Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C@@H:5]([CH3:30])[CH2:6][O:7][C:8]1[N:13]=[CH:12][C:11]([NH:14][C:15](=[O:28])[C:16]2[CH:21]=[C:20]([F:22])[C:19]([O:23][CH2:24][CH:25]3[CH2:27][CH2:26]3)=[N:18][CH:17]=2)=[C:10](Cl)[CH:9]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.[Cu]I>[CH:25]1([CH2:24][O:23][C:19]2[N:18]=[CH:17][C:16]([C:15]3[O:28][C:10]4[CH:9]=[C:8]([O:7][CH2:6][C@@H:5]([NH:4][C:1](=[O:3])[CH3:2])[CH3:30])[N:13]=[CH:12][C:11]=4[N:14]=3)=[CH:21][C:20]=2[F:22])[CH2:27][CH2:26]1
Reactant: CC(=O)N[C@@H](C)COc1cc(Cl)c(NC(=O)c2cnc(OCC3CC3)c(F)c2)cn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N[C@@H](C)COc1cc2oc(-c3cnc(OCC4CC4)c(F)c3)nc2cn1
Temperature: 160 °C
Reaction time: 3 h
Yield: 5 %

Procedure:
A suspension of N-(6-(((2S)-2-acetamidopropyl)oxy)-4-chloropyridin-3-yl)-6-(cyclopropylmethoxy)-5-fluoronicotinamide (860 mg), potassium carbonate (544 mg) and copper(I) iodide (37.5 mg) in DMF (10 mL) was stirred at 160° C. for 3 hr under microwave irradiation. To the reaction mixture was added water, and the obtained mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and subjected to silica gel column chromatography (NH, ethyl acetate). The solvent was evaporated, and the obtained solid was washed with ethyl acetate/hexane to give the title compound (39.8 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:6]1[C@@H:9]([CH2:10][CH:11]=[O:12])[NH:8][C:7]1=[O:13])([CH3:5])[CH3:4].CC(C)=[O:16].OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CC(C)=O>[CH3:1][O:2][C:3]([C@H:6]1[C:7](=[O:13])[NH:8][C@@H:9]1[CH2:10][C:11]([OH:16])=[O:12])([CH3:5])[CH3:4]
Reactant: COC(C)(C)[C@H]1C(=O)N[C@@H]1CC=O
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: COC(C)(C)[C@H]1C(=O)N[C@@H]1CC(=O)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (3S, 4R)-3-(1-methoxy-1-methylethyl)-4-(2-oxoethyl)azetidin-2-one (760 mg) in acetone (60 ml) was added dropwise 2N Jones Reagent (4.10 ml) at 0° C. After stirring for 30 minutes at 0° C., isopropyl alcohol (8 ml) was added to the resultant mixture, and then evaporated in vacuo. The residue was dissolved in a saturated aqueous sodium chloride (40 ml) and extracted with chloroform (80 ml×5). After drying over magnesium sulfate, the chloroform extracts were filtered and evaporated in vacuo. The residue was chromatographed on silica gel (30 g) eluting with a mixture of methylene chloride and methanol (10:1 to 1:2), and then a mixture of acetic acid and ethyl acetate (1:50) to give 2-[(2R, 3S)-3-(1-methoxy-1-methylethyl)-4-oxoazetidin-2-yl]acetic acid (545.1 mg) as an amorphous solid.
Reaction SMILES: Cl.[NH:2]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]3[N:21]=[CH:20][NH:19][C:17]3=2)[N:12]=[C:11]([CH3:22])[CH:10]=1)C1C=CC=CC=1.N[C:24]1[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[N:28][CH:29]=1.[NH4+].[OH-]>CN(C)C=O>[CH3:31][O:30][C:27]1[N:28]=[CH:29][C:24]([NH:2][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]4[N:21]=[CH:20][NH:19][C:17]4=3)[N:12]=[C:11]([CH3:22])[CH:10]=2)=[CH:25][CH:26]=1
Reactant: Cc1cc(Nc2ccccc2)c2c(ccc3nc[nH]c32)n1
Reactant: COc1ccc(N)cn1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1ccc(Nc2cc(C)nc3ccc4nc[nH]c4c23)cn1
Reaction time: 8 h

Procedure:
A stirred mixture of the compound of Example I, C. (22 g. 0.1 mole) and 5-amino-2-methoxypyridine (12 g., 0.1 mole) in 200 ml. of dimethylformamide, was refluxed for 6 hours. The reaction mixture, after standing at room temperature overnight, was filtered to give a tan solid. The solid was treated with dilute NH4OH and then filtered to yield 30 g. (98%) of tan product.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[O:12]=[C:13]([CH2:20][CH3:21])[CH2:14][C:15](OCC)=[O:16]>C1(C)C=CC=CC=1>[O:12]=[C:13]([CH2:20][CH3:21])[CH2:14][C:15]([O:9][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][CH:10]=1)=[O:16]
Reactant: CCOC(=O)CC(=O)CC
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Solvent: Cc1ccccc1
Product: CCC(=O)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 98.4 %

Procedure:
A suspension of 55.3 g (0.36 mole) of 4-nitrobenzyl alcohol and 56.2 g (0.39 mole) of ethyl 3-oxopentanoate in 360 ml of toluene was heated to boiling. About 300 ml of toluene were distilled out over the course of 10 h, then the mixture was cooled and another 200 ml were added and this procedure was repeated. After cooling, the mixture was filtered through kieselguhr, which was washed with toluene, and the filtrate solution was evaporated in vacuo. 89 g (98%) of the title compound were obtained as an oil, Rf: 0.42 (toluene:ethyl acetate 4:1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:50]=[CH:51][CH:52]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]5)=[C:22]([CH3:39])[CH:21]=4)[CH:18]=3)[N:13]([S:40]([C:43]3[CH:49]=[CH:48][C:46]([CH3:47])=[CH:45][CH:44]=3)(=[O:42])=[O:41])[CH:12]=2)[CH:8]=[N:7]1.CO.[ClH:55]>O1CCOCC1>[ClH:55].[F:1][C:2]1[CH:3]=[C:4]([CH:50]=[CH:51][CH:52]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]5)=[C:22]([CH3:39])[CH:21]=4)[CH:18]=3)[N:13]([S:40]([C:43]3[CH:44]=[CH:45][C:46]([CH3:47])=[CH:48][CH:49]=3)(=[O:41])=[O:42])[CH:12]=2)[CH:8]=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)c(C)c4)cnc32)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)c(C)c4)cnc32)cc1
Yield: 95.5 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(4-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-methylphenyl)piperazine-1-carboxylate (210 mg, 0.291 mmol) was deprotected in methanol/HCl in dioxane (5/10 ml) to afford 172 mg (95.5% yield) of the titled compound. MS: m/z=621.3 (M+1).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:36]([CH3:37])=[CH:35][C:15]2[N:16]=[C:17]([C:19]3[N:20]=[C:21]([C:25]4[CH:26]=[C:27]5[C:31](=[CH:32][CH:33]=4)[N:30]([CH3:34])[N:29]=[CH:28]5)[N:22]([CH3:24])[CH:23]=3)[S:18][C:14]=2[C:13]=1[C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.O>[C:1]([O:5][C@@H:6]([C:12]1[C:36]([CH3:37])=[CH:35][C:15]2[N:16]=[C:17]([C:19]3[N:20]=[C:21]([C:25]4[CH:26]=[C:27]5[C:31](=[CH:32][CH:33]=4)[N:30]([CH3:34])[N:29]=[CH:28]5)[N:22]([CH3:24])[CH:23]=3)[S:18][C:14]=2[C:13]=1[C:38]1[CH:39]=[CH:40][C:41]([Cl:44])=[CH:42][CH:43]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cn(C)c(-c4ccc5c(cnn5C)c4)n3)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc2nc(-c3cn(C)c(-c4ccc5c(cnn5C)c4)n3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 30 °C
Reaction time: 17 h

Procedure:
In a 25 mL round bottom flask, (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(1-methyl-2-(1-methyl-1H-indazol-5-yl)-1H-imidazol-4-yl)benzo[d]thiazol-6-yl)acetate 15 mg, 0.024 mmol) was dissolved in THF (1.5 mL) EtOH (0.7 mL) and water (0.5 mL). Then aqueous NaOH (2 N) (0.4 mL) was added. The reaction mixture was stirred at 30° C. in oil bath for 17 h. The resulting reaction mixture was concentrated. The residue was purified on Gilson reverse phase HPLC with CH3CN and water (10 mL) to afford the product. LCMS-ESI+: calc'd for: C32H30ClN5O3S: 600.2, 602.2, 601.2 (M+H+); Found: 600.3, 602.3, 601.3 (M+H+). 1H NMR (400 MHz, CD3OD) δ 8.03 (d, J=0.8 Hz, 1H), 7.99 (dd, J=1.6, 0.8 Hz, 1H), 7.93-7.88 (m, 1H), 7.83 (s, 1H), 7.67-7.58 (m, 3H), 7.50 (dd, J=8.6, 2.3 Hz, 1H), 7.42 (ddd, J=8.3, 5.5, 2.2 Hz, 2H), 5.01 (s, 1H), 4.03 (d, J=0.7 Hz, 3H), 3.75 (s, 3H), 2.55 (s, 3H), 0.82 (s, 9H).
Reaction SMILES: N(N(C)[C:4](N)=O)=O.[OH-].[K+].[CH2:10]([N:16]1[C:21]2[CH:22]=[C:23]([C:27]([N:29]([CH:43]([CH3:45])[CH3:44])[C@@H:30]3[CH2:35][CH2:34][CH2:33][N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:31]3)=[O:28])[C:24]([CH3:26])=[CH:25][C:20]=2[O:19][C:18]([CH3:47])([CH3:46])[C:17]1=[O:48])[CH2:11][CH2:12][CH2:13][CH:14]=[CH2:15].C(Cl)(Cl)Cl.C(OCC)C>C(OCC)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:14]1([CH2:13][CH2:12][CH2:11][CH2:10][N:16]2[C:21]3[CH:22]=[C:23]([C:27]([N:29]([CH:43]([CH3:44])[CH3:45])[C@@H:30]4[CH2:35][CH2:34][CH2:33][N:32]([C:36]([O:38][C:39]([CH3:40])([CH3:42])[CH3:41])=[O:37])[CH2:31]4)=[O:28])[C:24]([CH3:26])=[CH:25][C:20]=3[O:19][C:18]([CH3:46])([CH3:47])[C:17]2=[O:48])[CH2:4][CH2:15]1
Reactant: CN(N=O)C(N)=O
Reactant: C=CCCCCN1C(=O)C(C)(C)Oc2cc(C)c(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCOCC
Product: Cc1cc2c(cc1C(=O)N(C(C)C)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1)N(CCCCC1CC1)C(=O)C(C)(C)O2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 81.2 %

Procedure:
N-Nitroso-N-methylurea (2.62 g) was dissolved in diethyl ether (34 ml), and the mixture was added dropwise into a solution of potassium hydroxide (1.53 g) in water (9 ml) under ice-cooling, and the mixture was stirred at 0° C. for 15 minutes. Then, the obtained supernatant was added dropwise to a solution of tert-butyl (3R)-3-[[(4-hex-5-en-1-yl-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl](isopropyl)amino]piperidine-1-carboxylate (300 mg) with palladium acetate (15 mg) in a mixed solvent of chloroform/diethyl ether. The mixture was stirred at room temperature for one hour. After the reaction was complete, the mixture was filtered and concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to give the title compound (250 mg) as a colorless liquid.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([F:15])=[C:11]([CH:14]=2)[C:12]#[N:13])=[N:4][CH:3]=1.[C:16]([Si:20]([CH3:41])([CH3:40])[O:21][C@@H:22]1[C:30]2[C:25](=[C:26](B3OC(C)(C)C(C)(C)O3)[CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23]1)([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+].N#N>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.COCCOC.O>[Si:20]([O:21][C@@H:22]1[C:30]2[C:25](=[C:26]([C:2]3[S:6][C:5]([C:7]4[CH:8]=[CH:9][C:10]([F:15])=[C:11]([CH:14]=4)[C:12]#[N:13])=[N:4][CH:3]=3)[CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:41])[CH3:40]
Reactant: CC1(C)OB(c2cccc3c2CC[C@@H]3O[Si](C)(C)C(C)(C)C)OC1(C)C
Reactant: N#Cc1cc(-c2ncc(Br)s2)ccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CCc2c(-c3cnc(-c4ccc(F)c(C#N)c4)s3)cccc21
Temperature: 90 °C
Yield: 60 %

Procedure:
Prepared using General Procedure 1. A solution of 5-(5-bromothiazol-2-yl)-2-fluorobenzonitrile THZ INT-2 (0.12 g, 0.42 mmol), (5)-tert-butyldimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)oxy)silane IND INT-6 (0.16 g, 0.42 mmol), potassium carbonate (0.176 g, 1.2 mmol) and 3:1 mixture of DME/H2O (2 mL) was degassed with N2 for 10 min before the addition of Pd(PPh3)4 (0.034 g, 0.03 mmol). The mixture reaction was degassed with N2 for additional 2 min and then heated under microwave at 90° C. for 1.5 h. Upon cooling, the reaction mixture was diluted with EA (20 mL) and washed with brine (20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. The crude product was purified by silica gel flash chromatography (30% EA/hexanes) to produce 0.116 g (60%) of (S)-5-(5-(1-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-fluorobenzonitrile as a white solid. LCMS-ESI (m/z) calculated for C25H27FN2OSSi: 450.6; found 451.1 [M+H]+, tR=4.86 min (Method 1). 1H NMR (400 MHz, CDCL3) δ 8.30-8.14 (m, 2H), 7.95 (s, 1H), 7.45 (dd, J=7.0, 0.9, 1H), 7.32 (ddd, J=23.9, 14.6, 11.0, 3H), 5.32 (t, J=7.0, 1H), 3.19 (ddd, J=15.9, 8.8, 2.7, 1H), 2.95 (dt, J=16.1, 8.1, 1H), 2.59-2.40 (m, 1H), 2.08-1.89 (m, 1H), 0.94 (s, 9H), 0.17 (dd, J=13.7, 7.8, 6H).
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)\[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.O[C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[CH2:32][CH:31]2[C:33]([O:35]CC)=[O:34])=[CH:26][CH:25]=1>>[CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)\[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][O:14][C:24]2[CH:29]=[CH:28][C:27]([CH:30]3[CH2:32][CH:31]3[C:33]([OH:35])=[O:34])=[CH:26][CH:25]=2)=[CH:11][CH:12]=1
Reactant: CO/N=C(\COc1ccc(CO)cc1)c1ccc(OC)cc1
Reactant: CCOC(=O)C1CC1c1ccc(O)cc1
Product: CO/N=C(\COc1ccc(COc2ccc(C3CC3C(=O)O)cc2)cc1)c1ccc(OC)cc1
Yield: 13.26 %

Procedure:
Compound 46 was synthesized from (1Z)-2-[4-(hydroxymethyl)phenoxy]-1-(4-methoxyphenyl)ethanone O-methyloxime (0.146 g, 0.48 mmol) and ethyl 2-(4-hydroxyphenyl)cyclopropanecarboxylate (0.1 g, 0.4 mmol) by following the procedure described in scheme 18 (0.01 g, yield: 13.26%); Purity: 92.24%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][NH:11][N:12]1[C:20]2[C:15](=[CH:16][C:17]([OH:21])=[CH:18][CH:19]=2)[CH:14]=[CH:13]1.C(=O)([O-])[O-].[K+].[K+].[CH3:28][N:29]=[C:30]=[O:31]>C1COCC1>[CH3:28][NH:29][C:30](=[O:31])[O:21][C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][CH:18]=1)[N:12]([NH:11][CH2:10][CH2:9][CH2:8][C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[F:1])[CH:13]=[CH:14]2
Reactant: CN=C=O
Reactant: Oc1ccc2c(ccn2NCCCc2ccncc2F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CNC(=O)Oc1ccc2c(ccn2NCCCc2ccncc2F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-[(3-fluoro-4-pyridinyl)propylamino]-1H-indol-5-ol (2.5 g) in 50 ml THF was added potassium carbonate (1.2 g), followed by methyl isocyanate (0.53 ml). After stirring at ambient temperature for three hours, the mixture was filtered, and the filtrate was concentrated to give a solid, 3.0 g, m.p. 165°-166° C. This material was eluted on a silica gel column with ethyl acetate/dichloromethane (1:1) via HPLC. The desired fractions were combined and concentrated to give a solid, 2.7 g, m.p. 177°-178° C.
Reaction SMILES: N1CCCCC1.BrC1SC(C=O)=CC=1.[N:15]1([C:21]2[S:25][C:24]([CH:26]=O)=[CH:23][CH:22]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[CH2:33][C:34]#[N:35]>>[CH3:28][O:29][C:30]1[CH:31]=[C:32](/[C:33](=[CH:26]/[C:24]2[S:25][C:21]([N:15]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]3)=[CH:22][CH:23]=2)/[C:34]#[N:35])[CH:36]=[CH:37][C:38]=1[O:39][CH3:40]
Reactant: O=Cc1ccc(N2CCCCC2)s1
Reactant: COc1ccc(CC#N)cc1OC
Agent: O=Cc1ccc(Br)s1
Solvent: C1CCNCC1
Product: COc1ccc(/C(C#N)=C/c2ccc(N3CCCCC3)s2)cc1OC
Yield: 52.4 %

Procedure:
Through the procedure as employed in Production step 1, an amine moiety derived from piperidine (1.02 g) was introduced into 5-bromothiophene-2-carboxaldehyde (764 mg), to thereby yield 5-piperidin-1-yl-thiophene-2-carbaldehyde (yield: 500 mg, 64%). The produced 5-piperidin-1-yl-thiophene-2-carbaldehyde (293 mg) was condensed with 3,4-dimethoxybenzyl cyanide (266 mg) through Method A (production step 2), to thereby yield the target product (yield: 279 mg, 53%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([Br:8])[CH:7]=1.Br[C:13]([CH3:15])=[CH2:14]>C1COCC1.C([O-])([O-])=O.[Na+].[Na+].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>[Br:1][C:2]1[CH:3]=[C:4]([C:13]([CH3:15])=[CH2:14])[CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: OB(O)c1cc(Br)cc(Br)c1
Reactant: C=C(C)Br
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: C1CCOC1
Product: C=C(C)c1cc(Br)cc(Br)c1
Temperature: 40 °C
Reaction time: 5 h

Procedure:
To a degassed mixture of 5.0 g (17.9 mmol) of 3,5-dibromophenylboronic acid in 50 mL of THF and 25 mL of 2 M Na2CO3 (aqueous) was added 1.13 g (0.975 mmol) of Pd(PPh3)4 and 2.3 mL of 2-bromopropene. The mixture was stirred at 40° C. for 5 h, and the mixture was extracted with EtOAc. The organic layer was washed with 25 mL of brine, dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (10% EtOAc/hexanes) provided 1,3-dibromo-5-(prop-1-en-2-yl)benzene with some impurity.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.CC1(C)COB([C:22]2[CH:23]=[CH:24][C:25]([F:37])=[C:26]([C:28]3[C:29]([C:35]#[N:36])=[C:30]([F:34])[CH:31]=[CH:32][CH:33]=3)[CH:27]=2)OC1>>[F:34][C:30]1[CH:31]=[CH:32][CH:33]=[C:28]([C:26]2[CH:27]=[C:22]([C:2]3[N:6]4[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]4=[N:4][CH:3]=3)[CH:23]=[CH:24][C:25]=2[F:37])[C:29]=1[C:35]#[N:36]
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Reactant: CC1(C)COB(c2ccc(F)c(-c3cccc(F)c3C#N)c2)OC1
Product: N#Cc1c(F)cccc1-c1cc(-c2cnc3nc(C(F)(F)F)ccn23)ccc1F

Procedure:
3-Bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine was coupled with 5′-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-3,2′-difluorobiphenyl-2-carbonitrile as described in Example 1 to give 3,2′-difluoro-5′-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)biphenyl-2-carbonitrile as an off-white solid: δH (360 MHz, CDCl3) 7.31 (2H, dd, J 7 and 3), 7.43-7.49 (2H, m), 7.64-7.75 (3H, m), 8.10 (1H, s), 9.04 (1H, d, J 7); m/z (ES+) 401 (M++H).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:15][CH3:16])(=[O:14])[CH2:10][C:11]([CH3:13])=O>>[CH2:1]([NH:8]/[C:11](/[CH3:13])=[CH:10]\[C:9]([O:15][CH3:16])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CC(C)=O
Reactant: NCc1ccccc1
Product: COC(=O)/C=C(/C)NCc1ccccc1
Reaction time: 8 h
Yield: 62.7 %

Procedure:
96.4 grams (0.9 mole) of benzylamine was added dropwise with stirring while the temperature was maintained below 45° C. to a solution of 116.1 grams (1 mole) of methyl acetoacetate and the reaction mixture allowed to stand overnight to obtain a white solid. The latter was dried and then stripped of the solvent to obtain a residue which was crystallized from hexane to obtain 115.9 grams of the methyl 3-benzylaminocrotonate, m.p. 36°-37.5° C. 4.1 grams (20 millimoles) of the product was dissolved in 5 milliliters of benzene and used in the preparation of the dihydropyridine compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[C:3]=1[NH:18][C:19](=S)[NH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[Cl:29].C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]2[N:18]=[C:19]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=3[Cl:29])[N:12]([CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[C:4]=2[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(Cl)c(NC(=S)Nc2ccc(OC)cc2Cl)c1NCCCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)c2nc(Nc3ccc(OC)cc3Cl)n(CCCCO)c12
Temperature: 50 °C
Reaction time: 1 h
Yield: 89759 %

Procedure:
A suspension of methyl 4-chloro-3-{[(2-chloro-4-methoxyphenyl)carbamothioyl]amino}-2-[(4-hydroxybutyl)amino]benzoate (1.57 g, 3.32 mmol), triethylamine (509 μL, 3.65 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (700 mg, 3.65 mmol) in tetrahydrofuran (15 mL) was stirred at 50° C. for 1 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting solid was washed with diisopropyl ether to give the title compound as a pale brown solid (1.31 g, 2.98 mol, 90%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][N:20]2[C:24](=[O:25])[C:23]3=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]3[C:21]2=[O:30])[O:7][C@@H:6]1Br)(=[O:3])[CH3:2].[NH2:32][C:33]([NH2:35])=[S:34]>CC(C)=O>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][N:20]2[C:24](=[O:25])[C:23]3=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]3[C:21]2=[O:30])[O:7][C@H:6]1[S:34][C:33](=[NH:32])[NH2:35])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](Br)O[C@H](CN2C(=O)c3ccccc3C2=O)[C@@H]1OC(C)=O
Reactant: NC(N)=S
Solvent: CC(C)=O
Product: CC(=O)O[C@H]1[C@@H](OC(C)=O)[C@@H](CN2C(=O)c3ccccc3C2=O)O[C@@H](SC(=N)N)[C@@H]1OC(C)=O
Yield: 85.8 %

Procedure:
A solution of 2,3,4-tri-O-acetyl-6-deoxy-6-phthalimido-α-D-galactopyranosyl bromide (4.0 g.) and thiourea (0.67 g.) in dry acetone (20 ml.) is heated under reflux for 4 hours. The solution is evaporated in vacuo to a syrup which is partitioned between water and dichloromethane. The organic layer is reextracted with water three times. The combined aqueous extracts are evaporated to give 2-S-(2,3,4-tri-O-acetyl-6-deoxy-6-phthalimido-β-D-galactopyranosyl)-2-thiopseudourea (3.40 g.).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH3:8])[C:4]([CH3:12])([CH2:9][CH2:10][NH2:11])[CH:3]1[CH3:13].C(N(CC)CC)C.[S:21]1[CH:25]=[CH:24][C:23]([C:26](Cl)=[O:27])=[CH:22]1>C(Cl)Cl.CCOCC>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH3:8])[C:4]([CH2:9][CH2:10][NH:11][C:26]([C:23]2[CH:24]=[CH:25][S:21][CH:22]=2)=[O:27])([CH3:12])[CH:3]1[CH3:13]
Reactant: O=C(Cl)c1ccsc1
Reactant: CC1CCN(C)C(C)C1(C)CCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC1CCN(C)C(C)C1(C)CCNC(=O)c1ccsc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.6 %

Procedure:
A solution of 1,2,3,4-tetramethyl-3-piperidineethanamine (2.9 g, I6 mmol), triethylamine (10 mL) and methylene chloride (25 mL) was cooled to 0° C. and 3-thiophenecarboxylic acid chloride (2.3 g, 16 mmol) in methylene chloride (15 mL) was added. The reaction mixture was warmed to room temperature and stirred for 16 hours. The reaction mixture was diluted with ether (200 mL) and washed with saturated sodium bicarbonate (2×50 mL), water (50 mL), then brine (50 mL). The organic layer was separated, dried over Na2SO4 and treated with charcoal. The solvent was removed in vacuo and the residue was purified by column chromatography on silica eluting with ether (100%), then 2% diisopropylamine/ether, followed by 5% isopropylamine/ether to afford 2.9 g (62%) of N-[2-(1,2,3,4-tetramethyl-3-piperidinyl)-ethyl]-3-thiophenecarboxamide as an oil. The product was dissolved in ethanol (7 mL), cooled to 0° C., treated with 3.2N ethanolic HCl and diluted with ether to afford 3.1 g of the hydrochloride salt as a yellow solid. The salt was recrystallized from ethanol/ether and had a melting point of 228°-229° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[N:9][CH:10]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>>[OH:18][C:15]1[CH:14]=[CH:13][C:12]([O:11][C:8]2[N:9]=[CH:10][C:5]([O:4][CH2:3][C@@H:2]([NH:1][C:20](=[O:22])[CH3:21])[CH3:19])=[CH:6][CH:7]=2)=[CH:17][CH:16]=1
Reactant: C[C@H](N)COc1ccc(Oc2ccc(O)cc2)nc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N[C@@H](C)COc1ccc(Oc2ccc(O)cc2)nc1

Procedure:
4-[5((S)-2-Aminopropoxy)pyridin-2-yloxy]phenol (42 mg, 0.16 mmol) were reacted with acetic anhydride in analogy to example 2a. Yield: 33 mg (68%), M+H+: 303.05.