Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([N:17]4C=CN=C4)=[O:16])=[C:10]3[C@@H:9]3[CH2:22][CH2:23][CH2:24][N:8]3[C:7](=[O:25])[C:6]=2[CH:26]=1.N>CN(C)C=O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([NH2:17])=[O:16])=[C:10]3[C@@H:9]3[CH2:22][CH2:23][CH2:24][N:8]3[C:7](=[O:25])[C:6]=2[CH:26]=1
Reactant: O=C1c2cc(F)ccc2-n2cnc(C(=O)n3ccnc3)c2[C@@H]2CCCN12
Agent: N
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1cc(F)ccc1-2

Procedure:
20 g (57 mmol) of 1-[[(S)-7-fluoro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-1-yl]carbonyl]imidazole are suspended in 55 ml of N,N-dimethylformamide, the suspension is treated with 9.9 ml of 25 percent ammonia solution in water, the mixture is stirred for a half hour and then poured into 300 ml of water. The precipitated product is filtered off under suction, washed with water and dried at 80° for 48 hours in a water-jet vacuum. There is obtained (S)-7-fluoro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxamide of melting point 239°-240°.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16](=[O:20])[NH:15][N:14]=[CH:13]3)=[CH:4][CH:3]=1>CN(C=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16](=[O:20])[NH:15][N:14]=[CH:13]3)=[CH:6][CH:7]=1
Reactant: O=c1[nH]ncc2cc(/C=C/c3ccc(O)cc3)ccc12
Solvent: CN(C)C=O
Product: O=c1[nH]ncc2cc(/C=C\c3ccc(O)cc3)ccc12
Temperature: 45 °C
Reaction time: 2 h

Procedure:
Trans-6-[2-(4-Hydroxyphenyl)ethenyl]-1(2H)-phthalazinone (12.4 gm) (produced in Example 2) was dissolved in 415 ml DMF by warming to 45° C. The solution was cooled back to 20° C. and diluted with an additional 200 ml DMF. The slightly cloudy solution was clarified by filtration, and the clear solution was irradiated in a soft glass container with 254 nm ultraviolet light for about 24 hours. The resulting solution was added with stirring to 6 L. water and allowed to settle for about 2 hours. The supernatant fluid, was decanted and the solid residue was filtered and washed with water and dried. Wt=7.4 gm, >95% cis by HPLC. mp=210°-22-° C (d).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:8][NH2:9])=[CH:6][CH:7]=1.[C:10](Cl)(=O)[CH:11]([CH3:13])[CH3:12].O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[N:4]([C:10]([CH:11]([CH3:13])[CH3:12])=[N:9][N:8]=2)[N:3]=1
Reactant: NNc1ccc(Cl)nn1
Reactant: CC(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)c1nnc2ccc(Cl)nn12
Temperature: 90 °C
Yield: 94 %

Procedure:
A mixture of 3-chloro-6-hydrazinylpyridazine (200 g, 1.38 mol) and isobutyryl chloride (175 mL, 1.66 mol) in 1,4-dioxane (2 L) was heated at about 90° C. overnight. The suspension was cooled to about 5° C. in an ice bath and then water (2 L) was added followed by slow addition of Na2CO3 (275 g, 2.59 mol). The resulting solution was extracted with DCM (3×1 L). The combined organic extracts were dried over MgSO4, concentrated under reduced pressure, and dried under vacuum overnight to give the title compound (255 g, 94%): LC/MS (Table 1, Method a) Rt=2.04 min; MS m/z: 197.1 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[CH2:6]([CH:9]1[CH2:14][CH2:13][CH:12]([C:15]2([C:21]3[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=3)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:11][CH2:10]1)[CH2:7][CH3:8].O.Cl>N1C=CC=CC=1>[C:1]([O:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:15]2([CH:12]3[CH2:13][CH2:14][CH:9]([CH2:6][CH2:7][CH3:8])[CH2:10][CH2:11]3)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:22]=1)(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)Cl
Reactant: CCCC1CCC(C2(c3cccc(O)c3)CCCCC2)CC1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCC1CCC(C2(c3cccc(OC(=O)CC)c3)CCCCC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 109.9 %

Procedure:
Under a nitrogen atmosphere, 1.7 g of propanoyl chloride was added to 5.0 g of 3-((4-propylcyclohexyl)cyclohexyl)phenol (3) dissolved in 10 mL of pyridine under cooling with iced water, and after completing dropwise addition, the mixture was stirred at ambient temperature for 2 hours. The resulting solution was added to 20 mL of 3N hydrochloric acid. The aqueous layer was extracted with diethyl ether, which was added to the organic layer, and the organic layer was washed with a saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain 6.52 g of 3-((4-propylcyclohexyl)cyclohexyl)phenyl propanoate (4).
Reaction SMILES: [C:1]([NH:20][CH:21]1[CH2:26][CH2:25][CH2:24][NH:23][C:22]1=O)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>O1CCCC1>[NH:23]1[CH2:24][CH2:25][CH2:26][CH:21]([NH:20][C:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:22]1
Reactant: O=C1NCCCC1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(C(NC2CCCNC2)(c2ccccc2)c2ccccc2)cc1
Yield: 85 %

Procedure:
Add 3-(trityl-amino)-piperidin-2-one (3.56 g, 10.0 mmol) in portions to a suspension of LiAlH4 (1.00 g, 26.5 mmol) in tetrahydrofuran (25 mL). Heat the reaction to reflux under nitrogen overnight. Cool the reaction to room temperature, add 1.0 mL water, follow by adding 3.0 mL 15% NaOH and 3.0 mL water. Filter the mixture, wash with tetrahydrofuran and concentrate. Patition the material between diethyl ether and water. Add 5.0N sodium hydroxide until the aqueous layer cleared. Extract he product from the aqueous layer with diethyl ether. Dry the combined organic layers over magnesium sulfate and concentrate to give 2.91 g of the title compound as a clear oil, 85% yield. 1H NMR: consistent with structure.
Reaction SMILES: C1COCC1.[CH3:6][N:7]1[CH:12]=[CH:11][C:10]([C@@H:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][C@H:14]2[C:26]([O:28]CC)=[O:27])=[CH:9][C:8]1=[O:31].[OH-].[Li+]>CO>[CH3:25][C:22]([O:21][C:19]([N:16]1[CH2:17][CH2:18][C@@H:13]([C:10]2[CH:11]=[CH:12][N:7]([CH3:6])[C:8](=[O:31])[CH:9]=2)[C@H:14]([C:26]([OH:28])=[O:27])[CH2:15]1)=[O:20])([CH3:23])[CH3:24]
Reactant: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1c1ccn(C)c(=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1ccc([C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2C(=O)O)cc1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a 3:2 (v/v) THF:MeOH solution (0.07 M) of trans-1-(1,1-dimethylethyl) 3-ethyl 4-(1-methyl-2-oxo-1,2-dihydro-4-pyridinyl)-1,3-piperidinedicarboxylate (1 eq.) from the previous step was added lithium hydroxide (1 M aq. solution, 3.1 eq.). The resulting cloudy solution was stirred vigorously at RT for 18 h. The volatiles were then removed in vacuo and the residue was partitioned between EtOAc and 10% aq. HCl. The aqueous layer was separated and back-extracted with EtOAc. The combined organic extracts were washed further with water and brine, dried over Na2SO4 and filtered. Concentration of the filtrate in vacuo afforded the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]([OH:7])([CH2:5][CH3:6])[C:3]#[CH:4].Br[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1/[C:11](=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][C:24]=1[O:25][CH3:26])/[C:12](=[O:18])[NH:13]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[OH:7][C:2]([CH3:1])([CH2:5][CH3:6])[C:3]#[C:4][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1/[C:11](=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][C:24]=1[O:25][CH3:26])/[C:12](=[O:18])[NH:13]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Reactant: C#CC(C)(O)CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(C)(O)C#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method D above, 3-methyl-1-pentyn-3-ol (75 mg, 0.75 mmol) (Aldrich) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (Starting Material 1 supra) (200 mg, 0.63 mmol) using (Ph3P)2PdCl2 (25 mg) and CuI (12 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 70° C. for 17 h to yield rac-(Z)-1,3-dihydro-4-(3-hydroxy-3-methyl-1-pentynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 66 mg, 31%).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CN(C)C(Cl)=[S:17]>>[SH:17][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CN(C)C(=S)Cl
Reactant: Oc1ccc(-c2ccccc2)cc1
Product: Sc1ccc(-c2ccccc2)cc1
Yield: 39 %

Procedure:
The reaction of p-hydroxybiphenyl with dimethylthiocarbamoyl chloride followed by Newman-Kwart rearrangement and finally hydrolysis (see J. Het. Chem. 15, 281 (1978) and WO 96/25 936) affords 4-mercaptobiphenyl only in a yield of 39%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]([CH3:17])[C:14]([OH:16])=O)[CH:5]=[CH:6][C:7]=1[CH2:8][S:9]([CH3:12])(=[O:11])=[O:10].[C:18]([C:22]1[CH:26]=[C:25]([CH2:27][NH2:28])[N:24]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=2)[N:23]=1)([CH3:21])([CH3:20])[CH3:19].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>C1COCC1>[C:18]([C:22]1[CH:26]=[C:25]([CH2:27][NH:28][C:14](=[O:16])[CH:13]([C:4]2[CH:5]=[CH:6][C:7]([CH2:8][S:9]([CH3:12])(=[O:10])=[O:11])=[C:2]([F:1])[CH:3]=2)[CH3:17])[N:24]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=2)[N:23]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C(=O)O)c1ccc(CS(C)(=O)=O)c(F)c1
Reactant: CC(C)(C)c1cc(CN)n(-c2cccc(Cl)c2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C(=O)NCc1cc(C(C)(C)C)nn1-c1cccc(Cl)c1)c1ccc(CS(C)(=O)=O)c(F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 80.4 %

Procedure:
To a stirred solution of 2-(3-fluoro-4-(methylsulfonylmethyl)phenyl)propanoic acid (60 mg, 0.231 mmol) and (3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methanamine (60 mg, 0.231 mmol) in THF (1.8 mL) were added O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluorborat (73 mg, 0.231 mmol), 1-hydroxybenzotriazole (30 mg, 0.231 mmol) and N-ethyldiisopropylamine (0.078 mL, 0.462 mmol). The reaction mixture was stirred for 48 h at room temperature, concentrated in vacuo and the residue was purified by CC (eluent: ethyl acetate/cyclohexane (3:2)) to give N-[[5-tert-butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(methylsulfonyl-methyl)-phenyl]-propionamide (94 mg, 80%).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C@@H:14]2[CH2:16][C@@H:15]2[CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[N:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=3)[CH2:19][CH2:18]2)(=O)=O)=CC=1.C(OC([NH:37][C:38]1[CH:39]=[C:40]([Cl:59])[C:41]([N:44](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[N:42][CH:43]=1)=O)(C)(C)C>>[Cl:29][C:26]1[CH:27]=[N:28][C:23]([N:20]2[CH2:19][CH2:18][CH:17]([C@H:15]3[CH2:16][C@H:14]3[CH2:13][CH2:12][NH:44][C:41]3[C:40]([Cl:59])=[CH:39][C:38]([NH2:37])=[CH:43][N:42]=3)[CH2:22][CH2:21]2)=[N:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)Nc1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)OCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)cc1
Product: Nc1cnc(NCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)c(Cl)c1

Procedure:
The title compound was synthesized by procedure analogous to Step 2 of Example 11 from cis-2-{(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethyl 4-methylbenzenesulfonate from Step 1 of Example 5 and di-tert-butyl {5-[(tert-butoxycarbonyl)amino]-3-chloropyridin-2-yl}imidodicarbonate from Step 1 of this example.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][CH2:7][NH:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)=[O:10])C.O=CCCCNC(C1CCCCC1)=O>>[O:3]=[CH:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)=[O:10]
Reactant: CCOC(CCCNC(=O)N1CCc2ccccc2C1)OCC
Agent: O=CCCCNC(=O)C1CCCCC1
Product: O=CCCCNC(=O)N1CCc2ccccc2C1

Procedure:
3,4-Dihydro-1H-isoquinoline-2-carboxylic acid (4-oxo-butyl)-amide is prepared from 24B as described for 20B.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH:8]([CH3:23])[C:9]([NH:11][C:12]1[N:13]=[C:14](Br)[C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:10])([CH3:4])([CH3:3])[CH3:2].[C:25]([Si:27]([CH3:30])([CH3:29])[CH3:28])#[CH:26].CCN(C(C)C)C(C)C>CN1C(=O)CCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6](=[O:24])[NH:7][CH:8]([CH3:23])[C:9](=[O:10])[NH:11][C:12]1[N:13]=[C:14]([C:26]#[C:25][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)Nc1cc2ccccc2c(Br)n1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)OC(C)(C)C)C(=O)Nc1cc2ccccc2c(C#C[Si](C)(C)C)n1

Procedure:
A mixture of tert-butyl-N-[1-[(1-bromoisoquinolin-3-yl)amino]-1-oxopropan-2-yl]-carbamate B4a (500 mg, 1.27 mmol), ethynyl(trimethyl)silane (137 mg, 1.4 mmol), copper(I) iodide (23 mg, 0.12 mmol), Dichlorobis(triphenylphosphine)palladium(II) (90 mg, 0.13 mmol) and DIPEA (700 μl, 4.12 mmol) is stirred under argon atmosphere in NMP (4 ml) for 1 h at 80° C. The mixture is concentrated in vacuo and the product purified by RP HPLC. Yield: 319 mg (61%). HPLC-MS: M+H=412; tR=2.11 min (*Method—4).
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH2:5][CH2:6][CH2:7][CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18]C)[CH:14]=2)[CH2:9]1)[CH3:4].[OH-].[Na+].C(=O)([O-])[O-].[K+].[K+]>Br>[ClH:1].[CH3:2][N:3]([CH2:5][CH2:6][CH2:7][CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=2)[CH2:9]1)[CH3:4]
Reactant: COc1ccc2c(c1)CCC(CCCN(C)C)C2
Agent: Br
Agent: Cl
Agent: O=C([O-])[O-]
Product: CN(C)CCCC1CCc2cc(O)ccc2C1
Yield: 58.4 %

Procedure:
2-[3-(N,N-Dimethylamino)propyl]-6-methoxytetralin hydrochloride (3.6 g) was added to 48% hydrobromic acid (20 ml), and the reaction mixture was heated under reflux for 3 hours, and then left cooled. This was neutralized with an aqueous solution of 1 N sodium hydroxide, and an aqueous solution of 10% potassium carbonate was added thereto, which was then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried, and concentrated. The residue was recrystallized from methanol-diisopropyl ether to obtain the entitled compound (2.0 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.ClC1C=CC=C(C(OO)=[O:19])C=1>CC(C)=O>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:19]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Nc1ncccc1[N+](=O)[O-]
Solvent: CC(C)=O
Product: Nc1c([N+](=O)[O-])ccc[n+]1[O-]
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 2-amino-3-nitropyridine (5.0 g; 36 mmol) in acetone (250 mL) was added a solution of m-chloroperbenzoic acid (7.5 g; 100 mmol) in acetone (50 mL). The shiny orange solution was stirred at room temperature for 3 days. The resulting precipitate was dissolved again under heating and the solution poured onto a silica gel column. Column chromatography using acetone as eluant gave the title compound as an orange solid.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[N:14]2[CH:15]=[N:16][CH:17]=[C:13]2[CH:12]=[CH:11][CH:10]=1)(O)=[O:2].[H-].C([Al+]CC(C)C)C(C)C.CO.O>C(Cl)Cl.CCCCCC>[CH:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[N:14]2[CH:15]=[N:16][CH:17]=[C:13]2[CH:12]=[CH:11][CH:10]=1)=[O:2]
Reactant: O=C(O)CCCCCc1cccc2cncn12
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: O=CCCCCCc1cccc2cncn12
Reaction time: 0.33 h

Procedure:
To a cooled (-60°) solution of 4.9 g of 5-(5-methoxycarbonylpentyl)-imidazo[1,5-a]pyridine (obtained by esterification of 5-(5-carboxypentyl)-imidazo[1,5-a]pyridine of Example 2 with diazomethane in methylene chloride) in 140 ml of methylene chloride is added 40 ml of a 1.75 M solution of di-isobutyl aluminum hydride in hexane in a dropwise manner over a 20 minute period. On completion of the addition, the reaction is allowed to stir at -60° for a further 20 minutes. Then, 10 ml of methanol, followed by 100 ml of water, are added to quench the reaction. The reaction mixture is stirred at room temperature for 15 minutes, the methylene chloride layer is separated and the solvent evaporated under reduced pressure to yield 5-(5-formylpentyl)-imidazo[1,5-a]pyridine as an oil; NMR (CDCl3) 9.7 (m, 1H); IR (CH2Cl2) 1710 cm-1.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:17][CH:16]3[NH:18][CH:12]([CH2:13][O:14][CH2:15]3)[CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[BH3-][C:22]#N.[Na+]>CC#N.CC(O)=O>[CH3:22][N:18]1[CH:12]2[CH2:13][O:14][CH2:15][CH:16]1[CH2:17][N:10]([S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:9])=[O:8])[CH2:11]2
Reactant: O=S(=O)(c1ccccc1)N1CC2COCC(C1)N2
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CN1C2COCC1CN(S(=O)(=O)c1ccccc1)C2
Reaction time: 2 h
Yield: 70.8 %

Procedure:
To a solution of 112f (2.0 g, 7.5 mmol) in MeCN (60 ml) was added HCHO (1.4 ml, 16 mmol) and 5 drops of AcOH at room temperature. Then NaCNBH3 (1 g, 16 mmol) added and the mixture was stirred for 2 h. It was poured onto water and extracted with EA (100*3). The organic layer was dried over Na2SO4, filtered off, evaporated, and purified through a silica gel column eluting with PE:EA=5:1 to 1:1 to give 112g as a colorless oil (1.5 g, 72%) MS: [M+H]+: 283
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([Br:8])=[CH:4][N:3]=1.ClCCl.N1C=CC=CC=1.[CH3:18][C:19]([CH3:24])([CH3:23])[C:20](Cl)=[O:21]>C(O)C>[Br:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][C:20](=[O:21])[C:19]([CH3:24])([CH3:23])[CH3:18])=[N:3][CH:4]=1
Reactant: Nc1cnc(Br)cn1
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1cnc(Br)cn1
Temperature: 40 °C
Reaction time: 2 h
Yield: 90.4 %

Procedure:
A 3-necked 1 L round bottomed flask equipped with a magnetic stirrer, thermometer, condenser and nitrogen inlet/outlet was charged with 50.00 g (287.4 mmol) of 2-amino-5-bromopyrazine (1), 218 mL of dichloromethane and 30.50 mL (377.1 mmol) of pyridine. Then, 39.30 mL (319.1 mmol) of trimethylacetyl chloride (PivCl) was added dropwise over 5 min. An exotherm ensued that raised the temperature of the mixture from 22° C. to 44° C. After stirring at ca. 40° C. for 2 h, HPLC analysis indicated complete reaction. The reaction mixture was diluted with 200 mL of ethanol, then concentrated by distillation at atmospheric pressure. After 240 mL of distillate had collected and the temperature of the mixture reached 68° C., 100 mL of water was added slowly, while maintaining the temperature of the mixture at ca. 68° C. After the addition was complete, the resulting suspension was allowed to cool to room temperature and stirred overnight. The solid was collected by filtration, washed with 100 mL of ethanol:water 1:1 and dried by suction to give 67.08 g (90.4% yield) of the title compound as a light beige solid; 98.21% pure as determined by HPLC analysis (HPLC column Zorbax Eclipse XDB-C8, 4.6×50 mm, 1.8 μm, eluent 5-100% acetonitrile/water+01. % TFA over 5 min at 1 mL/min, detection at UV 250 nm, retention time 4.22 min).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][S:19]([C:22]([F:25])([F:24])[F:23])(=[O:21])=[O:20])[N:6]2[CH:26]=1)[CH3:2].[CH2:27]=O>C(O)(=O)C>[CH2:1]([C:3]1[N:4]=[C:5]2[N:6]3[C:7]([CH2:11][N:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][S:19]([C:22]([F:25])([F:24])[F:23])(=[O:20])=[O:21])[CH2:27][C:26]=13)=[CH:8][CH:9]=[CH:10]2)[CH3:2]
Reactant: CCc1cn2c(CNCCCCCNS(=O)(=O)C(F)(F)F)cccc2n1
Reactant: C=O
Solvent: CC(=O)O
Product: CCc1nc2cccc3n2c1CN(CCCCCNS(=O)(=O)C(F)(F)F)C3
Temperature: 100 °C
Yield: 65.2 %

Procedure:
To a solution of 785 mg (2.00 mmol) of 2-ethyl-5-[N-[5-(trifluoromethanesulfonamido)pentan-1-yl]aminomethyl]imidazo[1,2-a]pyridine in 5 ml of acetic acid was added 2.25 ml (30.00 mmol) of a 37% aqueous solution of formalin. The mixture was heated for 30 minutes at 100° C. The solvent was then distilled off under reduced pressure. The residue was dissolved in 100 ml of a saturated aqueous solution of potassium carbonate. This solution was neutralized, under ice-cooling, with 1N HCl, which was extracted twice with 100 ml of chloroform. The organic layer was dried over magnesium sulfate, then the solvent was distilled off under reduced pressure. The residue was purified by silicagel column chromatography (eluent: chloroform/methanol=20:1) to give 527 mg of the desired compound (65.2%, colorless liquid).
Reaction SMILES: [C:1]([O:11][CH3:12])(=[O:10])/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(O[CH2:17][C:18]([CH2:20][Si](C)(C)C)=[CH2:19])(=O)C>C1COCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:17]=[C:18]1[CH2:20][C@@H:2]([C:1]([O:11][CH3:12])=[O:10])[C@H:3]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:19]1
Reactant: COC(=O)/C=C/c1ccccc1
Reactant: C=C(COC(C)=O)C[Si](C)(C)C
Agent: [Pd]
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=C1C[C@@H](C(=O)OC)[C@H](c2ccccc2)C1
Reaction time: 16 h
Yield: 92.5 %

Procedure:
A mixture of methyl trans-cinnamate (5.0 g, 31 mmol), tetrakis(triphenylphosphine) palladium(0) (2.6 g, 2.3 mmol), 1,2-bis(diphenylphosphino)ethane (0.70 g, 1.8 mmol) and 2-((trimethylsilyl)methyl)-2-propen-1-yl acetate (6.90 g, 37 mmol) in THF (60 mL) under argon was heated to reflux for 4 h. An additional aliquot of 2-((trimethylsilyl)methyl)-2-propen-1-yl acetate (3.40 g was added and the reaction was continued for another 16 h. The volatiles were then removed in vacuo and the residue was purified by FC (10% ethyl acetate in hexanes) to afford the title compound (6.2 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH2:19][CH2:18][N:17](C=O)[CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[ClH:22]>CO>[ClH:22].[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]3)=[N:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: O=CN1CCN(c2ccc(-c3ccc(F)cc3)cn2)CC1
Agent: Cl
Solvent: CO
Product: Fc1ccc(-c2ccc(N3CCNCC3)nc2)cc1
Temperature: 25 °C

Procedure:
4-(5-(4-Fluoro-phenyl)-pyridine-2-yl)-piperazine-1-carbaldehyde (98 mg, 0.34 mmol) was dissolved in MeOH (5 ml) and conc. HCl (12M, 5 ml) was added. The mixture was stirred at room temperature over night. The solvents were removed in vacuo and the remaining water was removed by azeotropic evaporation using EtOH/Toluene affording 102 mg (100%) of the title compound as a yellow powder.