Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([OH:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][CH:15]=2)[CH2:3][CH2:2]1.[H-].[Na+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>CN(C)C=O>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH:21]([O:27][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][CH:19]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(O)Cc1ccc(OCCN2CCOc3ccccc32)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccc(OCCN2CCOc3ccccc32)cc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48.5 %

Procedure:
A solution of ethyl 3-[4-[2-(2,3dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoate (0.5 g, 1.34 mmol) obtained in example 13 in dry dimethyl formamide (5 mL) was added to a stirred ice cooled suspension of sodium hydride (60% dispension in oil) (0.08 g, 1.66 mmol) in dry dimethyl formamide (3 mL) under nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 30 minutes followed by the addition of benzyl bromide (0.46 g, 2.69 mmol). The mixture was allowed to warm to 25° C. and stirring was continued for further 18 h. Water (25 mL) was added and extracted with ethyl acetate (2×50 mL). The combined organic layer was washed with water (50 mL), brine (50 mL) and dried Na2SO4 and filtered. The solvent was evaporated under reduced pressure and the residue was chromatographed over silica gel using a mixture of ethyl acetate and pet. ether (2:8) as eluent to afford the title compound (0.3 g) along with benzyl 3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-benzyloxypropanoate. This mixture (1:1) is used in example 47 without any separation.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:15]Br>CN(C)C=O>[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:15][N:6]1[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]1
Reactant: Clc1ccc(CBr)cc1Cl
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccn(Cc2ccc(Cl)c(Cl)c2)n1
Yield: 76.6 %

Procedure:
To a solution of 3-nitro-1H-pyrazole (prepared in example 3, 200 mg, 1.77 mmol) in anhydrous N,N-dimethylformamide (2 mL), a 60% dispersion of sodium hydride in mineral oil (92 mg, 2.30 mmol) was added while stirring under nitrogen. After the effervescence ceased and the mixture was stirred for additional 20 min, 3,4-dichlorobenzylbromide (550 mg, 2.30 mmol) was added. The mixture was continued to stir under nitrogen for an additional 2 h. The solvent was removed in vacuo and purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 2% methanol/methylene chloride to 5% methanol/methylene chloride) afforded 1-(3,4-dichloro-benzyl)-3-nitro-1H-pyrazole (369 mg, 77%) as a white solid: H1-NMR (400 MHz, CDCl3) δ: 5.32 (2H, s), 6.92 (1H, d, J=2.3 Hz), 7.12 (1H, m), 7.36 (1H, d, J=2.2 Hz), 7.44 (2H, m).
Reaction SMILES: C(OC1C2N(C(CN(C)C)=CN=2)C=CC=1)C1C=CC=CC=1.[CH2:22]([O:29][C:30]1[C:31]2[N:32]([C:36]([CH2:41][N:42]([CH3:44])[CH3:43])=[C:37]([CH2:39]O)[N:38]=2)[CH:33]=[CH:34][CH:35]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([O:29][C:30]1[C:31]2[N:32]([C:36]([CH2:41][N:42]([CH3:43])[CH3:44])=[C:37]([CH3:39])[N:38]=2)[CH:33]=[CH:34][CH:35]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CN(C)Cc1c(CO)nc2c(OCc3ccccc3)cccn12
Agent: CN(C)Cc1cnc2c(OCc3ccccc3)cccn12
Product: Cc1nc2c(OCc3ccccc3)cccn2c1CN(C)C

Procedure:
8-benzyloxy-3-dimethylaminomethyl-imidazo[1,2-a]pyridine and the corresponding 2-hydroxymethyl analogues thereof (e.g. 8-benzyloxy-3-dimethylaminomethyl-2-hydroxymethylimidazo[1,2-a]pyridine.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([O:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[N:14]=[C:13]([N:23]3[CH:27]=[CH:26][CH:25]=[N:24]3)[CH:12]=2)[CH2:7][N:6]1[C:28](=[O:42])[C@@H:29]([NH:34][C:35]([NH:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:30]([CH3:33])([CH3:32])[CH3:31])=[O:4].[CH3:43]O.[OH-].[Na+]>O1CCCC1>[CH3:43][C@@:5]1([C:3]([OH:2])=[O:4])[CH2:9][C@@H:8]([O:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[N:14]=[C:13]([N:23]3[CH:27]=[CH:26][CH:25]=[N:24]3)[CH:12]=2)[CH2:7][N:6]1[C:28](=[O:42])[C@@H:29]([NH:34][C:35]([NH:37][C:38]([CH3:40])([CH3:41])[CH3:39])=[O:36])[C:30]([CH3:32])([CH3:31])[CH3:33]
Reactant: COC(=O)[C@@H]1C[C@@H](Oc2cc(-n3cccn3)nc3cc(OC)ccc23)CN1C(=O)[C@@H](NC(=O)NC(C)(C)C)C(C)(C)C
Reactant: CO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc2c(O[C@H]3CN(C(=O)[C@@H](NC(=O)NC(C)(C)C)C(C)(C)C)[C@](C)(C(=O)O)C3)cc(-n3cccn3)nc2c1
Reaction time: 1 h

Procedure:
(2S,4R)-methyl-1-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-4-(7-methoxy-2-(1H-pyrazol-1-yl)quinolin-4-yloxy)-pyrrolidine-2-carboxylate was treated with methanol (6.0 mL), tetrahydrofuran (3.0 mL) and 1N sodium hydroxide (6. mL). After 1 hour at room temperature, the reaction mixture was concentrated, acidified with 1N HCl and extracted with ethyl acetate. The combined ethyl acetate layers were then washed with brine and dried (MgSO4). The ethyl acetate layer was then filtered and evaporated to dryness to give (2S,4R)-methyl-1-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-4-(7-methoxy-2-(1H-pyrazol-1-yl)quinolin-4-yloxy)-pyrrolidine-2-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:39])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([OH:29])=O)([CH3:26])[CH3:25])[CH2:14][C:13](=[O:30])[NH:12][CH:11]3[C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[CH3:38])[C:5]2=[CH:4][CH:3]=1.CC[N:42]=[C:43]=[N:44]CCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.N#CN>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:39])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27](=[O:29])[NH:44][C:43]#[N:42])([CH3:26])[CH3:25])[CH2:14][C:13](=[O:30])[NH:12][CH:11]3[C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[CH3:38])[C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC(C)(C)C(=O)O)C12C(=O)Nc1cc(Cl)ccc12
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N#CN
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC(C)(C)C(=O)NC#N)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
To a mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-hydroxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (30 mg, 0.05 mmol) prepared in Example 1f, EDCl (20 mg, 0.1 mmol), HOBt (16 mg, 0.1 mmol) and DIPEA (20 mg, 0.15 mmol) in THF (1 mL) was added cyanamide (50% in H2O) (20 mg, 0.24 mmol). The mixture was stirred at room temperature overnight and purified by prep-HPLC to give the title compound as a white solid (14 mg).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9](=[S:18])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>C(O)C>[C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: S=c1[nH]c(-c2ccccc2)c(-c2ccccc2)o1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)CSc1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 25 °C
Yield: 67.9 %

Procedure:
In a three-necked, 500 ml flask provided with reflux condenser and mechanical stirrer, 25.3 g 4,5-diphenyl-4-oxazolin-2-thione, 27.6 g anhydrous potassium carbonate, 14.5 ml ethyl bromoacetate and 200 ml absolute ethanol were refluxed for 5 hours with vigorous stirring. The mixture was cooled to room temperature, filtered and washed with absolute ethanol on the filter. The filtrate was evaporated to dryness in vacuo and the residue was suspended in 150 ml ether and 150 ml water. The ethereal phase was separated, dried on anhydrous sodium sulphate, filtered and evaporated to dryness in vacuo to give 23 g ethyl S-(4,5-diphenyloxazol-2-yl)-mercaptoacetate as an oil which was recrystallized from an anhydrous ether-petroleum ether mixture: m.p. 53°-55° C; yield = 67.9%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[ClH:17].Cl.[NH2:19][C:20]1[C:29]([NH2:30])=[C:28]2[C:23]([CH:24]=[C:25]([C:32]([OH:34])=[O:33])[CH:26]=[C:27]2[OH:31])=[CH:22][CH:21]=1.S(=O)(O)[O-].[Na+]>CCO.O>[ClH:17].[C:11]1([C:10]2[C:3]([O:2][CH3:1])=[C:4]([C:5]3[NH:19][C:20]4[CH:21]=[CH:22][C:23]5[C:28](=[C:27]([OH:31])[CH:26]=[C:25]([C:32]([OH:34])=[O:33])[CH:24]=5)[C:29]=4[N:30]=3)[CH:7]=[CH:8][CH:9]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COc1c(C=O)cccc1-c1ccccc1
Reactant: Nc1ccc2cc(C(=O)O)cc(O)c2c1N
Agent: Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1c(-c2ccccc2)cccc1-c1nc2c(ccc3cc(C(=O)O)cc(O)c32)[nH]1
Temperature: 60 °C
Reaction time: 18 h
Yield: 25.6 %

Procedure:
To an agitated solution of 2-methoxy-3-phenylbenzaldehyde (0.020 g, 0.08 mmol) in EtOH (0.80 mL) was added 7,8-Diamino-1-hydroxy-3-naphthoic acid dihydrochloride (0.02 g, 0.07 mmol) and sodium bisulfite (0.02 g) in water (0.20 mL). The solution was heated to 60° C. and agitated over 18 hours. The solution was cooled to room temperature and concentrated under reduced pressure. The tan residue was subjected to HPLC (ODS-A, gradient 10-90% CH3CN/water 0.1% TFA) to provide the title compound (0.008 g, 20%) MS(ES) m/z 411 [M+H].
Reaction SMILES: [N+:1]([C:4]1[CH:46]=[CH:45][C:7]([CH2:8][NH:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([NH:20][C@H:21]([C:25]([N:27]3[CH2:44][CH2:43][CH2:42][C@H:28]3[C:29]([NH:31][CH:32]([CH:39]([CH3:41])[CH3:40])[C:33](=[O:38])[C:34]([F:37])([F:36])[F:35])=[O:30])=[O:26])[CH:22]([CH3:24])[CH3:23])=[O:19])=[CH:14][CH:13]=2)=[O:11])=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:46]=[CH:45][C:7]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([NH:20][C@H:21]([C:25]([N:27]3[CH2:44][CH2:43][CH2:42][C@H:28]3[C:29]([NH:31][CH:32]([CH:39]([CH3:40])[CH3:41])[C:33](=[O:38])[C:34]([F:37])([F:35])[F:36])=[O:30])=[O:26])[CH:22]([CH3:24])[CH3:23])=[O:19])=[CH:16][CH:17]=2)=[O:11])=[CH:6][CH:5]=1
Reactant: CC(C)C(NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)c1ccc(C(=O)NCc2ccc([N+](=O)[O-])cc2)cc1)C(C)C)C(=O)C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)C(NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)c1ccc(C(=O)NCc2ccc(N)cc2)cc1)C(C)C)C(=O)C(F)(F)F
Yield: 96.5 %

Procedure:
A solution of 3(RS)-[[4-[(4-nitrobenzyl)aminocarbonyl]phenylcarbonyl]-L-valyl-L-prolyl]amino-1,1,1-trifluoro-4-methyl-2-oxopentane (50 mg) in methanol (10 ml) was hydrogenated over 10% palladium on carbon (10 mg) at 4 atmosphere pressure of hydrogen for 2 hours. The catalyst was removed by filtration and the filtrate was evaporated under reduced pressure to give 3(RS)-[[4-[(4-aminobenzyl)aminocarbonyl]phenylcarbonyl]-L-valyl-L-prolyl]amino-1,1,1-trifluoro-4-methyl-2-oxopentane (46 mg).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:12])[N:10]=2)[CH:7]=1.[NH:20]1[CH:24]=[N:23][CH:22]=[N:21]1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[C:14]1([NH:13][C:11]([C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([C:24]4[N:23]=[CH:22][NH:21][N:20]=4)=[CH:7][N:6]3[CH:8]=2)=[O:12])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Nc1ccccc1)c1cn2cc(I)ccc2n1
Reactant: c1nc[nH]n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)c1cn2cc(-c3nc[nH]n3)ccc2n1
Yield: 19.1 %

Procedure:
250 mg of 6-iodo-N-phenylimidazo[1,2-a]pyridine-2-carboxamide (Intermediate 2), 8 mL of N,N-dimethylformamide, 7.7 mg of palladium acetate, 197 mg of cuprous iodide and 71.3 mg of 1,2,4-triazole are placed in a microwave tube. The reaction mixture is heated for 2.5 hours in a microwave machine set at 200° C. The cooled reaction mixture is filtered, the insoluble matter is rinsed with N,N-dimethylformamide, dichloromethane and methanol and the combined filtrates are concentrated to dryness under reduced pressure. The residue is chromatographed on a silica cartridge, eluting with a 90/10 mixture of dichloromethane and methanol. The fractions containing the pure expected product are combined and evaporated to dryness under reduced pressure to give 40 mg of N-phenyl-6-(1H-1,2,4-triazol-3-yl)imidazo[1,2-a]pyridine-2-carboxamide in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.OO.[OH-].[Na+].C([OH:22])C>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]([NH2:15])=[O:22])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(-c2ccc(Cl)cc2)nc1
Reactant: CCO
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: NC(=O)c1ccc(-c2ccc(Cl)cc2)nc1
Reaction time: 1 h

Procedure:
6-(4-Chlorophenyl)-3-pyridinecarbonitrile (1.61 grams), 30% hydrogen peroxide (3.0 cc.), 6N sodium hydroxide (0.3 cc.), and about 6 ml ethanol were placed in a reaction vessel and cooled slightly. The reaction temperature rose to about 50° C. and the mixture was stirred for about 1 hour. After the reaction had cooled, a solid precipitate formed and was collected by filtration. As indicated by TLC, pure product was obtained by heating the solid in refluxing acetone, yield 0.4 gram, m.p. 245°-258° C.
Reaction SMILES: S([N:11]1[C:15]2[N:16]=[CH:17][C:18]3[N:19]([C:20]([CH2:23][C:24]4([CH2:28][NH2:29])[CH2:27][CH2:26][CH2:25]4)=[N:21][N:22]=3)[C:14]=2[CH:13]=[CH:12]1)(C1C=CC(C)=CC=1)(=O)=O.C(OC([NH:37][C:38]1([CH2:42][C:43](O)=[O:44])CCC1)=O)(C)(C)C.CCN=C=NCCCN(C)C.Cl.Cl.C(CC(O)=O)#N.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>O1CCOCC1.CN(C=O)C.O>[C:20]1([CH2:23][C:24]2([CH2:28][NH:29][C:43](=[O:44])[CH2:42][C:38]#[N:37])[CH2:25][CH2:26][CH2:27]2)[N:19]2[C:14]3[CH:13]=[CH:12][NH:11][C:15]=3[N:16]=[CH:17][C:18]2=[N:22][N:21]=1
Reactant: CC(C)(C)OC(=O)NC1(CC(=O)O)CCC1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc(CC4(CN)CCC4)n23)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N#CCC(=O)O
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: N#CCC(=O)NCC1(Cc2nnc3cnc4[nH]ccc4n23)CCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 17 %

Procedure:
To a solution of (1-((6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)methyl)-cyclobutyl)methanamine (0.225 g, 0.548 mmol) (prepared using A from Example #1, Step D, 2-(1-(tert-butoxycarbonylamino)cyclobutyl)acetic acid [prepared as described WO9921824A1], EDC•HCl, B with TEA, E with 4.0 M HCl in 1,4-dioxane) in DMF (10 mL) was added cyanoacetic acid (0.070 g, 0.822 mmol), HOBt (0.101 g, 0.658 mmol), EDC•HCl (0.126 g, 0.658 mmol) and DIEA (0.190 mL, 1.096 mmol) to give a brown solution. The mixture was stirred at ambient temperature for about 18 h. Water (20 mL) was added and the mixture was extracted with EtOAc (3×25 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concd in vacuo. The crude material was purified by flash chromatography on silica gel eluting with a gradient of 0-10% MeOH in DCM to give N-((1-((6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)methyl)cyclobutyl)methyl)-2-cyanoacetamide as an off-white solid (0.030 g, 17%): LC/MS (Table 1, Method a) Rt=1.48 min; MS m/z: 324 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14](Cl)=[O:15])=[CH:4][CH:3]=1.[O:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=[C:18]1[CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][NH:28]1.C(N(CC)CC)C>ClCCl>[O:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=[C:18]1[CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[C:14]([C:9]1[N:10]=[C:11]([CH3:13])[S:12][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:15]
Reactant: c1ccc2oc(CC3CCCCN3)cc2c1
Reactant: Cc1nc(C(=O)Cl)c(-c2ccc(F)cc2)s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(C(=O)N2CCCCC2Cc2cc3ccccc3o2)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24 %

Procedure:
5-(4-Fluorophenyl)-2-methyl-thiazole-4-carbonyl chloride (136 mg, 0.53 mmol) in dichloromethane (1 ml) was added to a solution of (RS)-2-(2-benzofuranylmethyl)piperidine (104 mg, 0.48 mmol) and triethylamine (0.20 ml, 1.45 mmol) in dichloromethane (4 ml) and the mixture shaken at ambient temperature for 30 min. The resultant was washed with saturated aqueous sodium hydrogen carbonate (8 ml). The organic layer was applied directly onto a pre-packed silica gel column and chromatographed eluting with ethyl acetate hexane mixtures to give the title compound (50 mg, 24%) as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:3]=1[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:14])[CH3:13])[CH2:8][CH2:7]1)=O.Cl.[NH2:21][OH:22].C([O-])(=O)C.[Na+]>CCO>[F:1][C:2]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:3]=1[C:4](=[N:21][OH:22])[CH:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:14])[CH3:13])[CH2:8][CH2:7]1
Reactant: CC(=O)N1CCC(C(=O)c2ccc(F)cc2F)CC1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(=O)N1CCC(C(=NO)c2ccc(F)cc2F)CC1

Procedure:
The title compound was prepared from 1-(4-(2,4-difluoro-benzoyl)piperidin-1-yl)ethanone, hydroxylamine hydrochloride and sodium acetate in refluxing EtOH.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[CH:19]1[CH2:25][C:24](=O)[O:23][C:21](=[O:22])[CH2:20]1.[ClH:27]>ClCCl.O1CCOCC1>[ClH:27].[N:7]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[NH:8][C:24]=1[CH2:25][CH:19]([C:10]1[CH:11]=[CH:12][C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=1)[CH2:20][C:21]([OH:23])=[O:22]
Reactant: O=C1CC(c2ccc3ccccc3c2)CC(=O)O1
Reactant: Nc1ccccc1N
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(O)CC(Cc1nc2ccccc2[nH]1)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1,2-Phenylenediamine (54 mg) and 3-(2-naphthyl)glutaric anhydride (120 mg) were dissolved in dichloromethane (2 ml) with heating. The solution was stirred at rt for 1 h. The precipitate formed was collected by suction filtration, washed with dichloromethane, and dried to give a mixture of regioisomeric amides (131 mg) as colourless solid. This solid was dissolved in 1,4-dioxane (1 ml) with heating, and 4M HCl in 1,4-dioxane (1 ml) was added. The solution was heated to reflux for 1 h. After removal of the solvent the residue was triturated with acetone to give 4-(2-benzimidazolyl)-3-(2-naphthyl)butanoic acid HCl (100 mg) as colourless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:14]([N+:15]([O-])=O)=[CH:13][C:12]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[CH:11][N:10]=1.O.O.[Sn](Cl)Cl>CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:14]([NH2:15])=[CH:13][C:12]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[CH:11][N:10]=1
Reactant: COc1ccccc1-c1cnc(-c2ccccc2OC)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccccc1-c1cnc(-c2ccccc2OC)c(N)c1
Temperature: 65 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of 2,5-bis(2-methoxyphenyl)-3-nitropyridine (97.3 mg, 0.29 mmol) in EtOAc (5.0 mL) was added tin(II) chloride dihydrate (0.33 g, 1.45 mmol) in portions. Upon complete addition of the reducing agent, the mixture was carefully heated to 65° C. After 2 h, the reaction was cooled to rt and diluted with EtOAc, then washed with 1M NaOH (15 mL), water (15 mL), and brine (15 mL). After drying over anhydrous sodium sulfate and filtration, the organic solvent was removed under reduced pressure. The residue was identified as mostly 2,5-bis(2-methoxyphenyl)-3-pyridinamine. Mass Spectrum (pos.) m/e: 307.1 (M+1).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3](=[O:19])[CH2:4][C:5]([C:8]1[C:16]2[O:15][CH2:14][CH2:13][C:12]=2[CH:11]=[C:10]([C:17]#[N:18])[CH:9]=1)([CH3:7])[CH3:6].[Cl:22][C:23]1[C:24]([F:35])=[C:25]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:26]Br>>[Cl:22][C:23]1[C:24]([F:35])=[C:25]([CH:28]=[C:29]([C:31]([F:33])([F:34])[F:32])[CH:30]=1)[CH2:26][C:3]([OH:19])([C:2]([F:1])([F:20])[F:21])[CH2:4][C:5]([C:8]1[C:16]2[O:15][CH2:14][CH2:13][C:12]=2[CH:11]=[C:10]([C:17]#[N:18])[CH:9]=1)([CH3:7])[CH3:6]
Reactant: Fc1c(Cl)cc(C(F)(F)F)cc1CBr
Reactant: CC(C)(CC(=O)C(F)(F)F)c1cc(C#N)cc2c1OCC2
Product: CC(C)(CC(O)(Cc1cc(C(F)(F)F)cc(Cl)c1F)C(F)(F)F)c1cc(C#N)cc2c1OCC2

Procedure:
The title compound was prepared from 7-(4,4,4-trifluoro-1,1-dimethyl-3-oxobutyl)-2,3-dihydrobenzofuran-5-carbonitrile and 3-chloro-2-fluoro-5-trifluoromethylbenzyl bromide using the procedure described in Example 5.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([C:23](O)=[O:24])=[C:16]2[N:15]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:50]([NH2:54])([CH3:53])([CH3:52])[CH3:51].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[C:50]([NH:54][C:23]([C:22]1[CH:21]=[N:20][N:17]2[CH:18]=[CH:19][C:14]([N:10]3[CH2:11][CH2:12][CH2:13][C@@H:9]3[C:3]3[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=3[F:1])=[N:15][C:16]=12)=[O:24])([CH3:53])([CH3:52])[CH3:51]
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Reactant: CC(C)(C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)NC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Reaction time: 18 h
Yield: 86.3 %

Procedure:
To a solution of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation C, 20.0 mg, 0.058 mmol) and HATU (24.3 mg, 0.064 mmol) in dry DMF (0.4 mL) was added tert-butyl amine (12.7 mg, 0.174 mmol) followed by diisopropylethylamine (22.5 mg, 0.174 mmol). The mixture was stirred under an atmosphere of N2 for 18 hours and was added to H2O (3 mL) and mixed. The mixture was extracted with EtOAc and combined extracts were washed with 1M HCl, H2O, saturated NaHCO3 and dried over MgSO4. The solution was eluted through a SPE SiOH column eluting first with 50% EtOAc-hexanes then with EtOAc. The EtOAc pool was concentrated and the residual colorless glass was treated with hexanes give a white suspension. The hexanes were removed, and the solid was washed with hexanes and dried in vacuum to afford the title compound as a white solid (20 mg, 90%). MS (apci) m/z=400.1 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][N:14]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN.O>C(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][NH2:14])=[CH:25][CH:26]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(OCc2ccccc2)cc1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCc1ccc(OCc2ccccc2)cc1
Reaction time: 8 h

Procedure:
Next, to a solution of the resulting 2-(4benzyloxybenzyl)-isoindol-1,3-dione (37 g, 0.107 mol) in ethanol (1 L) was added hydrazine monohydrate (8.04 g, 0.161 mol), and the solution was stirred for 8 hours under reflux. The reaction solution was allowed to room temperature, then, water was added, and ethanol was evaporated in vacuo. Ethyl acetate and water were added to the residue for partitioning, the organic layer was washed with water, an aqueous solution of 2N sodium hydroxide and water, in this order, and dried over anhydrous magnesium sulfate. The solvent was evaporated, the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=2:1; hereinafter, the NH silica gel used was manufactured by Fuji Silysia), and the title compound (15 g, 64%) was obtained as a white solid.