Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:17]3[O:16][C:15](=O)[NH:14][C:13](=[O:19])[C:12]=3[CH2:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[OH-].[NH4+:21]>>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:17]3[NH:21][C:15](=[O:16])[NH:14][C:13](=[O:19])[C:12]=3[CH2:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=c1[nH]c(=O)c2c(o1)C(c1cc(F)cc(F)c1)CC2
Reactant: [NH4+]
Agent: [OH-]
Product: O=c1[nH]c2c(c(=O)[nH]1)CCC2c1cc(F)cc(F)c1
Yield: 106.1 %

Procedure:
A solution of 7-(3,5-difluorophenyl)-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione (700 mg, 2.64 mmol) in concentrated ammonium hydroxide (50 mL, 1284 mmol) was heated at 100° C. in a high-pressure (350 mL) vessel overnight. The reaction mixture was cooled and concentrated in vacuum to give crude 7-(3,5-difluorophenyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione (740 mg, 2.80 mmol, 106% yield). LC-MS (M+H)+=265.0.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][CH:19]([CH2:22][CH:23]1[CH2:26][CH2:25][CH2:24]1)[CH2:20][OH:21]>>[CH:23]1([CH2:22][CH:19]([NH:18][C:15]([C:7]2[CH:6]=[N:5][C:4]([CH:1]3[CH2:2][CH2:3]3)=[C:9]([O:10][CH2:11][CH:12]3[CH2:13][CH2:14]3)[N:8]=2)=[O:17])[CH2:20][OH:21])[CH2:26][CH2:25][CH2:24]1
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Reactant: NC(CO)CC1CCC1
Product: O=C(NC(CO)CC1CCC1)c1cnc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 69, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g, 50 mg, 0.21 mmol) and 2-amino-3-cyclobutyl-propan-1-ol (38.7 mg, 0.3 mmol) as starting materials and isolated (30 mg, 41%) as white solid; LC-MS (UV peak area, ESI) 99.69%, 346.2 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH:5]([O:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH2:6][CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:1][CH2:2][CH2:3][CH2:4][CH:5]([O:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:6][CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: CCOC(=O)CCCC(CCCN)Oc1cccnc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: CCOC(=O)CCCC(CCCNS(=O)(=O)c1ccc(Cl)cc1)Oc1cccnc1

Procedure:
Ethyl 8-amino-5-(3-pyridyloxy)-octanoate is condensed with p-chlorophenylsulfonyl chloride according to methodology previously described to yield ethyl 8-(p-chlorophenylsulfonamido)-5-(3-pyridyloxy)-octanoate which is purified by chromatography on silica gel using 7:3 ethyl acetate, hexane as eluent; 1H NMR (CDCl3): delta 8.26 (br,1H), 8.20 (br,4H), 5.23 (t,1H), 4.28 (m,1H), 4.08 (q,2H).
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:25](=[O:26])[N:14]2[CH:15]([C:21]([O:23][CH3:24])=[O:22])[C:16](C)([CH2:18][Br:19])[S:17][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:27](Cl)(Cl)Cl>>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:25](=[O:26])[N:14]2[CH:15]([C:21]([O:23][CH3:24])=[O:22])[C:18]([Br:19])([CH3:27])[CH2:16][S:17][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1(C)CBr
Reactant: ClC(Cl)Cl
Product: COC(=O)C1N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SCC1(C)Br
Reaction time: 96 h

Procedure:
Methyl 6-(2-phenoxyacetamido)-2-methyl-2-bromomethylpenam-3-carboxylate (350 mg.) was dissolved in chloroform (10 cc), and then the mixture was allowed to stand for 4 days and purified by chromatography of silica gel to give an amorphous material (200 mg.) of methyl 7-(2-phenoxyacetamido)-3-bromo-3-methylcepham-4-carboxylate.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:9]([Cu])#[N:10].CN1C(=O)CCC1>CCOC(C)=O>[Cl:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([CH:7]=1)[C:9]#[N:10]
Reactant: N#C[Cu]
Reactant: Clc1cncc(Cl)c1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: N#Cc1cncc(Cl)c1
Temperature: 210 °C
Reaction time: 3 h

Procedure:
A mixture of 3,5-dichloropyridine (4.23 g, 28.6 mmol), CuCN (3.07 g, 34.3 mmol), and argon-bubbled NMP (8 mL) was placed in a 40 mL scintillation vial, flushed with argon for 1 min, and then quickly capped and stirred under argon at 210° C. for 3 h. The dark brown easily stirred solution was allowed to cool somewhat, and was then poured into concentrated NH4OH (50 mL) on an ice bath, and stirred vigorously for 5 min. DCM (50 mL) was added, the bilayer was stirred for an additional 5 min, and then filtered. The lower dark amber organic layer was saved, and the dark blue aqueous layer was extracted with DCM (2×50 mL). The organic layers were combined and washed with NH4OH (1×30 mL), 4 M NaCl (1×30 mL), dried (Na2SO4), and concentrated to give an amber oil heavily contaminated with NMP. Silica flash chromatography of this residue (90 mm×6″ column; 6:1 hex/EtOAc eluent; 100 mL fractions; fractions 15-19 combined) afforded, after rotary evaporation at 40° C., the title compound as brilliant white microcrystals (891 mg, 22%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:18]1[N:23]=[CH:22][N:21]=[C:20]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)[C:19]=1[N+:35]([O-:37])=[O:36]>CN(C)C(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][O:14][C:18]2[C:19]([N+:35]([O-:37])=[O:36])=[C:20]([NH:24][C:25]3[CH:26]=[CH:27][C:28]([S:31]([CH3:34])(=[O:32])=[O:33])=[CH:29][CH:30]=3)[N:21]=[CH:22][N:23]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(Cl)c2[N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)C1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCC(COc2ncnc(Nc3ccc(S(C)(=O)=O)cc3)c2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
3-Hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.65 mmol, 131 mg) and sodium hydride (1.3 mmol, 31 mg) were dissolved in N,N-dimethyl acetamide (1.5 mL) and stirred for 30 minutes at room temperature. Then, (6-chloro-5-nitro-pyrimidin-4-yl)-(4-methanesulfonyl-phenyl)-amine (0.26 mmol, 84 mg) was added. The reaction was stirred at 70° C. for 30 minutes. Its progress was monitored by thin layer chromatography and LCMS. Sodium hydride was quenched with water and the desired compound was extracted in ethyl acetate. Organic solvents were evaporated in vacuo. Flash chromatography (Silica gel 60; 50/50 EtoAc/Hexanes) provided Compound A16 as a yellow solid (96 mg, 54%). 1H NMR (400 MHz, CDCl3) δ (ppm): 10.21 (s, 1H), 8.41 (s, 1H), 7.97 (d, 2H), 7.86 (d, 2H), 4.52 (m, 2H), 3.49 (m, 2H), 3.11 (s, 3H), 2.75 (m, 1H), 1.84 (m, 2H), 1.65 (m, 2H), 1.46 (s, 9H). LCMS (ESI), m/z 394.1 (M+H+, 100%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1F)[C:5]([NH:7]C[Si](C)(C)C)=[O:6]>CN(C=O)C.C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#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>[C:5]([NH2:7])(=[O:6])[C:4]1[CH:13]=[CH:14][CH:15]=[CH:2][CH:3]=1
Reactant: C[Si](C)(C)CNC(=O)c1ccc(F)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=O)c1ccccc1
Temperature: 90 °C
Reaction time: 4 h
Yield: 200.9 %

Procedure:
3-bromo-4-fluoro-N-[(trimethylsilyl)methyl]benzamide (5.0 g) was dissolved in DMF, and zinc cyanide (1.4 g) and tetrakis(triphenylphosphine)palladium (1.9 g) were added thereto under argon atmosphere. The reaction mixture was stirred for 4 hours at 90° C. The reaction mixture was returned to room temperature. The mixture was diluted with ethyl acetate and washed with a saturated aqueous sodium hydrogen carbonate solution, subsequently dried over magnesium sulfate. After filtering the reaction mixture, the solvent was distilled off under reduced pressure, and the resulting mixture was purified by silica gel chromatography, to obtain 3-cyano-4-fluoro-N-[trimethylsilyl)methyl]benzamide (4.0 g) at a yield of 97%.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH3:12])[C:6]=2[N:5]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:4]1=[O:21])[CH3:2].[Br:22]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:22][CH2:12][C:11]1[C:6]2[N:5]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:19])([CH3:18])[CH3:20])[C:4](=[O:21])[N:3]([CH2:1][CH3:2])[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCn1c(=O)n(COCC[Si](C)(C)C)c2c(C)cccc21
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCn1c(=O)n(COCC[Si](C)(C)C)c2c(CBr)cccc21
Reaction time: 0.5 h

Procedure:
The mixture of 1.00 g of 1-ethyl-4-methyl-3-(2-trimethylsilanylethoxymethyl)-1,3-dihydrobenzimidazol-2-one, 0.469 g of N-bromosuccinimide, 0.025 g of 2,2′-azobis(2-methylpropionitrile) and 0.037 g of dibenzoyl peroxide in 60 ml of carbon tetrachloride is heated to reflux with stirring. The reaction vessel is irradiated with a 150 W lamp over the reaction time. After 0.5 hour, the reaction mixture is cooled and filtered through Hyflo. The filtrate is concentrated. The title compound is obtained as a yellow resin from the residue by means of flash chromatography (SiO2 60F). Rf=0.20 (40:1 dichloromethane-diethyl ether); Rt=5.80.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][CH:22]=O.Cl.[NH2:25][OH:26].C(N(CC)CC)C>C(O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][CH:22]=[N:25][OH:26]
Reactant: NO
Reactant: CSc1ccc(/C=C2/C(C)=C(CC=O)c3cc(F)ccc32)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CSc1ccc(/C=C2/C(C)=C(CC=NO)c3cc(F)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of the acetaldehyde derivative from Step 2 (3.3 g, 10.18 mmol), hydroxylamine hydrochloride (1.42 g, 20.4 mmol), ethanol (25 mL) and triethylamine (2.06 g, 20.4 mmol) was stirred at room temperature for 30 minutes. The solvent was evaporated away and the residue was partitioned between ethyl acetate and water. The crude product from the organic phase was purified by column chromatography on silica gel using a 1:2 mixture of ethyl acetate:hexane as eluent. The title compound was obtained as a yellow solid, mp: 146°-150° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].[C:22](Cl)([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>O.O1CCOCC1>[CH2:25]([O:24][C:22]([N:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][C@H:10]1[C:14]([OH:16])=[O:15])=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN[C@H](C(=O)O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)[C@H](C(=O)O)C1
Temperature: 25 °C
Yield: 82.2 %

Procedure:
To a stirred suspension of (S)-4-(tert-butoxycarbonyl) piperazine-2-carboxylic acid (1.0 g, 4.34 mmol) in water (5 mL) was added solid NaHCO3 (0.73 g, 8.68 mmol) at room temperature. The reaction mixture was stirred at room temperature to get clear solution. Solution of CBZ-Cl (1.22 mL, 8.68 mmol) in 1,4-dioxane (10 mL) was added dropwise and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2×20 mL). The aqueous layer was acidified with 0.5M aqueous HCl to pH 5 and extracted with EtOAc (2×50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (1.30 g) as white solid.
Reaction SMILES: C([Li])CCC.[CH:6]1([NH:9][C:10]([C:12]2[N:13]=[C:14]([CH:17]([CH3:19])[CH3:18])[O:15][CH:16]=2)=[O:11])[CH2:8][CH2:7]1.[C:20](=[O:22])=[O:21]>CCCCCC.O1CCCC1>[CH:6]1([NH:9][C:10]([C:12]2[N:13]=[C:14]([CH:17]([CH3:19])[CH3:18])[O:15][C:16]=2[C:20]([OH:22])=[O:21])=[O:11])[CH2:7][CH2:8]1
Reactant: O=C=O
Reactant: CC(C)c1nc(C(=O)NC2CC2)co1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)c1nc(C(=O)NC2CC2)c(C(=O)O)o1
Reaction time: 0.5 h
Yield: 81 %

Procedure:
0.12 mol of n-butyllithium (80.0 ml of a 1.5 molar solution in hexane) was added dropwise to a solution of 10.4 g (0.054 mol) of 2-(1-methylethyl)-oxazole-4 carboxylic acid cyclopropylamide in 250 ml of tetrahydrofuran under a nitrogen atmosphere of -70° C. and stirring was carried out for 30 minutes at this temperature. Thereafter, the reaction mixture was poured onto 500 g of solid CO2 and was left to stand overnight. The mixture was evaporated down, the residue was taken up in 200 ml of water and 30 ml of 10% strength NaOH, the solution was extracted twice with diethyl ether and the aqueous phase was acidified to pH 2 with concentrated hydrochloric acid and extracted with ethyl acetate. The organic phase was dried with magnesium sulfate and the solvent was stripped off under reduced pressure. 10.4 g (81%) of 4-cyclopropylaminocarbonyl-2-(1-methylethyl)-oxazole-5-carboxylic acid were obtained as a white powder of melting point 109°-112° C.
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[NH2:23][C@@H:24]1[CH2:29][CH2:28][C@H:27]([OH:30])[CH2:26][CH2:25]1.CCN(C(C)C)C(C)C>>[OH:30][C@@H:27]1[CH2:28][CH2:29][C@H:24]([NH:23][C:2]2[C:3]([CH3:22])=[N:4][C:5]3[C:10]([N:11]=2)=[C:9]([C:12]2[NH:20][C:19]4[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=4[CH:13]=2)[CH:8]=[CH:7][CH:6]=3)[CH2:25][CH2:26]1
Reactant: N[C@H]1CC[C@@H](O)CC1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1N[C@H]1CC[C@@H](O)CC1
Temperature: 100 °C

Procedure:
Prepared similarly to that described in Example 131 using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 41 mg, 0.138 mmol), cis-4-aminocyclohexanol (42.0 mg, 0.277 mmol, J&W Pharmlab, Levittown, Pa.), and DIPEA (121 μl, 0.692 mmol), heating at 100° C. for 1 h. Purification by silica gel (100% DCM to 10% MeOH/DCM) provided 2-(3-((cis-4-hydroxycyclohexyl)amino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (26% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.61-1.71 (m, 2H) 1.72-1.83 (m, 4H) 1.83-1.96 (m, 2H) 2.56 (s, 3H) 2.89 (t, J=6.85 Hz, 2H) 3.41-3.48 (m, 2H) 3.88 (br. s., 1H) 3.97-4.07 (m, 1H) 4.42 (br. s., 1H) 6.77 (d, J=7.04 Hz, 1H) 6.91 (br. s., 1H) 7.18 (d, J=1.76 Hz, 1H) 7.31 (t, J=7.82 Hz, 1H) 7.55 (d, J=7.82 Hz, 1H) 7.87 (d, J=7.63 Hz, 1H) 11.94 (br. s., 1H). MS (ESI, pos. ion) m/z: 392.1 (M+1).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[N:7]1.[N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[CH:17][C:16]=1[CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[N:6]1([CH2:5][CH2:4][CH2:3][CH2:2][N:28]2[CH2:27][CH2:26][CH:25]([C:16]3[CH:17]=[N:18][C:19]4[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:15]=3)[CH2:30][CH2:29]2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[N:7]1
Reactant: ClCCCCn1nnc2ccccc21
Reactant: c1ccc2nc(C3CCNCC3)cnc2c1
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc2nc(C3CCN(CCCCn4nnc5ccccc54)CC3)cnc2c1
Temperature: 25 °C
Yield: 63 %

Procedure:
1-(4-chlorobutyl)-1H-benzotriazole (7.55 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 4-(2-quinoxalinyl)piperidine (6.4 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred and mixed, then heated and refluxed to react for 20 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3 and purified, eluted with dichloromethane to produce 7.3 g compound (I-157) with a yield of 62.7%. ESI-MS [M+H]+: m/z 387.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](I)[CH2:9][S:10]([C:13]2[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:4][CH:3]=1.CCN(CC)CC>CC#N>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[S:10]([C:13]2[CH:14]=[CH:15][C:16]([CH3:17])=[CH:18][CH:19]=2)(=[O:11])=[O:12])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)CC(I)c2ccc(Cl)cc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)/C=C/c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
1-Chloro-4-(1-iodo-2-tosylethyl)benzene (28.5 g, 67.7 mmol) was dissolved in dry MeCN (376 mL) followed by addition of Et3N (18.83 mL, 135 mmol) and the mixture was stirred at room temperature for 1 h. Then the solvent was evaporated under reduced pressure and the residue partitioned between DCM (400 mL) and 1M aqueous KHSO4 (300 mL). The layers were separated and the organic phase was dried over Na2SO4, filtered and evaporated to dryness under reduced pressure to afford 19 g (96%) of the desired product.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:5][C@H:4]([C:6]#[N:7])[CH2:3]1.N1C=CN=C1.[CH3:13][C:14]([Si:17](Cl)([CH3:19])[CH3:18])([CH3:16])[CH3:15]>CN(C=O)C>[Si:17]([O:1][C@@H:2]1[CH2:5][C@H:4]([C:6]#[N:7])[CH2:3]1)([C:14]([CH3:16])([CH3:15])[CH3:13])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: N#C[C@H]1C[C@@H](O)C1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1C[C@@H](C#N)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of cis-3-hydroxy-cyclobutanecarbonitrile (500 mg, 5.15 mmol in DMF (3 mL) at room temperature was added imidazole (876 mg, 12.9 mmol) followed by TBDMS-Cl (854 mg, 5.66 mmol). The reaction mixture was stirred at room temperature overnight then quenched with water and extracted with EtOAc (2×). The combined organics were washed with water (3×), dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 0% to 10% EtOAc/hexanes to afford 890 mg (82%) of cis-3-(tert-butyldimethylsilanyloxy)-cyclobutanecarbonitrile as a colorless oil. 1H NMR (CDCl3, 400 MHz): δ (ppm) 4.10-4.19 (m, 1H), 2.57-2.67 (m, 2H), 2.43-2.54 (m, 1H), 2.22-2.34 (m, 2H), 0.84 (s, 9H), 0.00 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([CH3:13])[CH2:10][C@H:9]1[C:14](O)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].B.[NH4+].[Cl-].O>C1COCC1>[OH:15][CH2:14][C@@H:9]1[CH2:10][CH:11]([CH3:13])[CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7]
Reactant: CC1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: B
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CC1C[C@@H](CO)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.1 %

Procedure:
To a solution of (2S)-1-tert-butoxycarbonyl-4-methyl-pyrrolidine-2-carboxylic acid (26.6 g, 116.0 mmol) in THF (160 mL) is added 1 M borane in THF (243.6 mL, 243.6 mmol) at 0° C. The reaction mixture is stirred at rt overnight. Then a saturated aqueous solution of NH4Cl (50 mL) is carefully added (dropwise) at 4° C., followed by H2O (100 mL). The mixture is extracted with EtOAc and the organic phase is washed with H2O, dried over Na2SO4, filtered and concentrated to dryness. The residue is purified by flash column chromatography on silica gel (0 to 20% EtOAc in Hexanes) to give tert-butyl (2S)-2-(hydroxymethyl)-4-methyl-pyrrolidine-1-carboxylate (23.5 g, 94%).
Reaction SMILES: [CH2:1]=[C:2]1[C:19]2[C@:14]([CH3:21])([CH2:15][CH2:16][C:17](=[O:20])[CH:18]=2)[C@@H:13]2[C@H:4]([C@H:5]3[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:22])[CH2:7][CH2:6]3)[CH2:3]1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[CH2:1]=[C:2]1[C:19]2[C@:14]([CH3:21])([CH:15]=[CH:16][C:17](=[O:20])[CH:18]=2)[C@@H:13]2[C@H:4]([C@H:5]3[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:22])[CH2:7][CH2:6]3)[CH2:3]1
Reactant: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)C=C12
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)C=CC(=O)C=C12
Yield: 50.3 %

Procedure:
0.50 g of 6-methylenandrost-4-ene-3,17-dione and 0.57 g of dichlorodicyanobenzoquinone were refluxed in 20 ml of anhydrous dioxane for about 15 hours. To remove the DDQ the suspension was filtered through alumina. After evaporation of the solvent the residue was dissolved in ethyl acetate, the organic layer washed with water, dried over sodium sulfate and the solvent removed under vacuum. The crude product was chromatographed on silica gel using hexane/ethyl acetate 40% to yield 0.25 g of pure 6-methylenandrosta-1,4-diene-3,17-dione, m.p. 188°-191° C., λmax 247 mμ (ε 13.750).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([F:14])[F:13])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([OH:27])=O)[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.Cl.[N:29]([C@@H:32]1[CH2:36][C@@H:35]([NH2:37])[C@H:34]([F:38])[CH2:33]1)=[N+:30]=[N-:31]>>[N:29]([C@@H:32]1[CH2:36][C@@H:35]([NH:37][C:25]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:7]4[CH:8]=[C:9]([CH:12]([F:14])[F:13])[CH:10]=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:16]=3[NH:23][C:22]=2[CH3:24])=[O:27])[C@H:34]([F:38])[CH2:33]1)=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=N[C@@H]1C[C@@H](N)[C@H](F)C1
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)O
Agent: Cl
Product: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1C[C@@H](N=[N+]=[N-])C[C@H]1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.g1) and (1R*,2R*,4R*)-4-azido-2-fluorocyclopentanamine hydrochloride (example C45) the title compound is obtained as pale yellow foam.
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:22][CH2:23]Br)[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C(N(CC)CC)C>C(#N)C>[CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:22][CH2:23][N:35]3[CH2:34][CH2:33][N:32]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:37][CH2:36]3)[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: BrCCOc1cccc2c1c1ccccc1n2Cc1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(CCOc2cccc3c2c2ccccc2n3Cc2ccccc2)CC1
Yield: 78.7 %

Procedure:
A mixture of 9-benzyl-4-(2-bromoethoxy)-9H-carbazole (0.0647 g, 0.170 mmol), Boc-piperazine (0.0380 g, 0.204 mmol), triethylamine (0.0206 g, 0.204 mmol), and acetonitrile (2 mL) is heated at reflux for 24 h. After cooling, the mixture is partitioned between CH2Cl2 and aq. sodium bicarbonate. The organic layers are dried over sodium sulfate; chromatography on silica gel eluting with CH3OH—CH2Cl2 (2/98) gave poor separation of product and impurities. Re-chromatography (silica gel, 20 mL) using acetone-hexane (10/90 to 20/80) gave 0.0650 g (83%) of the title compound; IR (drift) 1693, 1457, 1420, 1365, 1341, 1332, 1291, 1266, 1243, 1174, 1154, 1145, 1129, 1112, 752 cm−1; 1H NMR (CDCl3) δ1.46, 2.65, 3.06, 3.48, 4.41, 5.51, 6.69, 6.99, 7.12, 7.2-7.4, 8.37. Anal. Calcd for C30H35N3O3: C, 74.20; H, 7.26; N, 8.65. Found: C, 73.82; H, 7.41; N, 8.52.