Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH3:17])[CH3:15])[C:11]([Cl:18])=[CH:10][C:9]=1[NH2:19])(C)(C)C.C(O[C:26](=[O:49])[CH2:27][C:28](=O)[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[O:36][CH:37]=[C:38]([CH2:40][O:41]C3CCCCO3)[N:39]=2)[CH:30]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:18][C:11]1[C:12]([N:14]([CH2:16][CH3:17])[CH3:15])=[CH:13][C:8]2[N:7]=[C:28]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]4[O:36][CH:37]=[C:38]([CH2:40][OH:41])[N:39]=4)[CH:30]=3)[CH2:27][C:26](=[O:49])[NH:19][C:9]=2[CH:10]=1
Reactant: CCN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2nc(COC3CCCCO3)co2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3nc(CO)co3)c1)=N2

Procedure:
The title compound was prepared from [2-amino-4-chloro-5-(ethyl-methyl-amino)-phenyl]-carbamic acid tert-butyl ester (0.15 g) (Example J7) and 3-oxo-3-[3-[4-(tetrahydro-pyran-2-yloxymethyl)-oxazol-2-yl]-phenyl]-propionic acid tert-butyl ester (0.22 g) (Example K11) according to the general procedure M. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (0.10 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[N:7](C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[N:6]=[C:5]2[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=1.C[N:39]([CH3:42])C=O>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>[F:37][C:33]1[CH:32]=[C:31]([C:5]2[C:4]3[C:8](=[C:9]([CH3:11])[CH:10]=[C:2]([C:42]#[N:39])[CH:3]=3)[NH:7][N:6]=2)[CH:36]=[CH:35][CH:34]=1
Reactant: Cc1cc(Br)cc2c(-c3cccc(F)c3)nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c12
Reactant: CN(C)C=O
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: CCOC(C)=O
Product: Cc1cc(C#N)cc2c(-c3cccc(F)c3)n[nH]c12
Temperature: 100 °C
Reaction time: 24 h

Procedure:
To a solution of 1.5 g of 5-bromo-3-(3-fluorophenyl)-7-methyl-1-trityl-1H-indazole in 15 ml dimethylformamide were added 0.64 g of zinc cyanide and 0.32 g of tetrakis(triphenylphosphine)palladium(0) at room temperature, and the mixture was stirred at 100° C. for one day. At the same temperature, 0.32 g of tetrakis(triphenylphosphine)palladium(0) was added and the mixture was stirred at 130° C. for one day. The reaction mixture was diluted with ethyl acetate, and the organic layer was sequentially washed with saturated aqueous ammonium chloride solution and brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=1:10 to 1:1) and the resulting crystals were washed with diethyl ether, to give 431 mg of the title compound as colorless crystals.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][NH:14][CH:15]=O)=[N:11][CH:12]=1>C1(C)C=CC=CC=1>[CH3:6][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([CH:15]=[N:14][CH:13]=2)[CH:12]=1
Reactant: Cc1ccc(CNC=O)nc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1ccc2cncn2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
In a round-bottomed flask, N-(5-methyl-pyridin-2-ylmethyl)-formamide (crude from step 2) was dissolved in toluene (30 ml) and phosphorus oxychloride (1.2 ml, 12.9 mmol) was added. The reaction mixture was stirred at 100° C. in an oil bath overnight then cooled to 0° C. and carefully quenched with ice. Aqueous 25% ammonium hydroxide was added until pH=˜9. The mixture was diluted with water and extracted with dichloromethane (2×). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was absorbed on silica gel and chromatographed with EtOAc/hexanes (gradient 0-80% EtOAc) to give 386 mg (41%, 3 steps) of 6-methyl-imidazo[1,5-a]pyridine as a light brown solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 8.09 (s, 1H), 7.74 (s, 1H), 7.32-7.43 (m, 2H), 6.60 (dd, J=9.4, 1.1 Hz, 1H), 2.25 (d, J=1.1 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][NH:10][CH:11]2[CH2:14][C:15]([OH:17])=[O:16])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[K+].Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].Cl>O>[C:25]1([CH2:24][O:23][C:21]([N:10]2[CH2:9][CH2:8][C:7]3[C:12](=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH:11]2[CH2:14][C:15]([OH:17])=[O:16])=[O:22])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(O)CC1NCCc2ccc([N+](=O)[O-])cc21
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CC1c2cc([N+](=O)[O-])ccc2CCN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 7-nitro-1,2,3,4-tetrahydroisoquinoline-1-acetic acid (5.0 g, 21.0 mmols) [Example 6(a)] in water (250 ml) at 0° C. was added 2M potassium hydroxide solution (15 ml). To this cooled solution was added in portions benzyl chloroformate (5.0 ml, 35 mmol) and the reaction mixture was stirred at 0° C. for 0.5 h. The solution was acidified with dilute hydrochloric acid and the precipitate which formed was collected. The dried solid was triturated with ether (200 ml) to give, after filtration, the title compound as a tan solid (4.83 g, 62%), m.p. 159.5-62° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:16]([NH:18][CH2:19][CH2:20][C:21]#[N:22])=O)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C[Si]([N:68]=[N+:69]=[N-:70])(C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:16]3[N:18]([CH2:19][CH2:20][C:21]#[N:22])[N:70]=[N:69][N:68]=3)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)NCCC#N
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)c1nnnn1CCC#N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85 %

Procedure:
To a solution of (S)-tert-butyl 3-(3′-chlorobiphenyl-4-yl)-1-(2-cyanoethylamino)-1-oxopropan-2-ylcarbamate (1.07 g, 2.500 mmol) in THF (50 ml) at room temperature was added Ph3P (1.640 g, 6.25 mmol), and the mixture was stirred at room temperature for 10 minutes. Then, to the mixture at 0° C. was added DIAD (1.215 ml, 6.25 mmol) and 2 minutes later was slowly added trimethylsilyl azide (0.828 ml, 6.25 mmol). The resulting light yellow suspension was slowly warmed up to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure. The obtained residue was purified by flash chromatography (silica gel, 25 to 50% EtOAc/Heptane) and gave the title compound: 423 mg (yield: 85%). LCMS (condition B): 453.2 (M+1); retention time=1.23 min.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[O:7]=[C:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1>C1COCC1>[OH:7][C:8]1([C:2]2[S:3][CH:4]=[CH:5][CH:6]=2)[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]1
Reactant: Brc1cccs1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cccs2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
A solution of 2-bromothiophene in THF (25 ml) was added drop wise to a suspension of Mg turnings in THF (100 mL). The mixture was stirred for 30 minutes, cooled to 0° C., and a solution of tert-butyl 4-oxopiperidine-1-carboxylate (25.0 g, 125.4 mmol) in THF (25 mL) was added dropwise. The reaction mixture was slowly warmed to RT and stirred for 1 hour until complete consumption of 2-bromothiophene was indicated by TLC. The reaction was quenched with sat. aq. NH4Cl solution (50 mL), extracted with EtOAc (200 mL), washed with H2O (50 mL) and brine solution, dried (Na2SO4), filtered, and evaporated to afford crude product as light brown oil. Purification by silica gel chromatography (25% EtOAc/hexanes) yielded tert-butyl 4-hydroxy-4-(thiophen-2-yl)piperidine-1-carboxylate (14.0 g, 40% yield).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:9]2[NH:8][C:7]3[CH2:12][CH:13]([NH:15][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])[CH2:14][C:6]=3[C:5]=2[CH:4]=1)#[N:2].[F:21][C:22]1[N:27]=[C:26]([CH2:28]Br)[CH:25]=[CH:24][CH:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[C:1]([C:3]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:28][C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([F:21])[N:27]=3)[C:7]3[CH2:12][CH:13]([NH:15][C:16](=[O:20])[CH:17]([CH3:18])[CH3:19])[CH2:14][C:6]=3[C:5]=2[CH:4]=1)#[N:2]
Reactant: CC(C)C(=O)NC1Cc2[nH]c3ccc(C#N)cc3c2C1
Reactant: Fc1cccc(CBr)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)C(=O)NC1Cc2c(n(Cc3cccc(F)n3)c3ccc(C#N)cc23)C1
Yield: 56.5 %

Procedure:
Mix (±)-N-(7-cyano-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-isobutyramide (6.28 g, 18.8 mmol), 6-fluoro-2-bromomethylpyridine (3.93 g, 20.7 mmol), and Cs2CO3 (12.25 g, 37.6 mmol) in DMF (25 mL). Heat the reaction at 50° C. for 18 h. Cool, dilute with EtOAc, and wash with water (3×200 mL). Dry the organic layer (MgSO4) and concentrate to give 7.1 g crude material. Purify by silica gel chromatography (5-20% EtOAc/CH2Cl2). Obtain 4.0 g (56%) yellow-tan solid. MS (m/z): 377 (M+1), 375 (M−1).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].S([CH2:29][N+:30]#[C-:31])(C1C=CC(C)=CC=1)(=O)=O>CO>[N+:10]([C:8]1[CH:7]=[CH:6][C:3]([C:4]2[O:5][CH:31]=[N:30][CH:29]=2)=[C:2]([CH3:1])[CH:9]=1)([O-:12])=[O:11]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: Cc1cc([N+](=O)[O-])ccc1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1cc([N+](=O)[O-])ccc1-c1cnco1
Temperature: 25 °C
Yield: 100.8 %

Procedure:
2Bromo-5-nitrotoluene (1.0 g, 4.54 mmol) and vinyltributyl tin (1.59 g, 4.99 mmol) were dissolved in toluene (25 mL) under argon. Palladium dibenzylidene acetone (4.15 g, 0.455 mmol) and triphenylphosphine (488 mg, 1.86 mmol) was added and the reaction refluxed overnight. The solvent was evaporated and the residue dissolved in 200 mL of methylene chloride and washed with 10% ammonium hydroxide, water, and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated. The crude product was purified by flash column chromatography heptane-methylene chlolride 1:1) to yield 726 mg of 2-methyl-4-nitrostyrene. 2-methyl-4-nitrostyrene (700 mg, 4.5 mmol) was dissolved in methylene chloride (20 mL) and cooled to −78° C., and treated with ozone until a blue color remained, after 5 minutes the excess ozone was removed by passing a stream of oxygen through the solution. Dimethyl sulfide (1 mL) was added and the reaction mixture stirred at room temperature overnight. The solvent was evaporated and the residue purified by flash column chromatography to yield 580 mg of the 2-methyl-4-nitrobenzaldehyde. 2-Methyl-4-nitrobenzaldehyde (570 mg, 3.45 mmol) and potassium carbonate (476 mg, 3.45 mmol) were suspended in methanol. Tosylmethylisocyanide (674 mg, 3.45 mmol) was added and the reaction mixture refluxed for 3 h, cooled to room temperature and concentrated. The residue was dissolved in methylene chloride (200 mL) and the organic layer was washed with water and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated to yield 710 mg (94%) of 5-(4-nitro-2-methylphenyl)oxazole. 5-(4-Nitro-2-methylphenyl)oxazole was dissolved in methanol (100 mL) and 10% palladium on carbon 200 mg was wetted with water and added. The reaction mixture was hydrogenated at 45 psi overnight. The catalyst was removed by filtration and 560 mg of 5-(4-amino-2-methylphenyl)oxazole was isolated in 92% purity by HPLC method A. Mass spectrum M+H+=175.1, 1H 400 MHz NMR (CDCl3): δ7.88 (s, 1H), 7.45 (m, 1H), 7.08 (s, 1H), 6.60 m(m, 2H), 2.38 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][C@@H:6]([N:8]2[CH:16]=[N:15][C:14]3[C:13](=[O:17])[NH:12][C:11]([NH2:18])=[N:10][C:9]2=3)[CH:5]=[CH:4]1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:19]([O:1][CH2:2][C@H:3]1[CH2:7][C@@H:6]([N:8]2[CH:16]=[N:15][C:14]3[C:13](=[O:17])[NH:12][C:11]([NH2:18])=[N:10][C:9]2=3)[CH:5]=[CH:4]1)(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc2c(ncn2[C@H]2C=C[C@@H](CO)C2)c(=O)[nH]1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CC(=O)OC[C@@H]1C=C[C@H](n2cnc3c(=O)[nH]c(N)nc32)C1
Yield: 70 %

Procedure:
(1R,4S)-9-(4-Hydroxymethyl-2-cyclopentenyl)guanine (150 mg, 0.607 mmole), acetic anhydride (freshly distilled, 65 mg, 0.161 mmole), 4-dimethylaminopyridine (3 mg), and dry dimethylformamide (5 mL) were stirred under nitrogen for 2 days. The solvent was evaporated and the residue applied to a silica gel column. Title compound was eluted with 10% methanol-chloroform as a waxy white solid. Crystallization from ethanol gave white powder (123 mg, 70%), m.p. 247°-249° C.; 1H-NMR (DMSO-d6) δ10.55 (br s, 1, NHCO), 7.55 (s, 1, purine H-8), 6.42 (br s, 2, NH2), 6.06 and 5.94 (both m, 2, CH=CH), 5.34 (m, 1, CH--N), 4.07 (d, J=6.0, 2, CH2O), 3.05 (m, 1, CH), 2.6 and 1.55 (both m, 2, CH2), 1.98 (s, 3, COCH3).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[CH2:7][CH2:8][NH:9]2)=[CH:4][CH:3]=1.[CH2:13]([N:15]([CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH:19]([NH2:21])[CH3:20])[CH3:14]>>[CH3:14][CH2:13][N:15]([CH2:16][CH2:17][CH2:18][CH:19]([NH:21][C:6]1[CH:7]=[CH:8][N:9]=[C:10]2[CH:11]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=12)[CH3:20])[CH2:22][CH3:23]
Reactant: CCN(CC)CCCC(C)N
Reactant: O=C1CCNc2cc(Cl)ccc21
Product: CCN(CC)CCCC(C)Nc1ccnc2cc(Cl)ccc12
Yield: 94.9 %

Procedure:
19.116 millimols, i.e. a yield of 94.9% relative to the 7-chloro-1,2,3,4-tetrahydroquinolin-4-one converted, and a yield of 97.5% relative to the 1-diethylamino-4-amino-pentane converted, and
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:26])=[C:5]([C:12]([C:14]2[CH:15]=[CH:16][C:17]3[N:22]=[C:21]([CH3:23])O[C:19](=[O:24])[C:18]=3[CH:25]=2)=[O:13])[N:6]2[C:11]=1[CH:10]=[CH:9][CH:8]=[CH:7]2.[NH3:27].[OH-].[Na+].Cl>>[CH3:1][O:2][C:3]1[C:4]([CH3:26])=[C:5]([C:12]([C:14]2[CH:25]=[C:18]3[C:17](=[CH:16][CH:15]=2)[N:22]=[C:21]([CH3:23])[NH:27][C:19]3=[O:24])=[O:13])[N:6]2[C:11]=1[CH:10]=[CH:9][CH:8]=[CH:7]2
Reactant: N
Reactant: COc1c(C)c(C(=O)c2ccc3nc(C)oc(=O)c3c2)n2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1c(C)c(C(=O)c2ccc3nc(C)[nH]c(=O)c3c2)n2ccccc12

Procedure:
0.100 g (0.29 mmol) of 6-[(1-methoxy-2-methylindolizin-3-yl)carbonyl]-2-methyl-4H-3,1-benzoxazin-4-one in 2 ml of a 20% aqueous ammonia solution are heated for 2 hours at 50° C. and then hydrolysed with 3 ml of 10% aqueous sodium hydroxide solution and brought to 50° C. for 2 hours. The reaction medium is acidified with a 1N aqueous solution of hydrochloric acid, to pH=9. The precipitate obtained is filtered off, rinsed with water and then dried under reduced pressure at 40° C. overnight. The solid obtained is purified by silica gel column chromatography, elution being carried out with a dichloromethane/methanol (90/10) mixture. 67 mg of a yellow solid are obtained.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]1([CH3:22])[CH2:11][CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:9]2[CH:18]=[CH:19][CH:20]=[CH:21][C:8]=2[O:7]1.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>[N+](C)([O-])=O.C(OCC)C>[C:23]([C:19]1[CH:20]=[CH:21][C:8]2[O:7][C:6]([CH3:22])([CH3:5])[CH2:11][CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:9]=2[CH:18]=1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC1(C)CC(c2ccccn2)c2ccccc2O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Solvent: C[N+](=O)[O-]
Product: CC1(C)CC(c2ccccn2)c2cc(C(=O)c3ccccc3)ccc2O1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 27.6 %

Procedure:
264 mg of aluminum chloride were added to an ice-cooled solution of 237 mg of 3,4-dihydro-2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran in 6 ml of nitromethane. The mixture was stirred for 5 minutes, 349 mg of benzoyl chloride were added and the stirring was continued at 0° C. for 30 minutes and at room temperature for 16 hours. The o reaction mixture was diluted with diethyl ether and washed with sodium hydroxide solution. The organic phase was dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (2:3) for the elution to give 94 mg of 6-benzoyl-3,4-dihydro-2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N:7]1([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[F:20][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][C:30]=1F)[C:24]([O:26][CH3:27])=[O:25]>>[F:20][C:21]1[CH:22]=[C:23]([C:24]([O:26][CH3:27])=[O:25])[CH:28]=[CH:29][C:30]=1[N:10]1[CH2:11][CH2:12][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:9]1
Reactant: COC(=O)c1ccc(F)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(F)c1
Temperature: 90 °C
Reaction time: 24 h
Yield: 44.8 %

Procedure:
Potassium carbonate (5.56 g, 40.3 mmol) and tert-butyl piperazine-1-carboxylate (6.92 g, 37.2 mmol) were combined, methyl 3,4-difluorobenzoate (5.33 g, 31.0 mmol) was added and the reaction mixture was stirred at 90° C. for 1 d. The mixture was triturated with ethyl acetate (3×5 mL) and the combined organic extracts were filtered. This was concentrated down to about 5-10 mL and subjected to flash column chromatography on silica gel (120 g SiO2, hexanes: ethyl acetate 1:0 to 4:1) to afford tert-butyl 4-(2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (4.702 g, 13.90 mmol, 44.9% yield) as a white solid. ESI-MS: m/z 339 (M+H)+.
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].C([O-])([O-])=O.[K+].[K+].[CH3:11][C:12](=[O:17])[CH2:13][C:14](=[O:16])[CH3:15]>CC(C)=O>[CH2:3]([CH:13]([C:12](=[O:17])[CH3:11])[C:14](=[O:16])[CH3:15])[C:2]#[CH:1]
Reactant: C#CCBr
Reactant: CC(=O)CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCC(C(C)=O)C(C)=O
Temperature: 60 °C
Reaction time: 24 h
Yield: 80.4 %

Procedure:
The mixture of propargyl bromide (0.32 g, 2.70 mmol), K2CO3 (2.22 g, 16.10 mmol), and 2,4-pentane-dione (1.34 g, 13.40 mmol) in acetone (30 mL) was stirred for 24 hrs at 60° C. After filtration and removal of solvent under reduced pressure, the crude residue was purified by flash chromatography (hexane) to give 22 as colorless liquid (0.30 g, 69%). 1HNMR (400 MHz, CDCl3) δ 2.03-2.04 (t, J=5.28 Hz, 1H), 2.22 (s, 3H), 2.25 (s, 3H), 2.68-2.71 (m, 2H), 3.84-3.87 (t, J=15.08 Hz, 1H); 13CNMR (100 MHz, CDCl3) δ 14.45, 29.33, 29.41, 68.70, 70.79, 86.13, 202.18, 202.63.
Reaction SMILES: CN(C)C(N(C)C)=N.[CH2:9]([O:16][CH2:17][CH:18]=[O:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[N+:20]([CH:23]([CH3:25])[CH3:24])([O-:22])=[O:21]>C1COCC1>[CH2:9]([O:16][CH2:17][CH:18]([OH:19])[C:23]([CH3:25])([N+:20]([O-:22])=[O:21])[CH3:24])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=CCOCc1ccccc1
Reactant: CC(C)[N+](=O)[O-]
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Product: CC(C)(C(O)COCc1ccccc1)[N+](=O)[O-]
Temperature: 0 °C
Yield: 87.1 %

Procedure:
1,1,3,3-Tetramethylguanidine (620 μL, 5 mmol) was added slowly to a cold, 0° C., stirring solution of benzyloxy acetaldehyde (4.6 g, 31 mmol) and 2-nitropropane (30 mL, 333 mmol) in 100 mL of anhydrous THF. The reaction was stirred at 0° C. for ten minutes then allowed to warm to room temperature and stirred for 18 hours. The reaction was concentrated under reduced pressure and the product purified by column chromatography (5 to 50% ethyl acetate in hexanes) to give the title compound as a clear liquid (6.4 g, 27 mmol, 84%). 1H NMR (CDCl3, 400 MHz) δ 1.58 (s, 3H), 1.63 (s, 2H), 2.87-2.89 (d, J=5.0 Hz, 1H), 3.48-3.53 (dd, 6.8, 9.8 Hz, 1H), 3.60-3.63 (dd, J=4.5, 9.8 Hz, 1H) 4.29-4.33 (m, 1H), 4.57 (s, 2H), 7.32-7.39 (m, 5H). LRMS (ESI/APCI) m/z 238 [M−H+].
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24]Br)[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2].[CH2:27]([CH:29]([CH2:33][CH3:34])[C:30]([OH:32])=[O:31])[CH3:28]>CC(C)=O.[OH-].[Na+]>[CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24][O:32][C:30](=[O:31])[CH:29]([CH2:33][CH3:34])[CH2:27][CH3:28])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2]
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CBr
Reactant: CCC(CC)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCC(CC)C(=O)OCC(=O)O[C@H]1[C@@H](CC)C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21C

Procedure:
In 35 ml of acetone is dissolved 1.0 ml of 2-ethylbutyric acid, and 4.6 ml of 2N-NaOH and then 1.9 g of 16β-ethyl-17β-bromoacetoxy-4-estren-3-one are added to the above solution. The mixture is refluxed for 3 hours. The acetone is distilled off under reduced pressure and the residue is extracted with two 100 ml portions of ethyl acetate. The organic layers are combined, washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure and the residue is subjected to column chromatography. Following passage of 50 ml of ether, elution is carried out with 300 ml of the same solvent. The eluate is evaporated under reduced pressure to remove the solvent, giving 1.63 g of the above-identified compound as a light-yellow viscous oil.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([S:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)(=[O:13])=[O:12])[CH2:7][CH2:6]1)=[O:4].[C:24]1([CH2:30]CC(O)=O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.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>C(Cl)Cl>[CH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][C:14]=1[S:11]([N:8]1[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][CH2:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:6][CH2:7]1)(=[O:13])=[O:12]
Reactant: O=C(O)CCc1ccccc1
Reactant: O=C(CCl)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CCc1ccccc1)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Reaction time: 8 h
Yield: 83.5 %

Procedure:
To a stirred solution of 2-chloro-1-(4-(naphthalen-2-ylsulfonyl)piperazin-1-yl)ethanone (compound 4, 0.208 g, 0.66 mmol) and 3-phenylpropanoic acid (100 mg, 0.66 mmol) taken in dry DCM (30 mL), DIPEA (430 mg, 3.32 mmol) followed by HATU (504 mg, 1.33 mmol) was added at room temperature and stirred overnight. The mixture was then diluted with DCM washed with water (2×10 mL) & brine (2×10 mL). The organic extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to yield the title compound (0.225 g, 82.72%) as solid.