Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH2:5][CH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1.B.[OH-:17].[Na+].OO.Cl>O1CCCC1.O.C(O)C>[CH3:15][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][C@@H:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][C@H:7]1[OH:17]
Reactant: CN(C)CCCC1C=Cc2ccccc21
Reactant: [OH-]
Agent: B
Agent: Cl
Agent: OO
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CN(C)CCC[C@@H]1c2ccccc2C[C@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
A solution of 20.6 g (0.10 mole) of 1-[3-(dimethylamino)propyl]-indene in 100 ml of tetrahydrofuran is cooled to 0° under nitrogen and 200 ml of 1M borane in tetrahydrofuran added over 30 minutes. After stirring overnight at ambient temperature the solution is cooled to 0° and the following added in the given order: 30 ml of water added cautiously, 170 ml of 10% sodium hydroxide solution and 32 ml of 30% hydrogen peroxide solution. After 1 hour at 0° the mixture is diluted with 1 liter of water and extracted with chloroform (3 × 400 ml) to give a white solid which is refluxed with 300 ml each of ethanol and 5% hydrochloric acid for 1 hour. After addition of 300 ml of water, 400 ml of distillate is collected. The residue is cooled, extracted with chloroform (200 ml, discard), basified with excess sodium hydroxide and extracted with chloroform (3 × 300 ml). Drying and solvent removal give 17.6 g of oil (81%, 1 spot on TLC).
Reaction SMILES: [ClH:1].O1CCOCC1.[OH:8][C@@H:9]1[C@H:13]2[N:14]([C:18](=[O:32])[C@@H:19]([NH:24]C(=O)OC(C)(C)C)[C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:15][C@@H:16]([CH3:17])[C@H:12]2[O:11][CH2:10]1>>[ClH:1].[NH2:24][C@@H:19]([C:20]([CH3:21])([CH3:23])[CH3:22])[C:18]([N:14]1[CH2:15][C@@H:16]([CH3:17])[C@H:12]2[O:11][CH2:10][C@H:9]([OH:8])[C@@H:13]12)=[O:32]
Reactant: C[C@@H]1CN(C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)[C@H]2[C@@H]1OC[C@@H]2O
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H]1CN(C(=O)[C@@H](N)C(C)(C)C)[C@H]2[C@@H]1OC[C@@H]2O
Reaction time: 1.5 h

Procedure:
A solution of 4N HCl in 1,4-dioxan (20 mL, 80 mmol) was added to tert-butyl (S)-1-((3R,3aR,6R,6aR)-3-hydroxy-6-methyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate (1.43 g, assuming 4.0 mmol). The solution was stirred for 90 minutes then the solvents were removed in vacuo and the residue azeotroped with TBME (3×25 mL) to leave (S)-2-amino-1-((3R,3aR,6R,6aR)-3-hydroxy-6-methyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethylbutan-1-one, hydrochloride as a purple crystalline solid which was used without further purification. HPLC-MS 257.2 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[N:10]3[C:12]([CH3:15])=[N:13][CH:14]=[C:9]3[CH:8]=[N:7][C:6]=2[N:5]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:4]=1[C:24]1[CH:29]=[CH:28][C:27]([C:30](=[O:32])[CH3:31])=[CH:26][CH:25]=1)[CH3:2].[CH3:33][Mg]Cl.[NH4+].[Cl-]>C1COCC1.O.CCOC(C)=O>[CH2:1]([C:3]1[C:11]2[N:10]3[C:12]([CH3:15])=[N:13][CH:14]=[C:9]3[CH:8]=[N:7][C:6]=2[N:5]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:4]=1[C:24]1[CH:25]=[CH:26][C:27]([C:30]([OH:32])([CH3:33])[CH3:31])=[CH:28][CH:29]=1)[CH3:2]
Reactant: C[Mg]Cl
Reactant: CCc1c(-c2ccc(C(C)=O)cc2)n(COCC[Si](C)(C)C)c2ncc3cnc(C)n3c12
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCc1c(-c2ccc(C(C)(C)O)cc2)n(COCC[Si](C)(C)C)c2ncc3cnc(C)n3c12
Temperature: 0 °C
Yield: 113.4 %

Procedure:
1-(4-(8-Ethyl-1-methyl-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-7-yl)phenyl)ethanone (0.092 g, 0.205 mmol, Preparation #W.1) in THF (5 mL) was cooled to about −20° C. and MeMgCl (3.0 M in THF, 0.1 mL, 0.3 mmol) was added. After about 5 min MeMgCl (3.0 M in THF, 0.1 mL, 0.3 mmol) was added then the mixture was warmed to about 0° C. MeMgCl (3.0 M in THF, 0.2 mL, 0.6 mmol) was added and the mixture was allowed to warm to about 15° C. over about 2 h. MeMgCl (3.0 M in THF, 0.2 mL, 0.600 mmol) was added to THF (3 mL) and the solution was added to the mixture portion-wise. An aqueous solution of NH4Cl (4 mL) was added slowly. The mixture was diluted with water (20 mL) and EtOAc (25 mL). The layers were separated and the aqueous layer was extracted with EtOAc (15 mL). The combined organics were dried over anhydrous MgSO4, filtered and concentrated in vacuo to give 2-(4-(8-ethyl-1-methyl-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-7-yl)phenyl)propan-2-ol (0.108 g, 113%): LC/MS (Table 2, Method a) Rt=2.96 min.; MS m/z 465 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.Cl[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[OH:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][O:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]=[CH:7][C:8](=[O:12])[O:9][C:10]=2[CH:11]=1
Reactant: O=c1ccc2ccc(O)cc2o1
Reactant: OCCCCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1ccc2ccc(OCCCCCCO)cc2o1
Temperature: 100 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
4.87 g (30 mmol) of 7-hydroxy-coumarin, 6.17 g (45.2 mmol) of 6-chlorohexanol and 6.56 g (47.5 mmol) of potassium carbonate were treated with 50 ml of absolute N,N-dimethylformamide and stirred at 100° C. overnight. Subsequently, the batch was poured into water. The white precipitate which separated was filtered off and rinsed with water. The mother liquor was evaporated to dryness in a vacuum, taken up in a small amount of water and extracted several times with ethyl acetate. The precipitate and the ethyl acetate phases were combined, dried over sodium sulphate, evaporated and, for purification, chromatographed on silica gel with an eluent mixture of ethyl acetate and cyclohexane in the ratio 1:1. Therefrom there resulted 7 g of 7-(6-hydroxy-hexyloxy)-2H-1-benzopyran-2-one as white crystals.
Reaction SMILES: C(N(CC)C(C)C)(C)C.O(P(O[C:27]1[C@H:28]([CH3:44])[C@H:29]2[C@@H:39]([C@H:40]([OH:42])[CH3:41])[C:38](=[O:43])[N:30]2[C:31]=1[C:32]([O:34][CH2:35][CH:36]=[CH2:37])=[O:33])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[CH2:45]([O:48][C:49]([N:51]1[CH2:55][C@@H:54]([SH:56])[CH2:53][C@H:52]1[CH2:57][CH:58]1[CH2:62][CH2:61][NH:60][C:59]1=[O:63])=[O:50])[CH:46]=[CH2:47].C(OCC)(=O)C>C(#N)C>[CH2:45]([O:48][C:49]([N:51]1[CH2:55][C@@H:54]([S:56][C:27]2[C@H:28]([CH3:44])[C@@H:29]3[C@@H:39]([C@H:40]([OH:42])[CH3:41])[C:38](=[O:43])[N:30]3[C:31]=2[C:32]([O:34][CH2:35][CH:36]=[CH2:37])=[O:33])[CH2:53][C@H:52]1[CH2:57][CH:58]1[CH2:62][CH2:61][NH:60][C:59]1=[O:63])=[O:50])[CH:46]=[CH2:47]
Reactant: C=CCOC(=O)N1C[C@@H](S)C[C@H]1CC1CCNC1=O
Reactant: C=CCOC(=O)C1=C(OP(=O)(Oc2ccccc2)Oc2ccccc2)[C@H](C)[C@H]2[C@@H]([C@@H](C)O)C(=O)N12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](CC3CCNC3=O)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Temperature: 5 °C
Reaction time: 16 h
Yield: 51.8 %

Procedure:
N,N-diisopropylethylamine (0.26 ml, 1.52 mmol) was dropwise added to a solution of allyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (759 mg, 1.52 mmol) and (2R,4S)-N-allyloxycarbonyl-4-mercapto-2-(2-pyrrolidon-3-ylmethyl)pyrrolidine (432 mg, 1.52 mmol) in acetonitrile (11 ml) at -40° C. The reaction solution mixture was stirred at the same temperature for 3 hours and further at 5° C. for 16 hours. Ethyl acetate (60 ml) was added to the reaction solution. This solution mixture was washed sequentially with a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution, then dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel flash column chromatography (Wakogel™ C-300, 40 ml, acetone-ethyl acetate 2:3), and the fraction containing the desired product was concentrated to obtain allyl (1R,5S,6S)-2-[(2R, 4S)-N-allyloxycarbonyl-2-(2-pyrrolidon-3-ylmethyl)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (420 mg, yield: 51.8%) in the form of foam.
Reaction SMILES: C(OC([NH:8][C@:9]([C:18]1[O:22][C:21]([C:23]2[CH:24]=[C:25]([C:37]([OH:39])=[O:38])[CH:26]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]#[N:36])[CH:28]=2)=[N:20][N:19]=1)([CH3:17])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)(C)(C)C.Cl>O1CCOCC1>[NH2:8][C:9]([C:18]1[O:22][C:21]([C:23]2[CH:24]=[C:25]([C:37]([OH:39])=[O:38])[CH:26]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]#[N:36])[CH:28]=2)=[N:20][N:19]=1)([CH3:17])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)N[C@](C)(Cc1ccccc1)c1nnc(-c2cc(C(=O)O)cc(-c3ccccc3C#N)c2)o1
Agent: Cl
Solvent: C1COCCO1
Product: CC(N)(Cc1ccccc1)c1nnc(-c2cc(C(=O)O)cc(-c3ccccc3C#N)c2)o1
Reaction time: 1 h

Procedure:
To a solution of 5-(5-{(1R)-1-[(tert-butoxycarbonyl)amino]-1-methyl-2-phenylethyl}-1,3,4-oxadiazol-2-yl)-2′-cyanobiphenyl-3-carboxylic acid (Intermediate XVIII, 500 mg. 0.95 mmol) in dioxane (5 mL) at rt was added a solution of HCl in dioxane (7 mL of 4N HCl in dioxane, 28 mmol) and the solution allowed to stand for 1 hour at rt. The solvent was then evaporated at reduced pressure to give 5-[5-(1-amino-1-methyl-2-phenylethyl)-1,3,4-oxadiazol-2-yl]-2′-cyanobiphenyl-3-carboxylic acid (Intermediate XIX) as the derived hydrochloride salt. 1H NMR (400 MHz, CD3OD) δ 8.71 (t, J=1.5 Hz, 1H), 8.45-8.42 (m, 2H), 7.94 (dd, J=7.8, 1 Hz, 1H), 7.85 (dt, J=7.8, 1Hz, 1H), 7.72 (d, J=7.6 Hz, 1H), 7.66 (dt, J=7.6, 1.1 Hz), 7.34-7.28 (m, 3H), 7.15-7.09 (m, 2H), 3.47 (s, 2H), 1.90 (s, 3H). LCMS [(M)+H]+=425.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]O)=[CH:20][CH:19]=1.C(O)=O.C(O)(=O)C>O>[C:11]([C:7]1[CH:8]=[C:9]([CH2:22][C:21]2[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: COc1ccc(CO)cc1
Solvent: O=CO
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc1

Procedure:
2,6-Di-t-butyl-4-(4-methoxybenzyl)phenol was prepared as described for A above. A mixture of 2,6-di-t-butylphenol (51.5 g), 4-methoxybenzyl alcohol (34.5 g), formic acid (100 ml) and acetic acid (100 ml) was refluxed for 5 hours, diluted with water, and extracted with chloroform. Evaporation of the chloroform gave an oil which crystallized. Recrystallization from methanol gave colorless needles, mp 139° (58 g) (Found: C, 80.7; H, 9.30. Calc. for C22H30O2 : C, 80.9; H, 9.26%); pmr spectrum: δ1.42, 18H, S; δ3.79, 3H, S; δ3.86, 2H, S; δ5.04, 1H, S; δ6.83, 2H, D (J=8 Hz); δ6.98, 2H, S; δ7.12, 2H, D (J=8 Hz).
Reaction SMILES: [NH:1]([C:22]([O:24]C(C)(C)C)=O)[CH2:2][C:3]([N:5]([CH3:21])[C@H:6]([C:14]([NH:16][NH:17][C:18]([NH2:20])=[S:19])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[NH:29]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C@@H:30](C(O)=O)[CH2:31][CH2:32][C:33](=[O:35])[NH2:34].C1C2C3C(=O)N(O)C(=O)C3C1C=C2.C1CCC(N=C=NC2CCCCC2)CC1>FC(F)(F)C(O)=O.CN(C=O)C>[NH:29]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C@@H:30]([C:22]([NH:1][CH2:2][C:3]([N:5]([CH3:21])[C@H:6]([C:14]([NH:16][NH:17][C:18]([NH2:20])=[S:19])=[O:15])[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:4])=[O:24])[CH2:31][CH2:32][C:33](=[O:35])[NH2:34]
Reactant: CN(C(=O)CNC(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)NNC(N)=S
Reactant: CC(C)(C)OC(=O)N[C@H](CCC(N)=O)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1C2C3C=CC(C3)C2C(=O)N1O
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CN(C(=O)CNC(=O)[C@@H](CCC(N)=O)NC(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)NNC(N)=S
Reaction time: 0.17 h

Procedure:
In 10 ml of trifluoroacetic acid is dissolved 0.80 g of BOC-Gly-MePhe-NHNHCSNH2, and the solution is shaken for 10 minutes, concentrated, treated with ether and filtered to obtain a powder. This powder is dissolved in 10 ml of DMF, and after ice-cooling, the solution is neutralized with 10 ml of DMF and 0.05 g BOC-(D)-Gln-OH, 0.40 g of HONB and 0.45 g of DCC are added. The mixture is stirred for 20 hours. The precipitated DCU is filtered off, the solvent distilled off and the residue dissolved in n-butanol. The solution is washed with a saturated aqueous solution of sodium hydrogen carbonate and water in that order and dried over anhydrous sodium sulfate. The solvent is distilled off and the residue is treated with ether and filtered to obtain a powder. Yield 0.73 g; m.p. 120°-123° C.; [α]D24 -46.0° (c=1.0, DMF); Rf1 0.18.
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH2:12][OH:13])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[CH:5]=1)[CH3:2].S(=O)(=O)(O)O.[N:19](OC(C)C)=[O:20]>C(O)(C)C>[CH2:1]([N:3]([CH2:11][CH2:12][OH:13])[C:4]1[CH:9]=[CH:8][C:7]([N:19]=[O:20])=[C:6]([CH3:10])[CH:5]=1)[CH3:2]
Reactant: CC(C)ON=O
Reactant: CCN(CCO)c1cccc(C)c1
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: CCN(CCO)c1ccc(N=O)c(C)c1
Temperature: 10 °C
Reaction time: 4 h
Yield: 115 %

Procedure:
With 89.6 g (0.5 mole) of N-ethyl-N-(β-hydroxyethyl)-m-toluidine was mixed 270 ml of 80% v/v isopropanol, and 24.5 g (0.25 mole) of sulfuric acid was added with cooling and stirring at 10° C. or lower. After 49.0 g (0.55 mole) of isopropyl nitrite was added dropwise at 10° C. or lower, the reaction was carried out at 2° C. or lower for another 4 hours. After completion of the reaction, the crystals precipitated were collected by filtration to obtain 119.7 g of N-ethyl-N-(β-hydroxyethyl)-3-methyl-4-nitrosoaniline.1/2 sulfate as yellow-green powder. Yield: 93.0%. Decomposition point: 74° C.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([Cl:13])=[N:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.Cl.[Cl:15][C:16]1[CH:17]=[C:18]([CH2:27][NH2:28])[CH:19]=[N:20][C:21]=1[O:22][CH2:23][CH:24]([F:26])[F:25]>>[Cl:13][C:12]1[C:3]2[CH2:2][N:28]([CH2:27][C:18]3[CH:19]=[N:20][C:21]([O:22][CH2:23][CH:24]([F:25])[F:26])=[C:16]([Cl:15])[CH:17]=3)[C:5](=[O:7])[C:4]=2[CH:9]=[CH:10][N:11]=1
Reactant: NCc1cnc(OCC(F)F)c(Cl)c1
Reactant: COC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: O=C1c2ccnc(Cl)c2CN1Cc1cnc(OCC(F)F)c(Cl)c1
Yield: 75 %

Procedure:
The title compound is prepared in 75% yield (158 mg, colorless oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and (5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methanamine hydrochloride (147 mg, 0.57 mmol, Amine-12) in a similar manner to Intermediate-2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[CH:11]=[C:4]2[N:3]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:5]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[CH:11]=[C:4]2[N:3]=1
Reactant: C1COCCN1
Reactant: Clc1ccc(-c2cc3nc(Cl)cc(Cl)n3n2)cc1
Solvent: C1COCCO1
Product: Clc1ccc(-c2cc3nc(Cl)cc(N4CCOCC4)n3n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
There was dissolved, in 1,4-dioxane (5 mL), 5,7-dichloro-2-(4-chlorophenyl)-pyrazolo[1,5-a]pyrimidine (200 mg, 0.670 mM), then morpholine (117 μL, 1.34 mM) was added to the solution and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off from the reaction mixture and the resulting residue was diluted with water and extracted with methylene chloride. The extracts thus obtained were combined, dried over anhydrous sodium sulfate, the solvent was distilled off and then the resulting solid was washed with methanol to give the title compound (222 mg, yield: 94%).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[N:2].[CH3:12][NH:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:13]([CH3:12])[CH2:14][CH:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: CNCC1CCN(C)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCC(CN(C)C(=O)c2ccc(C#N)cc2)CC1
Temperature: 0 °C
Yield: 64.9 %

Procedure:
4-cyanobenzoylchloride (200 mg, 1.21 mmol) was dissolved in anhydrous CH2Cl2 (4 mL) and cooled to 0° C. Methyl-(1-methyl-piperidin-4-ylmethyl)-amine (172 mg, 1.21 mmol) in anhydrous CH2Cl2 (1 mL) was added followed by N,N-diisopropylethylamine (0.63 mL, 3.62 mmol). The reaction mixture was allowed to warm to RT over 2 h. The reaction mixture was concentrated in vacuo and the crude product purified by reverse phase preparative HPLC-MS to obtain 4-cyano-N-methyl-N-(1-methyl-piperidin-4-ylmethyl)-benzamide as an off-white solid (213 mg, 65%).
Reaction SMILES: N1C=CN2C=CN=CC=12.[CH2:10]([C:17]1[NH:22][C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:20][N:19]2[C:29](=[O:38])[C:30]([CH2:32][C:33]3[O:34][CH:35]=[CH:36][CH:37]=3)=[N:31][C:18]=12)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Br[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([B:47]2[O:51][C:50]([CH3:53])([CH3:52])[C:49]([CH3:55])([CH3:54])[O:48]2)=[CH:43][CH:42]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>>[CH2:10]([C:17]1[C:18]2[N:19]([C:29]([O:38][CH2:40][C:41]3[CH:42]=[CH:43][C:44]([B:47]4[O:48][C:49]([CH3:55])([CH3:54])[C:50]([CH3:53])([CH3:52])[O:51]4)=[CH:45][CH:46]=3)=[C:30]([CH2:32][C:33]3[O:34][CH:35]=[CH:36][CH:37]=3)[N:31]=2)[CH:20]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:22]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=c1c(Cc2ccco2)nc2c(Cc3ccccc3)[nH]c(-c3ccccc3)cn1-2
Reactant: CC1(C)OB(c2ccc(CBr)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CC1(C)OB(c2ccc(COc3c(Cc4ccco4)nc4c(Cc5ccccc5)nc(-c5ccccc5)cn34)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.6 %

Procedure:
Synthesis of 8-benzyl-2-(furan-2-ylmethyl)-6-phenyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)imidazo[1,2-a]pyrazine (4759). To a solution of 8-benzyl-2-(furan-2-ylmethyl)-6-phenylimidazo[1,2-a]pyrazin-3(7H)-one (50 mg, 0.13 mmol) was added 2-(4-(bromomethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (47 mg, 0.16 mmol), potassium carbonate (27 mg, 0.20 mmol) and potassium iodide (33 mg, 0.20 mmol). The reaction mixture was stirred at room temperature for 1 h and heat to 40° C. until HPLC shows the completion of the reaction. After cooling down, the reaction mixture was extracted with ethyl acetate/water. The organic layer was collected and dried over magnesium sulfate. After evaporation, the residue was purified with flash chromatography to give the product as yellow solid (30 mg, 49%). 1H NMR (300 MHz, CD2Cl2, δ): 7.79-7.23 (m, 18H), 7.32 (d, J=6.0 Hz, 2H), 5.11 (s, 2H), 4.53 (s, 2H), 4.15 (s, 2H), 1.53 (s, 12H); MS (ESI) m/z 597.41.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[CH2:11]O)=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14].S(Cl)([Cl:18])=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[CH2:11][Cl:18])=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(/C=C/CO)cc1[N+](=O)[O-]
Solvent: ClCCl
Product: COc1ccc(/C=C/CCl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.09 g of (E)-(4-methoxy-3-nitrophenyl)allyl alcohol was dissolved in 21 ml of methylene chloride. To the solution was added 1.79 g of thionyl chloride with ice-cooling. The mixture was stirred for 1 hour at room temperature. The solvent was removed by distillation under reduced pressure to obtain crystals of (E)-3-(4-methoxy-3-nitrophenyl)allyl chloride. The crystals were dissolved in 10 ml of methylene chloride.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[N:3]=1.Br[C:18]1[NH:22][C:21]([CH3:23])=[N:20][C:19]=1[N+:24]([O-:26])=[O:25].C(=O)(O)[O-].[K+]>O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:12][CH2:13][N:14]([C:18]3[NH:22][C:21]([CH3:23])=[N:20][C:19]=3[N+:24]([O-:26])=[O:25])[CH2:15][CH2:16]2)[N:3]=1
Reactant: Cc1nc([N+](=O)[O-])c(Br)[nH]1
Reactant: Cc1cccc(C#CC=C2CCNCC2)n1
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Product: Cc1cccc(C#CC=C2CCN(c3[nH]c(C)nc3[N+](=O)[O-])CC2)n1

Procedure:
A well homogenised mixture of the Compound of Example 3 (100 mg, 0.47 mmol), 5-bromo-2-methyl-4-nitro-1H-imidazole (97 mg, 0.47 mmol) and potassium bicarbonate was stirred at 120° C. for 8 h. The reaction mixture was poured into water and extracted with EtOAc The combined organic layers were washed with brine, dried on Na2SO4 and evaporated to dryness in vacuo to afford a residue, which was purified by automated flash liquid chromatography (Horizon™-Biotage), eluting with Petroleum Ether-EtOAc 7:3, affording the title product as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C:12](=[O:21])[C@H:11]([CH3:22])[CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1.[BH4-].[Na+].Cl.O>C(O)C>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C@@H:12]([OH:21])[C@H:11]([CH3:22])[CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)[C@H](C)C[C@@H]12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@H](C)C[C@@H]12
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.2 %

Procedure:
16.0 g of 3-methoxy-16α-methyl-1,3,5(10)-estratrien-17-one is dissolved in 200 ml of ethanol and, under ice cooling, combined dropwise with a solution of 2.1 g of sodium borohydride in 100 ml of 80% aqueous ethanol. The mixture is stirred for 16 hours at room temperature, then 1 N hydrochloric acid is gently added to the reaction solution, the latter is poured into water and extracted with ethyl acetate. Crystallization from acetonitrile yields 13.4 g of 3-methoxy-16α-methyl-1,3,5(10)-estratrien-17β-ol, m.p. 100°-102° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:11].C(C(O)=O)(F)(F)F.Br[CH2:26][C:27]([O:29][CH3:30])=[O:28].C(=O)(O)[O-].[Na+].Cl>C(O)C.C(OCC)C.O.O1CCCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([CH:12]1[CH2:17][CH2:16][N:15]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH2:14][CH2:13]1)=[O:11]
Reactant: O=C(c1nc2ccccc2s1)C1CCNCC1
Reactant: COC(=O)CBr
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CN1CCC(C(=O)c2nc3ccccc3s2)CC1
Temperature: 25 °C

Procedure:
Mix (2-benzothiazolyl)(4-piperidinyl)methanone.CF3CO2H (3.0 g, 8.33 mmol), methyl bromoacetate (1.34 g, 8.74 mmol), sodium bicarbonate (1.75 g, 20.83 mmol), tetrahydrofuran (120 mL) and water (30 mL). Heat at reflux for 4 hours, cool to room temperature and partition between ethyl acetate and water. Separate the organic phase and extract the aqueous phase with ethyl acetate. Combine the organic phases, wash with water and dry (MgSO4). Evaporate the solvent in vacuo to give a yellow oil. Dissolve the oil in ethanol/ethyl ether and treat with ethereal hydrogen chloride gas. Cool overnight, collect the resulting solid by filtration, wash with ethyl ether and dry to give the title compound as a white crystalline solid; mp 177°-178° C.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[CH:11]=[CH:10][S:9][CH:8]=1)=O.N[N:14]1[CH:18]=[N:17][N:16]=[CH:15]1>C1(C)C(C)=CC=CC=1>[S:9]1[CH:10]=[CH:11][C:7]([C:5]2[C:18]3[N:14]([CH:15]=[N:16][N:17]=3)[N:2]=[CH:3][CH:4]=2)=[CH:8]1
Reactant: CN(C)C=CC(=O)c1ccsc1
Reactant: Nn1cnnc1
Solvent: Cc1ccccc1C
Product: c1cc(-c2ccsc2)c2nncn2n1

Procedure:
As for Example 16, a mixture of 3-dimethylamino-1-(3-thienyl)-2-propen-1-one, 4-amino-1,2,4-triazole and xylene is refluxed for 16 hours to give the product of the Example.