Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([F:8])[C:5]([F:9])=[C:4](F)[C:3]=1[F:11].[CH2:12]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[F:8][C:6]1[C:5]([F:9])=[C:4]([N:22]2[CH2:23][CH2:24][N:19]([CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:20][CH2:21]2)[C:3]([F:11])=[C:2]([F:1])[N:7]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: Fc1nc(F)c(F)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Fc1nc(F)c(F)c(N2CCN(Cc3ccccc3)CC2)c1F
Temperature: 100 °C
Reaction time: 5 h
Yield: 94.1 %

Procedure:
To a solution of pentafluoropyridine (1.76 ml, 16.0 mmol) and 1-benzylpiperazine (2.64 g, 15.0 mmol) in DMSO (20 ml) was added potassium carbonate (4.20 g, 30.4 ml). The suspension was heated to 100° C. and stirred for five hours and allowed to cool to ambient temperature, poured onto water and then extracted with DCM. The extract was washed with brine, water, and dried. Volatile material was removed by evaporation to give the title compound (4.59 g) as an oil. NMR (CDCl3) 2.58 (m, 4H), 3.52 (m, 4H), 3.57 (s, 2H), 7.24-7.38 (m, 5H and CDCL3); m/z 326.
Reaction SMILES: [H-].[Na+].[CH2:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH:4]1[NH:12][C:13]1[N:14]=[CH:15][C:16]2[CH2:22][N:21]([C:23]([O:25][CH2:26][CH2:27][CH2:28]Cl)=[O:24])[CH2:20][CH2:19][C:17]=2[N:18]=1.[NH:30]1[CH:34]=[CH:33][N:32]=[CH:31]1.ClCCl>CN(C)C=O.O>[CH2:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH:4]1[NH:12][C:13]1[N:14]=[CH:15][C:16]2[CH2:22][N:21]([C:23]([O:25][CH2:26][CH2:27][CH2:28][N:30]3[CH:34]=[CH:33][N:32]=[CH:31]3)=[O:24])[CH2:20][CH2:19][C:17]=2[N:18]=1
Reactant: O=C(OCCCCl)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: O=C(OCCCn1ccnc1)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Reaction time: 18 h
Yield: 32.7 %

Procedure:
Add sodium hydride (0.050 g; 2.2 equiv; 1.25 mmoles) to a solution of 3-chloropropyl 2-(indan-2-ylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylate (0.22 g; 1.0 equiv; 0.57 mmoles) and 1H-imidazole (0.082 g; 2.1 equiv; 1.20 mmoles) in dimethylformamide (2 mL) and stir for 18 hours. Dilute the reaction with dichloromethane and water. Separate the layers and further extract the aqueous layer with dichloromethane (2×). Dry the combined organic extracts with sodium sulfate, filter, and concentrate. Purify the crude product by column chromatography (0 to 10% methanol in dichloromethane) to afford the desired 3-(1H-imidazol-1-yl)propyl 2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (0.078 g; 33%) as a white solid: MS (m/z): 419 (M+1).
Reaction SMILES: C([O:5][C:6](=[O:19])[C:7]1[CH:12]=[C:11]([CH2:13][CH:14]([CH3:16])[CH3:15])[N:10]=[C:9]([CH2:17][CH3:18])[CH:8]=1)(C)(C)C.[ClH:20]>>[ClH:20].[CH2:17]([C:9]1[CH:8]=[C:7]([CH:12]=[C:11]([CH2:13][CH:14]([CH3:15])[CH3:16])[N:10]=1)[C:6]([OH:19])=[O:5])[CH3:18]
Reactant: CCc1cc(C(=O)OC(C)(C)C)cc(CC(C)C)n1
Agent: Cl
Product: CCc1cc(C(=O)O)cc(CC(C)C)n1

Procedure:
A solution of 2-ethyl-6-isobutyl-isonicotinic acid tert-butyl ester (391 mg, 1.49 mmol) in 6 N aq. HCl (15 mL) is stirred at 65° C. for 2 days before the solvent is evaporated. The residue is dried under HV to give 2-ethyl-6-isobutyl-isonicotinic acid hydrochloride (334 mg) as a colourless solid, LC-MS: tR=0.58 min, [M+1]+=208.04.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6](O)=[O:7].COCCOC.C(Cl)(=O)C([Cl:25])=O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([Cl:25])=[O:7]
Reactant: COc1cc(C(=O)O)cc(OC)c1OC
Reactant: O=C(Cl)C(=O)Cl
Solvent: COCCOC
Solvent: CN(C)C=O
Product: COc1cc(C(=O)Cl)cc(OC)c1OC
Reaction time: 20 h

Procedure:
Combine 3,4,5-trimethoxybenzoic acid (3.5 kg, 16.5 mol) and 1,2-dimethoxyethane (14.2 kg) and dimethyl formamide (4 g). Cool in an ice bath. Add oxalyl chloride (2.99 kg, 23.5 mmol) over about 50 minutes not allowing the temperature of the reaction to raise above about 19° C. After 20 hours, concentrate in vacuo at 25° C. to remove about 3.7 kg of distillate to give a solution of 3,4,5-trimethoxybenzoyl chloride.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9][C@H:10]([CH2:12][CH3:13])[CH3:11])=[C:4]([F:14])[CH:3]=1.[CH3:15][N:16](C=O)C>O.[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:14][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([F:8])[C:5]=1[O:9][C@H:10]([CH2:12][CH3:13])[CH3:11])[C:15]#[N:16]
Reactant: CN(C)C=O
Reactant: CC[C@H](C)Oc1c(F)cc(Br)cc1F
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [C-]#N
Solvent: O
Product: CC[C@H](C)Oc1c(F)cc(C#N)cc1F
Temperature: 80 °C

Procedure:
A solution of 400 mg (1.5 mmol) of 1-bromo-3,5-difluoro-4-(2-(S)-butoxy)benzene (from Step A), 106 mg (0.9 mmol) of zinc cyanide, 69 mg of tris(dibenzylideneacetone)dipalladium(0) and 100 mg (0.18 mmol) of 1,1′-bis(diphenylphosino)ferrocene in 3 mL of DMF and 30 μL of water. The resulting solution was heated to 80° C. for 1 h and then cooled and concentrated. Chromatography on a Biotage 40M cartridge using 20:1 v/v hexanes/EtOAc as the eluant afforded 280 mg of the title compound: 1H NMR (500 Mhz) δ 1.01 (t, J=7.6, 3H), 1.35 (d, J=6.2, 3H), 1.68 (m, 1H), 1.79 (m, 1H), 4.47 (m, 1H), 7.25 (d, 2H).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]([CH3:26])[C:6]([CH:8]1[CH2:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[C:15]([F:25])[CH:14]=2)([OH:12])[CH2:9]1)=[O:7])[CH3:4].[CH3:27]I>C1COCC1>[CH2:3]([N:5]([CH3:26])[C:6]([CH:8]1[CH2:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[C:15]([F:25])[CH:14]=2)([O:12][CH3:27])[CH2:9]1)=[O:7])[CH3:4]
Reactant: CCN(C)C(=O)C1CC(O)(c2ccc(CN3CCCC3)c(F)c2)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(C)C(=O)C1CC(OC)(c2ccc(CN3CCCC3)c(F)c2)C1
Reaction time: 0.25 h

Procedure:
Sodium hydride (60% wt, 0.040 g, 1.00 mmol) was added to a solution of Example 14, 3-(3-Fluoro-4-pyrrolidin-1-ylmethyl-phenyl)-3-hydroxy-cyclobutanecarboxylic acid ethyl-methyl-amide (0.25 g, 0.748 mmol) in THF (5 mL). After stirring for 15 min, all gas evolution ceased and methyliodide (0.06 mL, 0.96 mmol) was added. The resulting mixture was stirred at room temperature for 16 h then quenched with water and extracted into EtOAc. The extract was washed with brine, dried over MgSO4 and concentrated to give the title compound as a light yellow oil (0.13 g): Rf=0.16 (20% MeOH/EtOAc); LRMS m/z Calcd for C20H29FN2O2, 348.5, found, 349.4 (M+H) APCI.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:8]=[C:7]([C:9]2[CH:33]=[CH:32][CH:31]=[CH:30][C:10]=2[O:11][CH2:12][CH2:13][N:14]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)C(=O)OC(C)(C)C)[S:6][C:5]=1[NH:34][C:35]([NH2:37])=[O:36])=[O:3].FC(F)(F)C(O)=O>>[NH2:37][C:35]([NH:34][C:5]1[S:6][C:7]([C:9]2[CH:33]=[CH:32][CH:31]=[CH:30][C:10]=2[O:11][CH2:12][CH2:13][NH:14][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)=[CH:8][C:4]=1[C:2]([NH2:1])=[O:3])=[O:36]
Reactant: CC(C)(C)OC(=O)N(CCOc1ccccc1-c1cc(C(N)=O)c(NC(N)=O)s1)Cc1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)Nc1sc(-c2ccccc2OCCNCc2ccc(F)cc2)cc1C(N)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The title compound was prepared by treating tert-butyl N-[2-(2-{3-(aminocarbonyl)-2-[(aminocarbonyl)amino]thien-5-yl}phenoxy)ethyl]-N-[4-fluorobenzyl]carbamate with 10% aqueous trifluoroacetic acid for 2 h at ambient temperature followed by purification using cation exchange chromatography. MS (ES) 429 (M+H)+. 1H NMR (DMSO-D6) 2.9 (m, 2H), 3.8 (s, 2H), 4.15 (m, 2H), 6.85 (br, 2H), 6.95 (m, 1H), 7.05 (m, 3H), 7.2 (m, 2H), 7.35 (m, 2H), 7.6 (m, 2H), 7.75 (s, 1H), 10.92 (s, 1H). b) tert-Butyl N-[2-(2-{3-(aminocarbonyl)-2-[(aminocarbonyl)amino]thien-5-yl)phenoxy)ethyl]-N-[4-fluorobenzyl]carbamate The title compound was prepared from tert-butyl N-[2-(2-bromophenoxy)ethyl]-N-[4-fluorobenzyl]carbamate in a similar manner to Example 1 (a) except that the concentrated reaction mixture was partitioned between DCM and saturated sodium carbonate. The solvent layer was washed (brine), dried and evaporated to leave an oil. The pure product was obtained by silica chromatography eluting with DCM/methanol mixtures. MS (ES) 529 (M+H)+. 1H NMR (DMSO-D6) 1.35 (s, 9H), 3.6 (m, 2H), 4.1 (m, 2H), 4.4 (m, 2H), 6.8 (m, 2H), 7.1 (m, 2H), 7.25 (m, 3H), 7.6 (m, 6H), 10.98 (s, 1H). c) tert-Butyl N-[2-(2-bromophenoxy)ethyl]-N-[4-fluorobenzyl]carbamate A solution of di-tert-butyl dicarbonate (1.86 g) in DCM (5 ml) was added over 5 min to a stirred solution of N-[2-(2-bromophenoxy)ethyl]-N-[4-fluorobenzyl]amine (2.5 g) in DCM (20 ml) and the resulting mixture was stirred at room temperature for 4 h. The reaction was diluted with DCM and then washed with water. After drying, the solvent was evaporated to yield an oil (2.9 g). MS (ES) 424 (M+H)+. d) N-[2-(2-Bromophenoxy)ethyl]-N-[4-fluorobenzyl]amine The title compound was prepared from 1-bromo-2-(2-chloroethoxy)benzene and 4-fluorobenzylamine in a similar manner to Example 1 (b). MS (ES) 324 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][CH2:10][NH:9][C:8]=2[CH:13]=1)([O-:3])=[O:2].Br[CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=1[O:26][CH3:27].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC(C)=O>[CH3:27][O:26][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][C:16]=1[CH2:15][N:9]1[C:8]2[CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=2[O:12][CH2:11][CH2:10]1)[C:20]([O:22][CH3:23])=[O:21]
Reactant: O=[N+]([O-])c1ccc2c(c1)NCCO2
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(CN2CCOc3ccc([N+](=O)[O-])cc32)c(OC)c1
Yield: 83.8 %

Procedure:
A mixture of 6-nitro-2,3-dihydrobenz-1,4-oxazine (0.45 g.), methyl 4-bromomethyl-3-methoxybenzoate (B) (0.65 g.), anhydrous potassium carbonate (0.35 g.), sodium iodide (0.38 g.) and acetone (25 ml.) was stirred and heated under reflux for 48 hours, under an atmosphere of nitrogen. The cooled reaction mixture was separated by filtration. The residue was washed with acetone, and the filtrate and washings were evaporated. The resulting solid was dissolved in dichloromethane and residual solid removed by filtration. The filtrate was evaporated. The product was purified by flash chromatography on silica gel (3 cm. diameter column), eluting with 1:10 v/v ethyl acetate:toluene, to give methyl 3-methoxy-4-(6-nitro-2,3-dihydrobenz-1,4-oxazin-4-ylmethyl)benzoate (G) (0.75 g., 84%), m.p. 130°-132° C.; NMR (80 MHz, CDCl3): 3.0(t,2H, OCH2.CH2N), 3.8(s,3H, OCH3), 3.95(s,3H, OCH3), 4.3(t, 2H, OCH2.CH2N), 4.5(s,2H, CH2.Ar), 6.8(d,1H), 7.5(m, 5H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[CH:13][C:12]3[CH:15]=[N:16][NH:17][C:11]=3[CH:10]=2)[CH:6]=[N:7][CH:8]=1)[CH3:2].Br[C:19]1[N:24]=[C:23]([F:25])[C:22]([Cl:26])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:26][C:22]1[CH:21]=[CH:20][C:19]([N:17]2[C:11]3[CH:10]=[C:9]([C:5]4[CH:6]=[N:7][CH:8]=[C:3]([CH2:1][CH3:2])[CH:4]=4)[N:14]=[CH:13][C:12]=3[CH:15]=[N:16]2)=[N:24][C:23]=1[F:25]
Reactant: CCc1cncc(-c2cc3[nH]ncc3cn2)c1
Reactant: Fc1nc(Br)ccc1Cl
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCc1cncc(-c2cc3c(cn2)cnn3-c2ccc(Cl)c(F)n2)c1
Temperature: 100 °C
Yield: 58.8 %

Procedure:
To a solution of the aforesaid 6-(5-ethyl-3-pyridyl)-1H-pyrazolo[4,3-c]pyridine (0.264 mmol; 95.9 mg) and 6-bromo-3-chloro-2-fluoro-pyridine (0.396 mmol; 83.4 mg) in 1,4-Dioxane (10 mL) under Nitrogen was added cesium carbonate (0.528 mmol; 172 mg), Xantphos (0.0449 mmol; 26.0 mg), and Tris(dibenzylideneacetone)dipalladium(0) (0.0264 mmol; 24.2 mg). The resulting mixture was sealed in a pressure tube and heated at 100° C. for 17 hours. The reaction mixture cooled to room temperature, and filtered through Celite. The filter cake was washed with DCM. The filtrate was concentrated. The residue was purified on silica eluted with 0 to 6% MeOH in DCM to afford 1-(5-chloro-6-fluoro-2-pyridyl)-6-(5-ethyl-3-pyridyl)pyrazolo[4,3-c]pyridine (54.9 mg, 59%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10](=[O:16])[N:9]([CH:17]([CH3:19])[CH3:18])[C:8]=2[S:7][C:6]=1[CH2:20]Br)=[O:4].[NH:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)[NH2:23]>C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.[Zn]>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10](=[O:16])[N:9]([CH:17]([CH3:19])[CH3:18])[C:8]=2[S:7][C:6]=1[CH2:20][C:5]1[C:6]([CH3:20])=[N:23][N:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[C:13]=1[CH3:8])=[O:4]
Reactant: COC(=O)c1c(CBr)sc2c1c(=O)n(C)c(=O)n2C(C)C
Reactant: NNc1ccccn1
Agent: CC(=O)/C=C(/C)O
Agent: [Zn]
Product: COC(=O)c1c(Cc2c(C)nn(-c3ccccn3)c2C)sc2c1c(=O)n(C)c(=O)n2C(C)C

Procedure:
Prepared from 6-(bromomethyl)-1,2,3,4-tetrahydro-3-methyl-1-(1-methylethyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic acid methyl ester, zinc acetylacetonate hydrate and 2-hydrazinopyridine by the method of example 1 part e) to give the sub-title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]([NH:38]C(OC(C)(C)C)=O)[CH2:15][C@H:16]([OH:37])[C@@H:17]([NH:25][C:26](=[O:36])[C@H:27]([CH:33]([CH3:35])[CH3:34])[NH:28][C:29]([O:31][CH3:32])=[O:30])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:9][CH:8]=1.CO.[ClH:48]>O1CCOCC1>[ClH:48].[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[CH:9][C:10]([CH2:13][N:14]([NH2:38])[CH2:15][C@H:16]([OH:37])[C@@H:17]([NH:25][C:26](=[O:36])[C@H:27]([CH:33]([CH3:35])[CH3:34])[NH:28][C:29]([O:31][CH3:32])=[O:30])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:11][CH:12]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(-c2cnccn2)cc1)NC(=O)OC(C)(C)C)C(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2cnccn2)cc1)C(C)C

Procedure:
3.4 g (5.5 mmol) of 1-[4-(pyrazin-2-yl)-phenyl]-4(S)-hydroxy-2-(tert-butoxycarbonyl)amino-5(S)-N-(N-methoxycarbonyl-(L)-valyl)amino-6-phenyl-2-azahexane in 100 ml of 4N hydrogen chloride in dioxane. (Aldrich) and 10 ml of methanol are stirred at room temperature for 2 hours. The solvents are removed; dioxane is added twice to the residue and evaporated off. The title compound is obtained in the form of a viscous oil, with the compound crystallising out on trituration with ether. M.p.: 194-198° C. TLC: Rf=0.35 (methylene chloride/methanol 10:1). HPLC20-100: tRet9.77.
Reaction SMILES: Br[C:2]1[C:3]([C:15]([O:17]CC)=[O:16])=[CH:4][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[OH-].[Na+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].C1COCC1.CO>[CH3:14][C:12]1[CH:13]=[C:8]([C:5]2[CH:4]=[C:3]([C:15]([OH:17])=[O:16])[C:2]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:7][N:6]=2)[CH:9]=[N:10][CH:11]=1
Reactant: C1CCNC1
Reactant: CCOC(=O)c1cc(-c2cncc(C)c2)ncc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1cncc(-c2cc(C(=O)O)c(N3CCCC3)cn2)c1
Temperature: 135 °C

Procedure:
To a solution of ethyl 5-bromo-5′-methyl-2,3′-bipyridine-4-carboxylate (2-1, 0.050 g, 0.156 mmol) in toluene (0.31 mL) at 25° C. was added pyrrolidine (0.026 mL, 0.311 mmol), BINAP (0.0096 g, 0.016 mmol) followed by Pd(OAc)2 (0.0035 g, 0.016 mmol) and cesium carbonate (0.076 g, 0.234 mmol) and the system was heated in the microwave reactor at 135° C. for 0.5 h. The system was partitioned between saturated aqueous sodium bicarbonate and EtOAc, washed with brine and dried over magnesium sulfate. Filtration and concentration followed by purification via normal phase chromatography (0→100% EtOAc in Hx) afforded a pale yellow oil. To this pale yellow oil (0.026 g, 0.083 mmol) in 1:1 THF/MeOH (0.40 mL) at 25° C. was added aqueous sodium hydroxide (0.0125 mL, 0.125 mmol, 10M) and the system was heated in the microwave reactor at 135° C. for 10 minutes. The solvents were removed in vacuo to afford the title compound (2-2) as a grey solid. ESI+MS C16H17N3O2: 284.2 found, 284.1 required.
Reaction SMILES: Br[C:2]1[CH:34]=[CH:33][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)([CH3:25])[CH3:24])[C:10]=3[OH:32])[N:8]=[C:4]2[CH:3]=1.[S:35]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C([O-])(=O)C.C([O-])(=O)C.[Pd+2].O.C(O)CC>[S:35]1[CH:39]=[CH:38][C:37]([C:2]2[CH:34]=[CH:33][C:5]3=[N:6][N:7]([C:9]4[CH:14]=[C:13]([C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:23]([C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=5)([CH3:24])[CH3:25])[C:10]=4[OH:32])[N:8]=[C:4]3[CH:3]=2)=[CH:36]1
Reactant: OB(O)c1ccsc1
Reactant: CC(C)(C)CC(C)(C)c1cc(-n2nc3ccc(Br)cc3n2)c(O)c(C(C)(C)c2ccccc2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCCO
Product: CC(C)(C)CC(C)(C)c1cc(-n2nc3ccc(-c4ccsc4)cc3n2)c(O)c(C(C)(C)c2ccccc2)c1
Yield: 78.7 %

Procedure:
The procedure of Example 1 is followed using 5-bromo-2-(2-hydroxy-3-α-cumyl-5-tert-octylphenyl)-2H-benzotriazole (5.21 g, 0.01 mol), thiophene-3-boronic acid (1.34 g, 0.0105 mol), 250 mL of n-propanol, palladium(II) diacetate (0.090 g, 0.0004 mol), triphenylphosphine (0.315 g, 0.0012 mol), 6 mL of 2M sodium carbonate (1.27 g, 0.012 mol) and 5 mL of water. The residue is purified by dry-column flash chromatography (toluene eluent), followed by recrystallization from heptane to give 4.12 g (78.6% yield) of the title compound as a light yellow solid melting at 147-149° C.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10](Cl)(=[O:15])[CH2:11][CH2:12][CH2:13][CH3:14].Cl.Cl.[N:19]1[C:27]2[CH2:26][CH2:25][NH:24][CH2:23][C:22]=2[S:21][C:20]=1[NH:28][C:29]([NH2:31])=[NH:30].[OH-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[C:10]([CH:23]1[C:22]2[S:21][C:20]([NH:28][C:29]([NH2:31])=[NH:30])=[N:19][C:27]=2[CH2:26][CH2:25][NH:24]1)(=[O:15])[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCC(=O)Cl
Reactant: N=C(N)Nc1nc2c(s1)CNCC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCC(=O)C1NCCc2nc(NC(=N)N)sc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Diisopropylethylamine (0.22 mmol) and then pentanoyl chloride (0.11 mmol) are added to a stirred suspension of N-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine-2-yl)-guanidine-dihydrochloride (0.1 mmol) in dimethylformamide (0.7 ml) and the reaction mixture is stirred for another 16 hours at room temperature. After the addition of 2M caustic soda solution (1 ml) extraction is carried out with ethyl acetate. The combined organic phases produce the pure title compound after drying over sodium sulphate and concentrating to dryness.
Reaction SMILES: [CH2:1]1[O:5][C:4]2[CH:6]=[C:7](Br)[C:8]([CH:10]=O)=[CH:9][C:3]=2[O:2]1.[H-].[Na+].[SH:15][CH2:16][C:17]([O:19][CH3:20])=[O:18]>>[O:2]1[C:3]2[CH:9]=[C:8]3[CH:10]=[C:16]([C:17]([O:19][CH3:20])=[O:18])[S:15][C:7]3=[CH:6][C:4]=2[O:5][CH2:1]1
Reactant: COC(=O)CS
Reactant: O=Cc1cc2c(cc1Br)OCO2
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1cc2cc3c(cc2s1)OCO3

Procedure:
Using 3.0 g (13.1 mmol) of 6-bromopiperonal, 0.79 g (19.7 mmol) of sodium hydride (60% pure) and 1.53 g (14.4 mmol) of methyl mercaptoacetate, 732 mg (18.5% of theory) of the title compound are obtained.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][NH:12][C:11]3=[O:15])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.Br[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[Cl:23].N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][N:12]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][C:22]=4[Cl:23])[C:11]3=[O:15])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Clc1ccncc1Br
Reactant: O=C1NCCN1c1ccc2ncsc2c1
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: O=C1N(c2ccc3ncsc3c2)CCN1c1cnccc1Cl
Yield: 37.6 %

Procedure:
Using the same reaction conditions as in Example 14, 1-benzothiazol-6-yl-imidazolidin-2-one (I-84b: 0.150 g, 0.684 mmol) was reacted with 3-bromo-4-chloro-pyridine (0.157 g, 0.820 mmol), 1,4-dioxane (20 mL), copper iodide (0.012 g, 0.0684 mmol), trans-1,2-diamino cyclohexane (0.022 g, 0.20 mmol) and potassium phosphate (0.362 g, 1.71 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in CHCl3) afforded 85 mg of the product (37.7% yield).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[NH:8][C:7]=12.[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17]Cl>>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:17][C:16]3[CH:19]=[CH:20][CH:21]=[C:14]([F:13])[CH:15]=3)[C:7]=12
Reactant: Cc1[nH]c2c(Cl)nccc2c1C
Reactant: Fc1cccc(CCl)c1
Product: Cc1c(C)n(Cc2cccc(F)c2)c2c(Cl)nccc12
Yield: 72 %

Procedure:
In accordance with the same procedures as in Step 2 of Example 198, except for using 7-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine prepared in Step 1 of Example 198 and 3-fluorobenzyl chloride, the titled compound was obtained as a white solid. (Yield: 72%)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]#[N:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:12]1([C:18]2[S:19][CH2:20][CH:21]([C:23]([OH:25])=[O:24])[N:22]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(#N)C1C=CC=CC=1.N[C@H](C(O)=O)CS.P([O-])([O-])([O-])=O>CO>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[S:19][CH2:20][C@@H:21]([C:23]([OH:25])=[O:24])[N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:12]1([C:18]2[S:19][CH2:20][CH:21]([C:23]([OH:25])=[O:24])[N:22]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: N#Cc1ccc2[nH]ccc2c1
Agent: N[C@@H](CS)C(=O)O
Agent: O=C(O)C1CSC(c2ccccc2)=N1
Agent: O=P([O-])([O-])[O-]
Solvent: N#Cc1ccccc1
Solvent: CO
Product: O=C(O)[C@@H]1CSC(c2ccc3[nH]ccc3c2)=N1
Temperature: 40 °C
Reaction time: 72 h

Procedure:
(R)-2-(1H-Indol-5-yl)-4,5-dihydrothiazole-4-carboxylic acid 63a was synthesized from 1H-indole-5-carbonitrile using the same method as used for 42a of U.S. application Ser. No. 12/981,233 (now US2011/0257196) and U.S. application Ser. No. 1/216,927 (now US2012/0071524), incorporated herein by reference in their entirety. Briefly, benzonitrile (40 mmol) was combined with L-cysteine (45 mmol) in 100 mL of 1:1 MeOH/pH 6.4 phosphate buffer solution. The reaction was stirred at 40° C. for 3 days. The precipitate was removed by filtration, and MeOH was removed using rotary evaporation. To the remaining solution was added 1 M HCl to adjust to pH=2 under 0° C. The resulting precipitate was filtered to yield a white solid 2-phenyl-4,5-dihydrothiazole-4-carboxylic acid 42a, which was used directly to next step without purification. To a vigorously stirring solution of 63a (1 mmol) and tetrabutylammonium hydrogen sulfate (0.15 mmol) in toluene (10 mL) at 0° C. was added 50% aqueous sodium hydroxide (10 mL) and sulfonyl chloride (2 mmol). The resultant solution was stirred at RT for 6 h. Then 1 N HCl was added to acidify the mixture to pH=2 and extracted with CH2Cl2, the organic layer was separated and dried (MgSO4); then evaporated to dryness to yield 64a, which were used in subsequent steps without further purification.