Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]Br>>[CH2:1]([O:8][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][Br:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: BrCCCCCCBr
Product: BrCCCCCCOCc1ccccc1
Yield: 36 %

Procedure:
6-Benzyloxyhexyl bromide was prepared from benzyl alcohol (4.75 g, 44 mmol) and 1,6-dibromohexane (9.76 g, 40 mmol) using the general procedure given above. Yield: 36%, bp 100-105° C./torr: 1H-NMR: 1.2-1.9 (m, 8H), 3.37 (t, 4H), 4.46 (s, 2H), 7.28 (m, 5H).
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].Br[C:7]1[N:11]([C@H:12]2[O:24][C@@H:23]([CH2:25][O:26]C(=O)C)[C@H:18]([O:19]C(=O)C)[C@@H:13]2[O:14]C(=O)C)[C:10]2[CH:30]=[C:31]([Cl:35])[C:32]([Cl:34])=[CH:33][C:9]=2[N:8]=1.C(O)C>CN(C=O)C>[Cl:34][C:32]1[C:31]([Cl:35])=[CH:30][C:10]2[N:11]([C@H:12]3[O:24][C@@H:23]([CH2:25][OH:26])[C@H:18]([OH:19])[C@@H:13]3[OH:14])[C:7]([NH:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[N:8][C:9]=2[CH:33]=1
Reactant: CC(C)CN
Reactant: CC(=O)OC[C@@H]1O[C@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(C)CNc1nc2cc(Cl)c(Cl)cc2n1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O
Temperature: 75 °C
Reaction time: 24 h

Procedure:
Isobutylamine (10 ml ) and 2-bromo-5,6-dichloro-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole (0.6 g, 1.1 mmol) were combined with absolute ethanol (50 mL) and stirred at 75° C. for 24 h. The reaction mixture was concentrated and purified on a silica gel column (2.5 cm×16 cm, 230-400 mesh) with 1:20 methanol:dichloromethane (500 mL), then 1:9 methanol:dichloromethane to give a tan solid (0.39 g, 1.0 mmol. 90%); m.p. 136° C.; [a]20D =(-) 28.4 (c=0.5 DMF).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([O:17]C)=[O:16])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+].Cl>O.C1COCC1.CO>[F:19][C:2]([F:1])([F:20])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=[O:16])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)C1CCN(c2cccc(C(F)(F)F)c2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1CCN(c2cccc(C(F)(F)F)c2)CC1

Procedure:
Methyl 1-[3-(trifluoromethyl)phenyl]piperidine-4-carboxylate (0.9 g, 3 mmol) was treated with the mixture of 2 M of sodium hydroxide in water (10 mL), THF (10 mL) and methanol (10 mL) at 50° C. for 1 h. After being neutralized with concentrated HCl (pH=3), the solution was concentrated. The resulting residue was azeotropically treated with benzene for 3 times to give the title compound which was used for the next reaction without purification. MS (M+H) 274.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.C(N(CC)CC)C.Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26]>>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:4]2[C:5]3[O:9][CH2:8][CH2:7][C:6]=3[CH:10]=[C:2]([NH:1][C:25](=[O:26])[O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:3]=2)[CH:12]=1
Reactant: Nc1cc2c(c(-c3cccnc3)c1)OCC2
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(Nc1cc2c(c(-c3cccnc3)c1)OCC2)Oc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
5-Amino-2,3-dihydro-7-(pyrid-3-yl)benzofuran (64) (0.13 g, 0.00062 mole) was dissolved in dichlomethane (10 ml) and cooled to 0° C. under argon. Triethylamine (0.09 ml, 0.00068 mole) was added, followed dropwise by phenyl chloroformate (0.08 ml, 0.00065 mole) and the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was washed with deionised water, dried (Na2SO4) and evaporated in vacuo to afford the title compound (0.20 g, 97%) as a cream solid.
Reaction SMILES: CC(C1C=[C:6]([O:10]C2N=CC(NC(=O)[C@@H](C)N)=CC=2)C=CC=1)C.[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=1[O:31][C:32]1[N:37]=[CH:36][C:35]([NH:38][C:39](=[O:43])[C@@H:40]([CH3:42])[NH2:41])=[CH:34][CH:33]=1>>[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=1[O:31][C:32]1[N:37]=[CH:36][C:35]([N:38]2[C:39](=[O:43])[C@@H:40]([CH3:42])[NH:41][C:6]2=[O:10])=[CH:34][CH:33]=1
Reactant: Cc1ccc(C)c(Oc2ccc(NC(=O)[C@@H](C)N)cn2)c1
Reactant: CC(C)c1cccc(Oc2ccc(NC(=O)[C@@H](C)N)cn2)c1
Product: Cc1ccc(C)c(Oc2ccc(N3C(=O)N[C@H](C)C3=O)cn2)c1

Procedure:
The title compound was made in a similar fashion to the preparation of Example 9 replacing N1-(6-{[3-(1-methylethyl)phenyl]oxy}-3-pyridinyl)-D-alaninamide with N1-{6-[(2,5-dimethylphenyl)oxy]-3-pyridinyl}-D-alaninamide (Intermediate 36, 48 mg) to afford the title compound as a yellow powder (31 mg).
Reaction SMILES: [NH:1]([C:3]1[N:4]=[N:5][C:6]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:7]=2[N:8]=1)[NH2:2].[CH2:15](OC(OCC)(OCC)C)[CH3:16]>C(O)C>[CH3:14][O:13][C:11]1[CH:10]=[CH:9][C:7]2[N:8]3[C:15]([CH3:16])=[N:2][N:1]=[C:3]3[N:4]=[N:5][C:6]=2[CH:12]=1
Reactant: COc1ccc2nc(NN)nnc2c1
Reactant: CCOC(C)(OCC)OCC
Solvent: CCO
Product: COc1ccc2c(c1)nnc1nnc(C)n12
Temperature: 145 °C
Yield: 88.7 %

Procedure:
A mixture of 3-hydrazino-7-methoxy-1,2,4-benzotriazine (0.5 g, 2.62 mmol) and 1,1,1-triethoxyethane (4.24 g, 26.15 mmol) was heated at 145° C. for 3 h, and the ethanol formed during the reaction was distilled off continuously. After cooling in a refrigerator for 12 h, the solid filtered off and washed with ether to give 7-methoxy-1-methyl[1,2,4]triazolo[3,4-c][1,2,4]benzotriazine (Compound Number 1, 0.5 g, 88% yield), 1H-NMR (300 MHz; CDCl3): 8.14 ppm (d, 1H, H-9); 8.14 ppm (d, 1H, H-9); 7.62 ppm (dd, 1H, H-8); 4.05 ppm (s, 3H, OMe); 3.19 ppm (s, 1H, CH3) (Compound no. 1 in table 1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[C:15]([C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)#[CH:16].C(N(CC)CC)C>CN(C)C=O.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:16]#[C:15][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[C:3]([C:11]([F:14])([F:13])[F:12])[CH:4]=1)([O-:10])=[O:9]
Reactant: C#Cc1ccncc1
Reactant: O=[N+]([O-])c1ccc(Br)c(C(F)(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(C#Cc2ccncc2)c(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
In 20 mL of dimethylformamide, 1.0 g (3.7 mmol) of 4-bromo-3-(trifluoromethyl)nitrobenzene was dissolved, and 0.502 g (3.7 mmol) of 4-ethynylpyridine, 43 mg (3 mol %) of copper iodide, 78 mg (3 mol %) of dichlorobis(triphenylphosphine)palladium and 2.06 mL (0.56 mmol) of triethylamine were added thereto and the mixture solution was stirred overnight at 50° C. in an argon atmosphere. The reaction solution was partitioned between water and ethyl acetate and the organic layer was washed with a saturated sodium chloride solution and concentrated under reduced pressure. The residue was purified by a silica gel column (n-hexane:ethyl acetate=3:1) to obtain 1.3 g (quantitative) of a target product as an pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])[CH2:25][CH2:24]2)=[CH:4][C:5]([O:20][CH2:21][CH3:22])=[C:6]([CH:19]=1)[C:7]([NH:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18])=[O:8].C(N(CC)C(C)C)(C)C.[O:45]1[CH:49]=[CH:48][CH:47]=[C:46]1[C:50](Cl)=[O:51]>ClCCl.O>[CH2:21]([O:20][C:5]1[C:6]([C:7](=[O:8])[NH:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])=[CH:19][C:2]([NH:1][C:50]([C:46]2[O:45][CH:49]=[CH:48][CH:47]=2)=[O:51])=[C:3]([N:23]2[CH2:24][CH2:25][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])[CH2:27][CH2:28]2)[CH:4]=1)[CH3:22]
Reactant: O=C(Cl)c1ccco1
Reactant: CCOc1cc(N2CCN(c3ccccc3C)CC2)c(N)cc1C(=O)NCCCN1CCCC1=O
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(N2CCN(c3ccccc3C)CC2)c(NC(=O)c2ccco2)cc1C(=O)NCCCN1CCCC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.6 %

Procedure:
To a solution of 5-amino-2-ethoxy-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide 8c (44.8 mg, 0.09 mmol, 100 mol %) and N,N-diisopropylethylamine (0.05 ml, 0.28 mmol, 300 mol %) in dichloromethane (2.0 ml) was added furan-2-carbonyl chloride (0.01 ml, 0.11 mmol, 120 mol %) and a catalytic amount of N,N-dimethylaminopyridine. The reaction was stirred for 16 h at room temperature and then diluted with water and extracted three times with dichloromethane. The combined organics were dried over sodium sulfate and concentrated and the residue was purified by column chromatography (dichloromethane to 10% methanol/dichloromethane) to afford furan-2-carboxylic acid [4-ethoxy-5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide 8g (30.7 mg, 0.05 mmol, 53.6%) as an off-white solid.
Reaction SMILES: O[C:2]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[OH:13])=O.C([O-])(=O)C.[Na+].Cl.[F:25][C:26]([F:37])([F:36])[O:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][NH2:35])=[CH:30][CH:29]=1>>[OH:18][C:16]1[CH:17]=[C:2]2[C:3]([C:4]([C:6]3[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=3[OH:13])=[N:35][N:34]2[C:31]2[CH:32]=[CH:33][C:28]([O:27][C:26]([F:25])([F:37])[F:36])=[CH:29][CH:30]=2)=[CH:14][CH:15]=1
Reactant: NNc1ccc(OC(F)(F)F)cc1
Reactant: O=C(c1ccc(O)cc1O)c1ccc(O)cc1O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: Oc1ccc(-c2nn(-c3ccc(OC(F)(F)F)cc3)c3cc(O)ccc23)c(O)c1
Yield: 22.4 %

Procedure:
Prepared according to Method B from 2,2′,4,4′-tetrahydroxybenzophenone (0.123 g, 0.5 mmol), sodium acetate (0.041 g, 0.5 mmol) and 4-trifluoromethoxyphenylhydrazine hydrochloride (0.114 g, 0.5 mmol) to give 0.045 g of product as a tan solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH2:6][N:7]([CH2:11][CH2:12][O:13]/[CH:14]=[C:15](/[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)\[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:8][CH2:9][CH:10]=1)=[O:4].[OH-].[Na+].Cl.ClCCl>C(O)C>[ClH:29].[Cl:29][C:25]1[CH:24]=[C:23]([C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])=[CH:14][O:13][CH2:12][CH2:11][N:7]2[CH2:8][CH2:9][CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH2:6]2)[CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)C1=CCCN(CCO/C=C(/c2cccc(Cl)c2)c2ccccc2C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: Cc1ccccc1C(=COCCN1CCC=C(C(=O)O)C1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 30 %

Procedure:
E or Z-1-(2-((2-(3-Chlorophenyl)-2-(2-methylphenyl)ethenyl)oxy)ethyl)-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid methyl ester (0.55 g, 0.0013 mol, prepared similarly to the method described in Example 70) was dissolved in ethanol (5 ml) and 12 N sodium hydroxide solution (0.33 ml) was introduced. After stirring the solution at room temperature for 3 h, 37% hydrochloric acid solution was added until pH 1. Dichloromethane (200 ml) was introduced, and the mixture was dried (Na2SO4), filtered and evaporated to a residue, which was co-evaporated twice with acetone. Recrystallization from acetone/ethyl acetate provided the title compound (0.17 g, 30%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.[OH-].[K+].Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)=[O:15]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9][CH2:13][C:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[O:15])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(S)c1
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C(=O)CSc2cccc(OC)c2)cc1
Reaction time: 3 h
Yield: 76.5 %

Procedure:
3-Methoxythiophenol (50.0 g, 0.356 mol) was dissolved in 700 mL of ethanol. To this mixture was added (20 g, 0.36 mol) of potassium hydroxide pellets. A total of (82.5 g, 0.36 mol) of 2-bromo-4′-methoxyacetophenone was added in small portions to keep the temperature of the reaction at approximately 25° C. The reaction was allowed to proceed at ambient temperature for three hours. The reaction was terminated by evaporation of the alcohol, which resulted in obtaining a brown oil. The oil was partitioned between 2 L of water and 1.5 L of diethylether. The ether layer was separated and washed with water, dried with anhydrous magnesium sulfate, and evaporated to a solid. The solid was crystallized from a mixture of diethylether-petroleum ether (3:1) to yield 78.5 g of the title compound as a pink crystalline solid. mp 53° C.-54° C. EA calculated for C16H16O3S: C, 66.64; H, 5.59; O, 16.64; S, 11.12. Found: C, 66.55; H, 5.87; O, 16.82; S, 10.86.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]2.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[N+](C1C=CC=C2C=1C=[N+](C)C=C2)([O-])=O.C(=O)(O)[O-].[K+].[CH3:43][O:44][C:45]1[CH:46]=[C:47]([CH:51]=[C:52]([O:56][CH3:57])[C:53]=1[O:54][CH3:55])[C:48](Cl)=[O:49].C1C2C(=CC=CC=2)CCN1>C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:57][O:56][C:52]1[CH:51]=[C:47]([CH:46]=[C:45]([O:44][CH3:43])[C:53]=1[O:54][CH3:55])[C:48]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]2)=[O:49]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: CN1CCc2cccc(N)c2C1
Agent: C[n+]1ccc2cccc([N+](=O)[O-])c2c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Solvent: c1ccccc1
Product: COc1cc(C(=O)Nc2cccc3c2CN(C)CC3)cc(OC)c1OC

Procedure:
8-Amino-2-methyl-1,2,3,4-tetrahydroisoquinoline (2 g) prepared from 8-nitro-2-methyl-isoquinolinium p-toluenesulfonate as described for the 5-nitro isomer in Example 4 was dissolved in dry benzene (100 ml) and 0.5 g of dry potassium bicarbonate was added. A 0.1 mole excess of 3,4,5-trimethoxybenzoyl chloride was dissolved in dry benzene (50 ml) and this solution was added to the solution of the tetrahydroisoquinoline. The solutions clouded on mixing and were then refluxed for 12 hours. After refluxing, the benzene was removed in vacuo leaving a viscous, yellow oil. This was suspended in 10% sodium carbonate solution to remove excess acid chloride. The insoluble oil was extracted from the aqueous sodium carbonate with chloroform which was dried over anhydrous magnesium sulfate. The chloroform was distilled off to leave a viscous, yellow oil. This was washed with ether and a white solid (3 g) formed. This was recrystallized from ethanol-water to yield the desired product as white felted needles, m.p. 177°-178.3° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[B]1OC2C(=CC=CC=2)O1>CO>[C:4]1([C@H:1]([OH:3])[CH3:2])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Agent: [B]1Oc2ccccc2O1
Solvent: CO
Product: C[C@@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80.2 %

Procedure:
The polymer of Example 1 (32 mg, 0.055 mmol based on the biphenyl subunit) and diethylzinc (0.01 mL, 0.1 mmol) were added to a Schlenk flask containing 10 mL of toluene (dried with Na and degassed with N2), under N2 and at room temperature, to form the organozinc species. The resulting mixture was stirred at r.t. for 20 minutes. Acetophenone (0.12 mL, 1 mmol) was then added. The resulting mixture was cooled to -30° C. and 1.5 mL of catecholborane (1.5 mmol, 1M in THF) was added. Stirring was continued at this temperature for 38 h. The reaction was then quenched with 1N HCl and the aqueous layer was extracted with ether. The combined organic extracts were washed with brine until pH=7 and then dried over anhydrous Na2SO4. Concentration of the organic layer with a rotary evaporator gave a yellow oil, which upon addition of methanol, precipitated the polymer. The filtrate was concentrated and purified by column chromatography on silica gel with EtOAc/hexanes (1:5) to give (R)-1-phenylethanol as a colorless liquid (98 mg, 81%). GC analysis on a β-Dex capillary column (Supelco Company), with helium as the carrier gas, a flow rate of 1 mL/min, and an increase in oven temperature from 100° C. at a rate of 1° C./min, showed an ee of 67.0%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11](=[O:18])[NH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[N:25]1[CH:30]=[CH:29][C:28]([CH2:31]Cl)=[CH:27][CH:26]=1.Cl>CN(C=O)C.O>[N:25]1[CH:30]=[CH:29][C:28]([CH2:31][N:10]2[CH:9]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:17]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11]2=[O:18])=[CH:27][CH:26]=1
Reactant: ClCc1ccncc1
Reactant: O=c1[nH]cc(-c2cccc(Cl)c2)c2ncccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2cccnc2c(-c2cccc(Cl)c2)cn1Cc1ccncc1
Reaction time: 1 h
Yield: 48 %

Procedure:
To a suspension of 8-(3-chlorophenyl)-1,6-naphthyridin-5-one (128 mg, 0.5 mmoles) and potassium carbonate (346 mg, 2.5 mmoles) in 20 ml DMF was added solid 4-picolyl chloride.HCl (164 mg, 1.0 mmole) under an atmosphere of nitrogen and stirred overnight at 21° C. The reaction mixture was poured into 100 ml water and after stirring for one hour the white precipitate was collected and dried. Crystallization from methanol gave 84 mg (48% yield) of the desired 6-(4-pyridylmethyl)-8-(3-chlorophenyl)-1,6-naphthyridin-5-one as a white solid. Characteristic analytical data are as follows: mp 170.5°-172.5° C.; TLC in 1:1 EtOAc/Hex; 1H NMR (CDCl3, 300 MHz) δ5.20 (s, 2H), 7.15 (dd, 2H, J=4.7, 1.5), 7.28-7.50 (m, 6H), 8.52 (dd, 2H, J=4.4, 1.5), 8.69 (dd, 1H, J=8.1, 2.1), 8.90 (dd, 1H, J=4.7, 1.8); 13C NMR (75 MHz, CDCl3) δ161.86, 154.58, 151.75, 150.46, 144.94, 136.83, 136.59, 134.20, 134.01, 130.01, 129.58, 128.23, 127.98, 122.37, 122.32, 121.93, 120.47, 51.25; IR (KBr) vmax 3435, 3051, 1668, 1630, 1591,1552, 1483, 1415, 1367, 1358, 1342, 1292, 1097, 997, 827, 794, 729, 702, 601, 472 cm-1 ; mass spectrum (EI), m/e 347. Anal. (C 20 H14ClN3O.3/8) Calcd.: C, 67.75; H, 4.19; N, 11.85; Cl, 9.99. Found: C, 67.95; H, 4.09; N, 11.84; Cl, 9.99.
Reaction SMILES: [CH3:1][C:2]([N:5]1[C:9]2[N:10]=[C:11]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH:12]=[C:13]([C:14]([O:16]CC)=[O:15])[C:8]=2[C:7]([CH3:25])=[N:6]1)([CH3:4])[CH3:3].[OH-].[Na+]>C(O)C>[CH3:4][C:2]([N:5]1[C:9]2[N:10]=[C:11]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH:12]=[C:13]([C:14]([OH:16])=[O:15])[C:8]=2[C:7]([CH3:25])=[N:6]1)([CH3:1])[CH3:3]
Reactant: CCOC(=O)c1cc(-c2cccnc2)nc2c1c(C)nn2C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nn(C(C)(C)C)c2nc(-c3cccnc3)cc(C(=O)O)c12
Temperature: 25 °C

Procedure:
Ethyl 1-(1,1-dimethylethyl)-3-methyl-6-(3-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (68 mg, 0.201 mmol) was suspended in ethanol (2 mL) followed by addition of sodium hydroxide (0.335 mL, 1.005 mmol). The mixture was stirred at room temperature for 2. 5 h. The mixture was concentrated and the residue was diluted with water (1 mL) and acidified to pH 3 using 1N HCl. The precipitate was collected by filtration and further dried under high vacuum to give the product as an HCl salt, 60 mg (86%). LCMS E-S (M+H)=311.5. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.82 (s, 9 H), 2.60 (s, 3 H), 7.60 (dd, J=7.96, 4.67 Hz, 1 H), 8.08 (s, 1 H), 8.57 (dt, J=8.34, 1.89 Hz, 1 H), 8.70 (dd, J=4.80, 1.52 Hz, 1 H), 9.39 (d, J=1.52 Hz, 1 H), 14.03 (br. s., 1 H).
Reaction SMILES: [CH3:1][S:2]([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[OH:19])[N:6]2[N:5]=1)=[O:3].Br[CH2:21][C:22]([NH2:24])=[O:23].C(=O)([O-])[O-].[K+].[K+].C(#N)C>>[CH3:1][S:2]([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH2:21][C:22]([NH2:24])=[O:23])[N:6]2[N:5]=1)=[O:3]
Reactant: NC(=O)CBr
Reactant: CS(=O)c1ncc2ccc(-c3ccccc3O)n2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CS(=O)c1ncc2ccc(-c3ccccc3OCC(N)=O)n2n1
Temperature: 60 °C
Yield: 87.1 %

Procedure:
2-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenol (0.68 g, 2.5 mmol), 2-Bromoacetamide (0.414 g, 3.00 mmol), Potassium carbonate (0.7049 g, 5.100 mmol), and Acetonitrile (20 mL, 500 mmol) were combined in a round bottom flask and heated at 60° C. for 19 hours. The solid was filtered through Celite and washed with DCM. The filtrate was concentrated and purified via normal phase silica gel chromatography eluting with dichloromethane /methanol to yield a yellow solid, 2-[2-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenoxy]-acetamide (719 mg, 87%). LCMS: m/z=331.16 (M+H+); 1H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1H), 7.75 (m, 1H), 7.50 (m, 2H), 7.36 (br s, 1H), 7.32 (d, 1H, J=4.7 Hz), 7.16 (m, 2H), 7.09 (d, 1H, J=8.4 Hz), 4.52 (s, 2H), 2.92 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[CH:11]=[N:12][CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=3)[N:7]([CH:20]3[CH2:22][CH2:21]3)[C:6]=2[CH:23]=1.CC1(C)C(C)(C)OB([C:32]2[CH:36]=[CH:35][NH:34][N:33]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O.C1(C)C=CC=CC=1.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>[CH:20]1([N:7]2[C:6]3[CH:23]=[C:2]([C:32]4[CH:36]=[CH:35][NH:34][N:33]=4)[CH:3]=[CH:4][C:5]=3[N:9]=[C:8]2[C:10]2[CH:11]=[N:12][CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=2)[CH2:22][CH2:21]1
Reactant: CC1(C)OB(c2cc[nH]n2)OC1(C)C
Reactant: FC(F)(F)c1cncc(-c2nc3ccc(Br)cc3n2C2CC2)c1
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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: FC(F)(F)c1cncc(-c2nc3ccc(-c4cc[nH]n4)cc3n2C2CC2)c1
Temperature: 80 °C

Procedure:
To a solution of 6-bromo-1-cyclopropyl-2-(5-trifluoromethyl-pyridin-3-yl)-1H-benzoimidazole (0.15 g, 0.00026 mol) in ethanol toluene water (6 ml 3 ml 1.5 ml respectively) mixture in a sealed tube was added 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.1 g, 0.00052 mol) and Na2CO3 (0.082 g, 0.000785 mol) and argon was purged for 15 min. Then Pd (PPh3)4 (0.015 g, 0.000013 mol) was added and heated at 80° C. for 5 h. The solvent was evaporated and the resulting residue was added water. The aqueous layer was extracted with ethyl acetate (3×20 ml). The combined organic layers were washed with brine dried over Na2SO4 and concentrated under vacuum to afford the crude compound which was purified by column chromatography to obtain title compound 1-cyclopropyl-6-(1H-pyrazol-3-yl)-2-[5-(trifluoromethyl)pyridin-3-yl]-1H-benzimidazole (321) as an off white solid. NMR (400 MHz, DMSO-d6), δ: 12.85 (s, 1H), 9.49 (s, 1H), 9.12 (s, 1H), 8.75 (s, 1H), 8.09 (s, 1H), 7.79-7.67 (m, 3H), 7.54-7.52 (m, 1H), 6.79 (s, 1H), 3.96 (bs, 1H), 1.15 (d, J=5.6 Hz, 2H), 0.73 (bs, 2H). MS (M+1): 370.6, Purity 99.94%.