Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[Cl:9][C:10]1[CH:11]=[C:12]([OH:17])[CH:13]=[CH:14][C:15]=1[Cl:16].[OH-].[K+].CCCCCCC>CS(C)=O>[Cl:8][C:5]1[N:4]=[N:3][C:2]([O:17][C:12]2[CH:13]=[CH:14][C:15]([Cl:16])=[C:10]([Cl:9])[CH:11]=2)=[CH:7][CH:6]=1
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: Clc1ccc(Cl)nn1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCCCCCC
Product: Clc1ccc(Oc2ccc(Cl)c(Cl)c2)nn1
Yield: 21.1 %

Procedure:
A solution of 3,6-dichloropyridazine (4.47 g, 30.0 mmol), 3,4-dichlorophenol (4.89 g, 30.0 mmol) and potassium hydroxide (1.68 g, 30.0 mmol) in dimethyl sulfoxide (20 mL) was heated at 60° C. overnight. The solvent was removed by evaporation in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane 50:50). Small amounts of starting material were removed by kugelrohr distillation. Crystallisation from ethyl acetate:heptane yielded the title compound (1.74 g, 21% yield) as a white solid.
Reaction SMILES: C([N:8]1[C@@H:13]([CH3:14])[CH2:12][C:11](=[O:15])[CH2:10][C@@H:9]1[CH3:16])C1C=CC=CC=1>CCO.[Pd]>[CH3:16][C@H:9]1[CH2:10][C:11](=[O:15])[CH2:12][C@H:13]([CH3:14])[NH:8]1
Reactant: C[C@H]1CC(=O)C[C@H](C)N1Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: C[C@H]1CC(=O)C[C@H](C)N1

Procedure:
trans-N-Benzyl-2,6-dimethylpiperidin-4-one (91; 7.5 g) was dissolved in EtOH (20 mL) and the catalyst (0.8 g, Pd/C5%) was added. The slurry was vigorously stirred and kept under a hydrogen atmosphere (60 psi) for 90 hr. The catalyst was removed by filtration through Celite and the filtrate was evaporated at 3 mmHg/40° C. The residue (ca. 5.2 g) was used without further purification.
Reaction SMILES: O1[C:5]2([CH2:9][CH2:8][N:7]([C@H:10]3[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]3[O:16][CH2:17][CH2:18][CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:6]2)[O:4]CC1.CC(=O)CC.[ClH:31]>>[ClH:31].[O:4]=[C:5]1[CH2:9][CH2:8][N:7]([C@@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]2[O:16][CH2:17][CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:6]1
Reactant: C1CCC(CCCO[C@H]2CCCC[C@@H]2N2CCC3(C2)OCCO3)CC1
Agent: Cl
Solvent: CCC(C)=O
Product: O=C1CCN([C@@H]2CCCC[C@@H]2OCCCC2CCCCC2)C1

Procedure:
(1R,2R)/(1S,2S)-2-[1,4-Dioxa-7-azaspiro[4.4]non-7-yl]-1-[3-(cyclohexyl)propoxy]cyclohexane (ii) in a mixture of 6M HCl aqueous solution-butanone (1:4, v/v, 100 mL) was refluxed for 16 hours. The cooled reaction mixture was concentrated in vacuo and the residual aqueous solution was diluted with water (˜50 mL). The acidic aqueous solution was extracted with diethyl ether (50 mL) and then with dichloromethane (3×50 mL). The dichloromethane extracts were dried over sodium sulfate and the solvent was evaporated in vacuo to provide the crude title compound. The hydrochloride salt was crystallized by triturating in a mixture of diethyl ether-hexanes (1:1, v/v, ˜200 mL) and then precipitated from a mixture of dichloromethane-diethyl ether-hexanes to yield 0.8 g of the title compound, having the elemental analysis indicated in Table 1.
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].[CH2:9]([NH:16][CH2:17][CH:18]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)[CH:19]([OH:22])[CH2:20][OH:21])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.O>C1COCC1>[CH2:9]([NH:16][CH2:17][CH:18]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)[CH:19]([OH:22])[CH2:20][O:21][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:8])[CH3:7])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCC(O)C(CNCc1ccccc1)c1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC(O)C(CNCc1ccccc1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.1 %

Procedure:
A solution of tert-butyldimethylchlorosilane (3.65 g) in THF (10 mL) was added dropwise to a solution of (2RS,3RS)-4-(benzylamino)-3-(3,4-dichlorophenyl)butane-1,2-diol (7.50 g) and triethylamine (9.22 mL) in THF (35 ml) at 0° C. Under nitrogen purging, the mixture was stirred at room temperature for 3 hr, water was added at 0° C., and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate (0%-100%)) to give the title compound (6.42 g) as a pale-yellow oil.
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[NH:5]1)([CH3:3])[CH3:2].[Li]CCCC.[C:15](Cl)(=[O:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>C1COCC1>[C:15]([N:5]1[C@@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:8][O:7][C:6]1=[O:9])(=[O:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCC(=O)Cl
Reactant: CC(C)[C@H]1COC(=O)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCC(=O)N1C(=O)OC[C@@H]1C(C)C

Procedure:
The synthesis of Fragment B is comprised of the following steps: (a) a solution of 4-(S)-isopropyl-oxazolidin-2-one 2 in THF at a temperature of −78° C. is treated with a solution of n-BuLi in hexanes, or any suitable base; (b) heptanoyl chloride 3 is added to the mixture to yield 3-heptanoyl-4-(S)-isopropyl-oxazolidin-2-one 4; (c) treatment of a solution of 4 in THF with lithium diisopropylamide, or similar bases, followed by bromoacetic acid tert-butyl ester yield 3-(4-(S)-isopropyl-2-oxo-oxazolidine-3-(S)-carbonyl)octanoic acid tert-butyl ester 5; (d) treatment of a mixture of 5 in THF/water with hydrogen peroxide in water followed by lithium hydroxide in water at 0° C. to yield 2-(R)-pentylsuccinic acid 4-tert-butyl ester 6; (e) treatment of a mixture of 6 and hydroxysuccinimide 7 in dimethylformamide or any suitable solvent, such as dioxane, with dicyclohexylcarbodiimide, or similar imides, to afford 2-(R)-pentylsuccinic acid 4-tert-butyl ester (should this be 1, if it is 4-t-butyl ester?)4-(2,5-dioxo-pyrrolidin-1-yl) ester 8 (Scheme 2, FIG. 3A).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])[CH2:8][C:9]([O:11][CH3:12])=[O:10])=[O:5].[CH3:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH2:30][CH2:31][CH2:32][C:33](O)=[O:34])[CH:24]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[CH3:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH2:30][CH2:31][CH2:32][C:33]([NH:2][CH2:3][C:4]([NH:6][CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[CH2:8][C:9]([O:11][CH3:12])=[O:10])=[O:5])=[O:34])[CH:24]=1
Reactant: COC(=O)CC(NC(=O)CN)c1ccccc1[N+](=O)[O-]
Reactant: Cc1ccnc(NCCCC(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)CC(NC(=O)CNC(=O)CCCNc1cc(C)ccn1)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
360 mg of methyl 3-(2-aminoacetylamino)-3-(2-nitrophenyl)propionate hydrochloride are dissolved in 35 ml of DMF, and 190 mg of 4-(4-methylpyridin-2-ylamino)butyric acid are added. After cooling the reaction mixture to 0°, 450 mg of TBTU and 63 mg of HOBt are added. It is neutralized with 0.15 ml of N-methylmorpholine and stirred at room temperature overnight. The solvent is distilled off, and the residue is mixed with 30 ml of ethyl acetate and washed with half-concentrated bicarbonate solution and saturated brine and worked up further as usual. Methyl 3-{2-[4-(4-methylpyridin-2-ylamino)butyrylamino]acetylamino}-3-(2-nitrophenyl)propionate is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:11][O:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[O:1][CH2:18][C:17]1[CH:20]=[CH:21][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1)[CH:6]=[O:7]
Reactant: COc1ccc(CCl)cc1
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2ccc(C=O)cc2OC)cc1
Temperature: 25 °C
Yield: 84.6 %

Procedure:
A mixture of 4-hydroxy-3-methoxybenzaldehyde (22.6 g, 149 mmol), 4-methoxybenzyl chloride (23.3 g, 149 mmol) and potassium carbonate (30.8 g, 223 mmol) was stirred in N,N-dimethylformamide (DMF) (150 mL) at 90 C for 2 hours. The solution was filtered hot, and cooled to room temperature. The filtrate was concentrated and dissolved ethyl acetate (300 mL) and extracted with aqueous sodium bicarbonate and water. The organics were dried with magnesium sulfate, filtered and concentrated. The crude product was recrystalized with ethyl acetate and hexanes to give product as an off-white solid (34.2 g, 126 mmol). 1H NMR (300 MHz, d6-DMSO): δ 9.86 (s, 1H), 7.58 (d, J=8.2 Hz, 1H), 7.44-7.40 (m, 3H), 7.30 (d, J=8.4 Hz, 1H), 6.98 (d, J=8.7 Hz, 2H), 5.15 (s, 2H), 3.84 (s, 3H), 3.78 (s, 3H). MS (ES+, m/z)=273 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:21])[C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N-:22]=[N+:23]=[N-:24].[Na+].[Mg+2].[Cl-].[Cl-].O>CN(C)C(=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:21])[C:13]2[CH:14]=[CH:15][C:16]([C:19]3[NH:24][N:23]=[N:22][N:20]=3)=[CH:17][CH:18]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)c1ccc(NC(=O)c2ccc(C#N)cc2)cc1
Agent: [Cl-]
Agent: [Mg+2]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)c1ccc(NC(=O)c2ccc(-c3nnn[nH]3)cc2)cc1
Temperature: 150 °C

Procedure:
The product from Example 4A (300 mg, 1.08 mmol) in N,N-dimethylacetamide (10 mL) was treated with NaN3 (0.7 g, 10.8 mmol) and MgCl2 (1.03 g, 10.8 mmol). The mixture was heated at 150° C. for 16 hours, allowed to cool to room temperature, and poured into H2O (50 mL). The mixture was filtered and the filter cake air-dried to provide the title compound as a solid. 1H NMR (300 MHz, DMSO-d6) δ 10.14 (s, 1H), 8.10 (d, J=8.4 Hz, 2H), 7.97 (d, J=8.4 Hz, 2H), 7.71 (d, J=8.5 Hz, 2H), 7.36 (d, J=8.4 Hz, 2H), 1.29 (s, 9H); MS (ESI+) m/z 322 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[NH:10][N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22](F)[C:19]=1[CH:20]=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+].C(O[Si](C)(C)C)C>CN(C=O)C>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:22]1[CH:23]=[CH:24][CH:25]=[C:18]([Cl:17])[C:19]=1[CH:20]=[O:21])[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(F)c2c(=O)[nH]ncc2c1
Reactant: O=Cc1c(F)cccc1Cl
Agent: CCO[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(Cl)c3C=O)ncc2c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 49.9 %

Procedure:
To a 10 mL round bottom flask were added 6-tert-butyl-8-fluoro-2H-phthalazin-1-one 101h (640 mg, 2.9 mmol), 2-chloro-6-fluorobenzaldehyde (506 mg, 3.2 mmol), and cesium carbonate (488 mg, 1.5 mmol). The flask was evacuated and backfilled with nitrogen three times then ethoxytrimethylsilane (684 mg, 5.8 mmol) and DMF (5 mL) were added to the reaction flask. The resulting mixture was heated to 60° C. After 4 h of stirring, the solution was allowed to cool down to ambient temperature and the reaction was quenched by addition of 2 mL of H2O drop-wise. The desired product started to precipitate from the DMF and water mixture. The solid was collected by filtration after cooling down to 5° C., and washed with DMF/water (2/1, 2 mL, pre-cooled to 6° C.) and H2O (2 mL). The filter cake was dried under vacuum oven at 65° C. for overnight to afford 519 mg (52%) of 101i as a yellow solid. MS: [M+H]+: 359
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH3:9].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.CC(C)([O-])C.[Na+].[NH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH3:9][S:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: Nc1ccccc1
Reactant: CSc1ccccc1Br
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: CSc1ccccc1Nc1ccccc1

Procedure:
(2-bromophenyl)(methyl)sulfane (25 g, 123 mmol), Pd2dba3 (6.75 g, 7.38 mmol), S-Phos (6.06 g,14.77 mmol) and sodium tert-butoxide (17.74 g, 185 mmol) were placed in a dry 3 neck flask under N2. The reaction mixture was vacuum evacuated and back filled with N2 three times. Aniline (22.93 g, 246 mmol) and 500 mL toluene were added to the reaction mixture. The reaction mixture was refluxed for 18 hours. The crude reaction mixture was run through a silica gel plug and eluted with toluene. The toluene portion was concentrated down and subjected to a silica gel column by using 3-5% DCM in hexanes to yield desired product. (24 g, 111 mmol, 91%)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])=[C:10]([C:23]([F:26])([F:25])[F:24])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.OC1CCNC1.[CH3:33][N:34]([CH3:44])[CH2:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[CH3:22][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:41]3[CH2:42][CH2:43][N:38]([CH2:37][CH2:36][CH2:35][N:34]([CH3:33])[CH3:44])[CH2:39][CH2:40]3)[CH:7]=2)=[CH:9][C:10]=1[C:23]([F:26])([F:25])[F:24]
Reactant: COc1ccccc1Sc1ccc(-c2ccnc(Cl)c2)cc1C(F)(F)F
Reactant: CN(C)CCCN1CCNCC1
Agent: OC1CCNC1
Product: COc1ccccc1Sc1ccc(-c2ccnc(N3CCN(CCCN(C)C)CC3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 96 (0.039 g, 0.0985 mmol) and 3-hydroxypyrrolidine with 1-(3-dimethylaminopropyl)piperazine. A yellow solid 113 was obtained (0.0414 g, 79%). 1H NMR (CDCl3, 400 MHz) δ 2.20–2.50 (br, 6H), 2.42–2.50 (m, 2H), 2.86 (s, 6H), 3.21–3.28 (m, 2H), 3.32–3.38 (br, 2H), 3.83 (s, 3H), 4.05–4.10 (br, 2H), 6.88 (s, 1H), 6.99–7.06 (m, 3H), 7.10 (d, J=8.2 Hz, 1H), 7.43–7.52 (m, 3H), 7.85 (s, 1H), 8.25 (d, J=5.5 Hz, 1H); MS (APCI) m/z 531 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:14])[CH2:4][O:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[C:8]#[N:9].O=[CH:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>CO>[C:8]([C:7]1[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=1[O:5][CH2:4][CH:3]([OH:14])[CH2:2][N:1]=[CH:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])#[N:9]
Reactant: CCOC(=O)CC=O
Reactant: N#Cc1ccccc1OCC(O)CN
Solvent: CO
Product: CCOC(=O)CC=NCC(O)COc1ccccc1C#N

Procedure:
In accordance with Example 10 above 2-(3-amino-2-hydroxypropoxy)benzonitrile was prepared. 1.9 g of this compound were dissolved in 30 ml of methanol and 1.16 g of ethyl 3-oxopropanoate were added, wereby ethyl N-[3-(2-cyanophenoxy)-2-hydroxypropyl]-3-iminopropanoate was obtained. Thesolution was cooled to 0° C. and at this temperature 3 g of sodium borohydride were added little by little, whereby the imino compound was reduced. The temperature was then allowed to rise to ambient temperature and after 1 hour 100 ml of H2O were added and the total mixture was extracted with ethyl acetate. The ethyl acetate phase was dried over MgSO4 and filtered. The residue was transformed into its hydrochloride. In this way ethyl N-[3-(2-cyanophenoxy)-2-hydroxypropyl]-3-aminopropanoate hydrochloride wasobtained. Melting point 120° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][C:3]=1[OH:14].[CH3:15][NH:16][C:17]([C:19]1[CH:24]=[C:23](Cl)[CH:22]=[CH:21][N:20]=1)=[O:18]>C(Cl)Cl>[CH3:15][NH:16][C:17]([C:19]1[CH:24]=[C:23]([O:14][C:3]2[CH:4]=[C:5]([N+:11]([O-:13])=[O:12])[C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=2[CH3:1])[CH:22]=[CH:21][N:20]=1)=[O:18]
Reactant: CNC(=O)c1cc(Cl)ccn1
Reactant: Cc1cc([N+](=O)[O-])c([N+](=O)[O-])cc1O
Solvent: ClCCl
Product: CNC(=O)c1cc(Oc2cc([N+](=O)[O-])c([N+](=O)[O-])cc2C)ccn1
Temperature: 170 °C

Procedure:
2-Methyl-4,5-dinitrophenol (Step A, 1.34 g, 6.77 mmol) and 4-chloro-pyridine-2-carboxylic acid methylamide (1.16 g, 6.77 mmol) were combined and heated at 160-180° C. (round bottom flask with condenser). The reaction was cooled to RT, the contents of the flask were dissolved in CH2Cl2 and the organic layer washed with 2 N NaOH, then water. The organic layer was dried with Na2SO4, filtered and evaporated. The mixture was purified by column chromatography using EtOAc/hexanes as the eluant. The title compound was obtained as a tan solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[CH:12][C:13](=[O:26])[CH:14]=[CH:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1.[CH3:27][NH2:28].O>CN(C)C=O>[CH:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:24]=[CH:25][C:16]=1[CH:15]1[CH2:14][C:13](=[O:26])[CH2:12][CH:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[N:28]1[CH3:27]
Reactant: CN
Reactant: O=C(C=Cc1ccc2ccccc2c1)C=Cc1ccc2ccccc2c1
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(c2ccc3ccccc3c2)CC(=O)CC1c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 21.9 %

Procedure:
1,5-Bis(2-naphthyl)-1,4-pentadien-3-one (25, 0.82 g, 2.5 mmol) was dissolved in dimethyl formamide (15 ml). Methylamine (51, 1.30 ml, 15.1 mmol, 40% in water) was added and the mixture stirred for 72 hr at room temperature. The mixture was poured into water (100 ml) and stirred for 24 hr at room temperature. The resulting mixture was extracted into ethyl acetate, washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to afford a solid. The crude solid was chromatographed on silica gel with ethyl acetate/hexane to afford a solid that was recrystallized twice from ethanol to give 0.20 g (22%) of a white solid: mp 209-212° C.; 1H NMR δ 1.89 (s, 3H), 2.59 (d, 2H, J=13.9 Hz), 2.97 (t, 2H, J=11.3 Hz), 3.66 (d, 2H, J=11.7 Hz), 7.49 (m, 4H), 7.81 (m, 10H); 13C NMR: δ 41.1, 50.7, 70.3, 124.6, 125.9, 126.0, 126.2, 127.6, 127.7, 128.9, 133.0, 133.4, 140.4, 206.6; Exact mass calcd for C26H23NO: 365.1780, observed (M+H) 366.1852.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH2:17][N+:18]([O-:20])=[O:19])(=[O:16])=[O:15])=[CH:10][CH:9]=1)([OH:7])=[O:6].[CH3:21]O>>[CH3:21][O:6][C:5]([C:8]1[CH:9]=[CH:10][C:11]([S:14]([CH2:17][N+:18]([O-:20])=[O:19])(=[O:15])=[O:16])=[CH:12][CH:13]=1)=[O:7]
Reactant: O=C(O)c1ccc(S(=O)(=O)C[N+](=O)[O-])cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(S(=O)(=O)C[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Thionyl chloride (0.33 ml, 4.5 mmol) was added dropwise to a stirred solution of (4-carboxyphenylsulphonyl)nitromethane (1.0 g, 4 mmol) in methanol (12 ml) cooled in an ice-salt bath. The mixture was stirred for 16 hours at ambient temperature and the solvent evaporated. The residue was purified by MPLC eluting with dichloromethane, gradually increasing to methanol/dichloromethane (1:50 v/v), to give (4-methoxycarbonylphenylsulphonyl)nitromethane (0.45 g), m.p. 106°-108° C.; microanalysis, found: C, 41.8; H, 3.5; N, 5.2%; C9H9NO6S requires: C, 41.7; H, 3.5: N, 5.4%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=3)=[CH:16][CH:17]=2)=[CH:11][C:10]([CH2:28][C:29]#[N:30])=[N:9]1.[N-:31]=[N+:32]=[N-:33].[Na+].[NH4+].[Cl-].CN(C=O)C>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:19]=3)=[CH:16][CH:17]=2)=[CH:11][C:10]([CH2:28][C:29]2[NH:33][N:32]=[N:31][N:30]=2)=[N:9]1
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(CC#N)nn3-c3ccccc3Cl)s2)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(Cc4nnn[nH]4)nn3-c3ccccc3Cl)s2)c1
Temperature: 120 °C
Reaction time: 24 h
Yield: 77.8 %

Procedure:
A mixture of [1-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]acetonitrile (136 mg, 0.3 mmol), NaN3 (59 mg, 0.9 mmol), NH4Cl (49 mg, 0.9 mmol), and anhydrous DMF (5 mL) was stirred in a sealed vial at 120° C. for 24 h. The mixture was poured into water, and extracted with DCM. The combined extracts were washed with water and brine, dried over Na2SO4, and evaporated in vacuo. The crude product was purified by flash chromatography (0-80% 20% MeOH/DCM) to give the title compound as a white solid (116 mg, 78%). 1HNMR (CDCl3): δ 8.04 (m, 1H), 7.85-7.83 (m, 1H), 7.74-7.71 (m, 1H), 7.62-7.46 (m, 5H), 7.22 (d, 1H), 6.8 (d, 1H), 6.66 (s, 1H), 4.52 (s, 2H), 3.08 (s, 3H). MS(ES): 497 [M+H]+.
Reaction SMILES: [CH2:1]([C@@H:3]([N:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12])[C:4](O)=[O:5])[CH3:2].C([N:15](CC)CC)C.CS(Cl)(=O)=O>C(Cl)Cl>[CH2:1]([C@@H:3]([N:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12])[C:4]([NH2:15])=[O:5])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CC[C@H](C(=O)O)N1CCCC1=O
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC[C@H](C(N)=O)N1CCCC1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.8 %

Procedure:
A suspension of (R)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid (35 g, 0.20 mol) in methylene chloride (225 ml) was cooled to 0° C. and triethylamine (41 g, 0.40 mol) and methanesulfonyl chloride (29 g, 0.26 mol) were added dropwise. The mixture was stirred at 0° C. for 30 min., then a stream of ammonia was purged in the solution at 0° C. for 2 hours. The insoluble solids were filtered and the filtrate was concentrated. The product was recrystallized from methyl isobutyl ketone to give 27.5 g (78%) of (R)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])[C:5]([CH3:21])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1.[N-:32]=[N+:33]=[N-:34].[Na+]>CN(C=O)C>[CH3:21][C:5]1[CH:4]=[C:3]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[C:2]2[N:7]([N:32]=[N:33][N:34]=2)[C:6]=1[C:8]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:12][CH2:11]1)=[O:9]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(Cl)nc1C(=O)N1CCC(N2CCCC2)CC1
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c2nnnn2c1C(=O)N1CCC(N2CCCC2)CC1
Temperature: 150 °C
Reaction time: 48 h
Yield: 47.1 %

Procedure:
A solution of 0.20 g (0.44 mmol) of [6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 3) in 2.0 ml of DMF was treated with 0.099 g (1.52 mmol) of a sodium azide and the reaction mixture was heated up to 150° C. After 48 hours, it was poured into crashed ice and extracted twice with EtOAc; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 98:2 to 4:1) to give 0.095 g (47%) of the title compound as colorless oil. MS: 459.4 (MH−).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:17][C:18](=[O:24])[C:19]([O:21]CC)=[O:20])[CH:6]=[C:7]([NH:9][C:10](=[O:16])[C:11]([O:13]CC)=[O:12])[CH:8]=1)#[N:2].[OH-].[Na+]>>[C:1]([C:3]1[CH:8]=[C:7]([NH:9][C:10](=[O:16])[C:11]([OH:13])=[O:12])[CH:6]=[C:5]([NH:17][C:18](=[O:24])[C:19]([OH:21])=[O:20])[CH:4]=1)#[N:2]
Reactant: CCOC(=O)C(=O)Nc1cc(C#N)cc(NC(=O)C(=O)OCC)c1
Agent: [Na+]
Agent: [OH-]
Product: N#Cc1cc(NC(=O)C(=O)O)cc(NC(=O)C(=O)O)c1

Procedure:
A solution of 1.51 gram (0.0045 mole) of diethyl N,N'-(5-cyano-m-phenylene)dioxamate in 10 ml. of 5% sodium hydroxide solution is stirred for 25 minutes and filtered. To the filtrate is added dilute hydrochloric acid. The resulting precipitate is removed by filtration; weight 0.86 grams, M. P. 230° C.