Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])=[CH:9][CH:10]=2)[C:5]([OH:20])=[C:4]([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])[N:3]=1.P(Br)(Br)([Br:30])=O>C(#N)C>[Br:30][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])=[CH:9][CH:10]=2)[C:5]([OH:20])=[C:4]([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])[N:3]=1
Reactant: CCCCOC(=O)c1nc(O)c2ccc(Oc3ccccc3C)cc2c1O
Reactant: O=P(Br)(Br)Br
Solvent: CC#N
Product: CCCCOC(=O)c1nc(Br)c2ccc(Oc3ccccc3C)cc2c1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of butyl 1,4-dihydroxy-6-(o-tolyloxy)isoquinoline-3-carboxylate (1.5 g, 4.2 mmol) and POBr3 (4.9 g, 16.8 mmol) in acetonitrile (32 mL) was heated to reflux for 90 minutes. After cooling to room temperature, the solvent was removed in vacuo. The residue was dissolved in CHCl3 (200 mL) and to the solution were added NaHCO3 (10 g) and H2O (13 mL). The resulting mixture was stirred vigorously at room temperature for 30 minutes before dried over MgSO4. The mixture was then filtered and the filtrate was concentrated in vacuo and then purified by flash chromatography (0-10% EtOAc/CH2Cl2) to give the title compound in 0.9 g. 1H NMR (CDCl3, 200 MHz): δ=11.74 (s, 1H), 8.21 (d, 1H, J=8.4 Hz), 7.52-7.44 (m, 2H), 7.34-7.15 (m, 3H), 7.03 (d, 1H, J=8.8 Hz), 4.46 (t, 2H, J=7.2 Hz)), 2.20 (s, 3H), 1.92-1.77 (m, 2H), 1.56-1.38 (m, 2H), 0.98 (t, 3H, J=7.2 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][CH:19]([CH3:26])[CH2:20][C:21]([O:23]CC)=[O:22])=[C:8]2[CH3:27])=[CH:4][CH:3]=1.[OH-].[Na+]>CO.C1COCC1>[Br:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][CH:19]([CH3:26])[CH2:20][C:21]([OH:23])=[O:22])=[C:8]2[CH3:27])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(C)Cc1c(C)n(Cc2ccc(Br)cc2)c2ccc(OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c(c1)c(CC(C)CC(=O)O)c(C)n2Cc1ccc(Br)cc1
Reaction time: 2 h

Procedure:
To a solution of ester from Step 5 (3.5 g, 7.6 mmol) in MeOH/THF (50 mL/35 mL) was added 1M NaOH (22.9 mL, 22.9 mmol). After heating at reflux for 2 h, the mixture was concentrated under vacuum and the residue was partitioned between EtOAc/H2O containing HOAc (3 mL). The organic layer was washed with H2O, brine, and was then dried (MgSO4), filtered, and evaporated. The resulting solid was stirred vigorously with 1:10 EtOAc/hexane for 2 h to give, after filtration, 2.81 g of white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[C:13]2[C:6]([NH:7][CH:8]=[C:9]2[CH2:10][CH2:11][NH2:12])=[CH:5][CH:4]=1.[C:15](OCC)(=O)[CH2:16][CH2:17][CH2:18][C:19](OCC)=[O:20]>CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:14]=[C:13]2[C:9]3[CH2:10][CH2:11][N:12]4[C:15]([C:8]=3[NH:7][C:6]2=[CH:5][CH:4]=1)=[CH:16][CH2:17][CH2:18][C:19]4=[O:20]
Reactant: COc1ccc2[nH]cc(CCN)c2c1
Reactant: CCOC(=O)CCCC(=O)OCC
Solvent: CCOC(C)=O
Product: COc1ccc2[nH]c3c(c2c1)CCN1C(=O)CCC=C31

Procedure:
A mixture of 5-methoxytryptamine (420 mg) and diethyl glutarate (460 mg) is heated at 175° C. for 18 h. eparation on a column (eluent: EtOAc) gives the amide ster 2. This product is treated with a trace of ara-toluenesulphonic acid in xylene and the water formed is removed using Dean-Stark apparatus. After refluxing for 9 h and separation on a silica plate, N-[2-(5-methoxy)indol-3-ylethyl)]glutarimide is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]([F:24])([F:23])[C:14](=O)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>O>[Br:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[C:14]([C:13]([F:23])([F:24])[F:12])[C:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[C:4]2[OH:6]
Reactant: O=C(Cc1ccccc1)C(F)(F)F
Reactant: Nc1ccc(Br)cc1C(=O)O
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Product: Oc1c(-c2ccccc2)c(C(F)(F)F)nc2ccc(Br)cc12
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
A mixture of 2-amino-5-bromobenzoic acid (3.01 g, 13.9 mmol), 1,1,1-trifluoro-3-phenylpropan-2-one (3.11 g, 16.5 mmol), and Eaton's reagent (9.3 mL) in a sealed tube was heated at 100° C. for 4 hours. The reaction mixture was then allowed to cool to room temperature, water was added slowly, and the mixture was stirred vigorously for about 15 minutes. The precipitated solid was collected by filtration, washed with water, and dried to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:17]=[C:16]([N:18]([CH3:20])[CH3:19])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([N+:21]([O-])=O)[CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[H][H]>[Pd].C(O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:17]=[C:16]([N:18]([CH3:19])[CH3:20])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([NH2:21])[CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)c1cc(-c2cccc(F)c2)nc2ccc([N+](=O)[O-])cc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CN(C)c1cc(-c2cccc(F)c2)nc2ccc(N)cc12
Reaction time: 18 h

Procedure:
The title compound was prepared by reduction of a nitro group by catalytic hydrogenation as follows. Into a 500 mL Parr shaker bottle was placed 4.0 g of the N-[2-(3-fluorophenyl)-6-nitro-4-quinolinyl]-N,N-dimethylamine along with 150 mg of a catalyst consisting of 5% palladium on calcium carbonate support. To this was added 150 mL of ethanol, followed by application of a 50 psi hydrogen atmosphere. The reaction was shaken for 18 hr then the hydrogen atmosphere was replaced by nitrogen. The catalyst was removed by filtration, and the solution concentrated. The residue was taken up in ethyl acetate, washed with 5% sodium hydroxide solution, then the organic layer was dried over Na2SO4, filtered and concentrated. The extract was recrystallised from methylene chloride and hexane to give 2.8 g (77%) of the product.
Reaction SMILES: CO[C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:14][O:15][C:16]=2[C:17]([F:20])([F:19])[F:18])=[N:6][CH:5]=1.[CH2:28]([CH2:30][NH2:31])[OH:29]>>[OH:29][CH2:28][CH2:30][NH:31][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:14][O:15][C:16]=2[C:17]([F:18])([F:19])[F:20])=[N:6][CH:5]=1
Reactant: NCCO
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C(F)(F)F)nc1
Product: O=C(NCCO)c1ccc(OCc2c(-c3ccccc3)noc2C(F)(F)F)nc1
Yield: 24 %

Procedure:
As described for example 129, 6-(3-phenyl-5-trifluoromethyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (100 mg, 0.26 mmol) was converted, using ethanolamine instead of methylamine (2 M in THF), to the title compound (26 mg, 24%) which was obtained as an off white solid. MS: m/e=408.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([C:10]=1[CH3:11])[C:7]([OH:9])=O.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH3:29])[CH:19]=[C:20]([O:27][CH3:28])[C:21]=1[O:22][C:23](=[O:26])[CH2:24][CH3:25].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([C:10]=1[CH3:11])[C:7]([C:19]1[C:18]([CH3:29])=[CH:17][C:16]([O:15][CH3:14])=[C:21]([O:22][C:23](=[O:26])[CH2:24][CH3:25])[C:20]=1[O:27][CH3:28])=[O:9]
Reactant: COc1ccc(Cl)c(C)c1C(=O)O
Reactant: CCC(=O)Oc1c(OC)cc(C)cc1OC
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: CCC(=O)Oc1c(OC)cc(C)c(C(=O)c2c(OC)ccc(Cl)c2C)c1OC

Procedure:
5-Chloro-2-methoxy-6-methylbenzoic acid (6.00 g, 0.03 mol) is reacted with 3,5-dimethoxy-4-propionyloxytoluene (6.73 g; 0.03 mol) in the presence of P2O5 (18.0 g) and dichloromethane (200 ml) as described in Example 6 yielding white crystals, 6.65 g (56.4% ), mp 150-151° C.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][C:11]12[CH2:18][CH2:17][C:14]([C:19]3[NH:27][C:26]4[C:25](=[O:28])[N:24]([CH2:29][CH2:30][CH3:31])[C:23](=[O:32])[N:22]([CH2:33][CH2:34][CH3:35])[C:21]=4[N:20]=3)([CH2:15][CH2:16]1)[CH2:13][CH2:12]2)(=[O:8])[O:5]CC)[CH3:2].Cl>[OH-].[Na+]>[CH2:1]([O:3][P:4]([CH2:9][CH2:10][C:11]12[CH2:18][CH2:17][C:14]([C:19]3[NH:27][C:26]4[C:25](=[O:28])[N:24]([CH2:29][CH2:30][CH3:31])[C:23](=[O:32])[N:22]([CH2:33][CH2:34][CH3:35])[C:21]=4[N:20]=3)([CH2:13][CH2:12]1)[CH2:15][CH2:16]2)(=[O:5])[OH:8])[CH3:2]
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(CCP(=O)(OCC)OCC)(CC3)CC4)nc2n(CCC)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCn1c(=O)c2[nH]c(C34CCC(CCP(=O)(O)OCC)(CC3)CC4)nc2n(CCC)c1=O
Temperature: 80 °C

Procedure:
Dissolved {2-[4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo-[2.2.2]oct-1-yl]-ethyl}-phosphonic acid diethyl ester (30 mg, 59 μmol) in 1 N NaOH (4 ml) and heated the solution at 80° C. for 3 h. The mixture was allowed to cool to rt and slowly acidified with concentrated HCl. The resulting precipitate was collected and dried (22 mg, 79%). 1H NMR (400 MHz, CDCl3); 0.93 (coincident triplets, 6H), 1.31 (t, 3H), 1.48 (m, 8H), 1.70 (br m, 6H), 1.95 (m, 6H), 3.95 (t, 2H), 4.07 (t, 2H), 12.2 (br s, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H].Cl>[Pd].CO.Cl>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C2=CCN(Cc3ccccc3)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1ccc(C2CCN(Cc3ccccc3)CC2)cc1
Reaction time: 8 h

Procedure:
Palladium on carbon (10%, 0.0695 g) is added to a mixture of 1-benzyl-1,2,3,6-tetrahydro-4-(4-methoxyphenyl)pyridine (XVI, Step 2, 0.6843 g, 2.4 mmol) in methanol/hydrochloric acid and the mixture is shaken overnight under approximately 40 psi of hydrogen. Additional palladium on carbon and concentrated hydrochloric acid are added and the mixture is again shaken overnight under hydrogen. The palladium on carbon then is filtered off and the filtrate is concentrated. The residue is partitioned between dichloromethane and saturated sodium bicarbonate and the combined organic phases are backwashed with saturated sodium bicarbonate, dried over magnesium sulfate, and concentrated to give 1-benzyl-4-(4-methoxyphenyl)piperidine (XVIII), NMR (CDCl3) 1.77, 2.07, 2.45, 3.00, 3.55, 3.78, 6.85, 7.16 and 7.31 δ.
Reaction SMILES: Cl.[CH2:2]([O:4][CH2:5][CH2:6][C:7]([OH:9])=O)[CH3:3].[CH2:10]([C@H:17]1[CH2:21][NH:20][C@H:19]([C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)=[CH:27][CH:26]=2)=[O:23])[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([C@H:17]1[CH2:21][N:20]([C:7](=[O:9])[CH2:6][CH2:5][O:4][CH2:2][CH3:3])[C@H:19]([C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=3)=[CH:27][CH:26]=2)=[O:23])[CH2:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOCCC(=O)O
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Agent: Cl
Product: CCOCCC(=O)N1C[C@H](Cc2ccccc2)C[C@H]1C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 28.5 %

Procedure:
Proceeding as in Example 1, but substituting 3-ethoxypropanoic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 86, (2S,4R)-4-benzyl-1-(3-ethoxypropanoyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (8.4 mg, 28.5%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 9.91 (s, 1H), 7.55 (m, 2H), 7.28 (m, 2H), 7.21-7.16 (m, 7H), 6.93 (m, 2H), 4.45 (m, 1H), 3.64 (m, 1H), 3.54 (m, 2H), 3.38 (m, 2H), 3.24 (m, 1H), 2.63 (m, 5H), 1.88 (m, 2H), 1.04 (m, 3H). MS (EI) for C29H31FN2O4. found 491.6 (MH+).
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:28])=[C:12]([CH2:14][C:15]([NH:17][C:18]2([C:24]([O:26]C)=O)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:16])[CH:13]=1.O.Cl>CN(C)C=O>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:28])=[C:12]([C:14]2[C:15](=[O:16])[NH:17][C:18]3([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)[C:24]=2[OH:26])[CH:13]=1
Reactant: COC(=O)C1(NC(=O)Cc2cc(Br)ccc2C)CCCCC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(Br)cc1C1=C(O)C2(CCCCC2)NC1=O
Temperature: 80 °C

Procedure:
1.71 g (15.2 mmol) of potassium tert-butoxide were added to 2.80 g (7.60 mmol) of the compound from Example 12A in 15 ml of N,N-dimethylformamide. The reaction mixture was heated at 80° C. for 15 minutes. After cooling, water was added and aqueous hydrogen chloride solution was added dropwise. The precipitate was filtered off with suction, washed with water and dried. This gave 2.33 g (90% of theory) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[CH:10]=[C:9]2[C:17](=O)[CH3:18])[CH:5]=[CH:6][CH:7]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:26].[Na+]>CO.C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[CH:10]=[C:9]2[CH:17]([NH2:26])[CH3:18])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cc2cccnc2n1-c1cccc(F)c1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: CC(N)c1cc2cccnc2n1-c1cccc(F)c1
Temperature: 65 °C
Yield: 133.3 %

Procedure:
A mixture of 1-[1-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]ethanone (0.24 g, 0.94 mmol) and ammonium acetate (0.73 g, 9.5 mmol) in methanol (3.0 mL) and acetonitrile (3.0 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, sodium cyanoborohydride (0.18 g, 2.8 mmol) was added to the resultant mixture. The reaction was heated at 65° C. overnight. The reaction was then cooled to room temperature and quenched with saturated NaHCO3 solution and then extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give the crude amine (0.32 g), which was used directly in the next step. LCMS calculated for C15H15FN3(M+H)+: m/z=256.1. Found: 256.1.
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17]([S:20]([C:23]5[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=5)(=[O:22])=[O:21])[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@@H:5]([NH:30]C(=O)C)[CH2:4]1)[CH3:2].Cl>O1CCOCC1>[CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17]([S:20]([C:23]5[CH:24]=[CH:25][C:26]([CH3:27])=[CH:28][CH:29]=5)(=[O:22])=[O:21])[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@@H:5]([NH2:30])[CH2:4]1)[CH3:2]
Reactant: CC[C@@H]1C[C@H](NC(C)=O)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Agent: Cl
Solvent: C1COCCO1
Product: CC[C@@H]1C[C@H](N)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Temperature: 95 °C
Yield: 55.9 %

Procedure:
To a solution of N-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)acetamide (6.0 g, 12.86 mmol, Example #8 Step L) in 1,4-dioxane (78 mL) was added HCl (6 N aqueous, 75 mL, 450 mmol). The reaction mixture was heated at about 95° C. for about 16 h. The reaction was cooled to ambient temperature and the solvent was removed under reduced pressure. The residue was diluted with DCM (50 mL) and washed with saturated aqueous NaHCO3 (100 mL). The aqueous portion was extracted with additional DCM (3×50 mL) and the combined organic layers were dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The crude material was purified by silica gel chromatography eluting with a gradient of 0-100% DCM/MeOH/NH4OH (950:45:5) in DCM to give (1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine (3.05 g, 56%) as a tan solid: LC/MS (Table 1, Method a) Rt=1.85 min; MS m/z: 425 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:8]=[O:9].[C:10]1([Mg]Br)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[OH:9]
Reactant: O=Cc1cnccc1Br
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1cnccc1Br
Reaction time: 0.25 h

Procedure:
To a solution of 4-bromo-pyridine-3-carbaldehyde (400 mg, 2.15 mmol) in THF (10 mL) at −78° C. was added dropwise 3.0 M phenylmagnesium bromide solution in THF (1.08 mL). After 15 min, the reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate, then purification by flash chromatography eluted with 50% ethyl acetate in hexane to yield (4-bromo-pyridin-3-yl)-phenyl-methanol as slight yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[C:13](=[O:17])[NH:14][CH2:15][CH2:16][C:11]=3[S:10][CH:9]=2)=[CH:4][CH:3]=1.I[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:24]=1[CH3:25].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[C:13](=[O:17])[N:14]([C:19]4[CH:20]=[N:21][CH:22]=[CH:23][C:24]=4[CH3:25])[CH2:15][CH2:16][C:11]=3[S:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccncc1I
Reactant: O=C1NCCc2scc(-c3ccc(F)cc3)c21
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCc2scc(-c3ccc(F)cc3)c2C1=O
Yield: 17 %

Procedure:
Using analogous reaction conditions as described in Example 1, 3-(4-fluoro-phenyl)-6,7-dihydro-5H-thieno[3,2-c]pyridin-4-one (I-15c: 150 mg, 0.61 mmol) was reacted with 3-iodo-4-methyl-pyridine (133 mg, 0.61 mmol), 1,4-dioxane (10 mL), copper iodide (11.6 mg, 0.061 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (25.98 mg, 0.183 mmol) and potassium phosphate (323.3 mg, 1.525 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% methanol in CHCl3) afforded 35 mg of the product (17.5% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12]/[C:11](=[C:19]3/[C:20]([CH2:25][CH2:26][CH3:27])=[N:21][NH:22][C:23]/3=[O:24])/[CH:10]=2)=[CH:4][CH:3]=1.[C:28](Cl)(=[O:32])[CH2:29][CH2:30][CH3:31]>C1COCC1>[O:24]=[C:23]1[NH:22][N:21]=[C:20]([CH2:25][CH2:26][CH3:27])/[C:19]/1=[C:11]1/[NH:12][C:13]2[C:18]([C:9]([S:8][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:28](=[O:32])[CH2:29][CH2:30][CH3:31])=[CH:7][CH:6]=3)=[CH:10]/1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: CCCC1=NNC(=O)/C1=C1/C=C(Sc2ccc(N)cc2)c2ccccc2N1
Reactant: CCCC(=O)Cl
Solvent: C1CCOC1
Product: CCCC(=O)Nc1ccc(SC2=C/C(=C3/C(=O)NN=C3CCC)Nc3ccccc32)cc1

Procedure:
The title compound was synthesized using (Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-one and butyryl chloride in THF according to the procedure described in the synthesis of Example 26. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.69 (t, J=7.33 Hz, 3H) 0.94 (t, J=7.33 Hz, 3H) 1.26-1.35 (m, J=7.36, 7.36, 7.36, 7.36, 7.20 Hz, 2H) 1.59-1.69 (m, J=7.38, 7.38, 7.38, 7.38, 7.38 Hz, 2H) 2.21 (t, J=7.20 Hz, 2H) 2.34 (t, J=7.20 Hz, 2H) 6.74 (s, 1H) 7.62 (t, J=7.71 Hz, 1H) 7.68 (d, J=8.59 Hz, 2H) 7.83-7.93 (m, 4H) 8.13 (d, J=8.34 Hz, 1H) 10.26 (s, 1H); ESI-MS: m/z calc'd for C25H26N4O2S 446.56. found 447.3 (M+H)+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)=[O:11].[Cl:19][C:20]1[C:25](Cl)=[N:24][CH:23]=[CH:22][N:21]=1.CS(C)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:25]2[C:20]([Cl:19])=[N:21][CH:22]=[CH:23][N:24]=2)=[CH:14][CH:13]=1)=[O:11]
Reactant: Clc1nccnc1Cl
Reactant: O=C(c1ccc(O)cc1)c1nc2ccccc2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(c1ccc(Oc2nccnc2Cl)cc1)c1nc2ccccc2s1
Temperature: 90 °C
Reaction time: 6 h

Procedure:
In 250 mL round bottom flask were charged benzo[d]thiazol-2-yl(4-hydroxyphenyl)methanone (6.0 g, 23.5 mmol), 2,3-dichloro-pyrazine (3.48 g, 23.5 mmol), DMSO (60 mL), and cesium carbonate (15 g, 47 mmol). The reaction mixture was stirred at 90° C. for 6 h. The reaction mixture was diluted with cold water and the precipitate was collected by filtration. The crude product was purified by silica gel column chromatography with hexane and ethyl acetate to give the title compound. [M+H]=368.
Reaction SMILES: [CH2:1]([C:8]1O[C:10]([O:14]CC)=[C:11]([CH3:13])[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]([CH:20]1[O:26][CH2:25][CH:24]=[CH:23][CH2:22][O:21]1)([CH3:19])[CH3:18]>>[CH:17]([CH:20]1[O:26][CH2:25][C:24]2[C:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[N:12][C:11]([CH3:13])=[C:10]([OH:14])[C:23]=2[CH2:22][O:21]1)([CH3:19])[CH3:18]
Reactant: CC(C)C1OCC=CCO1
Reactant: CCOc1oc(Cc2ccccc2)nc1C
Product: Cc1nc(Cc2ccccc2)c2c(c1O)COC(C(C)C)OC2
Temperature: 180 °C

Procedure:
A mixture of 12.6 g (60 millimoles) of 2-benzyl-4-methyl-5-ethoxy-oxazole and 42.6 g (300 millimoles) of 2-isopropyl-4,7-dihydro-1,3-dioxepine is heated for 5 hours at 180° C. On cooling the mixture in an ice bath, 4.2 g of 3-isopropyl-6-benzyl-8-methyl-1,5-dihydro-[1,3]dioxepino[5,6-c]pyridin-9-ol crystallize out. A further 2.0 are obtained by evaporating the mother liquor, partitioning the residue between methylene chloride and dilute sodium hydroxide solution and neutralizing the alkaline phase. Recrystallization from ethyl acetate gives a pure product, of melting point 193°-194° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=O)[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][C:10]([OH:16])=[CH:9][CH:8]=3.B#B.O.Cl>C1COCC1>[CH2:6]1[C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:15][C:14]=2[O:13][C:12]2[CH:11]=[C:10]([OH:16])[CH:9]=[CH:8][C:7]1=2
Reactant: O=c1c2ccc(O)cc2oc2cc(O)ccc12
Agent: B#B
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Oc1ccc2c(c1)Oc1cc(O)ccc1C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.2 %

Procedure:
To a suspension of 3,6-dihydroxyxanthone (46 g, 201 mmol.) obtained as in Example 1 in 1.6 L of THF was added over 1 hr 800 ml of borane-tetrahydrofuran complex (1.0M in THF, caution very vigorous raction at beginning). This mixture was stirred overnight under argon at room temperature to give a clear yellow solution. The excess diborane was decomposed by careful addition of water followed by 1N HCl to give a clear yellow solution. The tetrahydrofuran was removed by rotary evaporation and the resulting solid filtered, washed with water and redissolved in 10% NaOH. This solution was filtered, cooled and reprecipitated with slow addition of HCl to give a yellow solid which was filtered, washed with water and dried under vacuum to give 40.14 g (93%, mp 207-208) of 3,6-Dihydroxyxanthane. H1NMR (DMSO): 9.41 (s, 2H); 6.97 (d, 2H, J=8.4 Hz), 6.4 (dd, 2H, J=8.4, 2.4 Hz), 6.39 (d, 2H, J=2.4 Hz), 3,765 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:16][CH3:17])=[CH:5][C:6]=1[C:7](=[O:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14].O1CCN([CH:24]=[CH:25][N+:26]([O-:28])=[O:27])CC1.Cl.CC(C)=O>O>[Cl:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:7]([C:6]1[CH:5]=[C:4]([CH2:16][CH3:17])[S:3][C:2]=1[NH:1][CH:24]=[CH:25][N+:26]([O-:28])=[O:27])=[O:15]
Reactant: O=[N+]([O-])C=CN1CCOCC1
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(N)s1
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: CCc1cc(C(=O)c2ccccc2Cl)c(NC=C[N+](=O)[O-])s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
A mixture of 2-amino-3-(2-chlorobenzoyl)-5-ethylthiophene (5.30 g), 1-morpholino-2-nitroethene (3.16 g), 6N HCl (5 ml) and acetone (25 ml) was stirred at room temperature for one hour. Water was added to the mixture, which was extracted with ethene acetate. The extract was washed with water and dried over MgSO4, and then the solvent was distilled off to obtain 3-(2-chlorobenzoyl)-2-(2-nitroethenylamino)-5-ethylthiophene as crystals (5.65 g, 84.1%). The crystals were recrystallized from acetone to obtain yellow plates, mp: 125°-126° C.