Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[NH:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]2[N:30]=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=2)=[CH:16][CH:15]=1)=[O:13].Cl.[CH3:38][NH:39][O:40][CH3:41].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.ClCCl>[CH3:38][N:39]([O:40][CH3:41])[C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([NH:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21]3[N:30]=[C:29]([C:28]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:31]4[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:22]=3)=[CH:18][CH:19]=2)=[O:13])[CH:4]=1
Reactant: Cc1ccc(C(=O)O)cc1NC(=O)c1ccc(Nc2nc(-c3ccccc3)c3ccccc3n2)cc1
Reactant: CNOC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(C)c(NC(=O)c2ccc(Nc3nc(-c4ccccc4)c4ccccc4n3)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
To a mixture of 4-methyl-3-[({4-[(4-phenylquinazolin-2-yl)amino]phenyl}carbonyl)-amino]benzoic acid (1.10 g, 2.32 mmol), N,O-dimethylhydroxylamine hydrochloride (226 mg, 2.32 mmol), and Hunig's base (1.62 mL, 9.30 mmol) in dimethylformamide (15 mL) were added HATU (882 mg, 2.32 mmol) and the mixture was stirred at rt for 2 h. The mixture was diluted with dichloromethane and washed with 2 N sodium hydroxide. The separated organic layer was dried over sodium sulfate, concentrated on a rotary evaporator and the residue was purified by short flash column chromatography to give N,4-dimethyl-N-(methyloxy)-3-[({4-[(4-phenylquinazolin-2-yl)amino]phenyl}carbonyl)amino]benzamide (1.16 g, 97%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 10.34 (s, 1H), 9.80 (s, 1H), 8.19 (d, 2H), 8.00 (d, 2H), 7.90-7.79 (m, 5H), 7.67-7.63 (m, 4H), 7.44-7.40 (m, 2H), 7.35 (d, 1H), 3.59 (s, 3H), 3.27 (s, 3H), 2.31 (s, 3H). MS (EI) for C31H27N5O3: 518.3 (MH+).
Reaction SMILES: C(O[C:6]([N:8](C)[C@@H:9](CC(C)(C)C)[C:10](O)=[O:11])=O)(C)(C)C.[F:19][C:20]([F:37])([F:36])[C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:31][C@@H:30]3[C@@H:32]([NH2:35])[CH2:33][CH2:34][C@@H:29]3[CH2:28]2)=[CH:23][CH:22]=1.FC(F)(F)C1N=C(N2C[C@@H]3[C@@H](N)CC[C@@H]3C2)C=CC=1>>[CH3:6][NH:8][CH2:9][C:10]([NH:35][C@@H:32]1[C@@H:30]2[C@@H:29]([CH2:28][N:27]([C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:36])[F:37])=[CH:26][CH:25]=3)[CH2:31]2)[CH2:34][CH2:33]1)=[O:11]
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](CC(C)(C)C)C(=O)O
Reactant: N[C@H]1CC[C@@H]2CN(c3ccc(C(F)(F)F)cc3)C[C@@H]21
Agent: N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Product: CNCC(=O)N[C@H]1CC[C@@H]2CN(c3ccc(C(F)(F)F)cc3)C[C@@H]21

Procedure:
The title compound was prepared by substituting N-(tert-butoxycarbonyl)-N-methyl-L-glycine for (S)-2-(tert-butoxycarbonyl(methyl)amino)-4,4-dimethylpentanoic acid and (3aR,4S,6aS)-2-[4-(trifluoromethyl)phenyl]octahydrocyclopenta[c]pyrrol-4-amine from Example 607 for (3aR,4S,6aS)-2-(6-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 587: 1H NMR (400 MHz, pyridine-d5) δ ppm 8.11 (d, J=7.3, 1H), 7.57 (d, J=8.6, 2H), 6.61 (d, J=8.7, 2H), 4.42-4.27 (m, 1H), 3.51 (dd, J=10.2, 3.3, 1H), 3.42 (d, J=1.0, 2H), 3.32 (dd, J=10.1, 7.8, 1H), 3.21 (dd, J=9.8, 8.1, 1H), 3.00 (dd, J=9.9, 4.1, 1H), 2.74-2.60 (m, 2H), 2.45-2.35 (bs, 1H), 2.40 (s, 3H), 2.08 (ddd, J=19.2, 7.0, 5.1, 1H), 1.92 (dtd, J=12.9, 7.9, 5.0, 1H), 1.62 (ddd, J=16.0, 12.6, 7.9, 1H), 1.42-1.27 (m, 1H); MS (ESI+) m/z 342 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[C:5](=[O:15])[NH:4][C:3]=1[C:16]([NH2:18])=[O:17].[C:19]1(=O)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(#N)C.[Fe](Cl)(Cl)Cl>[CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[C:5](=[O:15])[N:4]2[C:19]3([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[NH:18][C:16](=[O:17])[C:3]=12
Reactant: Cc1nc(Nc2ccncn2)c(=O)[nH]c1C(N)=O
Reactant: O=C1CCCCC1
Agent: Cl[Fe](Cl)Cl
Solvent: CC#N
Product: Cc1nc(Nc2ccncn2)c(=O)n2c1C(=O)NC21CCCCC1
Temperature: 80 °C

Procedure:
To a solution of 3-Methyl-6-oxo-5-(pyrimidin-4-ylamino)-1,6-dihydropyrazine-2-carboxamide (5, 100 mg, 0.41 mmol) and cyclohexanone (199 mg, 2.03 mmol) in acetonitrile in a 20 mL microwave vial was added iron(III) chloride (197 mg, 1.21 mmol). The reaction was heated at 80° C. for 16 h. On completion of the reaction, solvent was removed under vacuum and the crude was purified by silica gel (200-400 mesh) column chromatography eluting with 5% methanol in dichloromethane. Appropriate column fractions were concentrated under reduced pressure to afford 8′-methyl-6′-(pyrimidin-4-ylamino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyrazine]-1′,5′-dione (Cpd. No. 216) as off white solid. Yield: 8.5 mg, 6%; MS (ESI) m/z 327.13 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 9.11 (s, 1H), 8.88 (s, 1H), 8.72 (d, J=4.0 Hz 1H), 8.47 (d, J=4.0 Hz, 1H), 2.85-2.74 (m, 2H), 2.54 (s, 3H), 1.80-1.50 (m, 7H), 1.30-120 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[CH2:3][N:4]=[C:5]([NH2:20])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]C)=O)[N:11]=1.[CH3:23][NH2:24]>>[CH3:23][NH:24][C:16](=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12][C:10]1[N:11]=[C:7]([NH:6][C:5]([NH2:20])=[N:4][CH2:3][C:2]([F:1])([F:22])[F:21])[S:8][CH:9]=1
Reactant: CN
Reactant: COC(=O)CCCCc1csc(NC(N)=NCC(F)(F)F)n1
Product: CNC(=O)CCCCc1csc(NC(N)=NCC(F)(F)F)n1
Reaction time: 48 h
Yield: 85 %

Procedure:
A mixture of methyl 5-[2-(2-[2,2,2-trifluoroethyl]guanidino)thiazol-4-yl]valerate (0.4 g.) and ethanolic methylamine (33% w/v, 60 ml.) was allowed to stand at room temperature for 2 days. The mixture was then evaporated to dryness and the residue recrystallised from EtOAc/ether to give N-methyl-5-[2-(2-[2,2,2-trifluoroethyl]guanidino)thiazol-4-yl]valeramide (yield 85%), m.p. 122°-126°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][C:9](=O)[CH2:8][CH2:7]2.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:8][CH2:7]2
Reactant: O=C1CCc2cccc(Cl)c2C1
Reactant: C1CCNC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: Clc1cccc2c1C=C(N1CCCC1)CC2

Procedure:
70.0 g of 8-chloro-3,4-dihydro-2(1H)-naphthalenone were boiled at reflux for 2.5 hours in 550 ml of benzene and 33 ml of pyrrolidine in the presence of 1.4 g of p-toluenesulphonic acid. The crude 1-(8-chloro-3,4-dihydro-2-naphthyl)-pyrrolidine obtained was processed without purification.
Reaction SMILES: C([O:3][C:4](=[O:20])[C:5]([C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=1)=[CH:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)C.C[O-].[Na+].O.[OH-].[Na+]>CO>[Br:19][C:16]1[CH:15]=[CH:14][C:13](/[C:5](=[CH:6]\[CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)/[C:4]([OH:20])=[O:3])=[CH:18][CH:17]=1
Reactant: CCOC(=O)C(=CC1CCCCC1)c1ccc(Br)cc1
Agent: C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)/C(=C/C1CCCCC1)c1ccc(Br)cc1
Temperature: 50 °C
Reaction time: 72 h
Yield: 63.9 %

Procedure:
Dissolve E/Z mixture of 2-(4-bromo-phenyl)-3-cyclohexyl-acrylic acid ethyl ester (158.9 g, 472 mmol) in methanol (800 mL) and add the solution to sodium methoxide in methanol (222 mL, 30%). Stir the reaction mixture at 50° C. for 72 h. Add water (17 mL) and 5 N aqueous sodium hydroxide solution (10 mL) and stir at 50° C. until all methyl ester is hydrolyzed (1-4,days). Add water and evaporate the methanol; Add ether (300 mL) and water (200 mL) and adjust the pH to a value of 1 with 1 N HCl. Separate the layers and extract the aqueous layer with ether. Dry the combined organic layers organic phase over sodium sulfate, filter and concentrate. Recrystallization of the residue in EtOAc affords the title compound as a white solid (93.3 g). MS (m/e): 309 (M+H).
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)=[O:2].[CH3:9][C:10]([CH3:12])=O>[C].[Pd]>[CH:1]([N:3]1[CH2:8][CH2:7][N:6]([CH:10]([CH3:12])[CH3:9])[CH2:5][CH2:4]1)=[O:2]
Reactant: O=CN1CCNCC1
Reactant: CC(C)=O
Agent: [Pd]
Product: CC(C)N1CCN(C=O)CC1
Reaction time: 60 h

Procedure:
To a solution of 1.02 g of formylpiperazine in 90 ml of acetone was added 0.1 g of 5% palladium carbon and the mixture was stirred under hydrogen atmosphere for 60 hours. The catalyst was filtered off and distilled off under reduced pressure to afford 1.31 g of the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]2[C:6]([CH2:9][C:10]3[CH:21]=[CH:20][C:13]4[N:14]=[C:15](S(C)=O)[S:16][C:12]=4[CH:11]=3)=[CH:7][N:8]=[C:2]12.[NH2:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]1[OH:29].CCN(C(C)C)C(C)C.O>CN1C(=O)CCC1>[S:1]1[CH:5]=[CH:4][N:3]2[C:6]([CH2:9][C:10]3[CH:21]=[CH:20][C:13]4[N:14]=[C:15]([NH:22][C@@H:23]5[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]5[OH:29])[S:16][C:12]=4[CH:11]=3)=[CH:7][N:8]=[C:2]12
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: CS(=O)c1nc2ccc(Cc3cnc4sccn34)cc2s1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cc3cnc4sccn34)cc2s1
Temperature: 130 °C
Reaction time: 24 h
Yield: 28 %

Procedure:
A mixture of 6-(imidazo[2,1-b]thiazol-5-ylmethyl)-2-(methylsulfinyl)benzo[d]thiazole (310 mg, 0.93 mmol), (1R,2R)-2-aminocyclohexanol (321 mg, 2.79 mmol) and DIEA (240 mg, 1.86 mmol) in NMP (10 mL) was stirred for 1 d at 130° C. The mixture was cooled to rt and water (50 mL) was added. The mixture was extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 50:1 to 10:1 DCM/MeOH, and the product was further purified by preparative HPLC to afford (1R,2R)-2-((6-(imidazo[2,1-b]thiazol-5-ylmethyl)benzo[d]thiazol-2-yl)amino)cyclohexanol as a brown solid (100 mg, 28%). 1H NMR (300 MHz, DMSO-d6) δ 7.84 (d, J=7.2 Hz, 1H), 7.68 (d, J=4.5 Hz, 1H), 7.54 (d, J=1.8 Hz, 1H), 7.27 (d, J=8.1 Hz, 1H), 7.20 (dd, J=0.9, 4.2 Hz, 1H), 7.10 (dd, J=1.8, 8.4 Hz, 1H), 7.02 (s, 1H), 4.71 (d, J=4.8 Hz, 1H), 4.15 (s, 2H), 3.52-3.49 (m, 1H), 3.39-3.36 (m, 1H), 2.05-2.01 (m, 1H), 1.90-1.86 (m, 1H), 1.65-1.59 (m, 2H), 1.30-1.16 (m, 4H). LCMS (ESI) m/z 385 (M+H)+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1(/[CH:34]=[C:35](\[C:39]2[CH:44]=[CH:43][C:42]([F:45])=[C:41]([F:46])[CH:40]=2)/[C:36]([OH:38])=O)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:47][C:48]1[S:49][CH:50]=[CH:51][N:52]=1>C(Cl)Cl>[CH:28]1(/[CH:34]=[C:35](\[C:39]2[CH:44]=[CH:43][C:42]([F:45])=[C:41]([F:46])[CH:40]=2)/[C:36]([NH:47][C:48]2[S:49][CH:50]=[CH:51][N:52]=2)=[O:38])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: O=C(O)/C(=C/C1CCCCC1)c1ccc(F)c(F)c1
Reactant: Nc1nccs1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1nccs1)/C(=C/C1CCCCC1)c1ccc(F)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
A solution of triphenylphosphine (847 mg, 3.2 mmol) in methylene chloride (10 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (575 mg, 3.2 mmol). The reaction mixture was stirred at 0° C. For 30 min and then treated with a solution of (E)-3-cyclohexyl-2-(3,4-difluoro-phenyl)-acrylic acid (507 mg, 1.9 mmol) in methylene chloride (4 mL). The clear solution was stirred for 10 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 1 h. The reaction mixture was then treated with 2-aminothiazole (476 mg, 4.75 mmol), and the resulting suspension was stirred for 15 h at 25° C. The reaction mixture was concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (75 mL). The organic layer was washed successively with a 1N aqueous hydrochloric acid solution (2×30 mL), a saturated aqueous sodium bicarbonate solution (2×30 mL), and a saturated aqueous sodium chloride solution (1×50 mL). The organic layer was then dried over anhydrous magnesium sulfate, filtered, and, concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 8/1 to 4/1 hexanes/ethyl acetate) afforded (E)-3-cyclohexyl-2-(3,4-difluoro-phenyl)-N-thiazol-2-yl-acrylamide (520 mg, 78%) as an amorphous solid: EI-HRMS m/e calcd for C18H18F2N2OS (M+) 348.1108, found 348.1104.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[O:13][C:12]([CH2:14][OH:15])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:16]1([CH2:22][OH:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C(Cl)Cl.O=[Mn]=O>[CH:1]1([CH2:7][O:8][C:9]2[O:13][C:12]([CH:14]=[O:15])=[CH:11][CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1.[CH:16]1([CH2:22][OH:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: OCc1ccc(OCC2CCCCC2)o1
Agent: O=[Mn]=O
Agent: OCC1CCCCC1
Solvent: ClCCl
Product: O=Cc1ccc(OCC2CCCCC2)o1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of (5-(cyclohexylmethoxy)furan-2-yl)methanol and cyclohexylmethanol (0.75 g) and MnO2 (3.16 g, 36.3 mmol) in anhydrous CH2Cl2 (16 mL) was stirred at room temperature for 3 days. The reaction mixture was filtered through Celite and concentrated under reduced pressure. Flash chromatography purification (10%-50% EtOAc—hexanes gradient) gave 5-(cyclohexylmethoxy)furan-2-carbaldehyde with cyclohexylmethanol as an impurity as a light yellow. Yield (0.68 g, 99%); 1H NMR (400 MHz, DMSO-d6) δ 9.20 (s, 1H), 7.52 (d, J=3.8 Hz, 1H), 5.79 (d, J=3.8 Hz, 1H), 4.03 (d, J=5.8 Hz, 2H), 1.55-1.80 (m, 6H), 0.96-1.25 (m, 5H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([OH:15])=[O:14])=[N:4][C:5](Br)=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1>[NH2:1][C:2]1[C:3]([C:13]([OH:15])=[O:14])=[N:4][C:5]([C:20]2[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=2)=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Nc1cc(C(F)(F)F)c(Br)nc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: Nc1cc(C(F)(F)F)c(-c2ccc(F)cc2)nc1C(=O)O
Temperature: 25 °C

Procedure:
A mixture comprising 3-amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid (Intermediate A) (1 g, 3.51 mmol), 4-fluorophenylboronic acid (0.736 g, 5.26 mmol) and 1,1′Bis(diphenylphosphoshio)ferrocene palladium dichloride (0.286 g, 0.351 mmol) and 1.0M Cs2CO3 (3.3 ml) in THF (10 ml) was heated to reflux for 10 hours. After cooling to RT, the mixture was partitioned between DCM (100 ml) and 1 M NaOH (2×100 ml). The aqueous phase was acidified with 5M HCl and the resulting milky solution was extracted into DCM (2×100 ml). The organic portion was separated, dried (MgSO4) and concentrated in vacuo to afford the product as a crude oil. The crude material was purified by flash chromatography on silica cartridge eluting with a gradient of DCM: MeOH from 0% to 10% MeOH to afford the title product as a pale yellow solid;
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH3:8][N:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10](Cl)=[O:11]>>[N:5]1[CH:6]=[CH:7][C:2]([O:1][C:10](=[O:11])[N:9]([CH3:8])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:3][CH:4]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: Oc1ccncc1
Product: CN(C(=O)Oc1ccncc1)c1ccccc1

Procedure:
The title product was prepared from 4-hydroxypyridine and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC. (11%, yellow solid). HPLC-MS: m/z=229.2 (M+1); Rt: 1.66 min, purity: 67%.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH:27]([F:31])[CH:26]([CH3:32])[CH2:25][CH:24]([O:33][CH3:34])[CH:23]2[O:35][C:19]([OH:39])([CH:20]([CH3:38])[CH2:21][CH:22]2[O:36][CH3:37])[C:18](=[O:40])[C:17](=[O:41])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:42])[O:9][CH:8]([C:43]([CH3:56])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([N:51]=[N+]=[N-])[CH:47]([O:54][CH3:55])[CH2:46]2)[CH:7]([CH3:57])[CH:6]([OH:58])[CH2:5][C:4]1=[O:59])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH:27]([F:31])[CH:26]([CH3:32])[CH2:25][CH:24]([O:33][CH3:34])[CH:23]2[O:35][C:19]([OH:39])([CH:20]([CH3:38])[CH2:21][CH:22]2[O:36][CH3:37])[C:18](=[O:40])[C:17](=[O:41])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:42])[O:9][CH:8]([C:43]([CH3:56])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([NH2:51])[CH:47]([O:54][CH3:55])[CH2:46]2)[CH:7]([CH3:57])[CH:6]([OH:58])[CH2:5][C:4]1=[O:59])[CH3:2]
Reactant: CCC1C=C(C)C(F)C(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N=[N+]=[N-])C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCC1C=C(C)C(F)C(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC

Procedure:
A solution of 17-ethyl-20-fluoro-1, 14-dihydroxy-12-[2'-(4"-azido-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (28 l mg) and triphenylphosphine (9 mg) in 1 ml of wet toluene is stirred at 70° C. overnight. The solvent is removed under reduced pressure, and the residue was purified by preparative tlc on silica gel to give the title compound.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:16]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[C:14](OS(C(F)(F)F)(=O)=O)=[CH:13][CH:12]=3)[CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[C:29]([C:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[CH:33][C:32]=1[NH:46][C:47](=[O:49])[CH3:48])#[N:30]>>[C:47]([NH:46][C:32]1[CH:33]=[CH:34][C:35]([C:14]2[C:15]([C:17]([O:19][CH3:20])=[O:18])=[N:16][C:11]([C:8]3[CH:9]=[C:10]4[C:5]([CH2:4][CH2:3][CH2:2][NH:1]4)=[CH:6][CH:7]=3)=[CH:12][CH:13]=2)=[CH:36][C:31]=1[C:29]#[N:30])(=[O:49])[CH3:48]
Reactant: CC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1C#N
Reactant: COC(=O)c1nc(-c2ccc3c(c2)NCCC3)ccc1OS(=O)(=O)C(F)(F)F
Product: COC(=O)c1nc(-c2ccc3c(c2)NCCC3)ccc1-c1ccc(NC(C)=O)c(C#N)c1

Procedure:
Methyl 3-(4-acetamido-3-cyanophenyl)-6-(1,2,3,4-tetrahydroquinolin-7-yl)picolinate (37C) was prepared following a similar procedure as that described in example 29, except methyl 6-(1,2,3,4-tetrahydroquinolin-7-yl)-3-(trifluoromethylsulfonyloxy)picolinate (29F) was used instead of tert-butyl 7-(6-(methoxycarbonyl)-5-(trifluoromethylsulfonyloxy)pyridin-2-yl)-3,4-dihydroquinoline-1(21)-carboxylate (29E), and 1-(2-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide (37B) was used instead of phenylboronic acid in step 7 of example 29.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH:10]=1.Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>CO.[OH-].[Na+]>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([N:15]2[CH2:20][CH2:19][N:18]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[CH2:17][CH2:16]2)[CH:10]=1
Reactant: c1cc(COC2CCCCO2)cc(N2CCNCC2)n1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(OCc1ccccc1)N1CCN(c2cc(COC3CCCCO3)ccn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
To a solution of 1-(4-((tetrahydro-2H-pyran-2-yloxy)methyl)pyridin-2-yl)piperazine (8.5 g, 30.6 mmol) in MeOH (30 mL), NaOH (2 M, 31 mL) was slowly added at RT, followed by the addition of benzyl chloroformate (6.4 g, 37 mmol) in portions at 0° C. The mixture was stirred at RT overnight. The solution was concentrated and diluted with H2O (500 mL), extracted with EtOAc (3×200 mL). The combined organic layers were washed with H2O (100 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated to afford the crude product, which was purified by silica gel column chromatography (Petroleum ether:EtOAc=1:1) to afford benzyl 4-(4-((tetrahydro-2H-pyran-2-yloxy)methyl)pyridin-2-yl)piperazine-1-carboxylate as a yellow oil (7.3 g, 58%). MS (ES+) C23H29N3O4 requires: 411, found: 412[M+H]+.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.C(#N)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCCCCCCCCCCCC>C1COCC1.O1CCCOC1.[Zn+2].[Br-].[Br-]>[C:1]1([C:7]#[C:8][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1ccccc1
Reactant: C#Cc1ccccc1
Agent: C1COCOC1
Agent: CCCCCCCCCCCCC
Agent: [Br-]
Solvent: C1CCOC1
Product: C(#Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 67 h
Yield: 38.5 %

Procedure:
A solution of phenylacetylene (0.439 ml; 0.409 g; 4.00 mmol) in THF (2 ml) was treated at 0° C. with n-butyllithium (1.6 ml; 4.0 mmol; 2.5 M in hexanes) and the resulting solution was allowed to warm to room temperature for 10 min. The solution was cooled to 0° C., then treated with a solution of ZnBr2 (0.923 g; 4.10 mmol) in THF (2 ml) and allowed to warm to room temperature for 30 min. Solvent was removed in vacuo, then 1,3-dioxane (2 ml) was added. This solution was then added to a room temperature solution of benzonitrile (0.204 ml; 0.206 g; 2.00 mmol), dichlorobis(trimethylphosphine)nickel (0.0564 g; 10 mol %), and tridecane (0.244 ml; 0.184 g; 1.00 mmol) in 1,3-dioxane (2 ml). The reaction mixture was then heated to 65° CX and stirred for 67 h; then a sample was withdrawn and quenched in a mixture of 1 M sodium citrate (aq) and MTBE. GC analysis of the organic phase of the hydrolyzed reaction sample showed the presence of 0.77 mmol (38% yield) of diphenylacetylene and 0.48 mmol of benzonitrile remaining in the reaction mixture.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11]C(=O)C)[O:8][C@@H:7]([N:15]2[CH:20]=[C:19]([C:21]#[C:22][CH3:23])[C:18]([N:24]3C=NC=N3)=[N:17][C:16]2=[O:29])[CH2:6]1)(=O)C>O1CCOCC1.O>[C:21]([C:19]1[C:18]([NH2:24])=[N:17][C:16](=[O:29])[N:15]([CH:20]=1)[C@@H:7]1[O:8][C@H:9]([CH2:10][OH:11])[C@@H:5]([OH:4])[CH2:6]1)#[C:22][CH3:23]
Reactant: CC#Cc1cn([C@H]2C[C@H](OC(C)=O)[C@@H](COC(C)=O)O2)c(=O)nc1-n1cncn1
Solvent: C1COCCO1
Solvent: O
Product: CC#Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)nc1N
Reaction time: 16 h
Yield: 30 %

Procedure:
Crude product of stage b) (0.2 g, 0.5 mmol) was dissolved in 5 ml of Dioxan/880NH3 /H2O (3:2:1) and the mixture was left standing at room temperature for 16 hrs. It was then evaporated to dryness and the residue co-evaporated with ethanol. The resulting white solid was recrystallised from ethanol to give 0.04 g (30%) of pure product decomposing at 195°-200° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[CH3:17]O>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[CH:4][C:5]([C:6]([O:8][CH3:17])=[O:7])=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 89 %

Procedure:
4-Chloro-3,5-dinitrobenzoic acid (25.0 gm.) is dissolved in a cooled solution of methanol (125 ml.) and concentrated sulfuric acid (3.0 ml.). The reaction mixture is allowed to warm to room temperature and then heated to reflux for 18 hours. The product precipitated as light yellow needles on cooling, which are collected by filtration and washed with 15 ml. of methanol (24.0 gm., m.p. 102°-104.5°). Recrystallization from methanol gives light yellow needles (23.6 g., m.p. 104°-105.5°), 89% yield).