Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N1C(C(O)=O)CSC1(C)C)(=[O:8])C1C=CC=CC=1.ON1C2C=CC=CC=2N=N1.[CH:29]1([N:35]=[C:36]=[N:37][CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>O1CCCC1>[C:36]([NH:35][CH:29]1[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1)([NH:37][CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)=[O:8]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC1(C)SCC(C(=O)O)N1C(=O)c1ccccc1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a solution of 48 g. (181 mmole) of 3-benzoyl-2,2-dimethyl-4-thiazolidinecarboxylic acid, prepared by the procedure described by Example 1, in 1.5 l. of tetrahydrofuran were added 27.8 g. (181 mmole) of 1-hydroxybenzotriazole followed by 37.4 g. (181 mmole) of dicyclohexylcarbodiimide. The mixture was stirred for 30 minutes at room temperature. The reaction mixture developed into a thick slurry resulting from the precipitation of dicyclohexylurea. To the heavy slurry was added 63 g. (181 mmole) of benzyl D-4-benzyloxyphenylglycinate and the reaction mixture was stirred at room temperature for about 2 hours. The reaction mixture was filtered to remove the dicyclohexylurea, the filtrate evaporated under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was washed successively with 5% hydrochloric acid, water, aqueous sodium bicarbonate, and finally with water. The washed solution was dried, treated with carbon, and evaporated to dryness under reduced pressure to yield 107 g. (99% yield) of N-[α-(benzyl D-4-benzyloxyphenylacetate]- 3-benzoyl-2,2-dimethyl-4-thiazolidinecarboxamide.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][C@@H:6]([O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH2:5][N:4]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:17].[C:29]([O:33][C:34]([NH:36][CH2:37][C:38](O)=[O:39])=[O:35])([CH3:32])([CH3:31])[CH3:30].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[Si:9]([O:8][C@H:6]1[CH2:5][N:4]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)=[O:17])[C@H:3]([CH2:2][NH:1][C:38]([CH2:37][NH:36][C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:35])=[O:39])[CH2:7]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CN)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)NC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 77.8 %

Procedure:
To a solution of (2S, 4R)-2-aminomethyl-4-t-butyldimethylsilyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (8.43 g) in dichloromethane (80 ml) were added t-butoxycarbonylglycine (3.61 g), 1-hydroxybenzotriazole (2.78 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.95 g) under ice-cooling. The mixture was stirred under ice-cooling for 1 hour and at ambient temperature for 15 hours. The solution was washed with water (80 ml), saturated aqueous sodium hydrogen carbonate (80 ml), and brine (80 ml) successively, dried over magnesium sulfate, and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (80 g) and eluted with a mixture of methanol and chloroform (2:98 v/v) to give (2S, 4R)-4-t-butyldimethylsilyloxy-2-[(t-butoxycarbonylamino)methylcarbonyl]aminomethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (9.07 g).
Reaction SMILES: S(Cl)(Cl)=O.[O:5]=[C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[N:7]1[CH:16]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:17]([OH:19])=O.[CH:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(O)C.CCCCCC>[O:15]=[C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6](=[O:5])[N:7]1[CH:16]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:17]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:19]
Reactant: CC(C)CC(C(=O)O)N1C(=O)c2ccccc2C1=O
Reactant: c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCO
Solvent: CCCCCC
Solvent: O=S(Cl)Cl
Product: CC(C)CC(C(=O)c1ccccc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
Thionyl chloride (34.8 ml, 480 mmol) was added to a mixture of 2-(1,3-dioxo-2-azaindan-2-yl)-4-methylpentanoic acid (83.61 g, 320 mmol) and benzene (320 ml). The resulting mixture was heated under reflux for 2 hours. The solvent and excess thionyl chloride were removed by distillation under reduced pressure, followed by addition of benzene (320 ml). The benzene was removed and fresh benzene (480 ml) was added to form a solution. Anhydrous aluminum chloride (106.7 g, 800 mmol) was added immediately to the solution and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into ice-water (700 ml). The aqueous layer was extracted with benzene (200 ml). After being washed first with water and then with an aqueous sodium bicarbonate solution and with brine, the combined organic layer was dried over sodium sulfate and then evaporated under reduced pressure. The residue was treated with ethanol to give crystals. The crystals were dissolved with heating in ethanol (80 ml) and hexane (160 ml) was added. Precipitated crystals were collected by filtration and washed first with a 1:2 mixed solution (240 ml) of ethanol and hexane and then with hexane. The crystals were dried in air to obtain 74.6 g of the title compound as white crystals (yield: 73%).
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]([C:13]2[N:18]=[C:17]3[N:19]([CH2:23][C:24]4[CH:29]=[CH:28][C:27](/[CH:30]=[CH:31]/[C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)=[CH:26][C:25]=4[Cl:38])[C:20]([CH3:22])=[N:21][C:16]3=[CH:15][CH:14]=2)=[O:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(Cl)Cl.O1CCOCC1>[Pt]=O.CO>[C:1]1([S:7]([NH:10][C:11]([C:13]2[N:18]=[C:17]3[N:19]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=5)=[CH:26][C:25]=4[Cl:38])[C:20]([CH3:22])=[N:21][C:16]3=[CH:15][CH:14]=2)=[O:12])(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1nc2ccc(C(=O)NS(=O)(=O)c3ccccc3)nc2n1Cc1ccc(/C=C/c2ccccc2)cc1Cl
Agent: O=[Pt]
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1nc2ccc(C(=O)NS(=O)(=O)c3ccccc3)nc2n1Cc1ccc(CCc2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 42.7 %

Procedure:
(E)-5-(Benzenesulfonylcarbamoyl)-3-(2-chloro-4-(2-phenylethenyl)-benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine (42 mg) was suspended in a mixed solvent of chloroform (4 ml), 1,4-dioxane (2 ml) and methanol (2 ml), and platinum oxide (2 mg) was added. The mixture was stirred at room temperature for 6.5 hr under a hydrogen atmosphere at 1 atm. The reaction mixture was filtrated and the solvent was evaporated. The resultant mixture was purified by silica gel column chromatography (chloroform/methanol=20/1) and crystallized from ethyl acetate/hexane to give 5-(benzenesulfonylcarbamoyl)-3-(2-chloro-4-(2-phenylethyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine (18 mg) as a white powder.
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:7]([C:14]#[N:15])([C:8]([O:10][CH3:11])=[O:9])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].N>[Ni].CO>[C:1]([N:4]1[CH2:13][CH2:12][C:7]([CH2:14][NH2:15])([C:8]([O:10][CH3:11])=[O:9])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COC(=O)C1(C#N)CCN(C(C)=O)CC1
Agent: [Ni]
Agent: N
Solvent: CO
Product: COC(=O)C1(CN)CCN(C(C)=O)CC1
Reaction time: 2 h

Procedure:
A mixture of methyl 1-acetyl-4-cyanoisonipecotate (3.95 g), Raney nickel (3 g), concentrated ammonia solution (15 ml) and methanol (100 ml) was stirred at 5 atms under hydrogen atmosphere for 2 hours, and the catalyst was filtered off. The reaction solution was concentrated to give light blue oil of methyl 1-acetyl-4-aminomethylisonipecotate. To a solution of the obtained methyl 1-acetyl-4-aminomethylisonipecotate and N-(2,2-diethoxyethyl)-Z-glycine (6.12 g) in acetonitrile (100 ml) was added WSC (6.12 g), and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated, and to the residue were added ethyl acetate and water. The separated organic layer was washed with water, sodium bicarbonate solution, citric acid solution and brine, dried and concentrated, and the residue was dissolved in toluene (100 ml). To the solution was added p-toluene sulfonic acid hydrate (164 mg), and the mixture was stirred at 100° C. for 30 minutes. The reaction solution was washed with saturated sodium bicarbonate solution and brine, dried and concentrated, and the residue was purified with silica gel column chromatography (ethyl acetate: methanol=50:1) to give colorless oil of 1-(1-acetyl-4-methoxycarbonylpiperidin-4-ylmethyl)-4-benzyloxycarbonyl-2-oxo-1,2,3,4-tetrahydropyrazine (2.4 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][N:3]=1.Cl.[CH3:18][N:19]([CH2:21][CH:22]([OH:32])[CH2:23][O:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1)[CH3:20].CO.N>C(O)CCC>[CH3:20][N:19]([CH2:21][CH:22]([OH:32])[CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([NH:29][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=3[F:16])[CH:5]=[CH:4][N:3]=2)=[CH:30][CH:31]=1)[CH3:18]
Reactant: Fc1ccc(Nc2ccnc(Cl)n2)c(F)c1
Reactant: CN(C)CC(O)COc1ccc(N)cc1
Agent: Cl
Agent: N
Solvent: CO
Solvent: CCCCO
Product: CN(C)CC(O)COc1ccc(Nc2nccc(Nc3ccc(F)cc3F)n2)cc1
Temperature: 100 °C
Yield: 41.5 %

Procedure:
2-Chloro-4-(2,4-difluoroanilino)pyrimidine (Reference Example A-2; 174 mg, 0.72 mmol) was dissolved in n-butanol (2 ml) and 4-[3-(N,N-dimethyl)amino-2-hydroxypropoxy]aniline hydrochloride (Reference Example D-1; 198 mg, 0.72 mmol) was added. The resulting suspension was treated with methanol until all the solid dissolved. The reaction mixture was heated at 100° C. for 12 hours and allowed to cool to ambient temperature. The reaction mixture was then basified to pH 9–10 using methanolic ammonia and evaporated onto silica (5 ml). The residue was purified by column chromatography eluting with methanol (15%): DCM:aqueous ammonia(1%). The resulting gum was recrystallized from acetonitrile to give the title product as a solid (124 mg, 41%). NMR (300 MHz): 2.18 (s, 6H), 2.34 (m, 2H), 3.78 (m, 1H), 3.88 (m, 2H), 4.75 (brd, 1H), 6.18 (d, 1H), 6.75 (d, 2H), 7.03 (t, 1H), 7.32 (t, 1H), 7.48 (d, 2H), 7.88 (dd, 1H), 7.95 (d, 1H), 8.88 (s, 1H), 8.95(s, 1H); m/z: (ES+) 416.4 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[CH2:7][CH2:6]2.[N:15]1[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][CH:16]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[C:7](=[CH:21][C:18]1[CH:19]=[CH:20][N:15]=[CH:16][CH:17]=1)[CH2:6]2
Reactant: O=Cc1ccncc1
Reactant: COc1cc2c(cc1OC)C(=O)CC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1OC)C(=O)C(=Cc1ccncc1)C2
Temperature: 25 °C
Yield: 90.2 %

Procedure:
A mixture of 5,6-dimethoxy-indan-1-one (10 g), pyridine-4-carboxaldehyde (7.8 g), p-toluenesulphonic acid (13.8 g) in toluene (120 ml) was refluxed azeotropically for 6 hours. The reaction mixture was cooled to room temperature and filtered. The wet solid so obtained was stirred with 10% aqueous sodium carbonate solution. The solid was filtered, washed with acetone and then dried to get the title compound (13.2 g).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=2)[CH:17]=1.[CH:27]1([NH2:31])[CH2:30][CH2:29][CH2:28]1>>[CH:27]1([NH:31][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:18]([N:16]3[CH:17]=[C:13]([C:3]4[C:4]([C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=5)=[N:5][O:6][C:2]=4[CH3:1])[N:14]=[CH:15]3)=[CH:19][CH:20]=2)[CH2:30][CH2:29][CH2:28]1
Reactant: NC1CCC1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc(C(=O)O)cc2)cn1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc(C(=O)NC3CCC3)cc2)cn1
Yield: 11 %

Procedure:
As described for Example 71c, 4-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid (100 mg, 0.29 mmol) was converted, using cyclobutylamine instead of cyclopropylmethylamine, to the title compound (13 mg, 11%) which was obtained as an off-white solid. MS: m/e=398.9 [M+H]+.
Reaction SMILES: [CH2:1]([Sn:5](=O)[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[CH2:11]([SH:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>O>[CH2:1]([Sn:5]([CH2:6][CH2:7][CH2:8][CH3:9])([S:23][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[S:23][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCCCCCCCS
Reactant: CCCC[Sn](=O)CCCC
Solvent: O
Product: CCCCCCCCCCCCS[Sn](CCCC)(CCCC)SCCCCCCCCCCCC

Procedure:
This compound was prepared from di-n-butyltin-oxide and 1 dodecanethiol by azeotropic removal of water using the method described in U.S. Pat. No. 2,648,650. All spectroscopic and analytical data were consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:17][C:18](=[O:20])[CH3:19].ClC1C(Cl)=C(O)C=CC=1>CC(C)=O.[I-].[K+]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([Cl:8])[CH:7]=1)[O:9][CH2:17][C:18](=[O:20])[CH3:19]
Reactant: CC(=O)CCl
Reactant: Oc1cc(Cl)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: Oc1cccc(Cl)c1Cl
Agent: [I-]
Solvent: CC(C)=O
Product: CC(=O)COc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
To a stirred solution of 3,5-dichlorophenol (0.49 g, 3 mmol) in acetone (10 mL) under a nitrogen atmosphere was added potassium carbonate (0.42 g, 3 mmol). In a separate flask, chloroacetone (0.34 mL, 4.2 mmol) and potassium iodide (0.02 g, 0.12 mmol) were dissolved in acetone (15 mL), heated at reflux for 10 min and then allowed to cool to room temperature. The chloroacetone solution was then added to the dichlorophenol solution dropwise via an addition funnel. The resulting mixture was stirred at room temperature overnight. The resulting solids were filtered off and the filtrate was concentrated under reduced pressure to yield the title compound of Step A (0.65 g) as a semisolid. 400 MHz 1H NMR (CDCl3): δ 7.01 (t,1H), 6.8 (d,2H), 4.5 (s,2H), 2.3 (s,3H). This material was used in Step D without further characterization.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[CH3:20])(=[O:12])=[O:11])[S:7][CH:8]=1.Br[CH2:22][CH2:23][CH2:24][C:25](OCC)=[O:26].CCN(C(C)C)C(C)C.[I-].[K+]>C(O)C.CS(C)=O>[Cl:19][C:15]1[C:14]([CH3:20])=[C:13]([S:10]([NH:9][C:6]2[S:7][CH:8]=[C:4]([CH2:3][CH2:2][N:1]3[CH2:22][CH2:23][CH2:24][C:25]3=[O:26])[N:5]=2)(=[O:11])=[O:12])[CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)CCCBr
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(CCN)cs1
Agent: [I-]
Agent: [K+]
Solvent: CCO
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(CCN2CCCC2=O)cs1
Temperature: 25 °C

Procedure:
A mixture of EXAMPLE 200A (200 mg, 0.60 mmol), ethyl 4-bromobutyrate (118 mg, 0.60 mmol), DIEA (156 mg, 1.20) and potassium iodide (10 mg, 0.06 mmol) in ethanol (5 mL)/DMSO (2 mL) was refluxed overnight, allowed to cool to room temperature, and extracted with ethyl acetate. The organic phase was separated, dried over sodium sulphate, filtered and the solvent was evaporated. The residue was purified by flash chromatography on silica gel eluting with 20% acetone in DCM giving 18 mg (7%) of solid material: 1H NMR (CDCl3) δ 2.00 (qn, 2H), 2.38 (t, 2H), 2.65 (s, 3H), 2.88 (t, 2H), 3.40 (t, 2H), 3.58 (t, 2H), 6.24 (s, 1H), 7.22 (t, 1H), 7.52 (dd, 1H), 8.01 (dd, 1H); MS (Ionspray, [M+H]+) m/z 399.
Reaction SMILES: P(CCCC)(CCCC)CCCC.CCN(CC)CC.[OH:21][CH:22]([CH:27]=[CH2:28])[C:23]([O:25][CH3:26])=[O:24].I[C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].O>[C:38]1([CH2:28][CH2:27][C:22](=[O:21])[C:23]([O:25][CH3:26])=[O:24])[C:39]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:35]=[CH:36][CH:37]=1
Reactant: C=CC(O)C(=O)OC
Reactant: Ic1cccc2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCP(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)C(=O)CCc1cccc2ccccc12
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 6.9 %

Procedure:
To a stirred solution of Pd(OAc)2 (340 mg), nBu3P (613 mg), and Et3N (1.99 g) in DMF (30 ml) was added methyl 2-hydroxy-3-butenoate (1.76 g) followed by 1-iodonaphthalene (5.0 g), and the reaction mixture was stirred at 100° C. for 2.5 hours. The reaction mixture was poured into water (300 ml) and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel (130 g) column chromatography eluting with hexane/ethyl acetate (50:1) to give methyl 4-(1-naphthyl)-2-oxobutyrate (254 mg) as a red oil.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[S:28][C:27]([CH2:29][N:30]4[CH2:35][CH2:34][N:33]([C:36]([CH3:41])([CH3:40])[C:37]([NH2:39])=[O:38])[CH2:32][CH2:31]4)=[CH:26][C:9]=3[N:10]=[C:11]([Sn](CCCC)(CCCC)CCCC)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[C:43]1[N:48]2[CH:49]=[N:50][N:51]=[C:47]2[CH:46]=[CH:45][CH:44]=1>O1CCOCC1.[Cu]I>[N:51]1[N:50]=[CH:49][N:48]2[C:43]([C:11]3[N:12]=[C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[C:8]4[S:28][C:27]([CH2:29][N:30]5[CH2:31][CH2:32][N:33]([C:36]([CH3:40])([CH3:41])[C:37]([NH2:39])=[O:38])[CH2:34][CH2:35]5)=[CH:26][C:9]=4[N:10]=3)=[CH:44][CH:45]=[CH:46][C:47]=12
Reactant: Brc1cccc2nncn12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2sc(CN3CCN(C(C)(C)C(N)=O)CC3)cc2n1
Agent: [Cu]I
Solvent: C1COCCO1
Product: CC(C)(C(N)=O)N1CCN(Cc2cc3nc(-c4cccc5nncn45)nc(N4CCOCC4)c3s2)CC1
Temperature: 150 °C
Yield: 12.2 %

Procedure:
A mixture of 2-[4-(4-morpholin-4-yl-2-(tributylstannanyl)thieno[3,2-d]pyrimidin-6-ylmethyl)piperazin-1-yl]isobutyramide (150 mg, 0.22 mmol), 5-bromo-[1,2,4]triazolo[4,3-a]pyridine (51 mg, 0.26 mmol), bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium (II) (15 mg, 0.02 mmol) and copper(I) iodide (41 mg, 0.22 mmol) in dioxane (2.5 mL) was purged with argon gas then heated at 150° C., for 20 min, in a microwave reactor. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was washed with MeOH then the desired product was eluted with 2 M NH3 in MeOH. The appropriate fractions were combined and evaporated. The resulting residue was purified by flash chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 10:90) followed by reverse phase HPLC (Phenomenex Gemini 5u C18, 20 mM triethylamine in water on a gradient of acetonitrile 95:5 to 2:98) to give 690 as a white solid (14 mg, 12%). LCMS (Method F) RT 5.50 min; [M+H]+ 522. 1H NMR (400 MHz, CHCl3-d): δ 10.53 (d, J=0.9 Hz, 1 H); 8.08 (dd, J=7.0, 0.9 Hz, 1 H); 7.93 (d, J=9.1 Hz, 1 H); 7.41 (dd, J=9.1, 7.0 Hz, 1 H); 7.38 (s, 1 H); 7.08 (d, J=5.3 Hz, 1 H); 5.20 (d, J=5.3 Hz, 1 H); 4.07 (t, J=4.8 Hz, 4 H); 3.92 (t, J=4.8 Hz, 4 H); 3.88 (s, 2 H); 2.62 (m, 8 H);1.25 (s, 6 H)
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([C:17]3[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=3)[CH:15]=[N:16][C:10]=2[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[C:19]1([CH3:23])[CH:20]=[CH:21][CH:22]=[C:17]([N:14]2[C:11]3[CH2:12][CH2:13][NH:8][CH2:9][C:10]=3[N:16]=[CH:15]2)[CH:18]=1
Reactant: Cc1cccc(-n2cnc3c2CCN(Cc2ccccc2)C3)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1cccc(-n2cnc3c2CCNC3)c1
Yield: 32.2 %

Procedure:
A mixture of 5-benzyl-1-m-tolyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine 17a (500 mg, 1.6 mmol), ammonium formate (1.0 g), and 700 mg 5% Pd/C (50% with water) in 80% aqueous methanol was heated at reflux for 12 hr, and then allowed to reach ambient temperature. The catalyst was removed by filtration through Celite®. The filtrate was evaporated in vacuo. Purification by silica gel chromatography provided 1-m-tolyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine (110 mg) 18a as an oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[CH2:32]([O:34][C:35]1[CH:36]=[C:37]([OH:82])[C:38]([F:81])=[C:39]([N:41]([CH2:50][C:51]2[N:52]([C:62]([C:75]3[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=3)([C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=3)[C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[CH:53]=[C:54]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[N:55]=2)[C:42]2[CH:49]=[CH:48][C:45]([C:46]#[N:47])=[CH:44][CH:43]=2)[CH:40]=1)[CH3:33].O[CH:84]1[CH2:89][CH2:88][N:87]([CH3:90])[CH2:86][CH2:85]1>C1COCC1>[CH2:32]([O:34][C:35]1[CH:36]=[C:37]([O:82][CH:84]2[CH2:89][CH2:88][N:87]([CH3:90])[CH2:86][CH2:85]2)[C:38]([F:81])=[C:39]([N:41]([CH2:50][C:51]2[N:52]([C:62]([C:75]3[CH:76]=[CH:77][CH:78]=[CH:79][CH:80]=3)([C:69]3[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=3)[C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[CH:53]=[C:54]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[N:55]=2)[C:42]2[CH:43]=[CH:44][C:45]([C:46]#[N:47])=[CH:48][CH:49]=2)[CH:40]=1)[CH3:33]
Reactant: CN1CCC(O)CC1
Reactant: CCOc1cc(O)c(F)c(N(Cc2nc(-c3ccccc3)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc(C#N)cc2)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOc1cc(OC2CCN(C)CC2)c(F)c(N(Cc2nc(-c3ccccc3)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc(C#N)cc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
To triphenylphosphine (117 mg, 0.447 mmol) in THF (2 mL) at 0° C., was added diethylazodicarboxylate (71 μL, 0.447 mmol). The mixture was stirred at 0° C. for 30 min, then a solution of Intermediate 113.3 (100 mg, 0.149 mmol) and 4-hydroxy-1-methylpiperidine (34 mg, 0.298 mmol) in 1 mL THF. The mixture was allowed to warm to rt and stir 15 h, then was concentrated. The crude mixture was purified by flash chromatography (0 to 10% MeOH/CH2Cl2, gradient) to afford 77 mg of Intermediate 113.4.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:24])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1)[CH2:11][C:10]2([CH3:23])[CH3:22])=[O:4].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.Cl.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[Cl:24][C:7]1[CH:8]=[C:9]2[C:14](=[C:5]([C:3]([OH:2])=[O:4])[CH:6]=1)[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:16]=1)[CH2:11][C:10]2([CH3:23])[CH3:22]
Reactant: C1COCCN1
Reactant: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(Br)c1)CC2(C)C
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CS(C)=O
Product: CC1(C)CC(c2cccc(N3CCOCC3)c2)Nc2c(C(=O)O)cc(Cl)cc21
Temperature: 25 °C
Yield: 96.2 %

Procedure:
A mixture solution of 2-(3-bromo-phenyl)-6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (8.9 g, 7 mmol), morpholine (6.1 mL, 70 mmol), copper(I) iodide (0.4 g, 2.1 mmol), N,N-dimethylglycine hydrochloride (0.4 g, 2.8 mmol), and potassium carbonate (2.9 g, 21 mmol) in dimethyl sulfoxide (20 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature. The reaction mixture was extracted with ethyl acetate (150 mL×2), washed with saturated aqueous ammonium chloride solution (50 mL×3) and brine (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 30-50% ethyl acetate in petroleum ether) to afford 6-chloro-4,4-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (2.7 g, 96%) as a white solid: MS (ESI) M+1=401.2.