Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3](=[O:15])[N:4]([CH3:14])[C:5](=[O:13])[C:6]=1[N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.C([O-])([O-])=O.[Cs+].[Cs+].O.CC1(C)C(C)(C)OB([C:31]2[CH:48]=[CH:47][C:34]([O:35][CH2:36][C:37]3[CH:46]=[CH:45][C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[N:38]=3)=[CH:33][CH:32]=2)O1>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:14][N:4]1[C:3](=[O:15])[C:2]([C:31]2[CH:32]=[CH:33][C:34]([O:35][CH2:36][C:37]3[CH:46]=[CH:45][C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[N:38]=3)=[CH:47][CH:48]=2)=[C:6]([N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[C:5]1=[O:13]
Reactant: CN1C(=O)C(Br)=C(N2CCOCC2)C1=O
Reactant: CC1(C)OB(c2ccc(OCc3ccc4ccccc4n3)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)C(c2ccc(OCc3ccc4ccccc4n3)cc2)=C(N2CCOCC2)C1=O
Temperature: 80 °C
Yield: 42.9 %

Procedure:
To a stirred solution of 3-bromo-1-methyl-4-morpholino-1H-pyrrole-2,5-dione (100 mg, 0.36 mol) in DMF (40 mL) were added Cs2CO3 (415 mg, 1.27 mmol), water (5 mL), and Pd(Ph3P)4 (84 mg, 0.072 mmol). 2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)quinoline (138 mg, 0.38 mmol) was then added and the reaction mixture was heated at 80° C. for 3 h, filtered through a pad of Celite® and the filtrate was then concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography eluting with 60% EtOAc in hexanes to afford 1-methyl-3-morpholino-4-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrole-2,5-dione (70 mg, 45%). 1H NMR (500 MHz, d6-DMSO): δ 8.42 (d, J=7.2 Hz, 1H), 8.1 (t, J=7.2 Hz, 2H) 7.78 (t, J=7.8 Hz, 1H), 7.70 (d, J=7.2 Hz, 1H), 7.64 (t, J=7.2 Hz, 1H), 7.28 (d, J=7.4 Hz, 2H), 7.12 (d, J=7.4 Hz, 2H), 5.38 (s, 2H), 3.62-3.58 (m, 4H), 3.45-3.39 (m, 4H), 2.96 (s, 3H); MS: M+H: m/z=430.2 HPLC: 96%, (Condition-C).
Reaction SMILES: [C:1]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:21][CH2:20][NH:19][C:18]2=[O:22])[CH2:13][CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[H-].[Na+].[CH2:25](I)[CH2:26][CH2:27][CH3:28]>CN(C)C=O>[CH2:25]([N:19]1[CH2:20][CH2:21][N:17]([CH:14]2[CH2:13][CH2:12][N:11]([C:1]([O:3][CH2:4][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)=[O:2])[CH2:16][CH2:15]2)[C:18]1=[O:22])[CH2:26][CH2:27][CH3:28]
Reactant: CCCCI
Reactant: O=C(OCc1ccccc1)N1CCC(N2CCNC2=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCN1CCN(C2CCN(C(=O)OCc3ccccc3)CC2)C1=O

Procedure:
25 g of 1-(1-carbobenzoxy-4-piperidyl)-imidazolidin-2-one are added in portions to a mixture, which has been warmed to 80° C., of 2.4 g of sodium hydride in 100 ml of absolute dimethylformamide, with stirring. The mixture is stirred for a further 2 hours at 80° C. and 18.2 g of n-butyl iodide are then allowed to run in slowly dropwise (highly exothermic reaction). After stirring for a further 2 hours at 80° C., the reaction mixture is evaporated under reduced pressure and the residue is freed from dimethylformamide which is still adhering, by treatment with toluene. The reaction product is dissolved in 250 ml of ethyl acetate and the solution is washed twice with, in each case, 50 ml of water, dried over sodium sulphate and evaporated to dryness. The residue is chromatographed on 1.5 kg of silica gel using a mixture of chloroform/methyl alcohol (95:5) as the eluant mixture. In this way, 3-n-butyl-1-(1-carbobenzoxy-4-piperidyl)-imidazolidin-2-one is obtained in the form of a colourless oil.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].C(N(CC)CC)C.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[N:33]=[C:32]([C:34]2[CH:39]=[C:38](O)[CH:37]=[C:36]([C:41]#[N:42])[CH:35]=2)[O:31][N:30]=1>ClCCl>[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[N:33]=[C:32]([C:34]2[CH:39]=[C:38]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[CH:37]=[C:36]([C:41]#[N:42])[CH:35]=2)[O:31][N:30]=1
Reactant: N#Cc1cc(O)cc(-c2nc(-c3ccccn3)no2)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cc(OS(=O)(=O)C(F)(F)F)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.2 %

Procedure:
Trifluoromethanesulfonic anhydride (22.9 μL, 0.14 mmol) and triethylamine (23.7 μL, 0.17) were added under argon to a vial containing 3-(2-pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadiazole (30 mg, 0.11 mmol) in dichloromethane (1 mL). The vial was then sealed and the reaction was left stirring overnight at ambient temperature. The reaction mixture was placed directly onto a flash column and purified by eluting with hexanes:ethyl acetate:dichloromethane 3.5:0.5:4 to afford 11 mg (25%) of 3-(2-pyridyl)-5-(3-cyano-5-(trifluoromethylsulfonyloxy)phenyl)-1,2,4-oxadiazole: 1H NMR (CDCl3), δ (ppm): 8.88 (d, 1H), 8.63 (s, 1H), 8.44 (s, 1H), 8.24 (d, 1H), 7.93 (t, 1H), 7.83 (s, 1H), 7.52 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[S:5][C:6]=1[C:7]([F:10])([F:9])[F:8].[CH3:15][N:16]1[C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][CH:18]=[N:17]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:15][N:16]1[C:20]([C:2]2[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[S:5][C:6]=2[C:7]([F:10])([F:9])[F:8])=[CH:19][CH:18]=[N:17]1
Reactant: COC(=O)c1cc(Br)c(C(F)(F)F)s1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccnn2C)c(C(F)(F)F)s1
Temperature: 70 °C
Reaction time: 12 h
Yield: 77.6 %

Procedure:
A mixture of methyl 4-bromo-5-(trifluoromethyl)-2-thiophenecarboxylate (0.8 g, 40% purity, 1.11 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.299 g, 1.434 mmol), tetrakis (0.128 g, 0.11 mmol) and K2CO3 (0.459 g, 3.32 mmol) in dioxane/H2O (5 mL/1 mL) was heated to 70° C. in a sealed tube. After 12 h, the reaction mixture was concentrated under vacuum and purified on silica (EtOAc/Hex, 40-60%) to afford the title compound (0.25 g, 70%) as a light yellow solid: LC-MS (ES) m/z 291 (M+H)+.
Reaction SMILES: CCO.[CH3:4][C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)=[CH:14][N:13]=2)[CH:8]=[CH:7][C:6]=1/[CH:27]=[CH:28]/[C:29]([O:31]CCCC)=[O:30].[OH-].[Na+]>O>[CH3:4][C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)=[CH:14][N:13]=2)[CH:8]=[CH:7][C:6]=1/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30]
Reactant: CCCCOC(=O)/C=C/c1ccc(Oc2ccc(OCc3ccc(C)cc3)cn2)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(COc2ccc(Oc3ccc(/C=C/C(=O)O)c(C)c3)nc2)cc1
Reaction time: 14 h
Yield: 99.9 %

Procedure:
To an EtOH (50 mL) solution of butyl (E)-3-[2-methyl-4-({5-[(4-methylbenzyl)-oxy]pyridin-2-yl}oxy)phenyl]prop-2-enoate (4.67 g) was added 5 M NaOH (3.25 mL) at room temperature. After stirring for 14 hours, 5 M NaOH (1.08 mL) and water (25 mL) were added, and then the reaction mixture was refluxed for 2 hours. The solvent was removed under reduced pressure. The residue was dissolved in water, and neutralized with 6 M HCl at 0° C. The resulting precipitate was collected by filtration and dried to afford (E)-3-[2-methyl-4-({5-[(4-methylbenzyl)oxy]pyridin-2-yl}oxy)phenyl]prop-2-enoic acid as a colorless solid (4.06 g).
Reaction SMILES: [OH:1][NH2:2].C(O[C:6](=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)C>CN(C=O)C.CO>[OH:1][NH:2][C:6](=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: NO
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(-c2ccc(F)cc2)ccn1
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(CCCCCCN(c1ccccn1)c1cc(-c2ccc(F)cc2)ccn1)NO
Reaction time: 23 h
Yield: 54 %

Procedure:
HONH2 (50% aqueous, 2 mL) was added to III (34 mg, 0.08 mmol) in DMF (0.5 mL) and MeOH (2 mL) at rt. The reaction mixture was stirred for 23 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (2×2 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:3 to 100:6) to furnish IV as a colourless oil (18 mg, 54%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[CH:6][CH:7]=1.[C-:9]#[N:10]>N1C=CC=CC=1>[Br:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: [C-]#N
Reactant: [O-][n+]1cccc(Br)c1
Solvent: c1ccncc1
Product: N#Cc1ncccc1Br

Procedure:
In Scheme I is described the preparation of pyridine intermediates (5) and (6). In Scheme I, Step 1,3-bromopyridine (1) is oxidized to 3-bromo-pyridine-N-oxide (2). In Scheme I, Step 2, cyanide addition gives 3-bromo-pyridine-2-carbonitrile (3). The nitrile of formula (3) is hydrolyzed to the carboxylic acid and esterified with acid catalysis to the ester of formula (4). In Scheme I, Step 4, the ester is reduced to the pyridylmethanol of formula (5a) using sodium borohydride.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5](/[C:18](/[CH2:23][CH3:24])=[C:19](/[F:22])\[CH2:20][OH:21])=[CH:6][C:7]2[C:8]([CH3:17])([CH3:16])[CH2:9][CH2:10][C:11]([CH3:15])([CH3:14])[C:12]=2[CH:13]=1)[CH3:2].ClCCl.C([N+](CCC)(CCC)CCC)CC.C[N+]1([O-])CCOCC1>C(#N)C>[CH2:1]([O:3][C:4]1[C:5](/[C:18](/[CH2:23][CH3:24])=[C:19](/[F:22])\[CH:20]=[O:21])=[CH:6][C:7]2[C:8]([CH3:17])([CH3:16])[CH2:9][CH2:10][C:11]([CH3:14])([CH3:15])[C:12]=2[CH:13]=1)[CH3:2]
Reactant: CCOc1cc2c(cc1/C(CC)=C(/F)CO)C(C)(C)CCC2(C)C
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: ClCCl
Product: CCOc1cc2c(cc1/C(CC)=C(/F)C=O)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of (E)-3-(3-ethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2-fluoropent-2-enol (3.55 g, 8.02 mmol) and dichloromethane (125 mL) in acetonitrile (25 mL) was treated with tetrapropylammonium peruthenate (0.476 g, 1.45 mmol), 4 Å molecular sieves (0.442 g), and N-methylmorpholine-N-oxide (2.78 g, 23.8 mmol), and the mixture was stirred for 0.5 h at ambient temperature. The solution was filtered through a sintered glass funnel containing a bed of silica gel about 1 inch thick using 20% ethyl acetate in hexane as the eluent. The solvent was removed in vacuo to give the title compound.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24]C)[N:12]2[CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([CH2:22][CH3:23])[CH2:17]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl>CO.O1CCOCC1>[NH2:26][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][N:18]([CH2:22][CH3:23])[CH2:17]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CC3CCCN(CC)C3)c2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CC3CCCN(CC)C3)c2n1
Reaction time: 5 h
Yield: 85.1 %

Procedure:
2-Butoxy-9-[(1-ethyl-3-piperidinyl)methyl]-8-methoxy-9H-purin-6-amine (99 mg) was dissolved in methanol (2 ml) and 4N hydrogen chloride in dioxan (1 ml) added. After 5 hours the reaction mixture was stripped, quenched with water then saturated sodium hydrogen carbonate added, when a solid precipitated. This was filtered, washed with water and dried to yield 81 mg of the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[C:4](Cl)[N:3]=1.[CH:13]([NH2:16])([CH3:15])[CH3:14]>>[CH:13]([NH:16][C:2]1[N:7]=[C:6]([NH:16][CH:13]([CH3:15])[CH3:14])[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([NH:9][CH:5]([CH3:6])[CH3:4])[N:3]=1)([CH3:15])[CH3:14]
Reactant: O=[N+]([O-])c1c(Cl)nc(Cl)nc1Cl
Reactant: CC(C)N
Product: CC(C)Nc1nc(NC(C)C)c([N+](=O)[O-])c(NC(C)C)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 148.5 %

Procedure:
1.15 g (0.005 mol) of 2,4,6-trichloro-5-nitropyrimidine are dissolved in 50 ml of alcohol and the solution is then treated with 2.9 g (0.05 mol) of isopropylamine. The mixture is stirred for 3 hours at room temperature after the temperature has first risen to 35° C, and then it is evaporated. The residue is treated with 100 ml of water and extracted twice with ether. The ethereal extract is dried over MgSO4 for 4 hours, filtered, and evaporated, to yield 1.1 g of 2,4,6-tri-isopropylamino-5-nitro-pyrimidine as an oil; b.p. 185° C at 0.001 Torr.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16](O)=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:23]=[CH:22][O:21][CH:20]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O=S(Cl)[Cl:26]>CN(C=O)C>[CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([Cl:26])=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:23]=[CH:22][O:21][CH:20]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The carboxylic acid of example 2 (0.550 g, 1.8 mmol) was dissolved in SOCl2(20 mL) and DMF (˜0.1 mL). The reaction mixture was stirred at room temperature for 20 h and then concentrated to dryness and co-evaporate with EtOAc to give a 1-cyclohexyl-2-furan-3-yl-1H-benzoimidazole-5-carbonyl chloride as a brown solid (580 mg). The acid chloride (0.050 g, 0.16 mmol) was dissolved in DMF (1 mL) and reacted with I-carnosine (0.036 g, 0.159 mmol) in the presence of DIEA (82 μL, 0.476 mmol). The reaction mixture was stirred for 3 days at room temperature before it was acidified with AcOH (1 mL) and purified by reversed phase C18 preparative HPLC. The title compound of example 145 was obtained as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.N>>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([C:12]2[N:11]=[C:10]([C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[NH2:1])[O:14][N:13]=2)[CH:16]=1
Reactant: O=[N+]([O-])c1cccc(-c2nc(-c3cccnc3)no2)c1
Agent: N
Product: Nc1cccc(-c2nc(-c3cccnc3)no2)c1

Procedure:
The title compound was prepared according to the procedure of Example 46 using the product of Example 40. 1H NMR (300 MHz, DMSO-d6) δ ppm 5.60 (s, 2H), 6.84-6.93 (m, 1H), 7.24-7.33 (m, 2H), 7.41 (d, J=1.7 Hz, 1H), 7.60-7.67 (m, 1H), 8.38-8.45 (m, 1H), 8.81 (dd, J=5.1, 1.7 Hz, 1H), 9.23 (d, J=2.4 Hz, 1) ppm; MS (DCl/NH3) m/z 239 (M+H)+, 256 (M+NH4)+.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].[CH2:8]([N:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:17][CH:16]1[CH2:28]Cl)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CN(C=O)C.CCOC(C)=O>[CH2:8]([N:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:17][CH:16]1[CH2:28][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: ClCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: c1ccc(CN2CCN(Cc3ccccc3)C(Cn3cncn3)C2)cc1
Reaction time: 0.17 h
Yield: 98.9 %

Procedure:
To a solution of 1,2,4-triazole (48.3 mg, 0.70 mmol) in DMF (2 ml) was added NaH (18.3 mg, 0.76 mmol). After 10 minutes stirring, 1,4-dibenzyl-2-(chloromethyl)piperazine (200 mg, 0.64 mmol) and KI (156 mg, 0.70 mmol) were added to the mixture. The mixture was stirred at 60° C. overnight. The mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by column chromatography on NH-silica gel (Hex/AcOEt=¼) to give 1,4-dibenzyl-2-(1H-1,2,4-triazol-1-ylmethyl)piperazine (220.0 mg, 99.7%): HPLC-MS (ESI): Calcd for C21H25N5 [M+H]+ 348, found: 348.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28].[CH3:31][O:32][C:33]1[CH:34]=[C:35]2[C:39](=[CH:40][CH:41]=1)[N:38]([CH3:42])[N:37]=[C:36]2[C:43]1[N:44]=[C:45]2[C:51]([C:52](O)=[O:53])=[CH:50][N:49]([CH2:55][O:56][CH2:57][CH2:58][Si:59]([CH3:62])([CH3:61])[CH3:60])[C:46]2=[N:47][CH:48]=1>CN(C=O)C>[OH:28][CH2:27][C:26]([NH:25][C:52]([C:51]1[C:45]2[C:46](=[N:47][CH:48]=[C:43]([C:36]3[C:35]4[C:39](=[CH:40][CH:41]=[C:33]([O:32][CH3:31])[CH:34]=4)[N:38]([CH3:42])[N:37]=3)[N:44]=2)[N:49]([CH2:55][O:56][CH2:57][CH2:58][Si:59]([CH3:60])([CH3:62])[CH3:61])[CH:50]=1)=[O:53])([CH3:30])[CH3:29]
Reactant: COc1ccc2c(c1)c(-c1cnc3c(n1)c(C(=O)O)cn3COCC[Si](C)(C)C)nn2C
Reactant: CC(C)(N)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(-c1cnc3c(n1)c(C(=O)NC(C)(C)CO)cn3COCC[Si](C)(C)C)nn2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
In a 16×100 mm screw cap test tube were added HATU (40.2 mg, 106 μmol.20) and 2-amino-2-methylpropan-1-ol (31.4 mg, 353 μmol) then 2-(5-methoxy-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (40 mg, 88.2 mmol) dissolved in DMF (2.00 mL) was added to give a light yellow solution. The reaction mixture stirred at 25° C. overnight, solvents evaporated and residue purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco) eluting with 0 to 50% EtOAc in hexanes over 25 min to yield N-(1-hydroxy-2-methylpropan-2-yl)-2-(5-methoxy-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (46.3 mg, 88.2 μmol, 100%) as an off-white solid. MS (M+Na)+=547 (>90% purity); 1H NMR (CDCl3) δ: 9.14 (s, 1H), 8.49 (s, 1H), 8.32 (s, 1H), 7.85 (d, J=2.3 Hz, 1H), 7.41 (d, J=9.1 Hz, 1H), 7.20 (dd, J=9.3, 2.5 Hz, 1H), 5.72 (s, 2H), 4.18 (s, 3H), 3.92 (s, 3H), 3.78 (s, 2H), 3.54-3.65 (m, 2H), 1.53 (s, 6H), 0.91-1.01 (m, 2H), −0.03 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[CH:5]=[C:4]([CH3:11])[N:3]=1.[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([N:24]=[C:25]=[O:26])(=[O:23])=[O:22])([O-:14])=[O:13]>C(#N)C>[C:8]([C:7]1[C:2]([NH:1][C:25]([NH:24][S:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N+:12]([O-:14])=[O:13])(=[O:22])=[O:23])=[O:26])=[N:3][C:4]([CH3:11])=[CH:5][C:6]=1[CH3:10])#[N:9]
Reactant: O=C=NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: Cc1cc(C)c(C#N)c(N)n1
Solvent: CC#N
Product: Cc1cc(C)c(C#N)c(NC(=O)NS(=O)(=O)c2ccccc2[N+](=O)[O-])n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of 0.5 g (4.3 mmol) 2-amino-4,6-dimethyl-3-pyridinecarbonitrile [Archiv. Pharm., 288, 174 (1955)] in 20 ml of acetonitrile was added 1.3 g (5.7 mmol) o-nitrobenzenesulfonyl isocyanate. The mixture was then heated to reflux (80°) for four hours followed by stirring at ambient temperature overnight. A crystalline product was collected, 0.5 g, m.p. 174°-176° dec. An infrared spectrum (nujol mull) exhibited absorptions at 1700, 1720 and 2240 cm-1 ; and a proton magnetic resonance spectrum (90 MHz NMR) exhibited absorptions at 2.5 (s, 3H), 2.6 (s, 3H), 7.05 (s, H), 7.7 (s br, NH), 7.8 (m, 3H), 8.4 (m, 1H), 9.7 (s br, NH) ppm indicating the title compound.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[N:13][CH:14]=2)=[CH:5][CH:4]=1.[CH:23](=O)[CH2:24][CH3:25]>>[CH2:23]([N:18]1[CH2:19][CH2:20][N:15]([C:12]2[CH:11]=[CH:10][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:21])[F:22])=[CH:8][CH:7]=3)=[CH:14][N:13]=2)[CH2:16][CH2:17]1)[CH2:24][CH3:25]
Reactant: CCC=O
Reactant: FC(F)(F)c1ccc(-c2ccc(N3CCNCC3)nc2)cc1
Product: CCCN1CCN(c2ccc(-c3ccc(C(F)(F)F)cc3)cn2)CC1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 213, starting from 4-(5-(4-trifluoromethylphenyl)pyridin-2-yl)piperazine and propionaldehyde.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12]>C(N(CC)CC)C.C(O)C>[F:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])[CH:7]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: O=c1ncc(F)c[nH]1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(Cn1cc(F)cnc1=O)c1ccccc1
Yield: 21.1 %

Procedure:
A solution of 5-fluoropyrimidin-2-one (480 mg) and α-bromoacetophenone (843 mg) in triethylamine (1 ml) and ethanol (20 ml) was stirred at ambient temperature for 31/2 hours. The resulting suspension was chilled in ice. The solid was collected by filtration, then crystallised twice from ethanol to give the title pyrimidinone (206 mg yield); m.p. 167°-175°, λmaxEtOH 243 nm (ε 15110), 331 nm (ε 3590), λinf 283 nm (ε 1870), 290 nm (ε 1890), 344 nm (ε 2740).
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:17][CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:13][CH:14]=2)[C:9]1=[O:23])[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:17][CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:13][CH:14]=2)[C:9]1=[O:23]
Reactant: O=[O+][O-]
Reactant: CC=CCC1Cc2ccc(OC3CCCC3)cc2C1=O
Solvent: ClCCl
Solvent: CO
Product: O=CCC1Cc2ccc(OC3CCCC3)cc2C1=O
Reaction time: 1 h
Yield: 73 %

Procedure:
An ozone stream (1.5 g ozone/hour) was conducted for 60 minutes while stirring through a solution, cooled to -70°, of 8.1 g of (RS)-2-(2-buten-1-yl)-6-cyclopentoxy-1-indanone in 150 ml of anhydrous dichloromethane and 30 ml of anhydrous methanol. Subsequently, the solution was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 3.29 ml of dimethyl sulfide, the mixture was stirred at room temperature for 21 hours. The reaction mixture was evaporated in a vacuum. The residue was treated with 75 ml of dichoromethane and, after the addition of 12.5 ml of water and 12.5 ml of trifluoroacetic acid, stirred at room temperature for 5 hours. The mixture was subsequently poured into 150 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 50 ml of water were added. The phases were separated and the aqueous phase was extracted twice with 150 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate and concentrated in a vacuum. 5.63 g (73%) of (RS)-2-(2-oxoethyl)-6-cyclopentoxy-1-indanone were obtained as an orange oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([S:10](=[O:13])(=[O:12])[NH2:11])[C:7]([Cl:14])=[C:6]([NH2:15])[CH:5]=1.[C:17]1(=O)[O:22][C:20](=[O:21])[CH2:19][CH2:18]1>CO>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([S:10](=[O:13])(=[O:12])[NH2:11])[C:7]([Cl:14])=[C:6]([N:15]2[C:20](=[O:21])[CH2:19][CH2:18][C:17]2=[O:22])[CH:5]=1
Reactant: COC(=O)c1cc(N)c(Cl)c(S(N)(=O)=O)c1
Reactant: O=C1CCC(=O)O1
Solvent: CO
Product: COC(=O)c1cc(N2C(=O)CCC2=O)c(Cl)c(S(N)(=O)=O)c1
Reaction time: 6 h

Procedure:
25.4 g of 4-chloro-3-amino-5-sulphamyl-benzoic acid methyl ester, m.p. 195°-196° C., are thoroughly mixed with 25 g of succinic acid anhydride and melted for 6 hours at 180° C. The melt is allowed to cool slowly and CH3OH is added carefully. The product crystallizes. A small amount of water added completes the crystallisation.