Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]=O)=[CH:13][CH:12]=2)=[C:9]([C:19]2[CH:24]=[C:23]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:22]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:21][C:20]=2[O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:8][N:7]=1)=[O:5])[CH3:2].[NH:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:1]([NH:3][C:4]([C:6]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([CH2:17][N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)=[CH:15][CH:16]=2)=[C:9]([C:19]2[CH:24]=[C:23]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:22]([O:29][CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:21][C:20]=2[O:37][CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[O:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)c1noc(-c2cc(CC(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)c1-c1ccc(C=O)cc1
Reactant: C1COCCN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCNC(=O)c1noc(-c2cc(CC(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)c1-c1ccc(CN2CCOCC2)cc1
Reaction time: 0.5 h

Procedure:
5-(2,4-Bis-benzyloxy-5-isobutyl-phenyl)-4-(4-formyl-phenyl)-isoxazole-3-carboxylic acid ethylamide (1 eq) was dissolved in methanol and powdered 3A sieves were added. Morpholine (2 eq) was added, followed by acetic acid (5 eq). After stirring for 30 minutes, sodium cyanoborohydride (2 eq) was added portionwise and the suspension was stirred under nitrogen at ambient temperature for 16 hours. The reaction mixture was filtered through celite and concentrated to dryness. Column chromatography, eluting with 5% MeOH in DCM gave 5-(2,4-bis-benzyloxy-5-isobutyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide as a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:13])[NH:10]2)=[N:5][CH:4]=1.[H-].[Na+].Br[CH2:17][CH:18]1[O:22][CH2:21][CH2:20][O:19]1.O>CN(C)C=O.C(OCC)(=O)C>[O:19]1[CH2:20][CH2:21][O:22][CH:18]1[CH2:17][N:10]1[C:11]2[C:6](=[N:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[CH:7]=[CH:8][C:9]1=[O:13]
Reactant: COc1cnc2ccc(=O)[nH]c2c1
Reactant: BrCC1OCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cnc2ccc(=O)n(CC3OCCO3)c2c1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 0.23 g of 7-methoxy-1,5-naphthyridin-2(1H)-one in 3 mL of N,N-dimethylformamide, 79 mg of 60% sodium hydride was added at room temperature, the temperature was increased to 50° C., and the mixture was stirred for 15 minutes. Thereto was added 0.41 mL of 2-bromomethyl-1,3-dioxolan, the temperature of the reaction mixture was increased to 90 to 100° C., and the reaction mixture was stirred for 3 hours. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added thereto. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by flash silica gel column chromatography using gradient elution with hexane:ethyl acetate=100:0 to 33:67, then gradient elution with chloroform:methanol=100:0 to 90:10 to obtain 0.11 g of 1-(1,3-dioxolan-2-ylmethyl)-7-methoxy-1,5-naphthyridin-2(1H)-one as a light brown solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.FC(F)(F)C(O)=O.[NH2:37][CH2:38][CH2:39][N:40]1[C:44]2[CH:45]=[CH:46][C:47]([C:49]([N:51]3[CH2:57][C:56]4([CH3:59])[CH2:58][CH:52]3[CH2:53][C:54]([CH3:61])([CH3:60])[CH2:55]4)=[O:50])=[CH:48][C:43]=2[N:42]=[CH:41]1>C1COCC1>[CH3:59][C:56]12[CH2:58][CH:52]([N:51]([C:49]([C:47]3[CH:46]=[CH:45][C:44]4[N:40]([CH2:39][CH2:38][NH:37][C:6]([C:2]5[O:1][CH:5]=[CH:4][CH:3]=5)=[O:8])[CH:41]=[N:42][C:43]=4[CH:48]=3)=[O:50])[CH2:57]1)[CH2:53][C:54]([CH3:61])([CH3:60])[CH2:55]2
Reactant: CC1(C)CC2CC(C)(CN2C(=O)c2ccc3c(c2)ncn3CCN)C1
Reactant: O=C(O)c1ccco1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC1(C)CC2CC(C)(CN2C(=O)c2ccc3c(c2)ncn3CCNC(=O)c2ccco2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.7 %

Procedure:
To a solution of 2-furoic acid (37 mg, 0.33 mmol) in dry THF (2 mL) at room temperature under an inert atmosphere of nitrogen were added HOBt (49 mg, 0.36 mmol) and EDAC (82 mg, 0.43 mmol), and the resulting solution was stirred for 30 min. [1-(2-Aminoethyl)-1H-benzoimidazol-5-yl]-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone trifluoroacetate (150 mg, 0.33 mmol) was added to the solution followed by TEA (0.184 mL, 1.32 mmol), and the reaction mixture was stirred for 16 h at room temperature. The volatiles were evaporated in vacuo and the resulting solid was purified by preparative HPLC, dried in vacuo at 50° C. affording 100 mg (70%) of the title compound as a solid. MS-ESI m/z 435; 1H NMR (400 MHz, DMSO-d6) δ 0.88-0.99 (m, 6H), 1.07 (d, 3H), 1.29-1.41 (m, 4H), 1.50-1.52 (m) and 2.10-2.11 (m, 1H), 1.76-1.79 (m, 1H), 3.02 (d), 3.13 (d), 3.32 (d) and 3.47 (d, 2H), 3.69 (t, 2H), 3.87-3.89 (m) and 4.39-4.41 (m, 1H), 4.56 (t, 2H), 6.58 (s, 1H), 6.98 (d, 1H), 7.48 (dd, 1H), 7.77-7.82 (m, 2H), 7.89 (t, 1H), 8.54-8.58 (m, 1H), 9.07 (d, 1H).
Reaction SMILES: [C:1]([CH:4]([CH:6]1[C:18]2[N:17]3[CH:19]=[CH:20][N:21]=[C:16]3[C:15](=[O:22])[NH:14][C:13]=2[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]1=2)O)([OH:3])=[O:2].C(OC(=O)C)(=O)C>[Cl-].[Zn+2].[Cl-].O>[C:1]([CH:4]=[C:6]1[C:18]2[N:17]3[CH:19]=[CH:20][N:21]=[C:16]3[C:15](=[O:22])[NH:14][C:13]=2[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]1=2)([OH:3])=[O:2]
Reactant: O=C(O)C(O)C1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: O=C(O)C=c1c2ccccc2c2[nH]c(=O)c3nccn3c12
Yield: 23.1 %

Procedure:
2.4 g of 10-(1-carboxy-1-hydroxymethyl)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one, 20 ml of acetic anhydride and 20 mg of zinc chloride are heated to reflux for 4 hours, under cover of argon. The reaction mixture is treated with 25 ml of water and the precipitate formed is filtered off, washed with 25 ml of water and then with 2×25 ml of acetone and dried at 80° C. under vacuum (1 mmHg; 0.13 kPa) to give 0.52 g of 10-(carboxymethylene)-5H,10H-imidazo[1,2-a]indeno-[1,2-e]pyrazin-4-one in the form of an orange-yellow solid, which product is converted into the sodium salt of formula C15H8N3O3Na (Analysis, % calculated C: 59.81, H: 2.68, N: 13.95, O: 15.93, Na : 7.63, % found C 59.5, H: 2.1, N: 13.6).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:24]2[CH2:27][CH:26]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=3[CH3:36])[CH2:25]2)=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)=[O:8].[OH-].[Na+]>C1OCCOC1.O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:24]2[CH2:25][CH:26]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=3[CH3:36])[CH2:27]2)=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1([C:13]2[CH:22]=[CH:21][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)=[O:8]
Reactant: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CC(Nc4ccc(F)cc4C)C3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(F)ccc1NC1CN(c2ncc(Cl)cc2C(=O)NC2(c3ccc(C(=O)O)cc3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 4-(1-(5-chloro-2-(3-((4-fluoro-2-methylphenyl)amino)azetidin-1-yl)nicotinamido)cyclopropyl)benzoate (D168) (105 mg, 0.206 mmol) in a mixture 1-4 dioxane/water (3 ml/1 ml), 1N NaOH (0.309 ml) was added. The reaction mixture was stirred at room temperature overnight. Organic solvent was evaporated in vacuo and the reaction mixture was acidified with 2N HCl (pH=5-6). The solid obtained was filtered off and dried to afford the title (E34) (65 mg
Reaction SMILES: CC(C)([O-])C.[K+].[Cl-].[NH2:8][C:9]([NH2:11])=[NH2+:10].[CH2:12]([N:14]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]1[CH2:24][C:25](OCC)=[O:26])[CH3:13]>O>[CH2:12]([N:14]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]1[CH2:24][C:25]([NH:10][C:9]([NH2:11])=[NH:8])=[O:26])[CH3:13]
Reactant: CCOC(=O)CC1c2ccccc2C(=O)N1CC
Reactant: NC(N)=[NH2+]
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: CCN1C(=O)c2ccccc2C1CC(=O)NC(=N)N
Temperature: 20 °C
Reaction time: 20 h
Yield: 28 %

Procedure:
N-[(2-Ethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetyl]guanidine is prepared as described in Example 1, starting with 4.3 g of potassium tert-butoxide, 3.7 g of guanidinium chloride and 1.9 g of ethyl (2-ethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate. The reaction mixture is stirred at a temperature in the region of 20° C. for 20 hours, followed by addition of 60 cm3 of water. The aqueous phase is extracted with 3 times 50 cm3 of ethyl acetate and is then concentrated to dryness under reduced pressure (0.6 kPa) at a temperature in the region of 45° C. The residue is taken up in water, triturated and filtered. The solid is taken up in methanol and the solvent is then evaporated to dryness under reduced pressure (0.6 kPa) at a temperature in the region of 45° C. 0.56 g of N-[(2-ethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetyl]-guanidine is thus obtained in the form of an off-white solid melting at 223° C. Mass spectrum EI: m/e 260 (M+), m/e 173, m/e 160, m/e 132.
Reaction SMILES: [CH:1]([Mg]Cl)([CH3:3])[CH3:2].[O:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH:11][C:12]1C=CC(C#N)=[N:16][CH:17]=1.Cl.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O1CCCC1>[OH:11][C:12]1[CH:7]=[CH:8][C:9]([C:10](=[O:6])[CH:1]([CH3:3])[CH3:2])=[N:16][CH:17]=1
Reactant: CC(C)[Mg]Cl
Reactant: N#Cc1ccc(O)cn1
Reactant: C1CCOC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)C(=O)c1ccc(O)cn1
Reaction time: 3 h
Yield: 48.7 %

Procedure:
1.0 M Isopropylmagnesium chloride-tetrahydrofuran solution (104 mL, 104 mmol) was slowly added to a tetrahydrofuran (80 mL) solution of 5-hydroxypyridin-2-carbonitrile (5.00 g, 41.6 mmol) at 0° C., and the mixture was stirred at the same temperature for 3 hours. 1 M Hydrochloric acid was added to the reaction mixture, subsequently, a saturated aqueous solution of sodium hydrogen carbonate was added to the resulting mixture to adjust the pH to 6, and then the mixture was extracted twice with ethyl acetate. The organic layer thus obtained was washed with brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=80:20→50:50, v/v) to give the title compound (3.35 g, yield: 49%).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:21])[CH2:16][CH2:15]2)[CH:3]=1>CO.[C].[Pd]>[C:22]1([C:20]([N:17]2[CH2:18][CH2:19][N:14]([C:4]3[CH:3]=[CH:2][N:7]=[N:6][C:5]=3[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:15][CH2:16]2)=[O:21])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(c1ccccc1)N1CCN(c2cc(Cl)nnc2-c2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: O=C(c1ccccc1)N1CCN(c2ccnnc2-c2ccccc2)CC1
Reaction time: 3 h

Procedure:
To (4-(6-chloro-3-phenylpyridazin-4-yl)piperazin-1-yl)(phenyl)methanone (1 g) dissolved in methanol (40 ml), and palladium carbon (10 mol %) was added very slowly under nitrogen atmosphere and the reaction mixture was stirred under hydrogen atmosphere (1 kg pressure) for 3 hrs. The progress of reaction was monitored by TLC. After consumption of starting material, the reaction mixture was filtered through celite, washed with methanol and the filtrate was concentrated under reduced pressure to get phenyl(4-(3-phenylpyridazin-4-yl)piperazin-1-yl)methanone as white solid.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([N:5]=C=O)=[O:4].[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1/[C:15](=[N:33]/[O:34][CH3:35])/[C:16]([NH:18][C@@H:19]1[C:31](=[O:32])[N:21]2[C:22]([C:28]([OH:30])=[O:29])=[C:23]([CH2:26][OH:27])[CH2:24][S:25][C@H:20]12)=[O:17].C([O-])(=O)C.[Na+:40]>CO.C1COCC1.ClCCl>[CH3:35][O:34]/[N:33]=[C:15](\[C:16]([NH:18][C@@H:19]1[C:31](=[O:32])[N:21]2[C:22]([C:28]([O-:30])=[O:29])=[C:23]([CH2:26][O:27][C:3]([NH2:5])=[O:4])[CH2:24][S:25][C@H:20]12)=[O:17])/[C:11]1[O:10][CH:14]=[CH:13][CH:12]=1.[Na+:40]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12)c1ccco1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(COC(N)=O)CS[C@H]12)c1ccco1
Reaction time: 0.17 h

Procedure:
A mixture of THF (60 ml), dichloromethane (25 ml), and trichloroacetyl isocyanate (6.2 ml) was protected from moisture and cooled to -10°.To the stirred mixture was added (6R,7R)-7-[Z-2-(fur-2-yl)-2-methyoxyiminoacetamido]-3-hydroxymethylceph-3-em-4-carboxylic acid (10 g) in one charge followed by THF (20 ml). The mixture was stirred for 10 minutes at 0° to +5° to give a clear solution. Methanol (6.6 ml) was added, followed by portionwise addition of anhydrous sodium acetate (0.3 g) to raise the pH to 3.5. Charcoal (1 g) and filter aid (0.5 g Hyflo Supercel) were added and the mixture stirred at 10° for 20 minutes. Further anhydrous sodium acetate (5 g) was then added and the mixture stirred at 10° to 15° for 5 minutes by which time the pH had risen to 7.2. The charcoal, undissolved sodium acetate, and filter aid were removed by filtration and the filter bed washed with methanol (23 ml ) containing dichloromethane (10 ml). The filtrate and washes were combined, warmed to 25°, and left undisturbed at that temperature. Crystallisation commenced after 12 minutes. After 1 hour the mixture was stirred briefly and then left undisturbed for a further 11/2 hours. The crystalline material was collected by filtration, washed with THF (2×50 ml) and dried in vacuo at 35° to give sodium cefuroxime in a yield of 78.5%theory corrected for THF and sodium acetate.
Reaction SMILES: [CH:1]1(/[CH:7]=[CH:8]/[C:9]#[N:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:11]([OH:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>[Na].CCOCC>[CH2:11]([O:18][CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:8][CH2:9][NH2:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N#C/C=C/C1CCCCC1
Reactant: OCc1ccccc1
Agent: [Na]
Solvent: CCOCC
Product: NCCC(OCc1ccccc1)C1CCCCC1
Reaction time: 4 h

Procedure:
The foregoing mixture of 2-cis and 2-trans-3-cyclohexylacrylonitrile (26.50 g) was dissolved in sodium benzylate solution prepared from sodium (0.65 g) and benzyl alcohol (90 ml) and the resulting solution heated on the steam-bath with stirring for 4 hours then set aside at room temperature for 18 hours. The resulting dark solution was diluted with ether and washed with water. The ethereal extract was dried (Na2SO4), the solvent removed in vacuo, and the residue unchanged nitrile removed by distillation under high vacuum. The residual material was taken up in ether, decolorised with activated charcoal, filtered, and the solvent removed in vacuo. The residual yellow syrup (ca. 22 g) was dissolved in dry ether (40 ml) and added dropwise at +5° to a stirred suspension of lithium aluminium hydride (3.4 g) in dry ether (125 ml). After 1 hour at room temperature, the reaction mixture was treated with water and the resulting gel filtered through Celite. The yellow organic phase was separated, dried (MgSO4), the solvent removed in vacuo, and the residual orange oil distilled, giving 3-benzyloxy-3-cyclohexylpropylamine as a colourless viscous oil, b.p. 120°-5°/0.05-0.06 mm.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12](Cl)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][OH:28])=[CH:22][CH:21]=1>>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][OH:28])=[CH:22][CH:21]=2)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc(CCO)cc1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Product: CC(C)(C)NS(=O)(=O)c1ccc(Nc2ccc(CCO)cc2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from N-(tert-butyl)-4-chloro-3-nitrobenzenesulfonamide (step 1) and 4-aminophenylethyl alcohol.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25](B(O)O)[C:24]=1[F:32])#[N:16]>>[F:32][C:24]1[C:25]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]3=[N:4][CH:3]=2)=[CH:26][CH:27]=[CH:28][C:23]=1[C:18]1[C:17]([C:15]#[N:16])=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Reactant: N#Cc1ccccc1-c1cccc(B(O)O)c1F
Product: N#Cc1ccccc1-c1cccc(-c2cnc3nc(C(F)(F)F)ccn23)c1F
Yield: 18 %

Procedure:
3-Bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine was coupled with 2′-cyano-2-fluorobiphenyl-3-boronic acid as described in Example 1 to give 2′-fluoro-3′-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)biphenyl-2-carbonitrile as an off-white solid (70 mg, 18%): δH (400 MHz, DMSO) 7.60-7.64 (2H, m), 7.70 (1H, d, J 1), 7.76 (1H, d, J 2), 7.83 (1H, s), 7.87-7.91 (2H, m), 8.05 (1H, dd, J 7 and 1), 8.35 (1H, s), 9.13 (1H, dd, J 7 and 3); m/z (ES+) 383 (M++H).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([N:12]2[C:24](=[O:25])[C:23]3[S:22][C:21]4[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=4[C:15]=3[CH:14]=[N:13]2)=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:27]1[CH:32]=[C:31]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([N:40]3[CH2:45][C@@H:44]([CH3:46])[N:43]([CH:47]4[CH2:50][O:49][CH2:48]4)[CH2:42][C@@H:41]3[CH3:51])=[CH:36][N:35]=2)[C:30](=[O:52])[N:29]([CH3:53])[CH:28]=1)(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[CH3:51][C@H:41]1[CH2:42][N:43]([CH:47]2[CH2:50][O:49][CH2:48]2)[C@H:44]([CH3:46])[CH2:45][N:40]1[C:37]1[CH:38]=[CH:39][C:34]([NH:33][C:31]2[C:30](=[O:52])[N:29]([CH3:53])[CH:28]=[C:27]([C:7]3[C:6]([CH2:5][OH:4])=[C:11]([N:12]4[C:24](=[O:25])[C:23]5[S:22][C:21]6[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=6[C:15]=5[CH:14]=[N:13]4)[CH:10]=[C:9]([F:26])[CH:8]=3)[CH:32]=2)=[N:35][CH:36]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(N4C[C@@H](C)N(C5COC5)C[C@@H]4C)cn3)c(=O)n(C)c2)cc(F)cc1-n1ncc2c3c(sc2c1=O)CCCC3
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1CN(c2ccc(Nc3cc(-c4cc(F)cc(-n5ncc6c7c(sc6c5=O)CCCC7)c4CO)cn(C)c3=O)nc2)[C@@H](C)CN1C1COC1
Temperature: 30 °C
Reaction time: 1 h
Yield: 38.2 %

Procedure:
A mixture of 118a (100 mg, 0.135 mmol) and lithium hydroxide (33 mg, 1.35 mmol) in i-propanol/THF (1:1, 4 mL) and water (1 mL) was stirred at 30° C. for 1 h. The mixture was evaporated under reduced pressure. The resulting residue was extracted with ethyl acetate (2×10 mL). The combined organic layer was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 118 (36 mg, 38%) as a white solid. MS: [M+H]+ 698.3. 1H NMR (500 MHz, CDCl3) δ 8.64 (d, J=2.0 Hz, 1H), 8.27 (s, 1H), 8.05 (d, J=2.0 Hz, 1H), 7.88 (s, 1H), 7.48 (d, J=2.5 Hz, 1H), 7.37 (d, J=5.5 Hz, 1H), 7.30 (dd, J=2.5, 9.0 Hz, 1H), 7.11 (dd, J=2.5, 8.5 Hz, 1H), 6.82 (d, J=9.0 Hz, 1H), 4.79-4.73 (m, 2H), 4.67-4.61 (m, 2H), 4.31 (s, 2H), 3.77 (t, J=7.0 Hz, 1H), 3.72 (s, 3H), 3.21-3.19 (m, 1H), 2.99-2.98 (m, 2H), 2.94-2.91 (m, 1H), 2.88-2.86 (m, 2H), 2.78-2.71 (m, 2H), 2.51-2.49 (m, 1H), 1.99-1.96 (m, 6H), 0.92-0.90 (m, 6H).
Reaction SMILES: [Cl:1]C(OC(Cl)C)=O.C([N:15]1[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17][CH2:16]1)C1C=CC=CC=1>C(Cl)Cl>[ClH:1].[F:21][C:18]1([F:22])[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]1
Reactant: FC1(F)CCN(Cc2ccccc2)CC1
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Product: Cl
Product: FC1(F)CCNCC1
Yield: 87 %

Procedure:
In an argon atmosphere, 1-chloroethyl chloroformate (2.62 mL) was added dropwise to the above-obtained N-benzyl-4,4-difluoropiperidine (4.66 g) in methylene chloride (93 mL) at 0° C., and the resultant mixture was stirred at 55° C. for 2 hours, and then cooled in air. The reaction solvent was removed under reduced pressure, and the residue in methanol (93 mL) was refluxed under heat for 4 hours, and then cooled in air. The reaction solvent was removed under reduced pressure, to thereby give the title compound as a solid (3.03 g, 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH3:12])[C:9]=1[OH:10])[CH:5]=O.C(C1C=C(C=C(C)C=1O)C#[N:19])C>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH3:12])[C:9]=1[OH:10])[C:5]#[N:19]
Reactant: COc1cc(C=O)cc(Cl)c1O
Reactant: CCc1cc(C#N)cc(C)c1O
Product: COc1cc(C#N)cc(Cl)c1O

Procedure:
The title compound is prepared from commercially available 3-chloro-4-hydroxy-5-methoxy-benzaldehyde in analogy to literature procedures (see 3-ethyl-4-hydroxy-5-methyl-benzonitrile). LC-MS: tR=0.82 min; 1H NMR (CDCl3): δ3.98 (s, 3H), 6.36 (s, 1H), 7.04 (s, 1H), 7.34 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]2[C:4]=1[C:5](=[O:19])[CH2:6][CH:7]([C:15]([O:17][CH3:18])=[O:16])[CH2:8]2.[C:20]1([CH3:26])C=CC=CC=1.CCCCCC.C1(C)C=CC(S(O)(=O)=[O:40])=CC=1>C(O)CO>[CH2:26]1[CH2:20][O:40][C:5]2([C:4]3[C:9](=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:3]=3[O:2][CH3:1])[CH2:8][CH:7]([C:15]([O:17][CH3:18])=[O:16])[CH2:6]2)[O:19]1
Reactant: COC(=O)C1CC(=O)c2c(OC)ccc(OC)c2C1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1ccccc1
Solvent: OCCO
Solvent: CCCCCC
Product: COC(=O)C1Cc2c(OC)ccc(OC)c2C2(C1)OCCO2
Temperature: 25 °C
Yield: 61 %

Procedure:
40 g of methyl rac-1,2,3,4-tetrahydro-5,8-dimethoxy-4-oxonaphthalene-2-carboxylate were added to a mixture of 800 ml of toluene, 800 ml of hexane, 30 ml of ethyleneglycol and 0.65 g of toluene-4-sulphonic acid. The mixture was heated under reflux for 24 hours using a Dean-Stark trap. The solution was cooled in an ice-bath and washed with three 124 ml portions of 10% potassium hydrogen carbonate solution and 200 ml of brine, dried and the solvent was evaporated. The residue was taken up in 200 ml of methanol at 70° C. and 0.5 g of a 50% dispersion of sodium hydride in mineral oil was added. The solution obtained was left to cool to room temperature and then cooled further in an ice-bath for 2 hours. The crystalline product was filtered off, washed with cold methanol and dried in vacuo. There were obtained 28.5 g (61%) of methyl rac-4,4-ethylenedioxy-1,2,3,4-tetrahydro-5,8-dimethoxynaphthalene-2-carboxylate in the form of colourless crystals of melting point 133°-134° C.