Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl/[CH:2]=[CH:3]/[CH2:4][N:5]([CH3:17])[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.C(N([CH2:34][C:35]([O-])=O)CC(O)=O)CN(CC([O-])=O)CC(O)=O.[Na+].[Na+]>Cl[Ni]Cl.C1COCC1>[CH3:6][C:7]([C:34]#[C:35]/[CH:2]=[CH:3]/[CH2:4][N:5]([CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=12)[CH3:17])([CH3:16])[CH3:8]
Reactant: CN(C/C=C/Cl)Cc1cccc2ccccc12
Reactant: O=C([O-])CN(CCN(CC(=O)[O-])CC(=O)O)CC(=O)O
Agent: Cl[Ni]Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C/C=C/C#CC(C)(C)C)Cc1cccc2ccccc12
Temperature: 50 °C

Procedure:
The mixture is cooled to 50° C. and 15.5 g (0.0572 mol) crude N-(trans-3-chloro-2-propenyl)-N-methyl-1-naphthalene-methylamine, 20 ml THF and 74 mg NiCl2 (0.77 molar percent) introduced. The reaction mixture is heated at 90°-95° C. for 1 hour, cooled to 20°/25° C. and 130 ml of a 2.5% (w/v) aqueous solution of EDTA disodium salt added, the phases are separated and the aqueous phase re-extracted with 70 ml chilled toluene. The combined organic phases are washed with 2×90 ml water and concentrated to a residue, thus giving 18.2 g (greater than theoretical yield) terbinafine with a purity of 83.6% (HPLC A %).
Reaction SMILES: [C:1]1([C:7]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:18][CH2:19][C:20]([NH2:22])=[O:21].[OH-].[Na+].Cl.C(=O)(O)[O-].[K+]>O.CO>[C:1]1([C:7]2[N:18]=[CH:19][C:20]([OH:21])=[N:22][C:9]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCC(N)=O
Reactant: O=C(C(=O)c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CO
Product: Oc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Reaction time: 3 h

Procedure:
First, 4.2 g (20 mmol) of benzil, 2.21 g (20 mmol) of glycinamide hydrochloride, and 40 mL of methanol were put into a three-neck flask equipped with a reflux pipe, the air in the flask was replaced with nitrogen, the mixture was refluxed, an aqueous solution of 1.6 g (40 mmol) of sodium hydroxide in 3.2 mL of water was added, and the reflux was continued for 3 hours. Then, stirring was performed until the temperature of the flask was returned to room temperature. After that, 2.5 mL of 12M concentrated hydrochloric acid, 2 g of potassium bicarbonate, and 25 mL of water were added to this mixture, and filtration was performed.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([O:16][CH:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][NH2:26])[CH2:19][CH2:18]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl[C:28]1[CH:29]=[CH:30][C:31]2[N:32]([CH:34]=[C:35]([C:37]([CH3:44])([CH3:43])[C:38]([O:40][CH2:41][CH3:42])=[O:39])[N:36]=2)[N:33]=1.C(=O)(O)[O-].[Na+]>CN1CCCC1=O>[CH:12]1[C:8]2[CH2:9][CH2:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH:6]([O:16][CH:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][NH:26][C:28]4[CH:29]=[CH:30][C:31]5[N:32]([CH:34]=[C:35]([C:37]([CH3:43])([CH3:44])[C:38]([O:40][CH2:41][CH3:42])=[O:39])[N:36]=5)[N:33]=4)[CH2:19][CH2:18]3)[C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: NCCCN1CCC(OC2c3ccccc3CCc3ccccc32)CC1
Reactant: CCOC(=O)C(C)(C)c1cn2nc(Cl)ccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)C(C)(C)c1cn2nc(NCCCN3CCC(OC4c5ccccc5CCc5ccccc54)CC3)ccc2n1
Temperature: 170 °C
Reaction time: 7 h
Yield: 24.3 %

Procedure:
1.69 g of 4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-oxy)-1-piperidinepropanamine and 645 mg of ethyl 2-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-methylpropionate were dissolved in 3 ml of 1-methyl-2-pyrrolidone, followed by stirring in an oil bath (170° C.) for 7 hours. After cooling, saturated aqueous sodium bicarbonate was added, followed by extraction with ethyl acetate; the extract was washed with water and saturated saline and dried with magnesium sulfate. The solution was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (50:5:1). The desired fraction was collected, concentrated, the residue was subjected to silica gel column chromatography again and eluted with dichloromethane:methanol:triethylamine (100:1:2). The desired fraction was collected and concentrated to yield 340 mg of the title compound.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].N1C=CC=CC=1.[OH:11][CH2:12][C:13]#[C:14][C:15]([C:17]1[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=1)=[O:16].P([O-])([O-])([O-])=O>C(Cl)Cl>[C:1]([O:11][CH2:12][C:13]#[C:14][C:15](=[O:16])[C:17]1[CH:18]=[C:19]([O:27][CH3:28])[C:20]([O:25][CH3:26])=[C:21]([O:23][CH3:24])[CH:22]=1)(=[O:3])[CH3:2]
Reactant: COc1cc(C(=O)C#CCO)cc(OC)c1OC
Reactant: CC(=O)Cl
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(C(=O)C#CCOC(C)=O)cc(OC)c1OC
Reaction time: 1 h

Procedure:
0.815 g of acetyl chloride and 0.827 g of pyridine were added simultaneously to a solution of 2.0 g (7.99 mmol) of 4-hydroxy-1-(3,4,5-trimethoxyphenyl)-2-butyn-1-one in 20 ml of methylene chloride. The reaction mixture was stirred at 0° for 1 hour, whereupon it was treated with 30 ml of phosphate buffer (pH 6) and the aqueous phase was extracted twice with methylene chloride. The combined organic phases were dried over magnesium sulphate and evaporated. The residue was recrystallized from ethyl acetate/hexane and there was obtained 3-(3,4,5-trimethoxy-benzoyl)-2-propynyl acetate of melting point 104°-105°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH2:13][CH2:12][S:11]3)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:30])C=1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH2:13][CH2:12][S:11]3=[O:30])=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2nc3n(c2-c2ccncc2)CCS3)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=S1CCn2c1nc(-c1ccc(F)cc1)c2-c1ccncc1
Reaction time: 1 h
Yield: 104.9 %

Procedure:
To 1.9 g of 6-(4-fluorophenyl)-5-(4-pyridyl)-2,3-dihydroimidazo[2,1-b]thiazole in 25 ml of methylene chloride cooled to ice-bath temperature was added 1.36 g of m-chloroperbenzoic acid. Stirring was continued for 1 hour then the solution was diluted with methylene chloride and washed with a 1:1 mixture of 5% sodium carbonate and brine. Treating with magnesium sulfate, filtering and stripping gave 2.1 g of the title product which was triturated with ether, filtered and dried to give 1.8 g, m.p.229°-231°.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([NH:16][C@H:17]([C:22]([O:24]C)=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[OH-].[Li+]>CO.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([NH:16][C@H:17]([C:22]([OH:24])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: COC(=O)[C@H](CC(C)C)NC(C(=O)N(C)C)c1ccc2occc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)C[C@H](NC(C(=O)N(C)C)c1ccc2occc2c1)C(=O)O
Reaction time: 24 h
Yield: 95.8 %

Procedure:
To a solution of methyl N-[1-(benzofuran-5-yl)-2-(dimethylamino)-2-oxoethyl]-L-leucinate (520 mg) in methanol (5 ml) was added a solution of lithium hydroxide (91 mg) in water (3 ml). After stirring vigorously for 24 hours the solvent was removed in vacuo. The residue was diluted with water (10 ml) then neutralised with 2N hydrochloric acid. This solution was applied to an Oasis™ cartridge (2×6 g) and eluted with water (×2) and methanol (×2). The required fractions were combined and evaporated to afford N-[1-(benzofuran-5-yl)-2-(dimethylamino)-2-oxoethyl]-L-leucine (478 mg).
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].P(Cl)(Cl)Cl.[N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[N:27]1[CH2:32][CH2:31][N:30]([CH:33]([CH3:40])[CH2:34][CH2:35][CH2:36][C:37](O)=[O:38])[CH2:29][CH2:28]1>N1C=CC=CC=1>[N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[N:27]1[CH2:28][CH2:29][N:30]([CH:33]([CH3:40])[CH2:34][CH2:35][CH2:36][C:37]([NH:1][C:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=2[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:38])[CH2:31][CH2:32]1
Reactant: CC(CCCC(=O)O)N1CCN(c2ccc3ccccc3n2)CC1
Reactant: CCOC(=O)C1=C(N)CCCC1
Solvent: c1ccncc1
Solvent: ClP(Cl)Cl
Product: CCOC(=O)C1=C(NC(=O)CCCC(C)N2CCN(c3ccc4ccccc4n3)CC2)CCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 38.1 %

Procedure:
To a solution of 170 mg of ethyl 2-aminocyclohex-1-enecarboxylate as synthesized in Step 7-1-B in 5 ml of pyridine, 70 mg of phosphorus trichloride was added under cooling with ice, followed by 15 minutes' stirring. Raising the temperature to room temperature, 327 mg of 5-(4-quinoline-2-ylpiperazin-1-yl)hexanoic acid as synthesized in above Step 7-14-C was added to the solution and stirred for 3 hours. Distilling the pyridine off under reduced pressure, the residue was extracted with ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified on silica gel column chromatography (ethyl acetate) to provide 182 mg (38%) of ethyl 2-[5-(4-quinolin-2-ylpiperazin-1-yl)hexanoylamino]cyclohex-1-enecarboxylate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([NH:8]C(=O)C)[CH:7]=1.ClC1C=CC([N+]([O-])=O)=C(C=1)N.[CH3:26][O:27][C:28]([C:30]1(OC)[CH2:34][CH2:33][CH:32](OC)O1)=[O:29]>CC(O)=O>[CH3:26][O:27][C:28]([C:30]1[N:1]([C:2]2[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([NH2:8])[CH:7]=2)[CH:32]=[CH:33][CH:34]=1)=[O:29]
Reactant: CC(=O)Nc1cc(N)ccc1[N+](=O)[O-]
Reactant: COC(=O)C1(OC)CCC(OC)O1
Agent: Nc1cc(Cl)ccc1[N+](=O)[O-]
Solvent: CC(=O)O
Product: COC(=O)c1cccn1-c1ccc([N+](=O)[O-])c(N)c1

Procedure:
The title compound was prepared from N-(5-amino-2-nitro-phenyl)-acetamide [prepared from commercially available 5-chloro-2-nitroaniline as described in Example F6] and 2,5-dimethoxy-tetrahydro-furan-2-carboxylic acid methyl ester [CAS-no. 39658-49-6] in HOAc at 60° C. for 2 h according to the general procedure F. Obtained as a light yellow solid (757 mg). Deacetylation of this material was perfomed by stirring with 10 eq. NaOMe-sol. in MeOH at 23° C. for 1 h. Obtained as a yellow solid (594 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]([C:19]2[N:20](S(C3C=CC=CC=3)(=O)=O)[C:21]3[C:26]([CH:27]=2)=[CH:25][C:24]([F:28])=[CH:23][CH:22]=3)=[O:18])([CH2:14][CH2:15][CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([C:17]([C:19]2[NH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][C:24]([F:28])=[CH:23][CH:22]=3)=[O:18])([CH2:14][CH2:15][CH3:16])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCC1(C(=O)c2cc3cc(F)ccc3n2S(=O)(=O)c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC1(C(=O)c2cc3cc(F)ccc3[nH]2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 75.8 %

Procedure:
To a solution of 4-(1-benzenesulfonyl-5-fluoro-1H-indole-2-carbonyl)-4-propyl-piperidine-1-carboxylic acid tert-butyl ester (290 mg, 0.55 mmol) in 30 mL of methanol was added 10 mL of 1M NaOH. The reaction mixture was warmed to 80° C. and was allowed to stir for one hour, then was concentrated in vacuo to remove the methanol. The remaining residue was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated in vacuo to afford a yellow colored oil. The oil was chromatographed over a 12 g SiO2 column eluting with 20% ethyl Acetate, 80% hexanes to afford 4-(5-fluoro-1H-indole-2-carbonyl)-4-propyl-piperidine-1-carboxylic acid tert-butyl ester 162 mg as a white solid in 76% yield.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH:10]1([N:15]2[CH:19]=[C:18]([C:20]([OH:22])=O)[N:17]=[N:16]2)[CH2:14][CH2:13][CH2:12][CH2:11]1.C1(N)CCCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:51][CH2:52][C:53]([N:55]1[CH2:60][CH2:59][CH:58]([O:61][C:62]2[CH:63]=[N:64][CH:65]=[C:66]([Cl:68])[CH:67]=2)[CH2:57][CH2:56]1)=[O:54]>CN(C=O)C.O>[Cl:68][C:66]1[CH:67]=[C:62]([O:61][CH:58]2[CH2:57][CH2:56][N:55]([C:53](=[O:54])[CH2:52][NH:51][C:20]([C:18]3[N:17]=[N:16][N:15]([CH:10]4[CH2:11][CH2:12][CH2:13][CH2:14]4)[CH:19]=3)=[O:22])[CH2:60][CH2:59]2)[CH:63]=[N:64][CH:65]=1
Reactant: O=C(O)c1cn(C2CCCC2)nn1
Reactant: NCC(=O)N1CCC(Oc2cncc(Cl)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NC1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCC(Oc2cncc(Cl)c2)CC1)c1cn(C2CCCC2)nn1
Reaction time: 0.03 h
Yield: 55 %

Procedure:
DIPEA (300 mg, 2.3 mmol) was added to a stirred solution of 1-Cyclopentyl-1H-[1,2,3]triazole-4-carboxylic acid (75 mg, 0.41 mmol (prepared by the method used for the synthesis of Intermediate 64, starting from cyclopentylamine) in DMF (5 mL) followed by HOBt (61 mg, 0.4 mmol) and EDCI (200 mg, 1 mmol). After 2 minutes of stirring, 2-amino-1-[4-(5-chloro-pyridin-3-yloxy)-piperidin-1-yl]-ethanone hydrochloride (prepared according to Step 1 and 5 of the General Scheme) (156 mg, 0.5 mmol) was added and the resulting mixture was stirred at ambient temperature overnight. Cold water was then added and filtered the precipitate was filtered. The solid obtained was purified by recrystallisation from a solvent system EtOAc:hexane:MeOH (3:7:0.2) to afford 98 mg (55% Yield) of 1-cyclopentyl-1H-[1,2,3]triazole-4-carboxylic acid {2-[4-(5-chloro-pyridin-3-yloxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+ 433, 98.59%. 1H NMR (300 MHz, DMSO-d6): δ 8.7 (s, 1H), 8.34 (m, 2H), 8.24 (s, 1H), 7.74 (s, 1H), 5.1 (m, 1H), 4.9 (m, 1H), 4.2 (d, 2H), 4.0 (bs, 1H), 3.8 (bs, 1H), 3.4 (s, 1H), 3.3 (m, 1H), 2.3 (m, 2H), 2.1 (m, 4H), 1.9-1.5 (m, 6H).
Reaction SMILES: [F:1][C:2]([CH:8]([O:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1)[CH3:9])([F:7])[C:3]([F:6])([F:5])[F:4].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[F:1][C:2]([CH:8]([O:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][NH2:16])=[CH:17][CH:18]=1)[CH3:9])([F:7])[C:3]([F:4])([F:6])[F:5]
Reactant: CC(Oc1ccc(C#N)cc1)C(F)(F)C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(Oc1ccc(CN)cc1)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.8 %

Procedure:
Add (±)-4-[1-(1,1,2,2,2-pentafluoroethyl)-ethoxy]-benzonitrile (1 g, 3.8 mmol) to a slurry of lithium aluminum hydride (400 mg, 10 mmol) in diethyl ether (30 mL) at 0° C. under a nitrogen atmosphere. Stir the mixture at ambient temperature for 2 h, and then quench the reaction sequentially with water (1 mL) and 5N sodium hydroxide (1 mL). Filter the slurry through Celite®, dry the filtrate over Na2SO4, filter and concentrate in vacuo to obtain the title compound (990 mg, 98%). GC-MS m/z: 268 (M+).
Reaction SMILES: C(OC([C:7]1[N:8]=[CH:9][C:10]2[N:11]([S:31]([C:34]3[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=3)(=[O:33])=[O:32])[C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][O:21][CH3:22])=[CH:16][C:15]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:14][CH:13]=3)=O)(C)C.C[Li].[Cl-].[NH4+].[O:45]1CC[CH2:47][CH2:46]1>>[CH2:24]([O:23][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]([S:31]([C:34]1[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=1)(=[O:32])=[O:33])[C:10]1[CH:9]=[N:8][C:7]([C:46](=[O:45])[CH3:47])=[C:19]([CH2:20][O:21][CH3:22])[C:18]2=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C1CCOC1
Reactant: COCc1c(C(=O)OC(C)C)ncc2c1c1cc(OCc3ccccc3)ccc1n2S(=O)(=O)c1ccc(C)cc1
Agent: [Cl-]
Agent: [Li]C
Agent: [NH4+]
Product: COCc1c(C(C)=O)ncc2c1c1cc(OCc3ccccc3)ccc1n2S(=O)(=O)c1ccc(C)cc1
Temperature: -60 °C
Reaction time: 4 h

Procedure:
8.4 g of 6-benzyloxy-4-methoxymethyl-9-tosyl-β-carboline-3-carboxylic acid isopropyl ester is dissolved in 500 ml absolute tetrahydrofuran and cooled to -60° C. 15 ml of a 1.5 molar ethereal methyllithium solution is added drop by drop to this solution under argon atmosphere and then stirred for another 4 hours at -60° C. After heating to room temperature the reaction solution is mixed with saturated ammonium chloride solution, extracted with methylene chloride, dried and concentrated by evaporation. The resulting crude product is chromatographed on silica gel with cyclohexane: ethyl acetate=8:2. 4.1 g of 6-benzyloxy-4-methoxymethyl-3-acetyl-9-tosyl-β-carboline with a melting point of 173-175° C. is obtained.
Reaction SMILES: [CH:1]1([CH:7]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:9]([C:11]([CH3:13])=[O:12])=[CH2:10].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH:7]1[C:1]2([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:10][CH2:9][C:11](=[O:12])[CH:13]=1
Reactant: C=CC(C)=O
Reactant: O=CC1CCCCC1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C1C=CC2(CCCCC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of cyclohexanecarbaldehyde (10.7 mL) in toluene (100 mL) were added successively methyl vinyl ketone (15 mL) and concentrated sulfuric acid (0.1 mL). The reaction mixture was stirred at room temperature for 1 hour and then heated under reflux while stirring for 4 hours. After cooling down to room temperature, saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by separation of the organic layer. Then, after the aqueous layer was extracted with toluene, the organic layers were combined, washed with saturated brine, dried and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:20 to 1:12) to give spiro[5.5]undec-1-en-3-one (8.9 g).
Reaction SMILES: C(N(CC)[C:4]1[CH:9]=CC=C[CH:5]=1)C.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]([CH3:30])[C:20]2=[O:31])=[C:15]([O:32]CC#C)[CH:14]=1.[F-].[Cs+]>O>[Cl:12][C:13]1[C:14]2[CH:5]=[C:4]([CH3:9])[O:32][C:15]=2[C:16]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[N:21]([CH3:30])[C:20]2=[O:31])=[CH:17][CH:18]=1
Reactant: CCN(CC)c1ccccc1
Reactant: C#CCOc1cc(Cl)ccc1-n1c(=O)cc(C(F)(F)F)n(C)c1=O
Agent: [Cs+]
Agent: [F-]
Solvent: O
Product: Cc1cc2c(Cl)ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1
Temperature: 185 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
200 ml of N,N-diethylaniline was added to 20.0 g (55.8 mmol) of 3-(4-chloro-2-propargyloxyphenyl)-1-methyl-6-trifluoromethyluracil and 17.0 g (112 mmol) of cesium fluoride, followed by stirring at 180 to 190° C. for 2 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed sequentially with a 10% hydrochloric acid aqueous solution, water and a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 7.0 g (yield: 35.0%) of the desired product as white crystals. Melting point: 206-207° C.
Reaction SMILES: CO[CH:3]1[CH2:7][CH2:6][CH:5](OC)O1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.[CH2:27]([O:29][C:30]([C:32]1[NH:33][CH:34]=[CH:35][C:36]=1[NH2:37])=[O:31])[CH3:28]>O1CCOCC1>[N:37]1([C:36]2[CH:35]=[CH:34][NH:33][C:32]=2[C:30]([O:29][CH2:27][CH3:28])=[O:31])[CH:3]=[CH:7][CH:6]=[CH:5]1
Reactant: CCOC(=O)c1[nH]ccc1N
Reactant: COC1CCC(OC)O1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1COCCO1
Product: CCOC(=O)c1[nH]ccc1-n1cccc1
Reaction time: 1 h
Yield: 53.1 %

Procedure:
To a stirred solution of 2,5-dimethoxytetrahydrofuran (b) (1.6 mL, 12.4 mmol, 1.3 equiv) and PPTS (3.2 g, 12.4 mmol, 1.3 equiv) in 1,4-dioxane (20 mL) at 50° C., a solution of aminopyrrole (a) (1.47 g, 9.55 mmol, 1.0 eq.) in 1,4-dioxane (6 mL) was added slowly. The resulting mixture was brought to reflux and stirred for 1 h. The reaction mixture was then concentrated, dissolved in EtOAc (50 mL) and dried over anhydrous MgSO4. The crude product was purified by flash column chromatography (10% EtOAc in Hexane) to give (c) as a yellow solid (1.036 g, 53% yield). 1H NMR (400 MHz, CDCl3) δ 8.99 (s, 1H), 7.04-7.01 (m, 2H), 6.89 (t, J=3.1 Hz, 1H), 6.29 (t, J=2.9 Hz, 1H), 6.27-6.24 (m, 2H), 4.28 (q, J=7.1 Hz, 2H), 1.29 (t, J=7.1 Hz, 3H).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:20]([OH:35])[CH2:21][NH:22][C:23]([CH3:34])([CH3:33])[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)C1C=CC=CC=1>CO.[Pd]>[F:32][C:26]1[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:25]=1[CH2:24][C:23]([NH:22][CH2:21][CH:20]([C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[C:18]2[C:13]=1[CH2:14][CH2:15][C:16](=[O:19])[NH:17]2)[OH:35])([CH3:33])[CH3:34]
Reactant: CC(C)(Cc1ccc(F)cc1F)NCC(O)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: [Pd]
Solvent: CO
Product: CC(C)(Cc1ccc(F)cc1F)NCC(O)c1ccc(O)c2c1CCC(=O)N2

Procedure:
A solution of 220 mg (0.5 mmol) 8-benzyloxy-5-{2-[2-(2,4-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-1H-quinolin-2-one in 10 mL methanol is hydrogenated in the presence of palladium on charcoal at ambient temperature and normal pressure. Then the catalyst is separated off, the filtrate is evaporated down and the residue is chromatographed (reverse phase; water/acetonitrile gradient).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([C:14]1[C:23]([CH3:24])=[N:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1)[CH2:11][C:12]#[CH:13]>>[F:9][CH2:8][C:4]1[N:3]=[C:2]([C:13]#[C:12][CH2:11][CH2:10][C:14]2[C:23]([CH3:24])=[N:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: C#CCCc1nc2ccccc2nc1C
Reactant: FCc1cccc(Br)n1
Product: Cc1nc2ccccc2nc1CCC#Cc1cccc(CF)n1
Yield: 16.2 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)-pyridine (24 mg, 0.13 mmol) and 2-but-3-ynyl-3-methyl-quinoxaline (25 mg, 0.13 mmol). Reaction time: 14 hours. The crude residue was purified by preparative chromatography plate (Et2O/pentane 7:3) to yield 6.4 mg (21 μmol, 13%) of 2-(4(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-3-methylquinoxaline as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][CH:38]=1)[C:5]([C:7]1[CH:35]=[CH:34][C:10]2[N:11]([CH2:15][CH2:16][O:17][C:18]3[CH:33]=[CH:32][C:21]([CH:22]=[C:23]([C:28]([O:30][CH3:31])=[O:29])[C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=3)[C:12](=[O:14])[S:13][C:9]=2[CH:8]=1)=[O:6].C(OC(C)C)(C)C>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][CH:38]=1)[C:5]([C:7]1[CH:35]=[CH:34][C:10]2[N:11]([CH2:15][CH2:16][O:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:22][CH:23]([C:24]([O:26][CH3:27])=[O:25])[C:28]([O:30][CH3:31])=[O:29])=[CH:32][CH:33]=3)[C:12](=[O:14])[S:13][C:9]=2[CH:8]=1)=[O:6]
Reactant: COC(=O)C(=Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4cccc(Cl)c4)ccc32)cc1)C(=O)OC
Solvent: CC(C)OC(C)C
Product: COC(=O)C(Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4cccc(Cl)c4)ccc32)cc1)C(=O)OC

Procedure:
The procedure is as in Example 40, starting from the compound obtained in Example 41. The recrystallisation solvent is isopropyl ether.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:7]=[C:6]([NH2:16])[CH:5]=1.CCN(CC)CC.[C:25](OC(=O)C)(=[O:27])[CH3:26]>C(Cl)Cl.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:7]=[C:6]([NH:16][C:25](=[O:27])[CH3:26])[CH:5]=1
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1cc(N)cc(N2CCCC2=O)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(NC(C)=O)cc(N2CCCC2=O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.3 %

Procedure:
To a solution of 3-amino-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid methyl ester (D4a) (80 mg, 0.34 mmol, 1 equiv) in CH2Cl2 (10 ml) was added NEt3 (0.142 ml, 1.02 mmol, 2 equiv) and acetic anhydride (0.078 ml, 0.82 mmol, 2.4 equiv). The resulting mixture was stirred at room temperature for 16 h. The reaction was then diluted with AcOEt (20 ml), washed with 2N aqueous HCl solution (20 ml), dried over MgSO4, and concentrated in vacuo to give 3-acetylamino-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid methyl ester (B50) (67 mg, 71%) as a pale yellow foam.