Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][C:5]([CH3:20])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:6]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].Cl>CC(C)=O>[CH:8]1([C:6](=[O:7])[C:5]([CH3:20])([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:4][CH:3]=[O:2])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: COC(CC(C)(C(=O)C1CCCCC1)c1ccccc1)OC
Agent: Cl
Solvent: CC(C)=O
Product: CC(CC=O)(C(=O)C1CCCCC1)c1ccccc1
Yield: 97.6 %

Procedure:
To a solution of 82.65 g (66.29 g, 0.2177 mol) of 4-cyclohexyl-3-methyl-4-oxo-3-phenylbutyraldehyde dimethyl acetal in 539 mL of acetone was added 539 mL of 3 N HCl (aq) at RT. After reaction completion (2 h), the mixture was concentrated to 426.5 g (or ⅓ volume) of residue (RT-40° C.). The residue contained mostly water (pH=0) and was extracted twice with 300 mL of MTBE. The MTBE extract was washed with 300 mL of 25% NaCl (aq), dried over MgSO4, gravity filtered and concentrated to afford 54.92 g (97.65%) of title compound as a pink oil: 1H NMR (d6-DMSO): δ 9.54 (t, J=2.0 Hz, 1H, —CHO), 7.36-7.45 (m, 2H, phenyl CH), 7.28-7.35 (m, 3H, phenyl CH), 2.95 (dd, J=16.6 Hz, J=1.9 Hz, 1H, CH2CHO), 2.85 (dd, J=16.6 Hz, J=1.7 Hz, 1H, CH2CHO), 2.41-2.49 (m, 1H, cyclohexyl CH), 1.72 (s, 3H, R2C(CH3)Ph), 0.85-1.66 (m, 10H, cyclohexyl —CH2).
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=2)[O:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:43]>C(#N)C>[Br:43][CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=2)[O:6][CH:7]=1
Reactant: CC(C)(C)c1cc(-c2nc(CO)co2)cc(C(C)(C)C)c1O
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CC(C)(C)c1cc(-c2nc(CBr)co2)cc(C(C)(C)C)c1O
Temperature: 22 °C
Reaction time: 3 h
Yield: 59.9 %

Procedure:
A suspension of 4-(hydroxymethyl)-2-(3,5-di-tert-butyl-4-hydroxyphenyl) oxazole (44.2 mmole, 13.41 g) in acetonitrile (230 ml) was treated with triphenylphosphine (53.0 mmole, 13.91 g) followed by carbon tetrabromide (53.0 mmole, 17.59 g). The resulting solution was stirred at approximately 22° C. for 3 hours. Next, additional carbon tetrabromide (22.0 mmole, 13.13 g) and triphenylphosphine 22.0 mmole, 5.79 g) was added to the reaction. After stirring for an additional 40 minutes, the reaction was quenched with water (5 mL), stirred 10 minutes and concentrated in vacuo and stored at 5° C. for approximately 16 hours. The material was then taken up into chloroform and subjected to prepatory chromatography eluting with 35 to 50% chloroform:hexane over a thirty-minute period. Fractions containing title compound were combined, dried over sodium sulfate, filtered, concentrated in vacuo to afford 9.7 g of the title compound that crystallized out upon standing at 22° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14].[N:22]([C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1)=[C:23]=[S:24]>C(#N)C.CCN(C(C)C)C(C)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:23](=[S:24])[NH:22][C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:32])=[O:33])=[CH:27][CH:26]=1
Reactant: NS(=O)(=O)c1ccc(N=C=S)cc1
Reactant: NCCCCCN(Cc1ccccn1)Cc1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: NS(=O)(=O)c1ccc(NC(=S)NCCCCCN(Cc2ccccn2)Cc2ccccn2)cc1
Yield: 19 %

Procedure:
A solution of tert-butyl 5-(bis(pyridin-2-ylmethyl)amino)pentylcarbamate (0.63 g, 1.64 mmol) in DCM (10 mL) and TFA (1.0 mL) was stirred at room temperature for 3 h. Upon completion the solvent was evaporated and the reaction mixture was diluted with DCM, washed with saturated aqueous potassium carbonate and concentrated under vacuum to afford N,N-bis(pyridin-2-ylmethyl)pentane-1,5-diamine. A solution of the above product N,N-bis(pyridin-2-ylmethyl)pentane-1,5-diamine, 4-isothiocyanatobenzenesulfonamide (0.35 g, 1.64 mmol) in acetonitrile (10 mL) and DIPEA (0.40 mL) was stirred at 50° C. under nitrogen for 3 h. The solvent was evaporated under reduced pressure to give a crude product, which was purified by flash chromatography eluting utilizing 5% MeOH in DCM followed by 15% MeOH in DCM to give 4-(3-(5-(bis(pyridin-2-ylmethyl)amino)pentyl)thioureido) benzenesulfonamide (0.145 g, 19%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H), 8.48 (d, 2H), 7.98 (s, 1H), 7.78-7.69 (m, 4H), 7.63 (d, 2H), 7.53 (d, 2H), 7.29-7.21 (m, 4H), 3.55 (s, 4H), 3.46-3.44 (m, 2H), 2.49-2.47 (m, 2H), 1.56-1.42 (m, 2H), 1.32-1.28 (m, 2H); ESMS m/z: 499.5 (M+H)+.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[C:13](=S)=[S:14]>C(O)C>[C:2]1([C:1]2[O:8][C:13]([SH:14])=[N:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: S=C=S
Reactant: NNC(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Sc1nnc(-c2ccccc2)o1

Procedure:
To a 100 ml flask were added 2.7 g of benzoyl hydrazine, a solution of 1.2 g potassium hydroxide in ethanol (20 ml) and 3 g of carbon disulfide. The mixture was heated under reflux for 6 hours with stirring. After the reaction was completed, the solvent was distilled under reduced pressure and water was added to dissolve the solid. The pH was adjusted to 6-7 with 10% hydrochloric acid and a lot of solid was precipitated, which was filtrated, and recrystallized with anhydrous ethanol to give 5-phenyl-2-mercapto-1,3,4-oxadiazole. MP: 212-214° C.
Reaction SMILES: N#N.[CH3:3][C:4]1([CH3:15])[C:8]2([CH3:14])[C:9]([O:11][C:12](=[O:13])[CH:5]1[CH2:6][CH2:7]2)=O.[OH:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:21].C1(C)C=CC=CC=1>O>[OH:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[C:12](=[O:13])[CH:5]2[C:4]([CH3:3])([CH3:15])[C:8]([CH3:14])([CH2:7][CH2:6]2)[C:9]1=[O:11]
Reactant: CC12CCC(C(=O)OC1=O)C2(C)C
Reactant: NCCCCO
Agent: N#N
Solvent: O
Solvent: Cc1ccccc1
Product: CC12CCC(C(=O)N(CCCCO)C1=O)C2(C)C

Procedure:
To a 125 ml round-bottomed flask equipped with Dean-Stark trap, condenser, and N2 inlet were added 5.35 g (29 mmol) of d-camphoric anhydride, 2.49 g (28 mmol) of 4-hydroxybutylamine, and 60 ml of toluene. The reaction was refluxed with separation of water for 20 hours. It was then cooled, concentrated to an oil, and the oil dissolved in ethyl acetate. The ethyl acetate solution was washed with 5% HCl, 5% NaOH, and brine, dried over sodium sulfate, and evaporated to an oil, 6.0 g (85%).
Reaction SMILES: C(OC([N:8]1[CH2:12]C[CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])[CH2:9]1)=O)(C)(C)C.N[CH2:32][C:33]1[CH:38]=CC=CN=1>>[N:8]1[CH:12]=[CH:38][CH:33]=[CH:32][C:9]=1[CH2:10][NH:13][C:14]([C:16]1[S:17][CH:18]=[CH:19][C:20]=1[NH:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[NH:28][CH:29]=[CH:30][C:23]=12)=[O:15]
Reactant: NCc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Product: O=C(NCc1ccccn1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using 2-(aminomethyl)pyridine instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 350 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.55 (1H, br. s.) 10.25 (1H, s) 8.75 (1H, t, J=5.95 Hz) 8.43-8.49 (1H, m) 8.02 (1H, d, J=5.47 Hz) 7.83 (1H, d, J=5.27 Hz) 7.69-7.77 (1H, m) 7.49 (1H, d, J=5.47 Hz) 7.28-7.34 (2H, m) 7.21-7.27 (1H, m) 6.82 (1H, d, J=5.47 Hz) 6.41 (1H, dd, J=3.51, 1.76 Hz) 4.55 (2H, d, J=6.05 Hz)
Reaction SMILES: [Br:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](O)=[O:4].B#B.O1CCCC1.O>O1CCCC1>[Br:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][OH:4]
Reactant: O=C(O)C(Br)c1ccccc1
Agent: B#B
Solvent: O
Solvent: C1CCOC1
Product: OCC(Br)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 25 g of alpha-bromophenylacetic acid in 100 ml of dry tetrahydrofuran was added 151 ml of 1.0M diborane in tetrahydrofuran dropwise at 5° C. under argon over 30 minutes. This mixture was stirred overnight at room temperature, then cooled to 0° C. and 130 ml of tetrahydrofuran:water (1:1) was added dropwise. The mixture was then saturated with potassium carbonate and the tetrahydrofuran removed. The aqueous remainder was extracted three times with ether. The extracts were combined and dried. The residue was triturated with hexane and the solid collected giving the desired compound as white needles, mp 38-39° C.
Reaction SMILES: [C:1]([NH:9][CH2:10][C:11]([OH:13])=[O:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]([O:16][CH:17](OCC)OCC)[CH3:15].C(OC(=O)C)(=O)C>CN(C1C=CN=CC=1)C>[CH2:14]([O:16]/[CH:17]=[C:10]1\[N:9]=[C:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[O:13][C:11]\1=[O:12])[CH3:15]
Reactant: O=C(O)CNC(=O)c1ccccc1
Reactant: CCOC(OCC)OCC
Agent: CN(C)c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CCO/C=C1\N=C(c2ccccc2)OC1=O
Temperature: 140 °C
Yield: 46.7 %

Procedure:
To a mixture of 2-benzamidoacetic acid (2.5 g, 13.8 mmol), DMAP (0.017 g, 0.138 mmol) and triethoxymethane (2.3 ml, 13.8 mmol), was added acetic anhydride (2.6 ml, 27.6 mmol). The mixture was heated to 140° C. for 30 min. The solvent was removed in vacuo and purification by silica gel chromatography (0-30% ethyl acetate in hexanes) gave 1.4 g (47%) of (Z)-4-(ethoxymethylene)-2-phenyloxazol-5(4H)-one as an orange solid. 1H NMR (400 MHz, CDCl3) 8.09-8.04 (m, 2H), 7.56-7.51 (m, 1H), 7.50-7.43 (m, 2H), 7.35 (s, 1H), 4.43 (q, 2H), 1.49 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:16][O:17][CH2:18][C:19]([O:21]CC)=[O:20])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[N:16][O:17][CH2:18][C:19]([OH:21])=[O:20])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CON=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CON=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Yield: 33 %

Procedure:
A solution of ethyl di-(4-chlorophenyl)methyleneamino-oxyacetate (3.8 g.) in ethanol (140 ml.) and water (5 ml.) containing sodium hydroxide (5 g.) was heated under reflux for 16 hours. The mixture was then evaporated and the residue was diluted with water (100 ml.) and ether (50 ml.). The ether layer was separated and discarded. The aqueous layer was acidified to pH 2-3 by addition of 20% v/v hydrochloric acid and the solid (3.0 g.) which formed was separated and crystallised from ethyl acetate to give di-(4-chlorophenyl)methyleneamino-oxyacetic acid, m.p. 147°-148° C., in 33% yield.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH3:24])[C@@H:10]([CH3:23])[O:11][C:12]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][N:15]=[C:14](Cl)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([CH:41]2[CH2:43][CH2:42]2)(=[N:34][C:35](=[O:40])[C:36]([F:39])([F:38])[F:37])=[O:33])=[CH:28][CH:27]=1.Cl>C(#N)C.O1CCOCC1>[CH2:1]([O:8][C@H:9]([CH3:24])[C@H:10]([O:11][C:12]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][N:15]=[C:14]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([S:32]([CH:41]3[CH2:43][CH2:42]3)(=[N:34][C:35](=[O:40])[C:36]([F:39])([F:37])[F:38])=[O:33])=[CH:30][CH:31]=2)[N:13]=1)[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(S(=O)(=NC(=O)C(F)(F)F)C2CC2)cc1
Reactant: C[C@@H](OCc1ccccc1)[C@@H](C)Oc1nc(Cl)ncc1C(F)(F)F
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: C[C@@H](OCc1ccccc1)[C@@H](C)Oc1nc(Nc2ccc(S(=O)(=NC(=O)C(F)(F)F)C3CC3)cc2)ncc1C(F)(F)F
Temperature: 80 °C
Reaction time: 5 h
Yield: 56 %

Procedure:
4-((1R,2R)-2-benzyloxy-1-methylpropoxy)-2-chloro-5-trifluoromethylpyrimidine and (RS)—S-(4-aminophenyl)-S-cyclopropyl-N-(trifluoroacetyl)sulphoximide in acetonitrile were admixed with a 4N solution of hydrogen chloride in dioxane and stirred for 5 hours at 80° C. After cooling, the mixture was diluted with acetic ester and washed with saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, dried (Na2SO4), filtered and concentrated by evaporation. The resulting residue was purified by means of chromatography (hexane/acetic ester 4:1) (yield: 56%).
Reaction SMILES: [Cl:1][C@H:2]1[C:23](=[O:24])[N:4]2[C:5]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[C:6]([CH2:11][O:12][C:13](=[O:15])[CH3:14])[CH2:7][S:8](=[O:10])(=[O:9])[C@H:3]12.[CH2:25](Cl)Cl.Cl.CNC.C=O>C(O)(C)(C)C>[Cl:1][C@H:2]1[C:23](=[O:24])[N:4]2[C:5]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])=[C:6]([CH2:11][O:12][C:13](=[O:15])[CH3:14])[C:7](=[CH2:25])[S:8](=[O:9])(=[O:10])[C@H:3]12
Reactant: ClCCl
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@H](Cl)[C@H]2S(=O)(=O)C1
Agent: C=O
Agent: CNC
Agent: Cl
Solvent: CC(C)(C)O
Product: C=C1C(COC(C)=O)=C(C(=O)OC(C)(C)C)N2C(=O)[C@H](Cl)[C@H]2S1(=O)=O
Temperature: 90 °C
Yield: 81.6 %

Procedure:
A mixture of t-butyl 7α-chloro-3-acetoxymethyl-3-cephem-4-carboxylate-1,1-dioxide (1.9 g), methylene chloride (3 ml), dimethylamine hydrochloride (0.817 g), t-butanol (80 ml) and formaldehyde solution (I.10 ml, 37% w/v in water) was heated to reflux at 90° C. for 3 hours. Solvent was removed under reduced pressure and the residue was dissolved in methylene chloride, washed with water, brine, dried and concentrated to give 1.6 g (81.6%) of t-butyl 7α-chloro-2-methylene-3-acetoxymethyl-3-cephem-4-carboxylate-1,1-dioxide, m.p. 148°-149° C. This product without further purification was used in the next step.
Reaction SMILES: Br[C:2]1[C:3]([N:22]([CH2:24][CH2:25][OH:26])[CH3:23])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:27][C:28]1[CH:29]=[N:30][CH:31]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:33]=1>>[F:27][C:28]1[CH:33]=[C:32]([C:2]2[C:3]([N:22]([CH2:24][CH2:25][OH:26])[CH3:23])=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])[CH:21]=2)[CH:31]=[N:30][CH:29]=1
Reactant: CC1(C)OB(c2cncc(F)c2)OC1(C)C
Reactant: CN(CCO)c1ncc(C(=O)Nc2ccc(SC(F)(F)F)cc2)cc1Br
Product: CN(CCO)c1ncc(C(=O)Nc2ccc(SC(F)(F)F)cc2)cc1-c1cncc(F)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 185 using 5-bromo-6-((2-hydroxyethyl)(methyl)amino)-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide (Stage 192.1) and 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine to afford an off-white foam. HPLC (Condition 4) tR=5.7 min, UPLC-MS (Condition 3) tR=1.10 min, m/z=467.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.69 (s, 3H) 3.41-3.63 (m, 4H) 4.66 (t, J=5.28 Hz, 1H) 7.68 (d, J=8.99 Hz, 2H) 7.82-7.97 (m, 3H) 8.11 (d, J=2.35 Hz, 1H) 8.49-8.63 (m, 2H) 8.74 (d, J=2.35 Hz, 1H) 10.31 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([CH3:19])[CH:12]=1.[N+:20]([O-])([O-:22])=[O:21].[K+]>S(=O)(=O)(O)O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:20]([O-:22])=[O:21])=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([CH3:19])[CH:12]=1
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1cc(-c2cc3ccccc3n2C)ccc1C#N
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1cc(-c2cc3cc([N+](=O)[O-])ccc3n2C)ccc1C#N

Procedure:
6.9 g (28 mmol) of 4-(1-methyl-1H-indol-2-yl)-methyl-benzonitrile are placed in 50 ml conc. sulphuric acid. At 2° C. 2.9 g (28 mmol) of potassium nitrate are added batchwise, whereupon the temperature rises to 10° C. After 30 minutes at 2° C. the mixture is poured onto ice and the product precipitated is suction filtered, washed with ice water, dried and recrystallised from acetone.
Reaction SMILES: [C:1]([OH:12])(=O)[CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O>[OH:4][CH2:3][CH:2]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:1]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12]
Reactant: O=C(O)C(CO)c1ccccc1
Reactant: C1CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(C(CO)c1ccccc1)N1CCCC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of tropic acid (0.12 mmol) and pyrrolidine (0.12 mmol) in DMF (20 mL) are added HOAt (0.18 mmol) and EDCI-HCl (0.18 mmol). The reaction mixture is stirred at room temperature for 14 h. The reaction mixture is diluted with water, then extracted with AcOEt. The organic extracts are successively washed with water, sat. aq, NaHCO3, H2O and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue is purified by silica gel column chromatography to give 3-hydroxy-2-phenyl-1-pyrrolidin-1-yl propan-1-one.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[C:15](=[O:16])[CH2:14][CH:13]3[N:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:10]([CH2:11][CH2:12]3)[CH2:9]2)=[CH:4][CH:3]=1.Cl[C:26]1[N:27]=[CH:28][C:29]2[CH:34]=[C:33]([C:35]([N:37]([CH3:39])[CH3:38])=[O:36])[N:32]([CH:40]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)[C:30]=2[N:31]=1>>[CH:40]1([N:32]2[C:30]3[N:31]=[C:26]([NH:1][C:2]4[N:7]=[CH:6][C:5]([N:8]5[C:15](=[O:16])[CH2:14][CH:13]6[N:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:10]([CH2:11][CH2:12]6)[CH2:9]5)=[CH:4][CH:3]=4)[N:27]=[CH:28][C:29]=3[CH:34]=[C:33]2[C:35](=[O:36])[N:37]([CH3:38])[CH3:39])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]1
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCCC1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(c1ccc(N)nc1)C(=O)C2
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CC5CCC(CC4=O)N5C(=O)OC(C)(C)C)cn3)nc2n1C1CCCCC1
Yield: 55.2 %

Procedure:
Following general N—C coupling procedure 1, tert-butyl 3-(6-aminopyridin-3-yl)-4-oxo-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate (120 mg, 0.361 mmol) was combined with 2-chloro-7-cyclohexyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (111 mg, 0.361 mmol) which gave tert-butyl 3-(6-(7-cyclohexyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)-4-oxo-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate (120 mg) in 55.1% yield. MS m/z 603.6 (M+H)+.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]1[C:15]([N+:16]([O-])=O)=[CH:14][C:13]([N+:19]([O-])=O)=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].Cl[Sn]Cl>C(O)C>[NH2:19][C:13]1[CH:12]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:5]2[CH:4]=[CH:3][NH:16][C:15]=2[CH:14]=1
Reactant: CCOC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1/C=C/N(C)C
Agent: Cl[Sn]Cl
Solvent: CCO
Product: CCOC(=O)c1cc(N)cc2[nH]ccc12
Yield: 39.7 %

Procedure:
A mixture of (E)-ethyl 2-(2-(dimethylamino)vinyl)-3,5-dinitrobenzoate (11 g, 0.037 mol) and SnCl2(83 g, 0.37 mol) in ethanol was heated at reflux for 4 h. The mixture was concentrated to dryness and the residue was poured into water and basified using sat. aq. Na2CO3 to pH 8. The precipitated solid was filtered and the filtrate was extracted with ethyl acetate (3×100 mL). The combined extracts were washed with water (2×100 mL) and brine (150 mL), dried over Na2SO4, and concentrated to dryness. The residue was purified by column on silica gel to give ethyl 6-amino-1H-indole-4-carboxylate (3.0 g, 40%). 1 HNMR. (DMSO-d6) δ 10.76(br s, 1 H), 7.11-7.14(m, 2 H), 6.81-6.82(m, 1 H), 6.67-6.68(m, 1 H), 4.94(br s, 2 H), 4.32-4.25(q, J=7.2 Hz, 2 H), 1.35-1.31(t, J=7.2, 3 H); MS (ESI) m/e (M+H+) 205.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.I[CH2:28][CH:29]1[CH2:31][CH2:30]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:28][CH:29]3[CH2:31][CH2:30]3)[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: ICC1CC1
Reactant: COc1cn(CC(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Product: COc1cn(C(CC2CC2)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
464 mg (1.24 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate and 293 mg (1.61 mmol) of (iodomethyl)cyclopropane were reacted according to General Method 7A. Yield: 379 mg (71% of theory)
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:14][NH:15][CH3:16]>C1COCC1>[CH3:14][N:15]([CH3:16])[C:2]1[N:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1ccc(C(F)(F)F)nc1Cl
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)c1nc(C(F)(F)F)ccc1C=O
Temperature: 50 °C
Reaction time: 3 h
Yield: 41.7 %

Procedure:
To a stirred solution of 2-chloro-6-(trifluoromethyl)nicotinaldehyde (115 mg, 0.549 mmol) in THF (1 mL) was added dimethylamine (823 μl, 1.65 mmol). The reaction was heated to 50° C. and stirred for 3 hours. The reaction was loaded onto silica gel and eluted with 5% ethyl acetate/hexanes to 50% ethyl acetate/hexanes to yield the desired compound (50 mg, 0.229 mmol, 41.8% yield).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH:17]([OH:20])[CH2:18]Cl)=[N:5][N:6]=1.[C:21]([NH2:25])([CH3:24])([CH3:23])[CH3:22]>O1CCOCC1>[CH3:1][C:2]1[S:3][C:4]([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH:17]([OH:20])[CH2:18][NH:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[N:5][N:6]=1
Reactant: Cc1nnc(C=Cc2ccccc2OCC(O)CCl)s1
Reactant: CC(C)(C)N
Solvent: C1COCCO1
Product: Cc1nnc(C=Cc2ccccc2OCC(O)CNC(C)(C)C)s1

Procedure:
1.6 g of 2-methyl-5-[2-(2-hydroxy-3-chloro-propoxy)-styryl]-1,3,4-thiadiazole and 10 ml of tert.-butylamine in 50 ml of dioxane are heated for 10 hours at 100° C. in an autoclave. After distilling off the volatile constituents under reduced pressure the highly viscous crude product is chromatographed over a dry silica gel column, using chloroform. The residue obtained on evaporating the eluates containing the product gives 2-methyl-5-[2-(2-hydroxy-3-tert.-butylamino-propoxy)-styryl]-1,3,4-thiadiazole. The compound, in its isolated form, is identical with the compound obtained as described in Example 3.
Reaction SMILES: Cl[P:2]1[N:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[P:4](Cl)[N:3]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19]([C:23]1[CH:24]=[C:25]([CH:49]=[C:50]([C:53]([CH3:56])([CH3:55])[CH3:54])[C:51]=1[OH:52])[CH2:26][CH2:27][C:28]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:29])([CH3:22])([CH3:21])[CH3:20]>C(N(CC)CC)C>[C:19]([C:23]1[CH:24]=[C:25]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:29])[CH:49]=[C:50]([C:53]([CH3:55])([CH3:54])[CH3:56])[C:51]=1[O:52][P:2]1[N:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[P:4]([O:52][C:51]2[C:23]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:24][C:25]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:29])=[CH:49][C:50]=2[C:53]([CH3:54])([CH3:56])[CH3:55])[N:3]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:20])([CH3:21])[CH3:22]
Reactant: CCCCCCCCCCCCCCCCCCOC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: ClP1N(c2ccccc2)P(Cl)N1c1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCOC(=O)CCc1cc(C(C)(C)C)c(OP2N(c3ccccc3)P(Oc3c(C(C)(C)C)cc(CCC(=O)OCCCCCCCCCCCCCCCCCC)cc3C(C)(C)C)N2c2ccccc2)c(C(C)(C)C)c1

Procedure:
The procedure of Example 1 is repeated using 2,4-dichloro-1,3-diphenyl-1,3,2,4-diazadiphosphetidine, n-octadecyl 3,5-di-tert-butyl-4-hydroxyhydrocinnamate and triethylamine to give the title compound.