Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[C:11](=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[CH2:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])(=O)=O>CC(C)=O.C(OCC)C>[CH3:11][O:9][C:8]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])=[CH:7][N:6]=1)=[O:10]
Reactant: O=C(O)c1ccc(O)cn1
Reactant: O=S(=O)(OCC(F)(F)C(F)F)C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: COC(=O)c1ccc(OCC(F)(F)C(F)F)cn1
Temperature: 22 °C
Reaction time: 4 h
Yield: 69 %

Procedure:
To 5-hydoxy-pyridine-2-carboxylic acid (2.0 g) in acetone (40 ml) was added potassium carbonate (5.4 g) and 2,2,3,3-tetrafluoropropyl trifluoromethanesulfonate (4.3 g) and the reaction mixture was stirred at 22° C. for 4 h. The suspension was diluted with diethyl ether, filtrated, the filtrate was evaporated and the residue purified by chromatography on silica to give 5-(2,2,3,3-tetrafluoro-propoxy)-pyridine-2-carboxylic acid methyl ester (2.65 g).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:28])[N:5]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:6]([C@@H:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])=[N:7]2.[CH3:29][N:30]1C(=O)CCC1>[C-]#N.[Zn+2].[C-]#N>[C:29]([C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:28])[N:5]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:6]([C@@H:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])=[N:7]2)#[N:30]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2cccc(Br)c2c(=O)n1-c1ccccc1
Reactant: CN1CCCC1=O
Agent: [C-]#N
Agent: [Zn+2]
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2cccc(C#N)c2c(=O)n1-c1ccccc1
Temperature: 90 °C

Procedure:
(S)-tert-butyl (1-(5-bromo-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamate (500 mg, 1.13 mmol), zinc cyanide (166 mg, 1.41 mmol), and tetrakis(triphenylphosphine)Pd(0) (124 mg, 0.11 mmol) were combined in NMP (5 mL). The mixture was degassed under Ar and heated to 90° C. overnight. The reaction was poured into EtOAc, washed with water (3×), and purified by flash chromatography (40 g silica, 0-50% EtOAc/hexanes) to give (S)-tert-butyl (1-(5-cyano-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamate as a white solid. ES/MS 391.2 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([CH:18]=1)[CH2:7][N:8]1[C:12]([CH:13]([F:15])[F:14])=[N:11][N:10]([CH3:16])[C:9]1=[O:17].C[C:21]([O:25][CH3:26])(C)[C:22]#[CH:23].[C:27]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:28]=1.C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I.COC(C)(C)C.C(#N)C>[F:14][CH:13]([F:15])[C:12]1[N:8]([CH2:7][C:6]2[CH:18]=[C:2]([C:27]#[C:28][CH:22]([CH3:23])[CH2:21][O:25][CH3:26])[CH:3]=[CH:4][C:5]=2[CH3:19])[C:9](=[O:17])[N:10]([CH3:16])[N:11]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: C#CC(C)(C)OC
Reactant: Cc1ccc(Br)cc1Cn1c(C(F)F)nn(C)c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: COC(C)(C)C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COCC(C)C#Cc1ccc(C)c(Cn2c(C(F)F)nn(C)c2=O)c1
Temperature: 25 °C
Yield: 686.9 %

Procedure:
498 mg (1.5 mmol) of 4-(5-bromo-2-methylbenzyl)-5-difluoromethyl-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (Compound 40), 378 mg (1.2 mmol) of 3-methyl-3-methoxy-1-butine, 21.1 mg (0.030 mmol) of PdCl2(PPh3)2, 19.0 mg (0.050 mmol) of copper iodide, 39.3 mg (0.15 mmol) of triphenylphosphine, 607 mg of triethylamine and 6.0 ml of acetonitrile were mixed, and the mixture was heated under reflux for 4.5 hours in nitrogen atmosphere. After cooling to room temperature, t-butyl methyl ether was added to the reaction solution, and the mixture was filtrated through celite, then, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluant: hexane/ethyl acetate=2/1 (v/v)) to obtain 360 mg of 5-difluoromethyl-2-methyl-4-{2-methyl-5-(3-methyl-methoxy-1-butynyl)-benzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (Compound 326).
Reaction SMILES: C([O:8][C:9]1[CH:29]=[CH:28][C:12]([CH2:13][N:14]([N:23]2[CH:27]=[N:26][N:25]=[CH:24]2)[C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)=[CH:11][C:10]=1[Cl:30])C1C=CC=CC=1>[Pd].CO.C1COCC1.CCOC(C)=O>[Cl:30][C:10]1[CH:11]=[C:12]([CH:28]=[CH:29][C:9]=1[OH:8])[CH2:13][N:14]([N:23]1[CH:24]=[N:25][N:26]=[CH:27]1)[C:15]1[CH:16]=[CH:17][C:18]([C:19]#[N:20])=[CH:21][CH:22]=1
Reactant: N#Cc1ccc(N(Cc2ccc(OCc3ccccc3)c(Cl)c2)n2cnnc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N(Cc2ccc(O)c(Cl)c2)n2cnnc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Palladium on charcoal (50 mg, 10% Pd) was added to a solution of 4-[(4-benzyloxy-3-chloro-benzyl)-[1,2,4]triazol-4-yl-amino]-benzonitrile (CAB02129, 1.04 g, 2.50 mmol) in MeOH/THF/EtOAc (25 mL/25 mL/25 mL). The mixture was stirred under hydrogen atmosphere (balloon) for 18 hours at room temperature. The reaction mixture was filtered through celite and the clear colourless filtrate was concentrated under reduced pressure. The residue was suspended in 2-propanol (20 mL) and heated to reflux for 5 minutes. The white solid was filtered off after cooling to room temperature and dried under high vacuum. Yield: 484 mg (59%). 1H-NMR (400 MHz, d6-DMSO) δ=4.93 (s, 2H), 6.76 (d, J=9.0 Hz, 2H), 6.86 (d, J=8.6 Hz, 1H), 7.02 (dd, J=8.2, 2.0 Hz, 1H), 7.27 (d, J=2.0 Hz, 1H), 7.76 (d, J=9.0 Hz, 2H), 8.77 (s, 2H), 10.29 (s, 1H, —OH). 13C-NMR (100 MHz, d6-DMSO) δ=56.87, 103.55, 114-48, 117.28, 119.73, 120.25, 126.72, 129.19, 130.91, 134.56, 144.02, 152.03, 153.50. LRMS (FAB+): 325.0 (100, [M+H]+).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[C:18]([CH3:30])[CH:17]=3)=[C:11]([CH2:31][CH2:32][CH3:33])[N:10]3[N:34]=[C:35]([CH3:37])[N:36]=[C:9]23)[CH2:4][CH2:3]1.[N+](=[CH:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])=[N-].O>C1(C)C=CC=CC=1.C([O-])(=O)C.[Rh+]>[C:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]1[CH:20]=[CH:21][C:16]([CH2:15][C:12]2[C:13](=[O:14])[N:8]([C@H:5]3[CH2:6][CH2:7][C@H:2]([O:1][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:3][CH2:4]3)[C:9]3[N:10]([N:34]=[C:35]([CH3:37])[N:36]=3)[C:11]=2[CH2:31][CH2:32][CH3:33])=[CH:17][C:18]=1[CH3:30])#[N:29]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)c(C)c2)c(=O)n([C@H]2CC[C@H](O)CC2)c2nc(C)nn12
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh+]
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)c(C)c2)c(=O)n([C@H]2CC[C@H](OCC(=O)OCC)CC2)c2nc(C)nn12
Reaction time: 0.5 h

Procedure:
To a mixture of 4′-{[4-(trans-4-hydroxycyclohexyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-2′-methylbiphenyl-2-carbonitrile (1.01 g), rhodium(I) acetate (0.30 g) and toluene (20 mL) was added dropwise a solution of ethyl diazoacetate (1.20 g) in toluene (10 mL) at 70° C., and the mixture was stirred at the same temperature for 30 min. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless oil (0.71 g, 60%).
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)[N:3]=1.[CH3:16][C@H:17]1[NH:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1.C(N(CC)CC)C>CN1CCCC1=O>[C:26]([O:25][C:23]([N:19]1[CH2:20][CH2:21][N:22]([C:2]2[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][N:11]=3)[N:3]=2)[C@H:17]([CH3:16])[CH2:18]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1nc(-c2ccncn2)cc(=O)n1C
Yield: 74.4 %

Procedure:
A solution of 2-chloro-3-methyl-6-(pyrimidin-4-yl)-3H-pyrimidin-4-one (5.3 g, 24 mmol), tert-butyl (3R)-3-methylpiperazine-1-carboxylate (5.0 g, 25 mmol) and triethylamine (7.6 g, 75 mmol) in N-methyl-2-pyrrolidone (25 ml) was stirred for 6 hours at 90° C. The solution was partitioned between water and ethyl acetate, and the organic layer was washed with water, brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; ethyl acetate) to afford (3R)-3-methyl-4-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (6.9 g, 71%).
Reaction SMILES: [N+:1]([C:4]1[N:9]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[C:7](=[O:14])[NH:6][CH:5]=1)([O-:3])=[O:2].[CH2:15](N(C(C)C)C(C)C)C.C[Si](C=[N+]=[N-])(C)C.Cl>O1CCOCC1.CCCCCC.CO>[CH3:15][O:14][C:7]1[C:8]([C:10]([O:12][CH3:13])=[O:11])=[N:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][N:6]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)c1nc([N+](=O)[O-])c[nH]c1=O
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: Cl
Solvent: CCCCCC
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)c1nc([N+](=O)[O-])cnc1OC
Reaction time: 15 h

Procedure:
In 2.0 L of dioxane was suspended 48.7 g of methyl 6-nitro-3-oxo-3,4-dihydro-2-pyrazinecarboxylate, to which were successively added 42.4 mL of N-ethyldiisopropylamine and 9.9 mL of methanol. Then, 122 mL of a 2.0 mol/L solution of trimethylsilyldiazomethane in hexane was added at room temperature, the mixture thus obtained was stirred at the same temperature as above for 15 hours, and the solvent was removed under reduced pressure. Then, 500 mL of ethyl acetate and 250 mL of water were added to the residue obtained above, pH was adjusted to 1.5 with 6 mol/L hydrochloric acid, and the organic layer was separated. The remaining aqueous layer was extracted with two 200 mL portions of ethyl acetate. All the organic layers were united, washed successively with 200 ml of water and 200 mL of saturated aqueous solution of sodium chloride and dried on anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel chromatography ]eluent: n-hexane:ethyl acetate=2:1] to obtain 24.3 g of methyl 3-methoxy-6-nitro-2-pyrazinecarboxylate as a solid product.
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:34][S:35][CH2:36][C@H:37]([O:53][C:54](=[O:66])[NH:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])[CH2:38][O:39][C:40](=[O:52])[NH:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[C:13](=[O:33])[NH:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=O)C1C=CC=CC=1.C([O-])=O.[NH4+].CO.O>CO.[Pd]>[NH2:11][C@@H:12]([CH2:34][S:35][CH2:36][C@H:37]([O:53][C:54](=[O:66])[NH:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])[CH2:38][O:39][C:40](=[O:52])[NH:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[C:13](=[O:33])[NH:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]
Reactant: CCCCCCCCCCNC(=O)OC[C@H](CSC[C@H](NC(=O)OCc1ccccc1)C(=O)NCCOCCOCCOCCC(=O)OC(C)(C)C)OC(=O)NCCCCCCCCCC
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CCCCCCCCCCNC(=O)OC[C@H](CSC[C@H](N)C(=O)NCCOCCOCCOCCC(=O)OC(C)(C)C)OC(=O)NCCCCCCCCCC
Temperature: 40 °C

Procedure:
A solution of (15R,19R)-tert-butyl 15-(benzyloxycarbonylamino)-19-(decylcarbamoyloxy)-14,22-dioxo-4,7,10,21-tetraoxa-17-thia-13,23-diazatritriacontan-1-oate in MeOH (0.1 M) was stirred under nitrogen at room temperature. A small scoop (catalytic) of Pd/C was then added and stirred. A solution of ammonium formate (8 eq) in 9:1 MeOH/water was then added, the reaction vessel purged with nitrogen and heated to 40° C. for 4 hours. The reaction was then cooled to room temperature and diluted with EtOAc. The reaction mixture was filtered through celite then Na2SO4 and concentrated to afford the title compound as a light yellow oil. The concentrated material was used with no further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.[CH3:13][O:14][CH2:15][CH2:16][C:17]#[N:18].CO.[OH-].[K+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=[C:16]([CH2:15][O:14][CH3:13])[C:17]#[N:18]
Reactant: COCCC#N
Reactant: COc1ccc(C=O)cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COCC(C#N)=Cc1ccc(OC)c(OC)c1
Temperature: 30 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 200 g (1.20 mole) of 3,4-dimethoxy-benzaldehyde, 150 g (1.75 mole) of β-methoxy-propinitrile, 260 ml of methanol and 10 g of a 55% methanolic potassium hydroxide solution is stirred at 60°-62° C. for 8 hours, whereupon the reaction mixture is cooled to 30° C., and 170 g of a 55% methanolic potassium hydroxide solution are added dropwise. The reaction mixture is stirred for 5 hours and diluted with 1000 ml of water. The precipitated crystalline product is filtered, washed with methanol and water. Thus 280 g of α-(3,4-dimethoxy-benzal)-β-methoxy-propionitrile are obtained, yield 85%, mp.: 82°-83° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:8].OS(O)(=O)=O.[N+:14]([O-])([OH:16])=[O:15]>>[Cl:1][C:2]1[CH:7]=[C:6]([N+:14]([O-:16])=[O:15])[CH:5]=[CH:4][N+:3]=1[O-:8]
Reactant: O=[N+]([O-])O
Reactant: [O-][n+]1ccccc1Cl
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc[n+]([O-])c(Cl)c1
Temperature: 0 °C
Yield: 56 %

Procedure:
2-Chloro-pyridine-1-oxide (10 g) is cooled in an ice bath and treated with concentrated H2SO4 (15 ml), followed by the dropwise addition of a mixture of concentrated H2SO4 (15 ml) and fuming HNO3 (27 ml, s.g. 1.5) over a 70 minute period. The acidic solution is heated in a steam bath for 2.5 hours, then allowed to reach room temperature and poured onto ice water (600 ml), stirring being continued until all the ice has melted. The resultant solid is filtered off and dissolved in hot chloroform, the solution being dried and the solvent evaporated in vacuo to give a yellow solid. The aqueous filtrate obtained after the removal of the original solid is neutralised with saturated aqueous Na2CO3 and extracted continuously with chloroform, the extract being dried and evaporated in vacuo to yield a yellow solid. The two yellow solids are combined and recrystallised from ethanol to give 2-chloro-4-nitro-pyridine-1-oxide as yellow crystals (7.46 g, 56%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([I:9])[CH:3]=1.[Si]([O:17][CH2:18][CH:19]=O)(C(C)(C)C)(C)C.FC(F)(F)C(O)=O.[BH3-]C#N.[Na+]>CO>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH2:19][CH2:18][OH:17])=[C:4]([I:9])[CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: Nc1cnc(Cl)cc1I
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: OCCNc1cnc(Cl)cc1I
Temperature: 25 °C
Reaction time: 12 h
Yield: 190.5 %

Procedure:
To a solution of 6-chloro-4-iodopyridin-3-amine (6.5 g, 25.5 mmol) in CH3OH (1500 mL) was added 2-(tert-butyldimethylsilyloxy)acetaldehyde (18.0 g, 103 mmol). Then trifluoroacetic acid (150 mL) and NaBH3CN (8.0 g, 127 mmol) were added slowly at 0° C. The mixture was allowed to warm to 25° C. and the stirring was continued for an additional 12 hours. The mixture was concentrated under reduced pressure and treated with NaOH (3M) to pH=8. The aqueous layer was extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. The solvent was concentrated in vacuo to afford crude product 2-(6-Chloro-4-iodopyridin-3-ylamino)ethanol (14.5 g), that was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10]([NH:11][CH2:12][CH2:13][OH:14])[C:5]2=[N:4][CH:3]=1.CS[C:17]1[N:22]=[C:21]([Sn](CCCC)(CCCC)CCCC)[CH:20]=[CH:19][N:18]=1.[NH2:36][CH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[O:40]1[CH2:41][CH2:42][CH:37]([NH:36][C:17]2[N:18]=[C:19]([C:2]3[N:6]4[CH:7]=[CH:8][N:9]=[C:10]([NH:11][CH2:12][CH2:13][OH:14])[C:5]4=[N:4][CH:3]=3)[CH:20]=[CH:21][N:22]=2)[CH2:38][CH2:39]1
Reactant: NC1CCOCC1
Reactant: OCCNc1nccn2c(Br)cnc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(SC)n1
Product: OCCNc1nccn2c(-c3ccnc(NC4CCOCC4)n3)cnc12

Procedure:
2-{3-[2-(Tetrahydro-pyran-4-ylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-ylamino}-ethanol was prepared by a process analogous to that described in Example 12 starting from 2-(3-bromo-imidazo[1,2-a]pyrazin-8-ylamino)-ethanol (from Example 2 supra), 2-methylsulfanyl-4-tributylstannanyl-pyrimidine, and 4-amino-tetrahydropyran. LC-MS: [M+H]+ 356.3.
Reaction SMILES: F[C:2](F)(F)[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[CH3:13][CH:14]([CH3:33])[CH:15]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:16]([NH:18][C@@H:19]1[C@@H:26]2[C@@H:22]([CH2:23][NH:24][CH2:25]2)[CH2:21][CH2:20]1)=[O:17].[CH:34]1(C(C2CCCCC2)C(N[C@@H]2[C@H]3[C@H](CNC3)CC2)=O)CCCC[CH2:35]1>>[CH3:13][CH:14]([CH3:33])[CH:15]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:16]([NH:18][C@@H:19]1[C@@H:26]2[C@@H:22]([CH2:23][N:24]([CH2:34][CH2:35][CH2:6][C:5]3[CH:8]=[CH:9][CH:10]=[C:3]([CH3:2])[CH:4]=3)[CH2:25]2)[CH2:21][CH2:20]1)=[O:17]
Reactant: CC(C)C(C(=O)N[C@H]1CC[C@@H]2CNC[C@@H]21)c1ccccc1
Reactant: O=C(N[C@H]1CC[C@H]2CNC[C@H]21)C(C1CCCCC1)C1CCCCC1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Product: Cc1cccc(CCCN2C[C@H]3CC[C@H](NC(=O)C(c4ccccc4)C(C)C)[C@H]3C2)c1

Procedure:
The title compound was prepared by substituting 3-m-tolylpropanol for 3-(trifluoromethyl)benzaldehyde and 3-methyl-N-[(3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-yl]-2-phenylbutanamide from Example 83 Step A for 2,2-dicyclohexyl-N-[(3aS,4S,6aR)-octahydrocyclopenta[c]pyrrol-4-yl]acetamide in the procedure described for Example 54: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.57 (dd, J=7.1, 13.5, 1H), 7.65 (dd, J=4.8, 7.0, 2H), 7.34 (t, J=7.5, 2H), 7.29-7.22 (m, 2H), 7.12 (d, J=5.9, 1H), 7.09 (d, J=7.1, 1H), 7.06-7.02 (m, 1H), 4.42-4.31 (m, 1H), 3.24 (d, J=10.4, 1H), 2.97 (d, J=6.8, 0.5H), 2.71-2.58 (m, 4H), 2.56-2.44 (m, 1H), 2.43-2.38 (m, 0.5H), 2.35 (t, J=6.6, 3H), 2.29 (s, 1.5H), 2.27 (s, 1.5H), 2.27-2.23 (m, 1H), 2.17-2.11 (m, 1.5H), 1.89 (dt, J=6.1, 11.8, 1H), 1.79 (dd, J=7.4, 14.7, 1.5H), 1.72 (dt, J=7.6, 15.1, 1H), 1.66 (dd, J=5.9, 13.1, 0.5H), 1.42 (dt, J=7.5, 12.0, 1H), 1.37-1.30 (m, 0.5H), 1.23 (dd, J=6.5, 11.7, 3H), 0.71 (dd, J=3.0, 6.6, 3H); MS (ESI+) m/z 419 (M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[Br:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH:16]=[C:15]2[OH:23].ClC1C2C(=CC=C(C(C3N(C)C(C)=NC=3)O)C=2)N=C(OC)C=1CC1C=NC(C(F)(F)F)=CC=1.CC1NC(C)=C(C(OCC)=O)CC=1C(OCC)=O>N1C=CC=CC=1>[Br:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([OH:22])[C:16]([CH2:7][C:6]1[CH:9]=[CH:10][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1)=[C:15]2[OH:23]
Reactant: CSc1ccc(C=O)cc1
Reactant: O=c1cc(O)c2cc(Br)ccc2[nH]1
Agent: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Agent: COc1nc2ccc(C(O)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)nc1
Solvent: c1ccncc1
Product: CSc1ccc(Cc2c(O)nc3ccc(Br)cc3c2O)cc1

Procedure:
A mixture of 4-(methylthio)benzaldehyde (3.00 g, 19.7 mmol), 6-bromo-4-hydroxyquinolin-2(1H)-one (4.72 g, 19.7 mmol, Intermediate 45: step a), diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (5.23 g, 20.7 mmol), and pyridine (100 mL) was stirred at 80° C. for 4 hours and then at room temperature overnight. The reaction was cooled and the formed precipitate was filtered, washed with Et2O (100 mL), and dried to afford the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:13]=[CH:12][C:11]([CH3:14])=[C:10]2[C:5]=1[CH:6]([C:19]1[CH:20]=[CH:21][CH:22]=[C:23]3[C:28]=1[O:27][C:26]([CH3:29])=[CH:25][C:24]3=[O:30])[C:7]([C:16](O)=[O:17])=[C:8]([CH3:15])[NH:9]2)[CH3:2].C(OCC)(=O)C.C(N1C=CN=C1)([N:39]1C=CN=C1)=O.N>CN(C=O)C>[CH2:1]([O:3][C:4]1[N:13]=[CH:12][C:11]([CH3:14])=[C:10]2[C:5]=1[CH:6]([C:19]1[CH:20]=[CH:21][CH:22]=[C:23]3[C:28]=1[O:27][C:26]([CH3:29])=[CH:25][C:24]3=[O:30])[C:7]([C:16]([NH2:39])=[O:17])=[C:8]([CH3:15])[NH:9]2)[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOc1ncc(C)c2c1C(c1cccc3c(=O)cc(C)oc13)C(C(=O)O)=C(C)N2
Agent: N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1ncc(C)c2c1C(c1cccc3c(=O)cc(C)oc13)C(C(N)=O)=C(C)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
335.0 mg (0.824 mmol) of the compound from Example 41A are introduced into 10 ml of ethyl acetate, and 167.1 mg (0.537 mmol) of 1,1′-carbonyldiimidazole are added. The suspension is then stirred at room temperature overnight. Since a clear solution is not produced, 2 ml of DMF are added and the mixture is stirred at room temperature for a further two hours. Complete conversion is then established by TLC check. The volatile components are removed in a rotary evaporator, and the residue is taken up in 4 ml of DMF. Then 2.293 ml of ammonia (28% by weight solution in water, 16.5 mmol) and 10.1 mg of 4-N,N-dimethylaminopyridine are added. The reaction mixture is heated at 100° C. in a closed vessel for thirty minutes. After cooling, the solvent is removed under reduced pressure, and the residue is purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5). The product fractions are concentrated and the residue is taken up in a little dichloromethane, and diisopropyl ether is added until the solution is cloudy. The precipitated solid is isolated and dried in vacuo. 207 mg (59% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][N:2]1[C:6](Cl)=[N:5][N:4]=[N:3]1.[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([CH2:16][CH2:17][CH2:18][SH:19])=[O:15].[OH-].[Na+]>CO>[CH3:1][N:2]1[C:6]([S:19][CH2:18][CH2:17][CH2:16][C:14]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][N:8]=2)=[O:15])=[N:5][N:4]=[N:3]1
Reactant: O=C(CCCS)c1ccccn1
Reactant: Cn1nnnc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1nnnc1SCCCC(=O)c1ccccn1
Yield: 7.6 %

Procedure:
1-Methyl-5-chloro-1,2,3,4-tetrazole (1.4 g) and 3-mercaptopropyl 2-pyridyl ketone (1.8 g) is dissolved in methanol (100 ml). Sodium hydroxide (0.6 g) is added to the solution and the mixture is refluxed for 3 hours. Methanol is distilled off and water is added to the residue. The mixture is extracted with chloroform. The chloroform solution is washed with dil. aqueous sodium hydroxide, water and saturated aqueous sodium chloride and dried over sodium sulfate. Chloroform is distilled off and the residue is purified by column chromatography (Wakogel C-200, eluant: chloroform) and the product is recrystallized from hexane-ether to obtain 1-methyl-5-[3-(2-pyridylcarbonyl)propyl]thio-1,2,3,4-tetrazole (0.2 g) as colorless needles, m.p. 73°-75° C.