Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][N:6]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[N+:17]([O-:19])=[O:18])[CH3:7])C>Br.C(#N)C>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][N:6]([CH2:5][C:4]([OH:20])=[O:3])[CH3:7])=[C:11]([N+:17]([O-:19])=[O:18])[CH:12]=1
Reactant: CCOC(=O)CN(C)CCc1ccc(Cl)cc1[N+](=O)[O-]
Agent: Br
Solvent: CC#N
Product: CN(CCc1ccc(Cl)cc1[N+](=O)[O-])CC(=O)O
Temperature: 70 °C
Reaction time: 8 h

Procedure:
{[2-(4-Chloro-2-nitro-phenyl)-ethyl]-methyl-amino}-acetic acid ethyl ester (22.5 g, 0.075 mole) dissolved in concentrated hydrobromic acid (48 wt. % in water, 200 mL) was allowed to stir at 70° C. overnight and then reduced to a small volume in vacuo. The residue oil was taken up in acetonitrile and the solution was evaporated in vacuo. This procedure was repeated until the water was removed and a crystalline residue remained. This material (18.5 g) was used in the next step without further purification.
Reaction SMILES: C([B:3]([CH2:6][CH3:7])CC)C.[B]=O.[OH2:10]>>[CH2:6]([B:3]1[O:10][B:3]([CH2:6][CH3:7])[O:10][B:3]([CH2:6][CH3:7])[O:10]1)[CH3:7]
Reactant: CCB(CC)CC
Reactant: O
Agent: [B]=O
Product: CCB1OB(CC)OB(CC)O1
Reaction time: 120 h

Procedure:
A 500 cc round bottom flask was equipped with water cooled reflux condenser an electrically heated mantle, and a nitrogen bubbler to maintain an inert atmosphere. To the flask under nitrogen was added 70.0 g of B2O3 (Aldrich Gold Label) which had been ground to a powder in a mortar under dry nitrogen. Neat triethylborane (100.0 g) was added to the boron oxide all at one time and the reaction flask was set up for refluxing. Reflux was continued for 5 days at which point the reflux condenser was changed for a distillation condenser and the liquid was distilled in two fractions. The second fraction yielded 60 cc of a colorless liquid which distilled at 148° C. The H-1 and B-11 NMR of the second fraction indicated that it was pure triethylboroxine.
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH:10]=[CH:9][C:8]1=[C:7]([CH3:22])[C:6](=[O:23])[CH2:5][CH2:4]2.OC[C@@]12[C@@H]3[C@H]([C@H]4[C@@](CC3)(C)C(=O)CC4)C=CC1=CC(=O)CC2>>[CH3:22][C:7]1[C:6](=[O:23])[CH2:5][CH2:4][C@@:3]2([CH:2]=[O:1])[C:8]=1[CH:9]=[CH:10][C@@H:11]1[C@@H:20]2[CH2:19][CH2:18][C@@:16]2([CH3:17])[C@H:12]1[CH2:13][CH2:14][C:15]2=[O:21]
Reactant: CC1=C2C=C[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(CO)CCC1=O
Agent: C[C@]12CC[C@H]3[C@@H](C=CC4=CC(=O)CC[C@@]43CO)[C@@H]1CCC2=O
Product: CC1=C2C=C[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C=O)CCC1=O

Procedure:
Substituting 19-hydroxy-4-methyl-4,6-androstadiene-3,17-dione for the 19-hydroxy-4,6-androstadiene-3,17-dione above results in the preparation of 4-methyl-4,6-androstadiene-3,17,19-trione.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[O:10][CH3:11].C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15].Cl>N1C=CC=CC=1.N1CCCCC1>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:13][C:14]([OH:16])=[O:15])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: COc1cc(C=O)ccc1F
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: COc1cc(C=CC(=O)O)ccc1F
Temperature: 120 °C
Yield: 96.9 %

Procedure:
A mixture of 4-Fluoro-3-methoxy-benzaldehyde (6.16 g, 40 mmol), and malonic acid (6.24 g, 60 mmol) in pyridine (30 ml) and piperidine (1 ml) was heated at 120° C. for 2 hrs. The mixture was cooled to room temperature and neutralized with concentrated HCl to PH<3, the white solid was collected and dried to give 7.6 g of product (97% yield). LC-MS: m/e 195 (M−1)
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[N:8]([CH:9]2[CH2:15][CH:14]3[N:16]([CH2:17][CH2:18][C:19]4([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[C:7]2[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=2[N:5]=1.C(N(CC)CC)C.[C:42](Cl)(=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>ClCCl>[C:42]([N:22]1[CH2:21][CH2:20][C:19]([CH2:18][CH2:17][N:16]2[C@H:14]3[CH2:13][CH2:12][C@@H:11]2[CH2:10][CH:9]([N:8]2[C:7]4[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=4[N:5]=[C:4]2[CH3:3])[CH2:15]3)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:24][CH2:23]1)(=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2ccccc2)CCN(C(=O)c2ccccc2)CC1
Reaction time: 0.5 h
Yield: 93 %

Procedure:
To a stirred solution of endo 2-methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole dihydrochloride II (0.53 g, 1.06 mmol) in dichloromethane (10 mL) and triethylamine (0.32 g, 3.18 mmol) was added benzoyl chloride (0.156 g, 1.11 mmol) at 0° C. The ice bath was then removed and the mixture allowed to stir for 30 min. The solvents were then removed in vacuo and the resulting solid was partitioned between ethyl acetate and water (3×). The organic layer was dried with magnesium sulfate and the solvent removed in vacuo, yielding crude 17, which was them purified using the supercritical fluid chromatography, resulting in 525 mg of pure 1-{(1R,5S)-8-[2-(1-benzoyl-4-phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-2-methyl-1H-benzimidazole 17 (yield 93%). 1H NMR (400 MHz, CDCl3) δ 7.20 (1H, m), 6.94 (7H, m), 6.82 (4H, m), 6.70 (2H, m), 4.15 (1H, m), 3.75 (1H, m), 3.11 (1H, m), 2.98 (4H, m), 2.93 (1H, m), 2.78 (3H, m), 2.05 (3H, s), 2.04 (2H, m), 1.88 (3H, m), 1.70 (1H, m), 1.59-1.24 (4H, m), 1.14 (2H, m). HRMS m/z (M+H)+Calc 533.3280; (M+H)+Obs 533.3300.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([F:13])[CH2:10][C@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC)=O.[OH-].[NH4+:24]>C1COCC1>[C:14]([C@@H:9]1[CH2:10][C@H:11]([F:13])[CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])(=[O:16])[NH2:24]
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1C(=O)O
Agent: CCOC(=O)Cl
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1C(N)=O
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a well stirred solution of (2S,4S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (50 g, 0.2145 mmol) in dry THF (1000 ml) was added TEA (32.49 g, 0.3217 mmol) at room temperature. The mixture was cooled to −10° C. and ethyl chloroformate (34.93 g, 0.3217 mmol) was added over period of 20 min. The mixture was stirred for 30 min at the same temperature under nitrogen atmosphere and aqueous ammonium hydroxide (500 ml) was added. The aqueous mixture was stirred at room temperature for 18 h and THF in the mixture was evaporated under reduced pressure. The aqueous mixture was further diluted with water (100 ml) and extracted with chloroform (3×100 ml). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The residue was stirred in petroleum ether (250 ml) for 20 min to give a white filterable solid. The product was collected by filtration and dried to give 44.7 g of the product as a white solid. 1H NMR (CDCl3, 300 MHz) δ 1.48 (s, 9H), 2.20-2.80 (m, 2H), 3.51-3.85 (m, 2H), 4.38 (br s, 1H), 5.21 (d, J=52.2 Hz, 1H), 5.50 (br s, 1H), 6.16 (br s, 0.5H, rotomer), 6.59 (br s, 0.5H, rotomer)
Reaction SMILES: C(N1CCNCC1)=O.[C:9]12([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2.[IH:25].CS[C:28](=[NH:30])[NH2:29]>>[IH:25].[C:9]12([N:19]3[CH2:24][CH2:23][N:22]([C:28](=[NH:29])[NH2:30])[CH2:21][CH2:20]3)[CH2:16][CH:15]3[CH2:14][CH:13]([CH2:12][CH:11]([CH2:17]3)[CH2:10]1)[CH2:18]2
Reactant: CSC(=N)N
Reactant: C1CN(C23CC4CC(CC(C4)C2)C3)CCN1
Agent: I
Agent: O=CN1CCNCC1
Product: N=C(N)N1CCN(C23CC4CC(CC(C4)C2)C3)CC1
Yield: 72.3 %

Procedure:
The title compound was prepared as described for 1-formylpiperazine in Example 1 of the published European patent application No. 39,190, starting with 1-(1-adamantyl)piperazine and S-methyl-isothiourea hydroiodide, mp. 278°-280° C., yield: 72.3 %.
Reaction SMILES: ClCCl.[CH:4]([O:7][C:8]([N:10]1[C:19]2[C:14](=[N:15][C:16](Br)=[CH:17][CH:18]=2)[C@H:13]([N:21]([C:37](=[O:39])[CH3:38])[CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)[CH2:12][C@@H:11]1[CH2:40][CH3:41])=[O:9])([CH3:6])[CH3:5].[CH3:42]B(O)O.[F-].[Cs+]>O1CCOCC1.O>[CH:4]([O:7][C:8]([N:10]1[C:19]2[C:14](=[N:15][C:16]([CH3:42])=[CH:17][CH:18]=2)[C@H:13]([N:21]([C:37](=[O:39])[CH3:38])[CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)[CH2:12][C@@H:11]1[CH2:40][CH3:41])=[O:9])([CH3:6])[CH3:5]
Reactant: CC[C@H]1C[C@@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(C)=O)c2nc(Br)ccc2N1C(=O)OC(C)C
Reactant: CB(O)O
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CC[C@H]1C[C@@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(C)=O)c2nc(C)ccc2N1C(=O)OC(C)C
Temperature: 80 °C
Yield: 84.8 %

Procedure:
Add 1,1′-bis(diphenylphosphino)(II) chloride, complex with dichloromethane (9 mg, 0.012 mmol) to a suspension of (+/−)-cis-4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-ethyl-6-bromo-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid isopropyl ester (50 mg, 0.08 mmol), methyl boronic acid (15 mg, 0.24 mmol) and cesium fluoride (40 mg, 0.28 mmol) in dry dioxane (1.5 mL) and heat the mixture at 80° C. in a sealed tube for 15 h. Cool the reaction mixture to room temperature, add water and extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter and remove the solvent under reduced pressure. Chromatograph the residue over a silica gel cartridge, eluting with hexanes/ethyl acetate to provide the title compound (37 mg, 84%). MS (ES+): 546 (M+H).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]([C:19]1[CH:24]=[C:23]([Cl:25])[C:22]([Cl:26])=[C:21]([Cl:27])[CH:20]=1)=[CH:4][C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12]1([CH2:18][NH:17][CH2:16]1)[O:11][CH2:10]2)=[O:6].CCN(CC)CC.[C:37](O)(=[O:41])[CH:38]([CH3:40])[CH3:39].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[F:29][C:2]([F:1])([F:28])[C:3]([C:19]1[CH:20]=[C:21]([Cl:27])[C:22]([Cl:26])=[C:23]([Cl:25])[CH:24]=1)=[CH:4][C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12]1([CH2:18][N:17]([C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[CH2:16]1)[O:11][CH2:10]2)=[O:6]
Reactant: CC(C)C(=O)O
Reactant: O=C(C=C(c1cc(Cl)c(Cl)c(Cl)c1)C(F)(F)F)c1ccc2c(c1)COC21CNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)C(=O)N1CC2(C1)OCc1cc(C(=O)C=C(c3cc(Cl)c(Cl)c(Cl)c3)C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To the stirred solution of hydrochloride salt of 5′-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-2-enoyl)-3′H-spiro[azetidine-3,1′-isobenzofuran](Preparation 26, 1.0 g, 2.2 mmol, 1 eq) in DMF (10 mL) was added Et3N (2.4 mL, 17.3mmol, 8 eq) followed by addition of iso-butyric acid (0.38 g, 4.32mmol, 2 eq), HOBt (0.29 g, 2.16 mmol, 1 eq) and EDC.HCl (0.62 g, 3.24 mmol, 1.5 eq) at room temperature. Resulting reaction mixture was stirred at room temperature for 18 hours under nitrogen atmosphere. After consumption of starting material, reaction mixture was quenched by water (30 mL) and extracted with ethyl acetate (3×25 mL). Combined organic layer was washed with aqueous sodium bicarbonate (50 mL), aqueous LiCl solution (2×50 mL), brine (50 mL) and dried over sodium sulfate. Organic layer was concentrated in vacuo to get brown sticky oil (1.0 g, Crude). Purification was done by Combiflash chromatography using 40 g Redisep column. Compound was eluted in 40% ethyl acetate in n-hexane to get title compound as off white solid (0.5 g, 43%). 1H NMR (400 MHz, CDCl3) δ: 1.13-1.17 (m, 6H), 2.46-2.53 (m, 1H), 4.25 (d, J=10.64 Hz, 1H), 4.30-4.34 (m, 2H), 4.52 (d, J=9.32 Hz, 1H), 5.15 (s, 2H), 7.27 (s, 2H), 7.40 (d, J=1.36 Hz, 1H), 7.49 (d, J=8.04 Hz, 1H), 7.68 (s, 1H), 7.84 (d, J=7.92 Hz, 1H). LC-MS (m/z): 531.9 (M+H).
Reaction SMILES: CO[C:3]1([O:9][CH3:10])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[C:11]([N+:15]#[C-])(C)(C)C.C(=O)([O-])O.[Na+]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:10][O:9][C:3]1([C:11]#[N:15])[CH2:4][CH2:5][O:6][CH2:7][CH2:8]1
Reactant: COC1(OC)CCOCC1
Reactant: [C-]#[N+]C(C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC1(C#N)CCOCC1
Temperature: -78 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
Under an argon atmosphere, 4,4-dimethoxytetrahydropyran (4.39 g, 30.0 mmol) was dissolved in dichloromethane (60 mL), and tert-butyl isocyanide (3.73 mL, 33.0 mmol) and titanium tetrachloride (3.95 mL, 36.8 mmol) were added thereto at −78° C., and then, the mixture was stirred overnight at room temperature. To the mixture, an aqueous sodium hydrogen carbonate solution was added, and the mixture was filtered through Celite, and then, the filtrate was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20) to give 4-methoxytetrahydropyran-4-carbonitrile (3.30 g, 23.4 mmol, yield: 78%).
Reaction SMILES: [OH:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[F:10][C:11]([F:27])([F:26])[C:12]1[CH:25]=[CH:24][C:15]([O:16][C:17]2[CH:22]=[CH:21][C:20](O)=[CH:19][CH:18]=2)=[CH:14][CH:13]=1>>[F:10][C:11]([F:26])([F:27])[C:12]1[CH:25]=[CH:24][C:15]([O:16][C:17]2[CH:22]=[CH:21][C:20]([O:1][CH:2]3[CH:7]4[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]4)[CH2:3]3)=[CH:19][CH:18]=2)=[CH:14][CH:13]=1
Reactant: OC1CN2CCC1CC2
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Product: FC(F)(F)c1ccc(Oc2ccc(OC3CN4CCC3CC4)cc2)cc1

Procedure:
3-Hydroxy quinuclidine (Aldrich, 254 mg, 2 mmol) was treated with 4-(4-trifluoromethyl-phenoxy)-phenol (Aldrich, 255 mg, 1 mmol) according to the procedure of Example 1A. The title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.50) as oil (180 mg, yield, 49%). H NMR (MeOH-d4, 300 MHz) δ 1.50–1.58 (m, 1H), 1.64–1.85 (m, 2H), 2.00–2.15 (m, 1H), 2.20–2.30 (m, 1H), 2.76–3.10 (m, 5H), 3.38–3.50 (m, 1H), 4.60 (m, 1H), 6.96–7.04 (m, 6H), 7.60 (d, J=8.5 Hz, 2H) ppm. MS (DCl/NH3) m/z 364 (M+H)+.
Reaction SMILES: Cl[Sn]Cl.[N+:4]([C:7]1[C:8]([NH2:16])=[N:9][CH:10]=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13])([O-])=O.N.C(O)(=O)C>Cl>[NH2:4][C:7]1[C:8]([NH2:16])=[N:9][CH:10]=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13]
Reactant: Nc1ncc(C(=O)O)cc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: N
Solvent: CC(=O)O
Product: Nc1cc(C(=O)O)cnc1N
Temperature: 100 °C

Procedure:
See Markwald, W. Chem. Ber. 1984, 27, 1317. To a stirred solution of SnCl2 (4.16 g, 22.0 mmol) in concentrated HCl (11 mL) at 0° C. was added in portions 5-nitro-6-aminonicotinic acid (1.01 g, 5.5 mmol). The resulting orange mixture was then heated to 100° C. under argon for 75 min. The mixture was then cooled to RT and was then placed in an ice bath and neutralized with concentrated aqueous ammonia (to pH 6-7), resulting in a thick cream-colored mixture. The mixture was then acidified to pH 4 with acetic acid and the precipitate collected by filtration, washed with H2O and dried under vacuum overnight to afford the title compound: 1H NMR (300 MHz, DMSO-d6): δ7.98 (d, J=2.1 Hz, 1H), 7.21 (d, J=2.1 Hz, 1H), 6.24 (br s, 2H), 5.00 (br s, 2H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]([OH:15])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=1.[C:16]1([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>Cl.C(O)CCC>[ClH:1].[ClH:1].[C:13]([C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][CH:4]([OH:15])[CH2:3][CH2:2][N:25]2[CH2:26][CH2:27][N:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:23][CH2:24]2)=[CH:8][CH:9]=1)#[N:14]
Reactant: N#Cc1ccc(OCC(O)CCCl)cc1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCCCO
Product: N#Cc1ccc(OCC(O)CCN2CCN(c3ccccc3)CC2)cc1

Procedure:
This compound was prepared according to the procedure of Example 25. A mixture of 6.8 g (0.03 mole) of 4-chloro-1-(4-cyanophenoxy)-2-butanol, 4.9 g (0.03 mole) of 1-phenylpiperazine, 16.0 g (0.15 mole) of anhydrous sodium carbonate and 0.3 g (0.002 mole) of potassium iodide in a total volume of 200 ml of 1-butanol gave an oil as residue. The hydrochloric acid salt was formed in ethereal hydrogen chloride and the collected solid was recrystallized from methanolethyl ether to give 3.7 g (35%) of white solid, m.p. 195°-198° C.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:19]=[C:18]([CH2:20][OH:21])[O:17][N:16]=1.Cl[C:23]1[C:28]([C:29]#[N:30])=[CH:27][CH:26]=[CH:25][N:24]=1.CN(C)C=O.[H-].[Na+]>O>[CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:19]=[C:18]([CH2:20][O:21][C:23]2[N:24]=[CH:25][CH:26]=[CH:27][C:28]=2[C:29]#[N:30])[O:17][N:16]=1
Reactant: Cc1sc(-c2ccccc2)nc1COc1cc(CO)on1
Reactant: N#Cc1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1sc(-c2ccccc2)nc1COc1cc(COc2ncccc2C#N)on1
Temperature: 25 °C
Reaction time: 5 h
Yield: 86.4 %

Procedure:
To a mixture of [3-(5-methyl-2-phenyl-4-thiazolylmethoxy)-5-isoxazolyl]methanol (1.80 g), 2-chloro-3-cyanopyridine (0.83 g) and N,N-dimethylformamide (80 mL) was added sodium hydride (60%, oil, 0.26 g) under ice-cooling. The reaction mixture was stirred at room temperature for 5 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (2.08 g, 86%) of 2-[[3-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]-5-isoxazolyl]methoxy]nicotinonitrile from a fraction eluted with ethyl acetate-hexane (1:2, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 135-136° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:7]([CH2:23][CH2:24][N:25]=3)[C:8]([NH:14][C:15]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[O:16])=[N:9][C:10]=2[C:11]=1[O:12][CH3:13].C(O)(C(F)(F)F)=O.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH2:44][C@@H:45]1[O:47][CH2:46]1)(=O)=O>CN(C=O)C>[CH3:13][O:12][C:11]1[C:10]2[N:9]=[C:8]([NH:14][C:15](=[O:16])[C:17]3[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=3)[N:7]3[CH2:23][CH2:24][N:25]=[C:6]3[C:5]=2[CH:4]=[CH:3][C:2]=1[O:1][CH2:44][C@H:45]1[CH2:46][O:47]1
Reactant: CS(=O)(=O)OC[C@H]1CO1
Reactant: COc1c(O)ccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COc1c(OC[C@H]2CO2)ccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
A mixture of N-{8-hydroxy-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}pyridine-3-carboxamide (Intermediate I, Step 2 (used as bis-TFA salt), 1.50 g, 2.65 mmol) and caesium carbonate (4.32 g, 13.3 mmol, 5.0 equiv.) in DMF (37 mL) was stirred at room temperature for 1 h, then was treated with (R)-glycidyl methanesulfonate (Intermediate F, Step 1, 21.2 mL, 0.25 M in DMF, 5.31 mmol, 2.0 equiv.). The resulting mixture was stirred at room temperature for 16 h at 60° C., then was cooled to room temperature and concentrated under reduced pressure. The resulting residue was seperated between water (50 mL) and a 4:1 CH2Cl2/isopropanol solution (50 mL). The organic phase was washed with a concentrated sodium bicarbonate solution, dried (anh. sodium sulfate), and concentrated under reduced pressure. The resulting material was triturated with EtOH and dried under reduced pressure to give N-{7-methoxy-8-[(2R)-oxiran-2-ylmethoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide (0.72 g, 69%): HPLC ret. time 0.94 min.; 1H NMR (DMSO-d6+1 drop TFA-d) δ 2.75 (dd, J=2.5, 5.1 Hz, 1H), 2.88 (app t, J=4.7, 1H), 3-42-3.47 (m, 1H), 4.01 (s, 3H), 4.14 (dd, J=6.6, 11.6 Hz, 1H), 4.20-4.29 (m, 3H), 4.52-4.59 (m, 2H), 4.68 (dd, J=2.3, 11.6 Hz, 1H), 7.47 (d, J=9.4 Hz, 1H), 7.92 (dd, J=5.6, 7.8 Hz, 1H), 8.03 (d, J=9.1 Hz, 1H), 8.90 (br d, J=7.8 Hz, 1H), 8.97 (dd, J=1.5, 5.6 Hz, 1H), 9.49 (d, J=1.5 Hz, 1H); mass spectrum m/z 394 ((M+1)+, 11%).
Reaction SMILES: C=C.[CH2:3]([C@H:10]1[CH2:14][O:13][C:12](=[O:15])[N:11]1[C:16](=[O:37])[CH2:17][C@@H:18]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:25][CH:24]=1)[CH2:19][N+:20]([O-])=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:38][C:39](OC(OC(OC(C)(C)C)=O)=O)(C)C>C(#N)C.CN(C1C=CN=CC=1)C>[CH2:3]([C@H:10]1[CH2:14][O:13][C:12](=[O:15])[N:11]1[C:16](=[O:37])[CH2:17][C@@H:18]([C:23]1[CH:24]=[CH:25][C:26]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[CH:27][CH:28]=1)[CH:19]1[CH:39]=[CH:38][O:21][NH:20]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: O=C(C[C@H](C[N+](=O)[O-])c1ccc(OCc2ccccc2)cc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: C=C
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: O=C(C[C@@H](c1ccc(OCc2ccccc2)cc1)C1C=CON1)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 88.8 %

Procedure:
Ethylene was bubbled into 7.3 (882 mg, 1.86 mmol) in 40 mL ACN at room temperature for 20 minutes. (Boc)2O (610 mg, 2.79 mmol) was added at room temperature, followed by the addition of DMAP (23 mg, 0.19 mmol). The mixture was stirred at room temperature for 6 hours. After HPLC indicated that all the 7.3 was consumed, the reaction mixture was taken into EtOAc (500 mL) and saturated sodium bicarbonate (400 mL). The organic layer was separated, washed with brine, dried, and concentrated under vacuum. The crude product was purified by flash chromatography to give 9.1 800 mg). MS ESI (pos.) m/e: 485 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH:9](/B(O)O)=[CH:10]\[CH3:11].C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>C1(C)C=CC=CC=1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Cl:8][C:5]1[N:4]=[CH:3][C:2](/[CH:9]=[CH:10]/[CH3:11])=[CH:7][N:6]=1
Reactant: C/C=C/B(O)O
Reactant: Clc1ncc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C/C=C/c1cnc(Cl)nc1
Yield: 42 %

Procedure:
To 5-bromo-2-chloropyrimidine (2.027 g, 10.48 mmol), (E)-prop-1-enylboronic acid (1.350 g, 15.72 mmol), PdCl2(dppf)-CH2Cl2 (0.428 g, 0.524 mmol), and potassium carbonate (4.35 g, 31.4 mmol) in toluene (20 mL) and water (0.5 mL) was bubbled nitrogen subsurface for 1 minute and then placed in a 90° C. oil bath for 5 hours. 200 mL EtOAc was added and the reaction was then washed with 3×200 mL of water, dried with MgSO4, filtered and concentrated to 1.53 g brown solids. This was purified by flash chromatography (5% EtOAc in hexanes) to yield product (681 mg) as an off-white solid. MS (ESI) 155.7 (M+1).