Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(Br)=NC=1.BrN1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C.[Br:29][C:30]1[CH:35]=[CH:34][C:33]([CH:36](Br)[Br:37])=[CH:32][N:31]=1>C(Cl)(Cl)(Cl)Cl>[Br:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][Br:37])=[CH:32][N:31]=1
Reactant: Brc1ccc(C(Br)Br)cn1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: Cc1ccc(Br)nc1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 43 %

Procedure:
To a stirred slurry of 10.320 g (60.0 mmol) of 5-methyl-2-bromopyridine and 5.339 g (30.0 mmol, 0.5 eq) of recrystallized N-bromosuccinimide in 150 mL of carbon tetrachloride was added 200 mg of AIBN. The reaction mixture was purged twice with argon and evacuated and set to reflux under argon. After 90 min, the reaction mixture was cooled to room temperature, filtered and the filtrate concentrated to give a yellow oil. Proton NMR indicated that the mixture contains 53% (mol) unreacted 5-methyl-2-bromopyridine, 43% of the title product and 4% of 2-bromo-5-(dibromomethyl)pyridine. The mixture was used immediately without further purification for the following procedure.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11](OCC)=[O:12])[C:4]=2[N:3]=1.O1CCCC1.[AlH4-].[Li+].C(OCC)(=O)C>O>[CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][OH:12])[C:4]=2[N:3]=1
Reactant: CCOC(=O)c1cccc2[nH]c(C)nc12
Agent: [AlH4-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nc2c(CO)cccc2[nH]1
Yield: 79.4 %

Procedure:
(a-2) A cooled (0° C.) solution of 10 parts of ethyl 2-methyl-1H-benzimidazole-4-carboxylate in 45 parts of tetrahydrofuran was added dropwise to a suspension of 4 parts of lithium tetrahydroaluminate in 45 parts of tetrahydrofuran. Upon complete addition, the temperature was allowed to reach room temperature. After the addition of ethyl acetate and water, the reaction mixture was filtered over diatomaceous earth. The filtrate was evaporated, yielding 6.3 parts (79.4%) of 2-methyl-1H-benzimidazole-4-methanol as a residue (int. 66).
Reaction SMILES: [Cl:1][C:2]1[CH:44]=[CH:43][C:5]([CH2:6][C:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH2:19][O:20]C4CCCCO4)[C:12](=[O:27])[N:11](COCC[Si](C)(C)C)[C:10]=3[O:9][C:8]=2[C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)=[CH:4][CH:3]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH2:19][OH:20])[C:12](=[O:27])[NH:11][C:10]=3[O:9][C:8]=2[C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)=[CH:43][CH:44]=1
Reactant: C[Si](C)(C)CCOCn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(Cc3ccc(Cl)cc3)c(-c3cccc(Cl)c3)oc21
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]c2oc(-c3cccc(Cl)c3)c(Cc3ccc(Cl)cc3)c2c(=O)n1CCCO
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.5 %

Procedure:
To a solution of 5-(4-chlorobenzyl)-6-(3-chlorophenyl)-3-(3-(tetrahydro-2H-pyran-2-yloxy) propyl)-1-((2-(trimethylsilyl)ethoxy)methyl)furo[2,3-d]pyrimidine-2,4(1H,3H)-dione (20 mg, 0.03 mmol) in DCM (0.8 mL) was added in TFA (0.8 mL). The reaction was stirred at RT for 2 h then diluted with DCM (5 mL) and water (2 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 5-(4-chlorobenzyl)-6-(3-chlorophenyl)-3-(3-hydroxypropyl)furo[2,3-d]pyrimidine-2,4(1H,3H)-dione (3 mg, 23% yield) as an oil. 1H NMR (DMSO-d6) δ: 7.43 (d, J=3.4 Hz, 3H), 7.34 (d, J=8.4 Hz, 3H), 7.26 (d, J=8.4 Hz, 2H), 4.53 (s, 1H), 4.28 (s, 2H), 3.85 (t, J=7.1 Hz, 2H), 3.40 (s, 2H), 1.71-1.58 (m, 2H). LCMS: MH+ 445 and TR=2.803 min.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([C:7]#[N:8])=[CH:3][CH:2]=1.C(Cl)(Cl)[Cl:11].C[OH:15]>>[ClH:11].[CH3:9][C:1]1[CH:6]=[CH:5][C:4]([C:7](=[NH:8])[OH:15])=[CH:3][CH:2]=1
Reactant: CO
Reactant: ClC(Cl)Cl
Reactant: Cc1ccc(C#N)cc1
Product: Cc1ccc(C(=N)O)cc1
Product: Cl
Temperature: 10 °C
Reaction time: 43 h
Yield: 99 %

Procedure:
To a solution of p-tolunitrile (10.1 g, 86.21 mmol) in 100 ml CHCl3:MeOH (1:1) cooled to 5° C. in an ice-water bath is bubbled HCl for 1 hour to reach saturation. The solution is stirred at 10° C. for 43 hours, then concentrated under reduced pressure to yield p-methylbenzimidate hydrochloride as pale yellow crystals (15.98 g, 99%). 1H NMR (CDCl3): δ 2.44 (s, 3H), 4.52 (s, 3H), 7.36 (d, 2H), 8.29 (d, 2H).
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][OH:11])[CH:7]=[CH:6][C:5]=1[C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=1[F:20].Cl[C:24]1[N:29]=[C:28]([CH3:30])[N:27]=[C:26]([CH:31]=[CH:32][C:33]([O:35]C)=[O:34])[CH:25]=1.[H-].[Na+].Cl>C1COCC1>[CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][C:24]2[N:29]=[C:28]([CH3:30])[N:27]=[C:26]([CH:31]=[CH:32][C:33]([OH:35])=[O:34])[CH:25]=2)[CH:7]=[CH:6][C:5]=1[C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=1[F:20]
Reactant: COc1ccc(F)c(-c2ccc(CO)nc2CC(C)(C)C)c1
Reactant: COC(=O)C=Cc1cc(Cl)nc(C)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(COc3cc(C=CC(=O)O)nc(C)n3)nc2CC(C)(C)C)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 48.5 %

Procedure:
To a solution of (6-(2,2-dimethylpropyl)-5-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)methanol (606 mg) and methyl 3-(6-chloro-2-methylpyrimidin-4-yl)acrylate (424 mg) in THF (10 mL) was added 60% sodium hydride (120 mg) at 0° C., and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (450 mg) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:16])([F:15])[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])=[CH:4][CH:3]=1.Br[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=1.C[Sn](C)C.C[Sn](C)C>O1CCOCC1.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[F:15][C:8]([F:16])([C:5]1[CH:6]=[CH:7][C:2]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=2)=[CH:3][CH:4]=1)[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10]
Reactant: Fc1ccc(Br)nc1
Reactant: CON(C)C(=O)C(F)(F)c1ccc(Br)cc1
Agent: [Pd]
Agent: C[Sn](C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Product: CON(C)C(=O)C(F)(F)c1ccc(-c2ccc(F)cn2)cc1

Procedure:
Palladium tetrakis(triphenylphosphine) (236 mg, 0.20 mmol) was added to a degassed, ambient temperature solution of 2-(4-bromophenyl)-2,2-difluoro-N-methoxy-N-methylacetamide (600 mg, 2.05 mmol), 2-bromo-5-fluoropyridine (360 mg, 2.05 mmol) and hexamethylditin (670 mg, 2.05 mmol) in 1,4-dioxane (20 mL). After stirring at reflux overnight, the reaction mixture was diluted with water and extracted with methylene chloride and ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-60% ethyl acetate/hexane afforded 2,2-difluoro-2-[4-(5-fluoropyridin-2-yl)phenyl]-N-methoxy-N-methylacetamide.
Reaction SMILES: Br[CH:2]1[C:20](=[O:21])[C:6]2=[CH:7][CH:8]=[C:9]3[C:14]([O:13][CH2:12][C:11]4[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:10]3=4)=[C:5]2[CH2:4][CH2:3]1.[N:22]1([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24]([OH:26])=[O:25].C(N(C(C)C)CC)(C)C>C(#N)C.C(OCC)(=O)C>[N:22]1([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:29][CH2:28][CH2:27][CH:23]1[C:24]([O:26][C@@H:2]1[C:20](=[O:21])[C:6]2=[CH:7][CH:8]=[C:9]3[C:14]([O:13][CH2:12][C:11]4[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:10]3=4)=[C:5]2[CH2:4][CH2:3]1)=[O:25]
Reactant: O=C1c2ccc3c(c2CCC1Br)OCc1cc(Cl)ccc1-3
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)O[C@H]1CCc2c(ccc3c2OCc2cc(Cl)ccc2-3)C1=O
Temperature: 50 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
To a solution of 2-bromo-8-chloro-2,3,4,6-tetrahydro-1H-dibenzo[c,h]chromen-1-one (1.05 g, 2.9 mmol) and Boc-Pro-OH (1.75 g, 8.1 mmol) in acetonitrile (9.0 mL) was added diisopropylethylamine (1.5 mL, 8.7 mmol). The solution was stirred under argon at 50° C. for two hours. Extra Boc-Pro-OH (620 mg, 2.9 mmol) and diisopropylethylamine (0.5 mL, 2.9 mmol) were added and the reaction was stirred at 50° C. for 16 hours. The reaction was cooled to room temperature and diluted with ethyl acetate. The organics were washed with water and brine, dried with magnesium sulfate and concentrated. The crude material was purified by flash column chromatography and the product (2S)-1-tert-butyl 2-(8-chloro-1-oxo-2,3,4,6-tetrahydro-1H-dibenzo[c,h]chromen-2-yl) pyrrolidine-1,2-dicarboxylate was isolated as a mixture of diastereomers (0.99 g, 69% yield).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl[CH2:11][CH2:12][NH:13][CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:20]=1.OCCN.ClCC1C=NC=C(C2C=CC=CC=2)C=1.P(Cl)(Cl)Cl>C(#N)C>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[O:1][CH2:11][CH2:12][NH:13][CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:20]=1)#[N:5]
Reactant: N#Cc1ccccc1O
Reactant: ClCCNCc1cncc(-c2ccccc2)c1
Agent: ClCc1cncc(-c2ccccc2)c1
Solvent: ClP(Cl)Cl
Solvent: CC#N
Solvent: NCCO
Product: N#Cc1ccccc1OCCNCc1cncc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 1.2 g 2-hydroxy-benzonitril and 2.5 g N-2-chloroethyl-N-(5-phenyl-3-pyridylmethyl)-amine [obtainable by reaction of 2-hydroxyethylamine with 3-chloromethyl-5-phenyl-pyridine and subsequent transformation of the product to the 2-chloroethyl-compound by reaction with PCl3 ] in 200 ml of acetonitrile is stirred for 5 hours at room temperature and worked up in a conventional manner to give N-[2-(2-cyanophenoxy)-ethyl]-N-(5-phenyl-3-pyridylmethyl)-amine. Stirring with 0.5 equivalenets of oxalic acid in 100 ml ethanol gives the oxalate, m.p. 208°.
Reaction SMILES: Cl.COC1C=C(N)C=CC=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([NH:19][CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=O)[CH:16]=[CH:17][CH:18]=1.C1(S)C=CC=CC=1>C(O)(=O)C>[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:16]([CH:22]=[C:21]([N+:24]([O-:26])=[O:25])[CH:20]=[N:19]2)=[CH:17][CH:18]=1
Reactant: COc1cccc(NC=C(C=O)[N+](=O)[O-])c1
Agent: COc1cccc(N)c1
Agent: Cl
Agent: Sc1ccccc1
Solvent: CC(=O)O
Product: COc1ccc2cc([N+](=O)[O-])cnc2c1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To the HCl salt of 3-methoxy-phenylamine (4.7 g, 29.7 mmol) in 30 mL acetic acid was added 3-(3-methoxy-phenylamino)-2-nitro-propenal (3.3 g, 14.9 mmol). The reaction mixture was heated to reflux, and thiophenol (0.3 mL, 2.98 mmol) was added. After 22 h, the reaction mixture was cooled to room temperature and the solvent was removed in vacuo. Addition of 70 mL EtOAc and filtration gave solid byproduct, 7-methoxy-3-nitro-quinoline, and a filtrate, which contained impure 5-methoxy-3-nitro-quinoline. The filtrate was loaded on to silica column and eluted from 5% to 25% EtOAc in hexanes at 85 mL/min for 30 minutes. The product-enriched fractions were concentrated and taken on to the next step as a mixture of 5- and 7-methoxy substituted 3-nitroquinolines. LC/MS (m/z): 205.1 (MH+), Rt 2.26 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:16]([OH:18])=O)[N:5]([C:7]2[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:6]=1.[NH2:19][C:20]1[C:28]([Br:29])=[CH:27][C:26]([Br:30])=[CH:25][C:21]=1[C:22](O)=[O:23].BrC1C=C(C(O)=O)N(C2C(Cl)=CC=CN=2)C=1.NC1C(C)=CC(Cl)=CC=1C(O)=O>>[Br:30][C:26]1[CH:27]=[C:28]([Br:29])[C:20]2[N:19]=[C:16]([C:4]3[N:5]([C:7]4[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=4)[CH:6]=[C:2]([Br:1])[CH:3]=3)[O:18][C:22](=[O:23])[C:21]=2[CH:25]=1
Reactant: O=C(O)c1cc(Br)cn1-c1ncccc1[N+](=O)[O-]
Reactant: Nc1c(Br)cc(Br)cc1C(=O)O
Agent: Cc1cc(Cl)cc(C(=O)O)c1N
Agent: O=C(O)c1cc(Br)cn1-c1ncccc1Cl
Product: O=c1oc(-c2cc(Br)cn2-c2ncccc2[N+](=O)[O-])nc2c(Br)cc(Br)cc12

Procedure:
According to the same manner as that of Reference Preparation Example 71-(5), 4-bromo-1-(3-nitro-2-pyridinyl)-1H-pyrrole-2-carboxylic acid and 2-amino-3,5-dibromobenzoic acid were used in place of 4-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrrole-2-carboxylic acid and 2-amino-5-chloro-3-methylbenzoic acid respectively to obtain 6,8-dibromo-2-[4-bromo-1-(3-nitro-2-pyridinyl)-1H-pyrrol-2-yl]-4H-3,1-benzoxazine-4-one of the formula:
Reaction SMILES: O.[C:2]1(C)[CH:7]=[CH:6][C:5]([S:8](O)(=O)=O)=CC=1.[CH2:13]([OH:16])[CH2:14][OH:15].[C:17]1(C)C=CC=CC=1>>[O:15]1[CH2:14][CH2:13][O:16][CH:17]1[C:7]1[CH:6]=[CH:5][S:8][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: OCCO
Reactant: Cc1ccccc1
Solvent: O
Product: c1cc(C2OCCO2)cs1
Temperature: 111 °C
Reaction time: 5 h

Procedure:
Under nitrogen atmosphere, to a solution of 3-thiophene-carboxyaldehyde (9.81 g) in toluene (200 mL) were added p-toluene-sulfonic acid monohydrate (190 mg) and ethylene glycol (6.52 g), and the mixture was stirred at 111° C. for 5 hours. The mixture was cooled to room temperature, washed twice with an aqueous NaHCO3 solution, dried over MgSO4. The solvent was evaporated under reduced pressure to give 3-(1,3-dioxolan-2-yl)thiophene (10.4 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11](=[O:34])[NH:12][C:13]1[C:14]([CH3:33])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][CH:19]=1)[CH3:9].[CH2:35]([O:37][C:38](=[O:48])[CH:39]([C:41]1[CH:46]=[CH:45][C:44](Br)=[CH:43][CH:42]=1)[CH3:40])[CH3:36]>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>[CH2:35]([O:37][C:38](=[O:48])[CH:39]([C:41]1[CH:46]=[CH:45][C:44]([C:21]2[CH:22]=[CH:23][C:18]([C:17]3[O:16][N:15]=[C:14]([CH3:33])[C:13]=3[NH:12][C:11]([O:10][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[CH3:9])=[O:34])=[CH:19][CH:20]=2)=[CH:43][CH:42]=1)[CH3:40])[CH3:36]
Reactant: CCOC(=O)C(C)c1ccc(Br)cc1
Reactant: Cc1noc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1NC(=O)OC(C)c1ccccc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)C(C)c1ccc(-c2ccc(-c3onc(C)c3NC(=O)OC(C)c3ccccc3F)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 17, Step 2 using {3-methyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-isoxazol-4-yl}-carbamic acid 1-(2-fluoro-phenyl)-ethyl ester, 2-(4-bromo-phenyl)-propionic acid ethyl ester, and bis(triphenylphosphine)palladium(II) dichloride; purification by preparative HPLC, followed by silica gel chromatography, was utilized.
Reaction SMILES: C(OC(=O)[NH:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[N:23]([CH2:24][C:25]3[S:26][CH:27]=[CH:28][CH:29]=3)[C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:17]3[N:16]=2)[CH2:10][CH2:9]1)C.[OH-].[K+].[CH3:33][CH:34](O)[CH3:35]>>[C:34]1([CH2:24][N:23]2[C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:17]3[N:16]=[C:15]2[CH2:14][CH:11]2[CH2:10][CH2:9][N:8]([CH2:7][C:6]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:13][CH2:12]2)[CH:35]=[CH:18][CH:17]=[CH:22][CH:33]=1.[S:26]1[CH:27]=[CH:28][CH:29]=[C:25]1[CH2:24][N:23]1[C:18]2=[N:19][CH:20]=[CH:21][CH:22]=[C:17]2[N:16]=[C:15]1[CH2:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:7][CH2:6][NH2:5])[CH2:9][CH2:10]1
Reactant: CC(C)O
Reactant: CCOC(=O)NCCN1CCC(Cc2nc3cccnc3n2Cc2cccs2)CC1
Agent: [K+]
Agent: [OH-]
Product: NCCN1CCC(Cc2nc3cccnc3n2Cc2cccs2)CC1
Product: c1ccc(CN2CCC(Cc3nc4cccnc4n3Cc3ccccc3)CC2)cc1
Yield: 76 %

Procedure:
A mixture of 20.7 parts of ethyl[2-[4-[[3-(2-thienylmethyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl]-1-piperidinyl]ethyl]carbamate, 22.1 parts of potassium hydroxide and 200 parts of 2-propanol was stirred and refluxed overnight. The reaction mixture was evaporated. Water was added to the residue. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated, yielding 13 parts (76%) of 4-[[3-(2-thienylmethyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl]-1-piperidinethanamine (325).
Reaction SMILES: Br.Br.[CH3:3][N:4]([CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9][NH:8]1)[CH3:5].[Cl:18][C:19]1[CH:20]=[C:21]([CH2:26][C:27](O)=[O:28])[CH:22]=[CH:23][C:24]=1[Cl:25].C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl>[CH3:5][N:4]([CH2:6][C:7]1([C:27](=[O:28])[CH2:26][C:21]2[CH:22]=[CH:23][C:24]([Cl:25])=[C:19]([Cl:18])[CH:20]=2)[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9][NH:8]1)[CH3:3]
Reactant: CN(C)CC1NCCc2cc(O)ccc21
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Agent: Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CN(C)CC1(C(=O)Cc2ccc(Cl)c(Cl)c2)NCCc2cc(O)ccc21

Procedure:
Prepared as Ex. No. 5, from 5 g (13.58 mmoles) of 1-dimethylaminomethyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline dihydrobromide, 3.7 g (18.13 mmoles) of 3,4-dichlorophenylacetic acid, 5 ml (35.57 mmoles) of triethylamine and 5.6 g (27.32 mmoles) of dicyclohexylcarbodiimide in 125 ml of dry chloroform.
Reaction SMILES: [CH2:1]([C:8]1([C:17]#[C:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH2:13][C:12](=[CH:14]O)[C:11](=[O:16])[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:24]O>C(O)C.O>[CH2:1]([C:8]1([C:17]#[C:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH2:13][C:12]2[CH:14]=[N:24][O:16][C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C#CC1(Cc2ccccc2)C=CC(=O)C(=CO)C1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: O
Product: C[Si](C)(C)C#CC1(Cc2ccccc2)C=Cc2oncc2C1
Temperature: 120 °C
Yield: 22.4 %

Procedure:
Under a nitrogen atmosphere a solution of 4-benzyl-6-hydroxymethylene-4-((trimethylsilyl)ethynyl)cyclohex-2-enone (76 mg, 0.245 mmol) in ethanol (6.13 mL) was added to a stirred solution of hydroxylamine hydrochloride (177.6 mg, 2.53 mmol, 10.3 eq) in water (256 μL) at room temperature. The mixture was heated to 120° C. and stirred at reflux for 1 hour. After heating, the reaction mixture was diluted with water (10 mL) and the aqueous layer was extracted with dichloromethane/ethyl ether (1:2, 3×10 mL). The organic layers were then combined and washed with saturated aqueous sodium bicarbonate solution (1×10 mL) and brine (2×10 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to give the crude product as a yellow-brown oil (76.4 mg). The crude was purified first by dissolving the product in petroleum ether/ethyl ether (5:1) and decanting the soluble portion from the insoluble solid. The insoluble material was washed with petroleum ether/ethyl ether (5:1) several times and the resulting mother liquor was found by thin layer chromatography (TLC) to contain the desired compound. The mother liquor was purified by flash column chromatography [petroleum ether-ethyl ether (5:1)] to give 32 (17.1 mg, 0.055 mmol, 22%) as a colorless oil: 1H NMR (CDCl3) δ 8.09 (1H, s), 7.32-7.22 (5H, m), 6.56 (1H, dd, J=1, 10 Hz), 6.0 (1H, d, J=10 Hz), 2.96 (1H, d? J=16 Hz), 2.94 (1H, d, J=13 Hz), 2.83 (1H, d, J=16 Hz), 2.73 (1H, d, J=13 Hz), 0.16 (9H, s); 13C NMR (CDCl3) δ 164.4, 148.7, 139.3, 135.0, 131.0, 128.0, 127.1, 114.4, 109.1, 88.4, 44.2, 39.2, 30.3, 0.13. MS (ESI+) m/z 308.1 [M+H]+, HRMS (ESI+) calcd for C19H21NOSi+H 308.1471. found 308.1467.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][NH:6][C:7]=1[C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[CH3:17])[C:11]([OH:13])=O.Cl.[NH:19]1[CH2:22][CH:21]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)[CH2:20]1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O.CN(C)C1C=CN=CC=1.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[N:5][NH:6][C:7]=1[C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[CH3:17])[C:11]([N:19]1[CH2:22][CH:21]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)[CH2:20]1)=[O:13]
Reactant: N#Cc1ccc(C2CNC2)cc1
Reactant: COc1cn[nH]c1-c1cc(C(=O)O)ccc1C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cn[nH]c1-c1cc(C(=O)N2CC(c3ccc(C#N)cc3)C2)ccc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.8 %

Procedure:
Into a 25-mL round-bottom flask, was placed a solution of 3-(4-methoxy-1H-pyrazol-5-yl)-4-methylbenzoic acid (compound 244.7, 60 mg, 0.26 mmol) in N,N-dimethylformamide (2 mL). 4-(Azetidin-3-yl)benzonitrile hydrochloride (75 mg, 0.39 mmol), EDC.HCl (99 mg, 0.52 mmol), and 4-dimethylaminopyridine (63 mg, 0.52 mmol) were added and the solution was stirred for 2 h at room temperature. The reaction was diluted with EtOAc (30 mL) and washed with brine (3×15 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product (150 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-010(Waters)): Column, SunFire Prep C18 OBD Column, 5 μm, 19*150 mm; mobile phase, water with 0.05% TFA and CH3CN (35.0% CH3CN up to 50.0% in 10 min, up to 100% in 1 min, down to 35.0% in 2 min); Detector, UV 254 & 220 nm. The fractions contained pure product were combined and lyophilized to obtain the title compound as an off-white solid (44.3 mg, 46%). m/z (ES+) 373 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)Br)=[CH:4][CH:3]=1.[C:20]1([CH2:26][CH2:27][C:28]([NH2:30])=[S:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:30]=[C:28]([CH2:27][CH2:26][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[S:29][C:9]=2[C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CSc1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Reactant: NC(=S)CCc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CSc1ccc(-c2sc(CCc3ccccc3)nc2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Yield: 65.3 %

Procedure:
To a solution of 2-bromo-1-(4-fluorophenyl)-2-(4-methylthiophenyl)ethanone (Example 1, Step 3)(0.115 g, 0.340 mmol) in ethanol (4 mL) in a 10 mL round bottom flask was added 3-phenylthiopropionamide from Step 1 (0.059 g, 0.357 mmol) and the mixture was heated to reflux overnight. The reaction was cooled to room temperature, diluted with ethyl acetate (50 mL), washed with Na2CO3 (10% solution), brine, dried over Na2SO4, filtered and concentrated in vacuo yielding 4-(4-fluorophenyl)-5-(4-methylthiophenyl)-2-(2-phenylethyl)thiazole (0.090 g, 65%) as oily crystals: mp 97°-99° C.; 1HNMR (CDCl3) 300 mHz 7.50 (d of d, J=5.38 and 8.80, 2 H), 7.35-7.15 (m, 9H), 6.99 (t, J=8.80, 2H), 3.35 (t, J=8.80, 2 H), 3.19 (t, J=8.56 Hz, 2H), 2.49 (s, 3H); MS (EI) m/z 405.10 (MH+), HRMS (M+) Δ=0.0 mmu.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[C:11]2[N:10]=[C:9](Cl)[NH:8][C:7]=2[CH:6]=[C:5]([C:13]([F:16])([F:15])[F:14])[CH:4]=1.[F:19][C:20]([F:34])([F:33])[C:21]1[C:22]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:23][CH:24]=[CH:25][CH:26]=1>>[F:1][C:2]([F:18])([F:17])[C:3]1[C:11]2[N:10]=[C:9]([N:30]3[CH2:31][CH2:32][N:27]([C:22]4[C:21]([C:20]([F:34])([F:19])[F:33])=[CH:26][CH:25]=[CH:24][N:23]=4)[CH2:28][CH2:29]3)[NH:8][C:7]=2[CH:6]=[C:5]([C:13]([F:16])([F:15])[F:14])[CH:4]=1
Reactant: FC(F)(F)c1cc(C(F)(F)F)c2nc(Cl)[nH]c2c1
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Product: FC(F)(F)c1cc(C(F)(F)F)c2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c2c1

Procedure:
The benzoimidazole from step (b) above (115 mg, 0.4 mmol) and 1-(3-trifluoromethylpyridin-2-yl)piperazine (140 mg, 0.6 mmol, Maybridge) reacted under the conditions of Example 3c to give the title compound as a white solid. M.p.142° C. MS (ESI, pos. ion) m/z: 484 (M+1).