36]=[CH:35][C:34]([O:37]CC5C=CC=CC=5)=[C:33]5[C:28]=4[CH:29]=[CH:30][C:31](=[O:45])[NH:32]5)[OH:26])[CH3:22])[CH:17]=[CH:18][CH:19]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2>[Pd]>[C:1]12([CH2:11][CH2:12][O:13][C:14]3[CH:15]=[C:16]([CH2:20][C@H:21]([NH:23][CH2:24][C@@H:25]([C:27]4[CH:36]=[CH:35][C:34]([OH:37])=[C:33]5[C:28]=4[CH:29]=[CH:30][C:31](=[O:45])[NH:32]5)[OH:26])[CH3:22])[CH:17]=[CH:18][CH:19]=3)[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: C[C@H](Cc1cccc(OCCC23CC4CC(CC(C4)C2)C3)c1)NC[C@H](O)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: [Pd]
Product: C[C@H](Cc1cccc(OCCC23CC4CC(CC(C4)C2)C3)c1)NC[C@H](O)c1ccc(O)c2[nH]c(=O)ccc12
Yield: 61.8 %

Procedure:
Obtained from Intermediate 70 (1.58 g, 2.6 mmol) and palladium on charcoal (10%, 0.28 g) by the same procedure described in Example 1 (reaction time: 2 hours). The crude obtained was purified by column chromatography with silica gel, eluting with methylen chloride/methanol (from 98:2 to 9:1) to give the title compound as a solid (0.83 g, 62%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:13](=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:23][O:24][NH2:25]>N1C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:13](=[N:25][O:24][CH3:23])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CN(C(=O)OCc2ccccc2)CC1=O
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)C1CN(C(=O)OCc2ccccc2)CC1=NOC
Reaction time: 0.17 h
Yield: 98.2 %

Procedure:
1-Benzyloxycarbonyl-4-ethoxycarbonyl-3-oxopyrrolidine (196.7 g, 600.0 mmol) was dissolved in pyridine (700 ml) and mixed with O-methylhydroxylamine hydrochloride (76.55 g, 916.5 mmol) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes and then at room temperature for 5 hours. Pyridine was evaporated under a reduced pressure, the residue was mixed with 1 N hydrochloric acid and ethyl acetate and then the mixture was shaken and subjected to separation of layers. The organic layer was washed with saturated brine, and the water layer was further extracted with ethyl acetate. The organic layers were dried over anhydrous sodium sulfate and filtered, the solvent was evaporated under a reduced pressure and then the residue was purified by a silica gel column chromatography (n-hexane:ethyl acetate=1:1) to obtain 187.5 g (589.1 mmol, 98.2%) of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[O:12][C:13]3[CH:19]=[C:18]([NH:20][S:21]([C:24]4[CH:25]=[CH:26][CH:27]=[C:28]5[C:33]=4[N:32]=[CH:31][CH:30]=[CH:29]5)(=[O:23])=[O:22])[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:5][CH:4]=1)#[N:2].Br[CH2:35][C:36]([O:38][CH3:39])=[O:37].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[O:12][C:13]3[CH:19]=[C:18]([N:20]([S:21]([C:24]4[CH:25]=[CH:26][CH:27]=[C:28]5[C:33]=4[N:32]=[CH:31][CH:30]=[CH:29]5)(=[O:23])=[O:22])[CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: COC(=O)CBr
Reactant: N#Cc1ccc(CCc2nc3ccc(NS(=O)(=O)c4cccc5cccnc45)cc3o2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)CN(c1ccc2nc(CCc3ccc(C#N)cc3)oc2c1)S(=O)(=O)c1cccc2cccnc12

Procedure:
Prepared analogously to Example 1d from 2-[2-(4-cyanophenyl)-ethyl]-6-[N-quinoline-8-sulphonylamino]-benzoxazole, methyl bromoacetate and potassium carbonate in acetone.
Reaction SMILES: C([O:4][C@H:5]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:7](=O)[C@H:6]1[C@H:19]([O:21][C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23])[CH3:20])(=O)C.[C:28]1([S:34][C:35]([O:37][Si](C)(C)C)=[CH2:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C[Si](OS(C(F)(F)F)(=O)=O)(C)C>C(Cl)Cl.C(OCC)(=O)C>[CH2:25]([O:24][C:22]([O:21][C@@H:19]([C@@H:6]1[C@@H:7]([CH2:36][C:35]([S:34][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:37])[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]1=[O:4])[CH3:20])=[O:23])[CH:26]=[CH2:27]
Reactant: C=C(O[Si](C)(C)C)Sc1ccccc1
Reactant: C=CCOC(=O)O[C@H](C)[C@@H]1C(=O)N(Cc2ccc(OC)cc2)[C@@H]1OC(C)=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N(Cc2ccc(OC)cc2)[C@@H]1CC(=O)Sc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
To a solution of 377 mg of (3S, 4R)-4-acetoxy-3-[(R)-1-(allyloxycarbonyloxy)ethyl]-1-(p-methoxybenzyl)-2-azetidinone in 2 ml of dry methylene chloride were added 448 mg (2 mmole) of 1-phenylthio-1-(trimethylsilyloxy)ethylene and then the mixture was stirred at room temperature, A catalytic amount of trimethylsilyltrifluoromethanesulphonate was added to the mixture, which was then left to stand at room temperature overnight. The precipitate produced was dissolved in 200 ml of ethyl acetate, and the resulting solution was washed successively with 100 ml of water and 100 ml of a saturated aqueous solution of sodium chloride. It was then dried over anhydrous magnesium sulphate and subjected to Lobar column chromatography eluted with a 1:1 by volume mixture of cyclohexane and ethyl acetate, to afford 430 mg (yield 91%) of the title azetidinone.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:28])[CH2:14][CH2:13][N:12]([CH:15]([F:27])[CH2:16][CH:17](F)[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:19])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH3:29][NH:30][CH3:31]>C1C=CC=CC=1>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:28])[CH2:14][CH2:13][N:12]([CH:15]([F:27])[CH2:16][CH:17]([N:30]([CH3:31])[CH3:29])[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:19])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: O=C(c1ccccc1)C(F)CC(F)N1CCC(O)(c2ccc(Cl)cc2)CC1
Reactant: CNC
Agent: Cl
Solvent: c1ccccc1
Product: CN(C)C(CC(F)N1CCC(O)(c2ccc(Cl)cc2)CC1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 27 h

Procedure:
To a suspension of γ-[4-(p-chlorophenyl)-4-hydroxypiperidin-1-yl]-2,4-difluorobutyrophenone hydrochloride (2.0 g) in benzene (160 ml) were added 80 g of 40 % aqueous solution of dimethylamine, and the resulting mixture was stirred at room temperature for 27 hours. The benzene layer was separated, washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was sufficiently triturated and washed with n-hexane to afford γ-[4-(p-chlorophenyl)-4-hydroxypiperidin-1-yl]-2-dimethylamino-4-fluorobutyrophenone. M.P. 83° - 85°C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH2:11])[C:5]([OH:7])=[O:6].Cl.[CH2:13](O)[CH3:14]>>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH2:11])[C:5]([O:7][CH2:13][CH3:14])=[O:6]
Reactant: Nc1ccc(C(=O)O)cc1N
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1ccc(N)c(N)c1

Procedure:
One mole (152 g.) of 3,4-diaminobenzoic acid was stirred with 2 liters of ethanol in a Morton flask. Hydrogen chloride gas was passed through the stirred suspension for about 2 hours. As the gas was absorbed, the slurry became gel-like in character. Ethanol (500 ml.) was added to the reaction mixture to disperse the gel. The reaction mixture was refluxed 24 hours. The mixture was filtered and the filtrate was evaporated to dryness in vacuo. The filter cake and the filtrate residue were dissolved in 9 liters of water. The aqueous solution was made basic by the addition of solid sodium carbonate. The product precipitated from the basic solution. The material was filtered and dried to yield 130 grams of ethyl 3,4-diaminobenzoate.
Reaction SMILES: [CH2:1]([N:3](CC)CCN)[CH3:2].CO[C:11]([C:13]1[N:14]=[N:15][N:16]([C:33]2[CH:38]=[C:37]([CH:39]([CH3:41])[CH3:40])[C:36]([O:42]CC3C=CC=CC=3)=[CH:35][C:34]=2[O:50]CC2C=CC=CC=2)[C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH:25][CH2:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[CH:20][CH:19]=1)=[O:12].[Br-]>C(#N)C>[CH2:1]([NH:3][C:11]([C:13]1[N:14]=[N:15][N:16]([C:33]2[CH:38]=[C:37]([CH:39]([CH3:41])[CH3:40])[C:36]([OH:42])=[CH:35][C:34]=2[OH:50])[C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH:25][CH2:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[CH:20][CH:19]=1)=[O:12])[CH3:2]
Reactant: CCN(CC)CCN
Reactant: CCN(CC)CCNCc1ccc(-c2c(C(=O)OC)nnn2-c2cc(C(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)cc1
Agent: [Br-]
Solvent: CC#N
Product: CCNC(=O)c1nnn(-c2cc(C(C)C)c(O)cc2O)c1-c1ccc(CNCCN(CC)CC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
1-(2,4-bis-benzyloxy-5-isopropyl-phenyl)-5-{4-[(2-diethylamino-ethylamino)-methyl]-phenyl}-1H-[1,2,3]triazole-4-carboxylic acid methyl ester N,N-diethylethylenediamine (0.6 mmol) was added at −10° C. to an acetonitrile solution of the bromide adduct obtained in Step A (125 mg, 0.2 mmol), and the reaction mixture was stirred for 30 minutes at this temperature and then warmed up to RT. After completion of the reaction (monitored by TLC), the solvent was removed under reduced pressure and the residue was purified by flash chromatography, the column being previously conditioned with ammonia (DCM/MeOH:80/10). The title compound was obtained as an oil (45%).
Reaction SMILES: Cl.[Br:2][C:3]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[S:5][C:4]=1[NH2:12].[C:13]1([S:19]([Cl:22])(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>N1C=CC=CC=1>[ClH:22].[Br:2][C:3]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[S:5][C:4]=1[NH:12][S:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:21])=[O:20]
Reactant: Nc1sc2cccnc2c1Br
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1sc2cccnc2c1Br)c1ccccc1
Temperature: 50 °C
Yield: 35.7 %

Procedure:
To a solution of compound 145-H (0.46 g, 1.52 mmol) in pyridine (4.6 mL), cooled to 0° C., was added benzenesulfonyl chloride (0.206 mL, 1.60 mmol), and the reaction was heated to 50° C. for 72 h. Additional benzenesulfonyl chloride (0.412 mL, 3.20 mmol) was added and the reaction mixture was heated at 50° C. for an additional 16 h. The solvent was evaporated in vacuo, the residue dissolved in dichloromethane and washed with aqueous sodium bicarbonate. The aqueous layer was acidified with 1N HCl, extracted with dichloromethane, and the organic layer was evaporated in vacuo to afford a yellow solid (0.22 g, 36%) as a 1/3.5 mixture of the 3-bromo—and 3-chloro-substituted compounds, 145-Ia and 145-Ib, respectively. 1H-NMR (DMSO-d6): δ 7.1-7.2 (m, 1H), 7.4-7.6 (m, 3H), 7.8 (m, 2H), 8.1-8.2 (m, 1H), 8.25-8.35 (m, 1H); MS: m/z 465 and 509 (MH+).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][O:7][C@H:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([O:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:23]=[C:24]([CH3:28])[CH:25]=[CH:26][CH:27]=3)[O:19][C:20]=2[CH3:21])[CH2:9]1)=[N+]=[N-].[H][H]>CO.[Pd]>[CH3:21][C:20]1[O:19][C:18]([C:22]2[CH:23]=[C:24]([CH3:28])[CH:25]=[CH:26][CH:27]=2)=[N:17][C:16]=1[CH2:15][O:14][C@H:10]1[CH2:11][CH2:12][CH2:13][C@@H:8]([O:7][CH2:6][CH2:5][CH2:4][NH2:1])[CH2:9]1
Reactant: [H][H]
Reactant: Cc1cccc(-c2nc(CO[C@@H]3CCC[C@H](OCCCN=[N+]=[N-])C3)c(C)o2)c1
Agent: [Pd]
Solvent: CO
Product: Cc1cccc(-c2nc(CO[C@H]3CCC[C@@H](OCCCN)C3)c(C)o2)c1

Procedure:
472 mg of ((1R,3S)-3-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]propyl 4-chloromethanesulfonate are dissolved in 3 ml of N-methylpyrrolidone, and 200 mg of sodium azide are added. The mixture is stirred at 60° C. for 3 h and, after cooling, taken up in 20 ml of ethyl acetate/20 ml with sat. NaCl solution. The organic phase is dried over sodium sulfate and the solvent is removed under reduced pressure. This gives 4-((1R,3S)-[3-(3-azidopropoxy)cyclohexyloxymethyl]-5-methyl-2-m-tolyloxazole as a colorless oil. C21H28N4O3 (384.48), MS (ESI): 385 (M+H+). The crude azide is taken up in 20 ml of methanol and hydrogenated with 50 mg of Pd/C 10% at a hydrogen atmosphere of 1 bar for 3 h. The catalyst is filtered off, giving (1R,3S)-3-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]propylamine as a colorless oil. C21H30N2O3 (358.48), MS (ESI): 359 (M+H+).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][N:11]1[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:18]1[C:19](=[O:26])[N:20]([CH3:25])[CH:21]=[C:22]([Br:24])[N:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:24][C:22]1[N:23]=[C:18]([NH:16][C:14]2[CH:13]=[N:12][N:11]([CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])[CH:15]=2)[C:19](=[O:26])[N:20]([CH3:25])[CH:21]=1
Reactant: Cn1cc(Br)nc(Br)c1=O
Reactant: CC(C)(C)[Si](C)(C)OCCn1cc(N)cn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1cc(Br)nc(Nc2cnn(CCO[Si](C)(C)C(C)(C)C)c2)c1=O
Temperature: 25 °C
Yield: 49.6 %

Procedure:
A 100-mL three-neck round-bottomed flask equipped with a reflux condenser, magnetic stirrer and nitrogen inlet was charged with 116b (400 mg, 1.66 mmol), 3,5-dibromo-1-methyl pyrazin-2(1H)-one (443 mg, 1.66 mmol), cesium carbonate (1.19 g, 3.65 mmol), and 1,4-dioxane (20 mL). After bubbling nitrogen through the resulting suspension for 30 min, Xantphos (144 mg, 0.249 mmol) and tris(dibenzylideneacetone)-dipalladium(0) (152 mg, 0.166 mmol) were added, and the reaction mixture was heated at reflux for 4 h. After this time, the mixture was cooled to room temperature and filtered, and the filter cake was washed with methylene chloride (2×20 mL). The filtrates were combined and concentrated under reduced pressure, and the resulting residue was purified by column chromatography to afford a 51% yield (353 mg) of 116c as a yellow solid: mp 172-173° C.; 1H NMR (500 MHz, CDCl3) d 8.17 (s, 1H), 8.06 (s, 1H), 7.65 (s, 1H), 6.70 (s, 1H), 4.28 (t, 2H, J=5.0 Hz), 3.97 (t, 2H, J=5.5 Hz), 3.51 (s, 3H), 0.85 (s, 9H), −0.79 (s, 6H); MS (APCI+) m/z 428.3 (M+H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([C:16]([NH:18][CH:19]3[CH2:21][CH2:20]3)=[O:17])=[CH:14][N:13]=[CH:12][CH:11]=2)=[C:6](F)[CH:5]=1>C1COCC1>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]2[C:10]3[C:15](=[CH:14][N:13]=[CH:12][CH:11]=3)[C:16](=[O:17])[N:18]([CH:19]3[CH2:21][CH2:20]3)[C:6]=2[CH:5]=1
Reactant: O=C(NC1CC1)c1cnccc1-c1ccc(Cl)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1c2cnccc2c2ccc(Cl)cc2n1C1CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.4 %

Procedure:
To a suspension of sodium hydride (72.6 mg, 3.03 mmol) in THF (8 mL) at 0° C. was added a solution of 4-(4-chloro-2-fluorophenyl)-N-cyclopropylnicotinamide (440 mg, 1.51 mmol) in THF (10 mL) dropwise over a period of 10 min. The reaction mixture was stirred at 0° C. for 1 h and then warmed to room temperature and stirred for another 1 h. The reaction mixture was then treated with ice and extracted with ethyl acetate (3×5 mL). The combined organic layers were washed with brine (2×5 mL), dried (Na2SO4) and concentrated under reduced pressure to afford crude 8-chloro-6-cyclopropylbenzo[c][2,7]naphthyridin-5(6H)-one (340 mg, 1.26 mmol, 83% yield) as an off-white solid. LC/MS (ESI) m/e 271.0 [(M+H)+, calcd for C15H12ClN2O 271.1]; LC/MS retention time (method C): tR=1.89 min.
Reaction SMILES: CN(C)C=O.[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][O:15][CH3:16])[C:8]=1[OH:17].C(=O)([O-])[O-].[K+].[K+].[CH:24]1([CH2:27]Br)[CH2:26][CH2:25]1>O>[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][O:15][CH3:16])[C:8]=1[O:17][CH2:27][CH:24]1[CH2:26][CH2:25]1
Reactant: BrCC1CC1
Reactant: COCOc1cccc(Br)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1cccc(Br)c1OCC1CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
To 200 ml of N,N-dimethylformamide solution containing 23.3 g (0.10 mol) of 2-bromo-6-methoxymethoxyphenol (see Synthesis, 2001, 741-744) were added 13.8 g (0.10 mol) of potassium carbonate and 19.5 ml (0.20 mol) of cyclopropylmethyl bromide, and the mixture was stirred at 80° C. for 2 hours. After completion of the reaction, water was added to the reaction mixture, and extracted with toluene. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=9:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 24.1 g of the title compound as a colorless oil. (Yield: 84%)
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([OH:20])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH2:3][CH2:2]1.C1(C2C=CC(C(O)=O)=NC=2OCC2CCCO2)CC1.C1(N(C2N=C(C)ON=2)C)CC1.[CH:51]1([CH2:54][C@H:55]([NH2:62])[C:56]2[N:60]=[C:59]([CH3:61])[O:58][N:57]=2)[CH2:53]C1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:54]1([CH:55]([NH:62][C:18]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]3[CH2:2][CH2:3]3)=[C:9]([O:10][CH2:11][CH:12]3[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)[N:8]=2)=[O:20])[C:56]2[N:60]=[C:59]([CH3:61])[O:58][N:57]=2)[CH2:51][CH2:53]1
Reactant: Cc1nc([C@@H](N)CC2CC2)no1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CCOCC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cc1nc(N(C)C2CC2)no1
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C(NC(=O)c2ccc(C3CC3)c(OCC3CCOCC3)n2)C2CC2)no1

Procedure:
In analogy to the procedure described in Example 47 b), 5-cyclopropyl-6-(tetrahydro-pyran-4-ylmethoxy)-pyridine-2-carboxylic acid (which can e.g. be prepared in a similar manner than 5-cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid (Example 4 b)) was reacted with cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methylamine (which can e.g. be prepared in a similar manner than (S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (Example 32 e)) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=413.1 [MH+].
Reaction SMILES: Cl.Cl.[CH2:3]([NH:5][CH2:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C@@H:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9][NH:8]1)[CH3:4].C(N(CC)CC)C.[C:30](OCC)(=[O:36])[C:31](OCC)=[O:32]>C(Cl)(Cl)Cl>[CH2:3]([N:5]1[C:31](=[O:32])[C:30](=[O:36])[N:8]2[CH2:9][C@@H:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]3[C:16]([C@@H:7]2[CH2:6]1)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH3:4]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCNC[C@@H]1NC[C@H](c2ccccc2)c2ccccc21
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCN1C[C@H]2c3ccccc3[C@H](c3ccccc3)CN2C(=O)C1=O
Yield: 60.8 %

Procedure:
To a stirred solution of cis-1,2,3,4-tetrahydro-1-(ethylamino)methyl-4-phenyl-isoquinoline dihydrochloride (19.5 g, 0.057 m) in chloroform (250 ml) maintained under nitrogen at ambient temperature was added triethylamine (26.0 g, 0.25 m) and then in one portion diethyl oxalate (36.4 g, 0.23 m) and the mixture heated to reflux for 5 hours. The mixture was cooled and washed with 10% HCl (3×150 ml) and water (200 ml) and dried over MgSO4. The solvent was evaporated to a yellow oil, which was dissolved in 200 ml ethanol, decolorized with Norite. Upon cooling and standing, a white solid crystallized which was collected by filtration and dried to give 11.2 g of cis-1,3,4,6,7,11b-hexahydro-2-ethyl-7-phenyl-2H-pyrazino[2,1-a]isoquinoline-3,4-dione.