Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.C(Cl)Cl>[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11]
Reactant: Nc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=Cc1cccc(Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C1CCC(N2Cc3c(NCc4cccc(Cl)c4)cccc3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.3 %

Procedure:
3-(4-Amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (1.04 g, 4 mmol) was dissolved in acetic acid (7 ml) with heat. The mixture was cooled slightly and methylene chloride (50 ml) was added slowly followed by 3-chlorobenzaldehyde (0.91 ml, 8 mmol) and sodium triacetoxyborohydride. (2.54 g, 12 mmol). The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 2 h, diluted with methylene chloride (100 ml), washed with water (2×100 ml), saturated aqueous sodium bicarbonate (2×100 ml), brine (100 ml), dried (magnesium sulfate), and filtered. The solvent was evaporated in vacuo to give a white solid. The solid was recrystallized from methylene chloride/methanol to give 0.48 g (31%) of product as a white solid: mp 253-255° C.; 1H NMR (DMSO-d6) δ 11.05 (s, 1H), 7.45 (s, 1H), 7.37-7.19 (m, 4H), 6.95 (d, J=7.4 Hz, 1H), 6.63 (d, J=8.0 Hz, 1H), 6.45 (t, J=5.9 Hz, 1H), 5.14 (dd, J=5.1 and 13.1 Hz, 1H), 4.41 (d, J=5.8 Hz, 2H), 4.34 (d, J=17.3 Hz, 1H), 4.20 (d, J=17.2 Hz, 1H) 3.01-2.87 (m, 1H), 2.66-2.60 (m, 1H), 2.42-2.25 (m, 1H), 2.08-2.04 (m, 1H); 13C NMR (DMSO-d6) δ 172.90, 171.24, 168.74, 143.03, 142.59, 133.08, 132.16, 130.19, 129.12, 126.80, 126.70, 125.73, 112.27, 110.55, 51.54, 45.73, 45.47, 31.25, 22.79; Anal. Calcd. For C20H18ClN3O3: C, 62.58, H, 4.73; N, 10.95. Found: C, 62.32; H, 4.61; N, 10.80.
Reaction SMILES: C(O[C:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7](OCCN2CCOCC2)[CH:6]=1)C.[NH2:21][C:22]1[N:26]([C:27]2[CH:28]=[C:29]([CH:36]=[CH:37][C:38]=2[CH3:39])[C:30]([NH:32][CH:33]2[CH2:35][CH2:34]2)=[O:31])[N:25]=[CH:24][C:23]=1[C:40](=[O:49])C1C=CC=C(CO)C=1.C(N(C(C)C)CC)(C)C>C(O)C>[NH2:21][C:22]1[N:26]([C:27]2[CH:28]=[C:29]([CH:36]=[CH:37][C:38]=2[CH3:39])[C:30]([NH:32][CH:33]2[CH2:35][CH2:34]2)=[O:31])[N:25]=[CH:24][C:23]=1[C:40](=[O:49])[C:8]1[CH:9]=[CH:10][C:5]([CH3:4])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cccc(OCCN2CCOCC2)c1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(CO)c2)c1N
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)c2cnn(-c3cc(C(=O)NC4CC4)ccc3C)c2N)cc1
Yield: 21.9 %

Procedure:
A mixture of 2-(4-methyl-benzoyl)-3-phenylamino-acrylonitrile 2 (205 mg, 0.78 mmol), N-cyclopropyl-3-hydrazino-4-methyl-benzamide trifluoroacetic acid salt 7 (Example 6C, 250 mg, 0.78 mmol) and diisopropylethylamine (0.14 mL, 0.78 mmol) in 8 mL of ethanol was heated at 650C in for 18 h. Solvent was removed and the residue was purified by silica gel column chromatography (EtOAc/hexanes, gradient from 1/3 to 3/1). The product can be further purified by trituration with Et2O to give 3-[5-amino-4-(4-methyl-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide 3 as a white solid (64 mg, 22%). HPLC (4 minute gradient) tR 2.26 min;
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5](/[C:11](=C\C2C=CC=CC=2)/[C:12]([NH2:14])=[O:13])[CH:6]=[C:7](OC)[CH:8]=1.[Cl-].[Al+3].[Cl-].[Cl-].C(Cl)(Cl)Cl.[CH3:30][OH:31]>ClC1C=CC=CC=1>[OH:31][C:30]1[CH:4]=[C:3]([OH:2])[CH:8]=[C:7]2[C:6]=1[CH:5]=[CH:11][C:12](=[O:13])[NH:14]2
Reactant: COc1cc(OC)cc(/C(=C\c2ccccc2)C(N)=O)c1
Reactant: CO
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Solvent: ClC(Cl)Cl
Product: O=c1ccc2c(O)cc(O)cc2[nH]1
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
A solution of compound 2 (19.0 g, 67.1 mmol) in chlorobenzene (120 mL) was taken in a 500 mL round bottom flask equipped with a mechanical stirrer and a reflux condenser. Aluminium chloride (44.6 g, 335.6 mmol) was added in portions over a period of 10 min. The reaction mixture was heated at 130° C. for 3 h and cooled to room temperature (TLC chloroform: methanol 9:1, Rf=0.2). Poured into crushed ice (1 Kg) and stirred at room temperature for further 30 min. The solid separated was filtered and washed with water till neutral to pH. The solid was then washed with hexane (2×50 mL) and dried at 100° C. for 1 h to furnish 5,7-dihydroxy-1,2-dihydro-2-quinolinone (3, 10 g) in 92% yield as a dark brown solid. M.P.>300° C. The quinolinone obtained was further characterised as its diacetate.
Reaction SMILES: [Cl:1][C:2]1([S:8](Cl)(=[O:10])=[O:9])[NH:6][C:5]([Cl:7])=[CH:4][S:3]1.[CH2:12]([NH2:15])[CH:13]=[CH2:14]>>[CH2:12]([NH:15][S:8]([C:2]1([Cl:1])[NH:6][C:5]([Cl:7])=[CH:4][S:3]1)(=[O:10])=[O:9])[CH:13]=[CH2:14]
Reactant: C=CCN
Reactant: O=S(=O)(Cl)C1(Cl)NC(Cl)=CS1
Product: C=CCNS(=O)(=O)C1(Cl)NC(Cl)=CS1

Procedure:
In analogy to Example 2, the N-allyl-2,4-dichloro-thiazole-sulphonamide was prepared by reacting 2,4-dichlorothiazolesulphonyl chloride from Example 1 with anhydrous allylamine. Following recrystallization from petroleum ether/acetone (6:1), 7.6 g of product were obtained (28% of the theoretical yield), m.p.: 80-81° C.
Reaction SMILES: [Br:1][C:2]1[C:9]([F:10])=[C:8]([F:11])[C:7](F)=[CH:6][C:3]=1C=O.C(N(CC)CC)C.[CH3:20][C@H:21]1[O:26][C@@H:25]([CH3:27])[CH2:24][NH:23][CH2:22]1.[C:28](=[O:31])(O)[O-].[Na+]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:6]([C:7]([N:23]2[CH2:24][C@H:25]([CH3:27])[O:26][C@H:21]([CH3:20])[CH2:22]2)=[C:8]([F:11])[C:9]=1[F:10])[CH:28]=[O:31]
Reactant: O=Cc1cc(F)c(F)c(F)c1Br
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(c2c(C=O)cc(Br)c(F)c2F)C[C@H](C)O1
Temperature: 25 °C

Procedure:
2-Bromo-3,4,5-trifluorobenzaldehyde (133.15 grams, 0.56 mol) was dissolved in 1000 ml dry acetonitrile. Triethylamine (118.65 ml, 0.85 mol) was added, followed by cis-2,6-dimethylmorpholine (Lancaster, 71.64 grams, 0.62 mol), and 125 ml additional acetonitrile. The mixture was refluxed for 24 hours, then cooled to room temperature, and poured into 1500 ml saturated sodium bicarbonate solution. The phases were separated and the aqueous phase extracted twice with 500 ml ethyl acetate. The combined organic portions were washed twice with 500 ml brine and then dried over magnesium sulfate. After filtering and rotary evaporation, 199.7 grams of oil was recovered. The oil was diluted to ˜300 ml with heptane to induce solidification and placed in the freezer overnight. The resulting yellow solid was filtered to yield 111.7 grams, 99.8% purity (HPLC) of title compound. Mp 88.1-92.0° C. HPLC analysis done on a Chromolith Performance column, RP-18e, 100-4.6 mm; Mobile phase: A=MeOH, B=0.1N TEAA (pH=7); Gradient: 60% A to 100% A over 5 minutes; wavelength: 254 nm; Retention time: 1.94 minutes.
Reaction SMILES: C([O:8][C:9]([NH:11][CH2:12][CH:13]=[CH2:14])=[O:10])C1C=CC=CC=1.ClC(OCC1C=CC=CC=1)=O.S(Cl)(C1C=[CH:34][C:32]([CH3:33])=[CH:31]C=1)(=O)=O.C(Cl)(=O)C1C(=CC=CC=1)C(Cl)=O.C(Cl)(=O)C1C=CC=CC=1>C(N(CC)CC)C>[C:32]([O:10][C:9]([NH:11][CH2:12][CH:13]=[CH2:14])=[O:8])([CH3:31])([CH3:33])[CH3:34]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C=CCNC(=O)OCc1ccccc1
Agent: O=C(Cl)OCc1ccccc1
Agent: O=C(Cl)c1ccccc1C(=O)Cl
Solvent: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Product: C=CCNC(=O)OC(C)(C)C

Procedure:
N-benzyloxycarbonyl allyl amine was made in the same manner by utilizing benzyl chloroformate and triethylamine at 0° C. Cbz chloride, tosyl chloride, phthaloyl chloride and benzoyl chloride can similarly be used to obtain the corresponding allyl amine.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=[O:6].C1C(=O)N(Br)C(=O)C1.[NH2:25][C:26]([NH2:28])=[S:27]>O>[NH2:28][C:26]1[S:27][C:4]([C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)=[O:6])=[C:3]([C:2]([F:16])([F:15])[F:1])[N:25]=1
Reactant: NC(N)=S
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(F)cc1
Agent: O=C1CCC(=O)N1Br
Solvent: O
Product: Nc1nc(C(F)(F)F)c(C(=O)c2ccc(F)cc2)s1
Temperature: 85 °C

Procedure:
A mixture of 4,4,4-Trifluoro-1-(4-fluoro-phenyl)-butane-1,3-dione (15 g, 64 mmol) and NBS (11.4 g, 64.1 mmol) was ground together at RT, which incited to give a homogeneous mixture and then solidified to give crude brominated product. Water was added to rinse the solid. The solid was taken up in ethanol (50 mL), and thiourea (4.9 g, 64 mmol) was added. The mixture was heated at 85° C. for 4 h, cooled to RT and partitioned between ethyl acetate and aq. K2CO3. The organic extract was dried over MgSO4, concentrated and chromatographed to give the title compound. m/z 291.0 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:4]=1[CH2:5][NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[CH2:20]([O:22][C@H:23]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:24][C:25]1[CH:35]=[CH:34][C:28]([O:29][CH2:30][C:31](O)=[O:32])=[CH:27][CH:26]=1)[CH3:21].C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:4]=1[CH2:5][N:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:31](=[O:32])[CH2:30][O:29][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][C@H:23]([O:22][CH2:20][CH3:21])[C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:35][CH:34]=1
Reactant: CCCCCCCNCc1cccc(OC)c1OC
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCN(Cc1cccc(OC)c1OC)C(=O)COc1ccc(C[C@H](OCC)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.8 %

Procedure:
To a solution of N-(2,3-dimethoxybenzyl)-N-heptylamine (1.46 g, 5.5 mmol) and {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (1.48 g, 5.0 mmol) in methylene chloride (50 mL) at 0° C. were added N,N-diisopropylethylamine (2.0 mL, 11.5 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (1.93 g, 6.0 mmol) and the reaction mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue was taken up in ethyl acetate (200 mL) and the organic phase was washed with saturated aqueous NaHCO3 (3×100 mL), 5% HCl (3×100 mL), and brine (100 mL), dried over Na2SO4, and concentrated in vacuo. Purification on silica gel (100 g) with methanol (0-2% gradient) in methylene chloride as the eluent and collection of pure fractions yielded 1.57 g (58%) of a pale yellow oil.
Reaction SMILES: [Si:1]([C:8]1[C:13]([Cl:14])=[C:12](F)[N:11]=[C:10]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[NH:18][N:17]=2)[C:9]=1[F:25])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1([Si:31]([CH3:34])([CH3:33])[CH3:32])C=CN=C1.[CH3:35][CH:36]([CH3:46])[C@:37]([CH:40]1[CH2:45][NH:44][CH2:43][CH2:42][NH:41]1)([OH:39])[CH3:38]>C1COCC1.C(OCC)(=O)C>[Si:1]([C:8]1[C:13]([Cl:14])=[C:12]([N:44]2[CH2:43][CH2:42][NH:41][C@H:40]([C@:37]([O:39][Si:31]([CH3:34])([CH3:33])[CH3:32])([CH:36]([CH3:46])[CH3:35])[CH3:38])[CH2:45]2)[N:11]=[C:10]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[NH:18][N:17]=2)[C:9]=1[F:25])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)[C@@](C)(O)C1CNCCN1
Reactant: CC(C)(C)[Si](C)(C)c1c(F)c(-c2n[nH]c3ncccc23)nc(F)c1Cl
Reactant: C[Si](C)(C)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)[C@@](C)(O[Si](C)(C)C)[C@@H]1CN(c2nc(-c3n[nH]c4ncccc34)c(F)c([Si](C)(C)C(C)(C)C)c2Cl)CCN1
Temperature: 95 °C
Reaction time: 48 h
Yield: 59 %

Procedure:
3-(4-(tert-butyldimethylsilyl)-5-chloro-3,6-difluoropyridin-2-yl)-1H-pyrazolo[3,4-b]pyridine (132.7 g, 348 mmol) was dissolved in anhydrous THF (265 mL). Imidazol-1-yl(trimethyl)silane (254 mL) was added followed by (2R)-3-methyl-2-(piperazin-2-yl)butan-2-ol (90 g, 522 mmol). The mixture was divided into four glass pressure vessel's and the sealed containers heated and stirred at 95° C. for 48 hours. The crude mixtures were cooled, combined and diluted with ethyl acetate (1.7 L). The solution was washed with saturated sodium bicarbonate (2×500 ml). The combined aqueous layers were back-extracted with ethyl acetate (500 ml). The combined organics were washed with brine (500 ml), dried over MgSO4, filtered and concentrated in vacuo to give a viscous brown oil. The diastereoisomers were separated on silica gel (10-100% ethyl acetate containing 2% triethylamine in petroleum ether). This gave the required (S,R)-diastereoisomer as a yellow foam (125.3 g, 59%); 1H NMR (CDCl3) 0.01 (9H, s), 0.42 (6H, s), 0.78-0.89 (15H, m), 1.09-1.13 (3H, m), 1.74 (1H, m), 2.61 (1H, m), 2.80-2.99 (4H, m), 3.12 (1H, m), 3.45 (1H, d), 3.69 (1H, d), 7.12 (1H, m), 8.55 (1H, m), 8.81 (1H, m), 12.75 (1H, brs); 19F NMR (decoupled) −108.9; MS ES 605.2 (M+). The (R,R)-diastereoisomer was isolated as a yellow foam (27.5 g, 13%); 1H NMR (CDCl3) 0.00 (9H, s), 0.38 (6H, m), 0.76-0.80 (15H, m), 0.85 (3H, s), 1.85 (1H, m), 2.50 (1H, m), 2.90-3.13 (4H, m), 3.42 (1H, m), 3.56 (1H, m), 3.91 (1H, m), 7.08 (1H, m), 8.51 (1H, m), 8.76 (1H, m), 12.70 (1H, brs); 19F NMR (decoupled) −109.0; MS ES 605.2 (M+).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[CH2:13][C@@H:12]([O:14][Si](C)(C)C)[CH:11]=[C:10]1[CH2:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H].Cl>O1CCCC1.[Pd].C(OCC)(=O)C.O>[CH2:1]([O:8][C@@H:9]1[C@H:10]([CH2:19][O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:11][C@H:12]([OH:14])[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)O[C@H]1C=C(COCc2ccccc2)[C@@H](OCc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O[C@H]1C[C@@H](COCc2ccccc2)[C@@H](OCc2ccccc2)C1
Reaction time: 18 h
Yield: 88.1 %

Procedure:
To a solution of ((1R,4S)-4-(benzyloxy)-3-(benzyloxymethyl)cyclopent-2-enyloxy)trimethylsilane (22) (478.00 g, 1.2494 mol) in tetrahydrofuran (9.6 L), Pd, 5 wt % on barium sulfate (265.9 g, 0.1249 mol) was added and the mixture was stirred under 100 psi of hydrogen at ambient temperature for 18 hours, stirring at 200 rpm. HPLC analysis after 18 hours indicated consumption of starting material. The reaction mixture was filtered through a medium frit funnel and the bed was washed with tetrahydrofuran (2000 mL). The filtrate was concentrated, yielding a yellow oil. The resulting oil was taken up in ethyl acetate (2000 mL) to which 2.0 M of hydrochloric acid in water (2000 mL) was added, and the biphasic mixture was stirred for 1 hour. The organic layer was separated and extracted once with saturated sodium bicarbonate in water (2000 mL), twice with 2.0 M of sodium hydroxide in water (2000 mL) and finally with saturated sodium chloride in water (2000 mL). The organic layer was concentrated to give a brown oil (344 g, 88%) which was used without further purification. 1H NMR (300 MHz, CD3OD, δ): 7.18 (m, 10H), 4.38 (m, 4H), 4.12 (m, 1H), 3.85 (t, 1H), 3.68 (m, 1H), 3.44 (m, 1H), 2.00 (m, 3H), 1.75 (m, 1H) and 1.42 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH3:10])[N:5]=[C:4]([N:18]2[CH:22]=[C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:20]=[N:19]2)[CH:3]=1.[NH2:28][C:29]1[CH:34]=[N:33][CH:32]=[CH:31][N:30]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C@@H:9]([NH:8][C:6]2[N:5]=[C:4]([N:18]3[CH:22]=[C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:20]=[N:19]3)[CH:3]=[C:2]([NH:28][C:29]3[CH:34]=[N:33][CH:32]=[CH:31][N:30]=3)[N:7]=2)[CH3:10])=[CH:12][CH:13]=1
Reactant: CCOC(=O)c1cnn(-c2cc(Cl)nc(N[C@@H](C)c3ccc(F)cc3)n2)c1
Reactant: Nc1cnccn1
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cnn(-c2cc(Nc3cnccn3)nc(N[C@@H](C)c3ccc(F)cc3)n2)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 78.2 %

Procedure:
50 mg of ethyl (S)-1-{6-chloro-2-[1-(4-fluorophenyl)ethylamino]pyrimidin-4-yl}-1H-pyrazole-4-carboxylate, 15 mg of 2-aminopyrazine, 12 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 17 mg of sodium t-butoxide and 7 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn to 10 ml of degassed toluene, and the mixture was stirred at 100° C. for 2 hours under argon atmosphere. The reaction solution was purified by silica gel column chromatography to obtain 45 mg of the objective compound as white powder.
Reaction SMILES: Cl.[O:2]=[C:3]1[CH:8]=[C:7]([CH2:9][N:10]2[C:14]([CH2:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)=[CH:13][N:12]=[CH:11]2)[CH:6]=[CH:5][N:4]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Cl:30]C1C=C(I)C=CC=1.IC1C=CC=CC=1>>[Cl:30][C:26]1[CH:25]=[C:24]([N:4]2[CH:5]=[CH:6][C:7]([CH2:9][N:10]3[C:14]([CH2:15][C:16]4[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=4)=[CH:13][N:12]=[CH:11]3)=[CH:8][C:3]2=[O:2])[CH:29]=[CH:28][CH:27]=1
Reactant: N#Cc1ccc(Cc2cncn2Cc2ccn(-c3ccccc3)c(=O)c2)cc1
Reactant: Clc1cccc(I)c1
Agent: Cl
Solvent: Ic1ccccc1
Product: N#Cc1ccc(Cc2cncn2Cc2ccn(-c3cccc(Cl)c3)c(=O)c2)cc1

Procedure:
4-{3-[1-(3-Chloro-phenyl)-2-oxo-1,2-dihydropyridin-4-ylmethyl]-3H-imidazol-4-ylmethyl}benzonitrile was prepared in a manner substantially similar to the procedure described above for 4-[3-(2-oxo-1-phenyl-1,2-dihydropyridin-4-ylmethyl)-3H-imidazol-4-ylmethyl]benzonitrile, hydrochloride, but substituting 3-chloroiodobenzene for the iodobenzene in Step 3.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]1[O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6]1.[CH3:13][CH:14]([CH3:30])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:19]=1)=[O:16]>>[CH3:11][C:8]1([CH3:12])[CH2:9][O:10][CH:5]([CH2:4][CH2:3][CH2:2][N:27]2[CH2:28][CH2:29][CH:24]([C:20]3[CH:19]=[C:18]([NH:17][C:15](=[O:16])[CH:14]([CH3:13])[CH3:30])[CH:23]=[CH:22][CH:21]=3)[CH2:25][CH2:26]2)[O:6][CH2:7]1
Reactant: CC1(C)COC(CCCBr)OC1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCC3OCC(C)(C)CO3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 2-(3-bromopropyl)-5,5-dimethyl-1,3-dioxane and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 403.2 (M+H)+.
Reaction SMILES: [CH2:1]=[O:2].[CH2:3](O)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[ClH:10]>ClC(Cl)CCl>[Cl:10][CH2:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCO
Reactant: C=O
Reactant: Cl
Solvent: ClCC(Cl)Cl
Product: CCCCCCOCCl

Procedure:
30 g (1 mole) of paraformaldehyde were stirred in 100 ml of 1,1,2-trichloroethane with 102 g (1 mole) of 1-hexanol at 0°-5° C. HCl gas was passed for 2 hours. The product is diluted to give a stock solution of 3M concentration.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]1[CH:24]=[CH:23][C:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[OH:22])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[C@@H:29]1[O:46][C@H:45]([CH2:47][O:48]C(=O)C)[C@@H:40]([O:41]C(=O)C)[C@H:35]([O:36]C(=O)C)[C@H:30]1[O:31]C(=O)C)(=O)C.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.ClCCl>[O:22]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:24][CH:23]=1)[C@@H:29]1[O:46][C@H:45]([CH2:47][OH:48])[C@@H:40]([OH:41])[C@H:35]([OH:36])[C@H:30]1[OH:31]
Reactant: Oc1ccccc1Cc1ccc(CCOCc2ccccc2)cc1
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: OC[C@H]1O[C@@H](Oc2ccccc2Cc2ccc(CCOCc3ccccc3)cc2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 14 h
Yield: 70.4 %

Procedure:
To a solution of 2-[4-(2-benzyloxyethyl)benzyl]phenol (3.2 g) and 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose (12 g) in toluene (34 mL) and dichloromethane (17 mL) was added boron trifluoride diethyl-ether complex (3.8 mL), and the mixture was stirred at room temperature for 14 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was dissolved in methanol (50 mL), sodium methoxide (28% methanol solution, 0.39 mL) was added to the solution, and the mixture was stirred at room temperature for 2.5 hours. The solvent of the reaction mixture was removed under reduced pressure, water was added to the residue, and the resulting mixture was extracted with ethylacetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to give 2-[4-(2-benzyloxyethyl)benzyl]phenyl β-D-glucopyranoside (3.4 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([N:17]([O:19][CH3:20])[CH3:18])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:21][NH:22][CH3:23]>C(O)C>[CH3:21][N:22]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([N:17]([O:19][CH3:20])[CH3:18])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)[CH3:23]
Reactant: CON(C)C(=O)c1ccc(-c2ccc(CBr)cc2)cc1
Reactant: CNC
Solvent: CCO
Product: CON(C)C(=O)c1ccc(-c2ccc(CN(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 52 %

Procedure:
1.95 g of 4'-bromomethyl-N-methoxy-N-methyl-4-biphenylcarboxamide was treated with 20 mL of a 33% solution of dimethylamine in ethanol, stirred at room temperature for 24 hours, the reaction mixture was evaporated, the residue was dissolved in 50 mL of ethyl acetate and washed with 50 mL of sodium hydroxide solution and with 50 mL of a saturated sodium chloride solution. The organic phases were dried over magnesium sulphate and evaporated. The crude product was chromatographed on 100 mL of silica gel with methylene chloride/methanol 9:1. There was obtained 1.16 g (52%) of 4'-[(dimethylamino)methyl]-N-methoxy-N-methyl-4-biphenylcarboxamide as a colorless solid with a m.p. of 42°-43° C.
Reaction SMILES: [Cl:1][C:2]1[C:18]([CH3:19])=[CH:17][CH:16]=[C:15]([Cl:20])[C:3]=1[NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[C:7](=[N:9][OH:10])[NH2:8].Cl[C:22](OCC)=[O:23]>N1C=CC=CC=1>[Cl:1][C:2]1[C:18]([CH3:19])=[CH:17][CH:16]=[C:15]([Cl:20])[C:3]=1[NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]1[NH:8][C:22](=[O:23])[O:10][N:9]=1
Reactant: CCOC(=O)Cl
Reactant: Cc1ccc(Cl)c(Nc2ccccc2C(N)=NO)c1Cl
Solvent: c1ccncc1
Product: Cc1ccc(Cl)c(Nc2ccccc2-c2noc(=O)[nH]2)c1Cl
Yield: 46.4 %

Procedure:
To a room temperature solution of 2-(2,6-dichloro-3-methylanilino)benzamide oxime (585 mg, 1.89 mmols) in 5 mL of pyridine is added ethyl chloroformate (250 μL, 2.62 mmols). The solution is heated at reflux for 1 hour, cooled, and concentrated in vacuo. Flash chromatography eluting with 2:1 hexane: ethyl acetate provides 295 mg (47%) of 3-[2-[(2,6-dichloro-3-methylphenyl)amino]phenyl]-1,2,4-oxadiazol-5(4H)-one as a white solid;
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:14]=[CH:13][C:9]2[N:10]=[CH:11][NH:12][C:8]=2[CH:7]=1)[CH:2]([CH3:4])[CH3:3].[CH3:15][S:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>>[CH3:15][S:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:6]2[CH:14]=[CH:13][C:9]3[NH:10][CH:11]=[N:12][C:8]=3[CH:7]=2)=[CH:19][CH:18]=1
Reactant: CSc1ccc(CBr)cc1
Reactant: CC(C)CNc1ccc2nc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CSc1ccc(CN(CC(C)C)c2ccc3[nH]cnc3c2)cc1

Procedure:
The compound was synthesized starting from N-isobutyl-benzimidazol-5-amine (95 mg; 0.5 mmol; 1 eq.), 4-methylthiobenzylbromide (120 mg; 0.55 mmol; 1.1 eq.) and K2CO3 (76 mg; 0.55 mmol; 1.1 eq.) according to method 6; Yield: 0.066 g (40.6%); MS m/z: 326.4 [M+H]+; 1H-NMR (400 MHz, DMSO d6): δ 0.92 (d, 6H, 3J=6.6 Hz); 2.01-2.08 (m, 1H); 2.41 (s, 3H); 3.21 (d, 2H, 3J=7.1 Hz); 4.53 (s, 2H); 6.68 (br s, 1H); 6.70 (dd, 1H, 3J=2.1 Hz, 3J=8.7 Hz); 7.13-7.18 (m, 4H); 7.34 (d, 1H, 3J=8.7 Hz); 7.90 (s, 1H); 11.91 (br s, 1H); HPLC (METHOD [A]): rt 16.40 min (99.5%)