Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[SH:5][C:6]1[S:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1.[C:15]([OH:23])(=[O:22])[C:16]([CH2:18][C:19]([OH:21])=[O:20])=[CH2:17].O>C(OCC)C.C(OCC)(=O)C>[S:7]1[C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=[C:6]1[S:5][CH2:17][CH:16]([C:15]([OH:23])=[O:22])[CH2:18][C:19]([OH:21])=[O:20]
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: Sc1nc2ccccc2s1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=C(O)CC(CSc1nc2ccccc2s1)C(=O)O
Reaction time: 24 h
Yield: 50.5 %

Procedure:
13.3 g of AlCl3 are dissolved in 100 ml of diethyl ether at 0° to 5°. 3.4 g of 2-mercaptobenzothiazole and 2.6 g of itaconic acid are then added. After the mixture has been stirred at 20°-25° for 24 hours, the ether solution is poured off and the residue is stirred with 100 ml of water and 100 ml of ethyl acetate. The organic phase is separated off, dried and evaporated. 3 g of 3-(benzothiazol-2-ylthio)-propane-1,2-dicarboxylic acid are obtained as the residue.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][CH2:9][CH2:10][CH2:11][OH:12]>C(OCC)C.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12]
Reactant: OCCCC#Cc1ccccn1
Agent: [Pd]
Solvent: CCOCC
Product: OCCCCCc1ccccn1

Procedure:
A solution of 5-(2-pyridyl)-4-pentyn-1-ol (1 g, 6.2 mmol) in diethyl ether (15 ml) was hydrogenated over 10% palladium on carbon at room temperature for 16 h. The mixture was filtered through celite and the filtrate on evaporation gave an oil, which was flash chromatographed on silica using 80% ethyl acetate/chloroform. Fractions with Rf of about 0.06 on evaporation gave the title alcohol as a yellow oil.
Reaction SMILES: O[CH2:2][CH:3]([CH2:5]O)O.[CH2:7]([C:9]([CH2:14][OH:15])([CH2:12][OH:13])[CH2:10][CH3:11])[OH:8].CCCCCC(=O)CCCCC.CC(C)=O>CCCCCC>[OH:8][CH2:7][C:9]1([CH2:10][CH3:11])[CH2:14][O:15][C:3]([CH3:5])([CH3:2])[O:13][CH2:12]1
Reactant: CCC(CO)(CO)CO
Reactant: OCC(O)CO
Agent: CCCCCC(=O)CCCCC
Solvent: CCCCCC
Solvent: CC(C)=O
Product: CCC1(CO)COC(C)(C)OC1

Procedure:
The same procedures as in Production Example 3 are carried out except that glycerol is replaced with 292.1 g (2.18 mol) of trimethylolpropane, 6-undecanone is replaced with 474.0 g (8.17 mol) of acetone, and the amount of paratoluenesulfonic acid monohydrate is changed to 6.0 g (0.0315 mol) and the amount of hexane is changed to 900 ml to give 5-hydroxymethyl-5-ethyl-2,2-dimethyl-1,3-dioxane.
Reaction SMILES: [CH2:1]([C:3]1[C:7]([C:8]([N:10]2[CH2:16][CH2:15][CH2:14][N:13]([CH2:17][CH2:18][OH:19])[CH2:12][CH2:11]2)=[O:9])=[C:6]([CH2:20][CH3:21])[N:5]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[C:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:23]=2)[N:4]=1)[CH3:2]>CO.[Pd]>[CH2:1]([C:3]1[C:7]([C:8]([N:10]2[CH2:16][CH2:15][CH2:14][N:13]([CH2:17][CH2:18][OH:19])[CH2:12][CH2:11]2)=[O:9])=[C:6]([CH2:20][CH3:21])[N:5]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:23]=2)[N:4]=1)[CH3:2]
Reactant: CCCCC#Cc1cccc(-n2nc(CC)c(C(=O)N3CCCN(CCO)CC3)c2CC)c1
Agent: [Pd]
Solvent: CO
Product: CCCCCCc1cccc(-n2nc(CC)c(C(=O)N3CCCN(CCO)CC3)c2CC)c1
Reaction time: 1 h

Procedure:
0.027 g of Pd—C (10%) was added to a solution of 0.11 g (0.30 mmol) of [3,5-diethyl-1-(3-hex-1-ynyl-phenyl)-1H-pyrazol-4-yl]-[4-(2-hydroxy-ethyl)-[1,4]diazepan-1-yl]-methanone in 5 ml of MeOH and the reaction mixture was then hydrogenated with H2 (1 bar) at RT for 1 hour. After removal the catalyst by filtration, the solvent was evaporated completely to afford the title compound as light yellow oil. MS: 455.3 (MH+).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([O:14][C:15]1[CH:38]=[CH:37][C:18]([O:19][C@@H:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][C@@H:21]2[NH:29][C:30](OC(C)(C)C)=O)=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O1CCCC1.C(O)C.C(Cl)(Cl)[Cl:48]>>[ClH:48].[CH2:7]([O:14][C:15]1[CH:38]=[CH:37][C:18]([O:19][C@@H:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][C@@H:21]2[NH:29][CH3:30])=[CH:17][CH:16]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1Cc2ccccc2[C@H]1Oc1ccc(OCc2ccccc2)cc1
Reactant: ClC(Cl)Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Product: CN[C@H]1Cc2ccccc2[C@H]1Oc1ccc(OCc2ccccc2)cc1
Product: Cl

Procedure:
The title compound was prepared in a similar manner to Example 12 from LiAlH4 (760 mg, 20 mmol), (±) cis-1-(4-benzyloxyphenoxy)-2-tert-butoxycarbonylaminoindane (1 g, 2.3 mmol) and tetrahydrofuran (50 ml). After a reaction time of 4 h the reaction was worked up as previously described and subjected to column chromatography on silica gel eluting with 5% ethanol in chloroform to afford a pale yellow oil (765 mg) which was converted to the HCl salt and crystallised to afford the title compound as a white solid. m.p. >195° C. dec.(from methanol-diethyl ether).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=2[O:19][CH:20]([CH3:22])[CH3:21])[CH2:4][CH2:3]1.[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:25]=1O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.C(OCC)C>[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:25]=1[O:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=2[O:19][CH:20]([CH3:22])[CH3:21])[CH2:4][CH2:3]1
Reactant: COC(=O)c1ccc(CN2CCC(O)CC2)c(OC(C)C)c1
Reactant: Cc1cccc(C)c1O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)c1ccc(CN2CCC(Oc3c(C)cccc3C)CC2)c(OC(C)C)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 36.3 %

Procedure:
To a solution of methyl 4-[(4-hydroxypiperidin-1-yl)methyl]-3-isopropoxybenzoate (0.72 g, 2.34 mmol), 2,6-dimethylphenol (0.43 g, 3.51 mmol) and tributylphosphine (0.88 mL, 3.51 mmol) in anhydrous tetrahydrofuran (14 mL) was added 1,1′-(azodicarbonyl)dipiperidine (0.89 g, 3.51 mmol), and the mixture was stirred at room temperature for 12 hr. To the reaction mixture were added reagents (2,6-dimethylphenol, tributylphosphine and 1,1′-(azodicarbonyl)dipiperidine) in the same amount as mentioned above, and the mixture was further stirred for 12 hr. Diethyl ether (40 mL) was added to the reaction solution, the precipitate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=2/1) to give the title compound (0.35 g, yield 36%) as a colorless oil.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:11][CH2:10]2)(=O)=O.[CH3:29]O>>[CH3:29][O:5][CH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:11][CH2:10]2
Reactant: CO
Reactant: CCOC(=O)C1c2ccc(COS(C)(=O)=O)cc2CCN1C(=O)OC(C)(C)C
Product: CCOC(=O)C1c2ccc(COC)cc2CCN1C(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
To a solution of 1-ethyl 2-tert-butyl 6-(((methylsulfonyl)oxy)methyl)-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate (500 mg, 1.21 mmol) in MeOH (5 mL) was added TEA (0.337 mL, 2.42 mmol), and the mixture was stirred at 70° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (solvent gradient; 3→60% ethyl acetate/hexane) to give 1-ethyl 2-tert-butyl 6-(methoxymethyl)-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate (169 mg, 0.484 mmol, 40.0%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[NH:12][CH:11]=[C:10]([C:13](OCC)=[O:14])[C:9]=2[CH3:18])=[CH:6][CH:5]=[CH:4][N:3]=1.C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.O>O1CCCC1>[F:1][C:2]1[C:7]([C:8]2[NH:12][CH:11]=[C:10]([CH2:13][OH:14])[C:9]=2[CH3:18])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)c1c[nH]c(-c2cccnc2F)c1C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(CO)c[nH]c1-c1cccnc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 41.3 %

Procedure:
A solution of ethyl 5-(2-fluoropyridin-3-yl)-4-methyl-1H-pyrrole-3-carboxylate (5.01 g) in tetrahydrofuran (50 mL) was cooled to −78° C., a 1.5 mol/L toluene solution (45 mL) of diisobutylaluminum hydride was added dropwise, and the mixture was stirred at 0° C. for 1 hr. Water was added to the reaction mixture, insoluble materials were filtered off, and the filtrate was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with diisopropyl ether to give the title compound as colorless crystals (yield 1.72 g, 41%).
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:12]([NH:14][CH2:15][C:16](N)=[O:17])=[O:13])[CH:5]=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32].Cl.N[CH2:35][C:36](N)=O>>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([C:12]([N:14]3[CH2:36][CH2:35][C@H:16]([OH:17])[CH2:15]3)=[O:13])[CH:19]=[CH:20][C:21]=2[CH3:22])[CH:5]=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32]
Reactant: Cc1ccc(C(=O)NCC(N)=O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O
Reactant: NCC(N)=O
Agent: Cl
Product: Cc1ccc(C(=O)N2CC[C@H](O)C2)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O

Procedure:
The title compound was prepared using a procedure similar to that used in Step 4 of the synthesis of 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-N-[1-(aminocarbonyl)methyl]-4-methylbenzamide by substituting (S)-3-hydroxypyrrolidine for glycineamide HCl. 1H NMR (CD3OD/400 MHz) δ8.31 (d, 1H, J=7.6 Hz), 7.62 (m, 2H), 7.52 (m, 2H), 7.01 (m, 2H), 5.59 (m, 2H), 4.42 (m, 1H), 3.64 (m, 4H), 2.19 (s, 3H), 2.00 (m, 2H). ESHRMS m/z 476.1147 (M+H calculated for C23H21ClF2N3O4 requires 476.1183).
Reaction SMILES: C([O:5][C:6](=O)[C:7]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([S:19][CH2:20][CH2:21][C:22](=[O:30])[NH:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][NH2:29])[N:16]=[C:15]([NH2:31])[N:14]=2)[C:10]([CH3:32])=[CH:9][C:8]=1[CH3:33])(C)(C)C.FC(F)(F)C(O)=O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[NH2:31][C:15]1[N:16]=[C:17]2[CH:18]=[C:13]([C:11]3[CH:12]=[C:7]([C:6](=[O:5])[NH:29][CH2:28][CH2:27][O:26][CH2:25][CH2:24][NH:23][C:22](=[O:30])[CH2:21][CH2:20][S:19]2)[C:8]([CH3:33])=[CH:9][C:10]=3[CH3:32])[N:14]=1
Reactant: Cc1cc(C)c(-c2cc(SCCC(=O)NCCOCCN)nc(N)n2)cc1C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)c2cc1C(=O)NCCOCCNC(=O)CCSc1cc-2nc(N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 3 %

Procedure:
5-(2-Amino-6-{2-[2-(2-aminoethoxy)ethylcarbamoyl]ethylsulfanyl}pyrimidin-4-yl)-2,4-dimethylbenzoic acid tert-butyl ester (78 mg, 0.159 mmol) obtained in Step 1 above was dissolved in dichloromethane (3 ml), and then trifluoroacetic acid (1 ml) was added thereto. After this solution was stirred at room temperature for two hours, the solvent was distilled off under reduced pressure. The resulting crude product was dissolved in a mixed solvent of N,N-dimethylformamide (25 ml) and tetrahydrofuran (75 ml), and then 1-hydroxybenzotriazole (134 mg, 0.795 mmol), diisopropylethylamine (137 μl, 0.795 mmol), and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (152 mg, 2.2 mmol) were sequentially added thereto. After the solution was stirred at room temperature for 16 hours, 1-hydroxybenzotriazole (270 mg, 1.59 mmol), diisopropylethylamine (274 μl, 1.59 mmol), and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (304 mg, 1.59 mmol) were added thereto. After the solution was stirred at 50° C. for seven hours, the solvent was distilled off under reduced pressure. The residue was diluted with ethyl acetate. The ethyl acetate solution was washed with a saturated aqueous sodium bicarbonate solution (twice), and dried over anhydrous sodium sulfate. After the inorganic salt was removed by filtration, the filtrate was concentrated. The resulting residue was purified by preparative thin layer silica gel chromatography (developing solvent: dichloromethane:methanol=15:1). The obtained crude product was washed with dichloromethane to yield 4-amino-20,22-dimethyl-14-oxa-7-thia-3,5,11,17-tetraazatricyclo[17.3.1.12,6]tetracosa-1(22),2(24),3,5,19(23),20-hexaene-10,18-dione (Compound 29) (2 mg) as a white solid material.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4](=[O:12])[N:3]=1.[C:13]([C:15]1([NH:24][C:25](=[O:35])[CH:26]([NH2:34])[CH2:27][CH2:28][C:29]([CH3:33])([CH3:32])[CH2:30][CH3:31])[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH3:23])[CH2:17][CH2:16]1)#[N:14].CN1CCOCC1>C(#N)C>[C:13]([C:15]1([NH:24][C:25](=[O:35])[CH:26]([NH:34][C:2]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[O:5][C:4](=[O:12])[N:3]=2)[CH2:27][CH2:28][C:29]([CH3:33])([CH3:32])[CH2:30][CH3:31])[CH2:16][CH2:17][N:18]([CH2:21][CH2:22][CH3:23])[CH2:19][CH2:20]1)#[N:14]
Reactant: O=c1nc(Cl)c2ccccc2o1
Reactant: CCCN1CCC(C#N)(NC(=O)C(N)CCC(C)(C)CC)CC1
Solvent: CN1CCOCC1
Solvent: CC#N
Product: CCCN1CCC(C#N)(NC(=O)C(CCC(C)(C)CC)Nc2nc(=O)oc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.5 %

Procedure:
A suspension of 4-chloro-benzo[e][1,3]oxazin-2-one (620 mg, 3.41 mmol, 2.0 eq), 2-amino-5,5-dimethyl-heptanoic acid (4-cyano-1-propyl-piperidin-4-yl)-amide (675 mg, 1.71 mmol, 1.00 eq), and 4-methylmorpholine (NMM) (0.56 mL, 5.09 mmol, 3.00 eq) in acetonitrile (9.0 mL) was stirred at room temperature overnight. The reaction mixture was then concentrated, resuspended in ethyl acetate (50 mL) and washed with saturated Na2CO3 solution. The organic phase was dried (MgSO4) and concentrated and the resulting residue was chromatographed over silica gel using a gradient of methanol in dichloromethane as the eluant to provide 124 mg (16% yield) of the title compound; m/z calculated for C26H37N5O3 467.6, found 468.4 (M+H)+.
Reaction SMILES: [C:1]1([S:7][C@@H:8]2[CH2:12][NH:11][C@H:10]([C:13]([OH:15])=[O:14])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:23]([O:27][C:28](ON=C(C1C=CC=CC=1)C#N)=[O:29])([CH3:26])([CH3:25])[CH3:24]>O.O1CCOCC1>[CH3:24][C:23]([CH3:26])([O:27][C:28]([N:11]1[CH2:12][C@@H:8]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:9][C@H:10]1[C:13]([OH:15])=[O:14])=[O:29])[CH3:25]
Reactant: O=C(O)[C@@H]1C[C@H](Sc2ccccc2)CN1
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H](Sc2ccccc2)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
To a solution of (cis)-4-(phenylthio)-L-proline (5 g) and triethylamine (3.4 g) in water (13 ml), a solution of 2-(t-butoxycarbonyloxyimino)-2-phenylacetonitrile (6.0 g) in dioxane (13 ml) is added. The mixture is stirred at ambient temperature. After one hour, water (50 ml) is added, the mixture is washed with ethyl acetate and acidified to a pH of 3-4 with 10% citric acid. The oil that separates is extracted into ethyl acetate, washed with brine, and dried (MgSO4). The residue is dissolved in saturated sodium bicarbonate (50 ml) plus water (600 ml). The alkaline solution is washed with ether and acidified to a pH of 4 with 10% citric acid. The oil that separates from solution is extracted into ethyl acetate, washed with brine, and dried (MgSO4). The solvent is removed in vacuo to give the product as an oil (5.9 g) that gradually solidifies, melting point 110°-118° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(Cl)(=O)C(Cl)=O.[Br:21][C:22]1[C:23]([CH3:39])=[C:24]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)[C:25]([NH2:28])=[N:26][CH:27]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[Br:21][C:22]1[C:23]([CH3:39])=[C:24]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:36])[F:37])[CH:30]=2)[C:25]([NH:28][C:12](=[O:14])[CH2:11][C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=2)=[N:26][CH:27]=1
Reactant: CS(=O)(=O)c1ccc(CC(=O)O)cc1
Reactant: Cc1c(Br)cnc(N)c1-c1cccc(C(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c(Br)cnc(NC(=O)Cc2ccc(S(C)(=O)=O)cc2)c1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 38.7 %

Procedure:
To a suspension of 4-(methylsulfonyl)phenylacetic acid (388 mg, 1.8 mmol) in dry DCM (5 mL) was added oxalyl chloride (320 μL, 3.6 mmol) followed by DMF (2 drops). The reaction mixture was stirred at RT for 3 hrs then the solvent was removed in vacuo. The resultant residue was taken up in DCM (2 mL) and added dropwise to a stirring solution of 5-bromo-4-methyl-3-(3-trifluoromethyl-phenyl)-pyridin-2-ylamine (Int. 1, 500 mg, 1.51 mmol) and triethylamine (420 μL, 36.02 mmol) in DCM (2 mL) at 0-5° C. The reaction mixture was stirred at 0-5° C. for 3 hrs then gradually warmed to RT over 5 hrs. The reaction mixture was partitioned between saturated sodium hydrogen carbonate solution and DCM. The organic phase was concentrated in vacuo and purified by flash chromatography eluting with a gradient of 0-100% EtOAc in cyclohexane to give the title compound as an orange glass (308 mg).
Reaction SMILES: C1([Mg]Br)C=CC=CC=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1.[Mg].[CH3:18][N:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](=[O:29])[N:21]2[CH2:30][CH2:31][N:32]=[C:20]12>O1CCCC1.O.C(OCC)C>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:22]2([OH:29])[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:19]([CH3:18])[C:20]3=[N:32][CH2:31][CH2:30][N:21]23)=[CH:12][CH:11]=1
Reactant: Clc1ccc(Br)cc1
Reactant: CN1C2=NCCN2C(=O)c2ccccc21
Agent: Br[Mg]c1ccccc1
Agent: [Mg]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CN1C2=NCCN2C(O)(c2ccc(Cl)cc2)c2ccccc21
Yield: 26.5 %

Procedure:
To a phenylmagnesium bromide solution prepared from 6.9 g of p-chlorophenyl bromide, 0.88 g of magnesium and 25 ml of dry diethyl ether was added dropwise a solution of 2.42 g of 10-methyl-2,3,5,10-tetrahydroimidazo[2,1-b]quinazoline-5-one in 30 ml of dry tetrahydrofuran with stirring and ice-cooling. The mixture was heated under reflux for 2 hours and then cooled. To the mixture were added dropwise 20 ml of water and stirring was continued for a while. The resulting mixture was extracted with hot chloroform and the insoluble material was filtered off and washed with hot chloroform. The chloroform layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was crystallized from ethanol and the crystals were further recrystallized from dimethylformamide to give 1.0 g of 5-(p-chlorophenyl)-5-hydroxy-10-methyl-2,3,5,10-tetrahydroimidazo[2,1-b]quinazoline as colorless needles, m.p. 207°-209° C. (decomp.).
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH:4]=[CH:5][CH2:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=1[OH:15].[CH3:20][N:21]1CCCC1=O>>[C:20]([C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH:4]=[CH:5][CH2:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=1[OH:15])#[N:21]
Reactant: COc1ccc(O)c(CC=Cc2ccccc2Br)c1
Reactant: CN1CCCC1=O
Product: COc1ccc(O)c(CC=Cc2ccccc2C#N)c1
Yield: 39 %

Procedure:
Cuprous cyanide (1.03 g; 11.5 mM) and 2-(o-bromocinnamyl)-4-methoxyphenol (1.03 g; 3.23 mM) were combined in 12 ml of anhydrous N-methylpyrrolidinone. Nitrogen was bubbled through the resulting suspension for five minutes and it was then heated to 175° under positive nitrogen pressure for 2 hours. The reaction was poured into 50 ml of conc. NH4OH and 50 ml of water. The emulsion was extracted three times with ether and the ether extracts were washed once with water. Drying over magnesium sulfate was followed by solvent removal leaving a brown oil. This crude product was purified by flash chromatography with 35% ethyl acetate in hexane on a 30 mm×6" column of silica gel. Recrystallization from ethyl acetate/hexane gave 2-(o-cyanocinnamyl)-4-methoxyphenol as a tan solid (335 mg, 39% yield) m.p. 72°-74°.
Reaction SMILES: [CH3:1][C:2]([CH3:26])([CH3:25])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH:20]=[C:19]([CH2:21][OH:22])[CH:18]=[CH:17][C:14]=3[C:15]#[N:16])=[CH:10][CH:11]=2)[N:6]([CH3:23])[C:5]1=[O:24].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>C(Cl)Cl.S([O-])([O-])(=O)=S.[Na+].[Na+]>[CH3:1][C:2]([CH3:26])([CH3:25])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH:20]=[C:19]([CH:21]=[O:22])[CH:18]=[CH:17][C:14]=3[C:15]#[N:16])=[CH:10][CH:11]=2)[N:6]([CH3:23])[C:5]1=[O:24]
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(-c3cc(CO)ccc3C#N)nc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(-c3cc(C=O)ccc3C#N)nc21
Reaction time: 2 h

Procedure:
To a microwave vial, 2-[1-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl]-4-(hydroxymethyl)benzonitrile (15-3) (300 mg, 0.86 mmol) and Dess-Martinperiodinane (545 mg, 1.28 mmol) was added under nitrogen and dissolved in DCM (4.3 ml). After stirring for 2 hours, the reaction was diluted with sodium thiosulfate, washed with DCM (3×), and then washed the combined organic layer with brine, dried over sodium sulfate, filtered and concentrated. The mixture was diluted with methanol, and passed through a syringe filter. The solution was purified using reverse phase chromatography (10-100%, 0.1% TFA in H2O/Acetonitrile) and the desired fractions were collected and concentrated to produce 2-[1-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl]-4-formylbenzonitrile (30-1). MS (M+H)+: observed=349.2, calculated=349.4.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C:5]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:6][C:7]1[N:8]([CH2:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[CH:14]=2)[CH:9]=[CH:10][N:11]=1)[CH3:2]>C(O)C.[Ni].O>[CH2:1]([O:3][C:4](=[O:28])[CH:5]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:6][C:7]1[N:8]([CH2:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[CH:14]=2)[CH:9]=[CH:10][N:11]=1)[CH3:2]
Reactant: CCOC(=O)C(=Cc1nccn1Cc1cc(Cl)cc(Cl)c1)Cc1ccccc1
Agent: [Ni]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(Cc1ccccc1)Cc1nccn1Cc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 93.2 %

Procedure:
To a solution of 2-benzyl-3-[1-(3,5-dichloro-benzyl)-1H-imidazol-2-yl]-acrylic acid ethyl ester, (409 mg, 0.99 mmol) in absolute ethanol (30 mL) was added Raney nickel active catalyst (approximately 1 g of a 50% suspension in water). The reaction flask was flushed with N2 prior to flushing with H2 via a balloon. The reaction was stirred at ambient temperature for 14 h under a balloon atmosphere of H2. After flushing with N2, the reaction was filtered through a plug of celite and the filtrate concentrated in vacuo. The resulting residue was partitioned with CH2Cl2 (10 mL) and saturated NaHCO3 (5 mL). The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo to afford 2-benzyl-3-[1-(3,5-dichloro-benzyl)-1H-imidazol-2-yl]-propionic acid ethyl ester (385 mg, 94%) as a colorless oil: ESI MS m/z 417 [C22H22Cl2N2O2+H]+.