Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2](=[CH2:5])[C:3]#[N:4].[CH2:6]([O:13][N:14]1[C:20](=[O:21])[N:19]2[CH2:22][C@H:15]1[CH2:16][CH2:17][C@H:18]2[C:23](Cl)=[N:24][OH:25])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)Cl>[CH2:6]([O:13][N:14]1[C:20](=[O:21])[N:19]2[CH2:22][C@H:15]1[CH2:16][CH2:17][C@H:18]2[C:23]1[CH:5]=[C:2]([C:3]#[N:4])[O:25][N:24]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C=C(Cl)C#N
Reactant: O=C1N2C[C@@H](CC[C@H]2C(Cl)=NO)N1OCc1ccccc1
Solvent: ClCCl
Product: N#Cc1cc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)no1
Temperature: -5 °C
Reaction time: 2 h
Yield: 16.2 %

Procedure:
2-Chloroacrylonitrile (1.08 g, 12.4 mmol) was added to a solution of (2S,5R)-6-(benzyloxy)-N-hydroxy-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbimidoyl chloride (1.9 g, 6.2 mmol) in DCM (19 mL) at −5° C., followed by dropwise addition of TEA (1.25 g, 1.24 mmol). The mixture was stirred at −5° C. for 2 hrs and was then quenched with 10% critic acid (20 mL). The organic phase was separated, washed with 10% critic acid, H2O, and saturated sodium chloride, then concentrated. The residue was purified by silica gel column chromatography (gradient elution 15:1 to 4:1 petroleum ether/EtOAc) to afford 3-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-2-yl)isoxazole-5-carbonitrile (325 mg, 16%) as a white solid. 1H-NMR (500 MHz, CDCl3): δ 7.45-7.35 (m, 5H), 7.04 (s, 1H), 5.09 (d, J=11.3 Hz, 1H), 4.94 (d, J=11.3 Hz, 1H), 4.64 (d, J=7.0 Hz, 1H), 3.34 (s, 1H), 2.90 (br d, J=12.0 Hz, 1H), 2.54 (d, J=12.0 Hz, 1H), 2.40-2.35 (m, 1H), 2.31-2.25 (m, 1H), 2.14-2.11 (m, 1H), 1.80-1.74 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8]([NH2:25])[C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][C:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:16]3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH2:40]=[C:41]1[CH2:44][CH:43]([C:45](O)=[O:46])[CH2:42]1>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH:8]([NH:25][C:45]([CH:43]2[CH2:44][C:41](=[CH2:40])[CH2:42]2)=[O:46])[C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][C:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:16]3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: C=C1CC(C(=O)O)C1
Reactant: NC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: C=C1CC(C(=O)NC(c2ccc3ccc(-c4ccccc4)nc3c2)c2nccnc2Cl)C1

Procedure:
C-(3-Chloro-pyrazin-2-yl)-C-(2-phenylquinolin-7-yl)-methylamine (690 mg, 1.99 mmol) was dissolved in 6.0 mL of CH2Cl2 followed by the addition of EDC (600 mg, 2.98 mmol) and HOBT (300 mg, 1.99 mmol). 3-Methylenecyclobutanecarboxylic acid (300 mg, 2.59 mmol) was dissolved in 1.0 mL of CH2Cl2 and added to the homogenous reaction mixture. After 24 h the reaction was concentrated in vacuo and dissolved in EtOAc and the organic layer was washed with sat. NaHCO3. The organic layer was washed with H2O and brine. The organic layers where combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography [Jones Flashmaster, 10 g cartridge, eluting with 50% EtOAc:Hex] to obtain the desired product as a white fluffy solid; 1H NMR (400 MHz, CDCl3): δ=2.82-2.92 (m, 2H), 2.99-3.06 (m, 2H), 4.77-4.80 (m, 2H), 6.81 (d, 1H, J=7.8 Hz), 7.45-7.54 (m, 3H), 7.83-7.88 (m, 3H), 8.10 (d, 2H, J=7.1 Hz), 8.22-8.23 (brm, 1H), 8.39 (d, 1H, J=1.79 Hz), 8.59 (d, 1H, J=2.5 Hz); MS (ES+): 440.93 (M+1), 442.91 (M+3).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[C:6]#[N:7].[CH3:21][NH:22][CH2:23][CH2:24][C:25]1[CH:35]=[CH:34][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][CH:26]=1>C1COCC1>[C:6]([C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:3][CH2:2][N:22]([CH3:21])[CH2:23][CH2:24][C:25]1[CH:35]=[CH:34][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][CH:26]=1)#[N:7]
Reactant: CCOC(=O)c1ccc(CCNC)cc1
Reactant: COc1ccc(C(C#N)(CCCBr)C(C)C)cc1OC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(CCN(C)CCCC(C#N)(c2ccc(OC)c(OC)c2)C(C)C)cc1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
A solution of 0.326 g (0.961 mmol) of 1f in 1 mL of THF and a separate solution of 0.292 g (1.41 mmol) of 2c in 1 mL of THF were combined. The resulting solution was heated in a 90° C. oil bath and the THF was evaporated under a slow stream of nitrogen. The resulting mixture was stirred under nitrogen at 85° C. for 18 h, cooled to 22° C. and partitioned between saturated NaHCO3 and ethyl acetate. The organic layer was dried (Na2SO4) and evaporated and the residue purified by flash chromatography on silica gel, eluting first with DCM and then gradually increasing to 2% methanol/DCM to give 3r as a colorless oil; MS found M+H=467. The oxalate salt of 3r was recrystallized from ethyl acetate; mp 111-112° C.
Reaction SMILES: [C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15](O)=[O:16])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH2:37]([NH:44][C:45](=[O:48])[CH2:46][NH2:47])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C1COCC1>[C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15]([N:44]([CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:45](=[O:48])[CH2:46][NH2:47])=[O:16])[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: NCC(=O)NCc1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NCC(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Yield: 34.2 %

Procedure:
Using the procedure described in example 3, a solution of 1-(2-adamantan-1-yl-2-oxoethyl) L-proline (104.6 mg, 0.36 mmol, 1.0 eq), triethylamine (150 uL, 1.07 mmol, 3.0 eq), and THF (1.5 mL), was treated with isobutyl chloroformate (51 uL, 0.39 mL, 1.1 eq), then with glycine N-benzylamide (88.2 mg, 537 umol, 1.5 eq). Workup as before provided 53.9 mg (34%) of glycine, N-[1-(2-adamantan-1-yl-2-oxoethyl)-L-prolyl] benzylamide. as a white foam.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[N:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[C:39]([C:42]([O:44][CH3:45])=[O:43])[S:40][CH:41]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][O:16][C:12]1[C:11]2[C:7]([C:37]3[CH:38]=[C:39]([C:42]([O:44][CH3:45])=[O:43])[S:40][CH:41]=3)=[N:8][N:9]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[C:10]=2[CH:15]=[CH:14][N:13]=1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cs1
Reactant: COc1ccc(Cn2nc(OS(=O)(=O)C(F)(F)F)c3c(OC)nccc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cc(-c2nn(Cc3ccc(OC)cc3)c3ccnc(OC)c23)cs1
Temperature: 100 °C
Reaction time: 8 h
Yield: 50.6 %

Procedure:
To a solution of 4-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (157 mg) obtained in Step C of Example 94 in DME (4 mL) were added methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (121 mg) and 2M aqueous sodium carbonate solution (0.940 mL), and then tetrakis(triphenylphosphine)palladium(0) (42.8 mg) was added thereto under nitrogen atmosphere. The reaction mixture was stirred overnight under nitrogen atmosphere at 100° C. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (77.9 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](P2(=O)CCCC2)[CH:5]=[CH:6][CH:7]=1.[PH3]=O.[N+:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1)([O-:18])=[O:17].N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1([SiH3])C=CC=CC=1.C(O)C1C=CC=CC=1>>[N+:16]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([O:25][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:24])=[CH:26][CH:27]=1)([O-:18])=[O:17]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: Cc1cccc(P2(=O)CCCC2)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: O=[PH3]
Agent: [SiH3]c1ccccc1
Solvent: OCc1ccccc1
Product: O=C(OCc1ccccc1)c1ccc([N+](=O)[O-])cc1
Temperature: 80 °C
Yield: 792.7 %

Procedure:
The reaction is illustrated in FIG. 9. In air, a 1-dram vial equipped with a stir-bar was charged with phosphine oxide 1 (9.7 mg, 10 mol %), 4-nitrobenzoic acid (51.7 μL, 0.5 mmol), and diisopropyl azodicarboxylate (DIAD, 147.5 μL, 0.75 mmol). The vial was then sealed with a septum, and purged with argon. Distilled Toluene (1.5 mL) was added. Reaction was allowed to stir. Phenylsilane (67.8 μL, 0.55 mmol), and benzyl alcohol (51.7 μL, 0.5 mmol) was added. The septum was replaced with a PTFE-lined screw cap under an inert atmosphere, and the reaction was heated at 80° C. for 24 hours. The crude reaction mixture was filtered through a plug of celite, concentrated in vacuo, and purified via flash chromatography yielding the title compound 63%, 81.0 mg. To the best of our knowledge this is the first example of a Mitsunobu reaction catalytic in phosphine.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[C:13]([Si:17](Cl)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:16])([CH3:15])[CH3:14]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Si:17]([O:5][CH2:4][CH2:3][NH:2][CH3:1])([C:13]([CH3:16])([CH3:15])[CH3:14])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CNCCO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 40 °C
Reaction time: 8 h
Yield: 52.8 %

Procedure:
To a solution of 2-(methylamino)ethanol (2.14 mL, 26.6 mmol) in DCM (60 mL) was added triethylamine (4.1 mL, 29.3 mmol),N,N-dimethylpyridin-4-amine (1.63 g, 13.3 mmol) and tert-butylchlorodiphenylsilane (7.6 mL, 29.3 mmol). The reaction was stirred overnight at 40° C. After cooling to RT, the reaction was quenched with water (20 mL) and ether (100 mL). The organic phase was washed with water, brine, dried over magnesium sulfate and concentrated to afford the crude product which was purified by flash chromatography on silica gel eluting with 0 to 10% MeOH in DCM. The solvent was evaporated to dryness to afford 2-(tert-butyldiphenylsilyloxy)-N-methylethanamine (4.4 g, 53%) as a colorless oil. NMR Spectrum (DMSOd6): 0.99 (s, 9H), 2.27 (s, 3H), 2.63 (t, 2H), 3.68 (t, 2H), 7.40-7.49 (m, 6H), 7.60-7.65 (m, 4H).
Reaction SMILES: CSC.S([O:9][CH3:10])(OC)(=O)=O.[C:11]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19](=O)[C:20]([CH3:24])([CH3:23])[CH:21]=[CH2:22])=[CH:13][CH:12]=1.C[O-].[Na+]>C(#N)C>[C:11]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:12]=[CH:13][C:14]([O:17][CH2:18][C:19]2([C:20]([CH3:24])([CH3:23])[CH:21]=[CH2:22])[CH2:10][O:9]2)=[CH:15][CH:16]=1
Reactant: COS(=O)(=O)OC
Reactant: C=CC(C)(C)C(=O)COc1ccc(-c2ccccc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CSC
Solvent: CC#N
Product: C=CC(C)(C)C1(COc2ccc(-c3ccccc3)cc2)CO1
Reaction time: 96 h
Yield: 80.4 %

Procedure:
A solution of 41.9 ml (0.567 mol) of dimethyl sulphide in 50 ml of acetonitrile was added dropwise to a solution of 49.4 ml (0.518 mol) of dimethyl sulphate in 250 ml of acetonitrile at 25° C., in the course of 2 hours, with external cooling. After the mixture had stood for 4 days at room temperature, 87.4 g (0.31 mol) of 5-(biphenyl-4-yloxy)-3,3-dimethylpent-1-en-4-one, dissolved in 90 ml of acetonitrile, were stirred in in the course of 1 hour. Thereafter, 31.6 g (0.58 mol) of sodium methylate were introduced at 25° C. After the mixture had been stirred for twelve hours at room temperature, the precipitated salt was filtered off, and the filtrate was concentrated. The oily residue was taken up in 500 ml of ethyl acetate, and the solution was washed with twice 500 ml of water and dried over anhydrous sodium sulphate. After the solution had been concentrated in vacuo, 73.4 g (80.4% of theory) of 2-(biphenyl-4-yloxymethyl)-2-(3,3-dimethylprop-1-en-3-yl)-oxirane were obtained as a colorless waxy mass. ##STR23##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[H-].[Na+].Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[CH:16]=[N:15][N:14]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH2:8][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[CH:16]=[N:15][N:14]=1
Reactant: COc1ccc2c(Cl)nncc2c1
Reactant: Cc1c(Cl)cncc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nncc2c1
Reaction time: 20 h
Yield: 79.4 %

Procedure:
A solution of 3,5-dichloro-4-methyl-pyridine (11.32 g, 70 mmoles) in dry DMF (100 ml) was stirred under N2 at room temperature, then added with 60% NaH in oil (2.8 g, 70 mmoles). After 1 hour at room temperature a solution of 1-chloro-6-methoxy-phthalazine (6.8 g, 35 mmoles), prepared as described in example 4, in DMF (250 ml) was added. The mixture was left at room temperature for 20 hours, then poured into water/ice (pH≅8) and extracted more times with CH2Cl2. The organic phases were washed with water, anhydrified and brought to dryness to give a solid which was triturated in isopropyl ether (100 ml) and filtered. The mother liquors were dried and the residue flash chromatographed with ethyl acetate to give 8.9 g of the title compound (yield: 79.5%). m.p.: 173-175° C. 1H-NMR (CDCl3) δ: 9.32(s,1H); 8.50(s,2H); 8.11(d,1H,J=9.0 Hz); 7.56(dd,1H); 7.20(d,1H,J=2.6 Hz); 4.90(s,2H); 4.00(s,3H).
Reaction SMILES: [CH:1]1[C:5]2=[CH:6][C:7]3[CH:14]=[CH:13][C:11](=[O:12])[O:10][C:8]=3[CH:9]=[C:4]2[O:3][CH:2]=1.C1CCCCC=1>C(O)C.[Pd]>[CH2:1]1[C:5]2[CH:6]=[C:7]3[C:8](=[CH:9][C:4]=2[O:3][CH2:2]1)[O:10][C:11](=[O:12])[CH:13]=[CH:14]3
Reactant: O=c1ccc2cc3ccoc3cc2o1
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: O=c1ccc2cc3c(cc2o1)OCC3
Yield: 72.3 %

Procedure:
A solution was prepared of 1.86 g (0.010 moles) of psoralen (7H-furo[3,2-g][1]benzopyran-7-one) in 200 ml of 95% ethanol, heated to reflux and treated by the addition of 5.0 ml of cyclohexene and a slurry of 5.0 g of 10% palladium on carbon in 30 ml of 95% ethanol. After 30 minutes of reflux with magnetic stirring the medium was filtered, evaporated in vacuo and the residue was recrystallized from 95% ethanol to give 1.36 g (72% yield) of tiny white needles, mp 198°-200° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[N:10]([CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:9]2[CH:17]=[CH:18][C:19]([C:21](O)=O)=[CH:20][C:8]=2[N:7]=1)(=[O:3])[CH3:2].C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[SH:42]>O1CCCC1>[C:1]([O:4][CH2:5][C:6]1[N:10]([CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:9]2[CH:17]=[CH:18][C:19]([C:21]3[S:42][C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=4[N:35]=3)=[CH:20][C:8]=2[N:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1nc2cc(C(=O)O)ccc2n1C1CCOCC1
Reactant: Nc1ccccc1S
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(=O)OCc1nc2cc(-c3nc4ccccc4s3)ccc2n1C1CCOCC1
Temperature: 50 °C
Reaction time: 5 h
Yield: 117.5 %

Procedure:
A 4-neck flask (500 mL) equipped with a reflux condenser was charged with 2-acetoxymethyl-1-(tetrahydropyran-4-yl)benzimidazole-5-carboxylic acid (5.98 g, 18.79 mmol), anhydrous tetrahydrofuran (158 mL), and oxalyl chloride (2.86 g, 22.50 mmol), and anhydrous N,N-dimethylformamide (1 mL) was then added dropwise at room temperature, after which the reaction mixture was stirred at 50° C. for 5 hours. After being allowed to cool to room temperature, the solvent was distilled off under reduced pressure to give a pale yellow residue, which was taken up in anhydrous tetrahydrofuran (100 mL), and then 2-aminobenzenethiol (2.35 g, 18.79 mmol) was added, and this was stirred for 19 hours at 50° C. This was allowed to cool to room temperature, and after the precipitated crystals were filtered off, they were successively washed with distilled water and dried under reduced pressure with heating to yield the title compound (9.00 g, quant.) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[C:6]=2[CH:21]=1.[Br:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([C:14]4[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=4)([CH3:13])[C:6]=3[CH:21]=2)=[CH:25][CH:24]=1
Reactant: CN1C(=O)OC(C)(c2ccc(Cl)cc2)c2cc(N)ccc21
Reactant: OB(O)c1ccc(Br)cc1
Product: CN1C(=O)OC(C)(c2ccc(Cl)cc2)c2cc(Nc3ccc(Br)cc3)ccc21

Procedure:
Prepared from 6-amino-4-(4-chlorophenyl)-1,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one and 4-bromophenyl boronic acid according to the coupling procedure described in example 1. MS (ESI) m/z [M+H]+ (457/459/461); MS (ESI) m/z [M−H]−(455/457/459); Anal. calcd for C22H18BrClN2O2: C, 57.73; H,3.96; N6.12. Found: C, 56.88; H, 3.90; N, 5.70.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11](O)[C:12]2[C:13]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)=[C:14]3[C:22](=[CH:23][C:24]=2[CH:25]([CH3:27])[CH3:26])[O:21][C:17]2([CH2:20][CH2:19][CH2:18]2)[CH2:16][C:15]3=[O:28])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(S(F)(F)[F:43])CC)C.O>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([F:43])[C:12]2[C:13]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)=[C:14]3[C:22](=[CH:23][C:24]=2[CH:25]([CH3:26])[CH3:27])[O:21][C:17]2([CH2:18][CH2:19][CH2:20]2)[CH2:16][C:15]3=[O:28])=[CH:7][CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(O)c1ccc(C(C)(C)C)cc1)C(=O)CC1(CCC1)O2
Reactant: CCN(CC)S(F)(F)F
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(F)c1ccc(C(C)(C)C)cc1)C(=O)CC1(CCC1)O2
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Under argon, 110 mg (0.23 mmol) of 6-[(4-tert-butylphenyl)(hydroxy)methyl]-5-(4-fluorophenyl)-7-isopropylspiro[chromen-2,1′-cyclobutan]-4(3H)-one (Example 55A) are dissolved in 2.3 ml of toluene, 36 μl (0.27 mmol) of diethylaminosulfur trifluoride are added slowly at −78° C. and the mixture is stirred at −78° C. for 1 h. The temperature is then slowly increased to −60° C. After 2 h, water is added and the mixture is extracted twice with ethyl acetate. The combined organic phases are washed once with saturated sodium bicarbonate solution and once with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The crude product is purified on a silica gel column (mobile phase: cyclohexane/ethyl acetate 12:1). This gives 92 mg (83% of theory) of the title compound.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:28])[C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[N:26][CH:25]=[N:24]3)=[CH:19][CH:18]=2)[CH2:12][CH2:11]1.[BH4-].[Na+]>CO>[CH2:1]([NH:9][CH:10]1[CH2:11][CH2:12][N:13]([C:16](=[O:28])[C:17]2[CH:18]=[CH:19][C:20]([N:23]3[CH:27]=[N:26][CH:25]=[N:24]3)=[CH:21][CH:22]=2)[CH2:14][CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: NC1CCN(C(=O)c2ccc(-n3cncn3)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C(c1ccc(-n2cncn2)cc1)N1CCC(NCc2ccccc2)CC1
Reaction time: 1 h

Procedure:
11.1 ml of benzaldehyde and 10 g of Molecular Sieve 3A were added to 50 ml of a solution of 2.97 g of 4-amino-1-[4-(1,2,4-triazol-1-yl)benzoyl]piperidine in methanol. The mixture was refluxed by heating, for 150 minutes. Thereto was added 4.97 g of sodium borohydride in small portions, under ice-cooling. The mixture was stirred for 1 hour under ice-cooling. The Molecular Sieve 3A was removed by filtration and the filtrate was subjected to distillation to remove the solvent. To the residue was added water. The mixture was made acidic with hydrochloric acid and then washed with ethyl acetate. The aqueous layer was made alkaline with an aqueous sodium hydroxide solution, under ice-cooling, followed by extraction with methylene chloride. The extract was washed with water, dried with anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluant: methylene chloride/methanol=50/1), followed by recrystallization from methylene chloride-ethyl acetate to obtain 2.92 g of 4-benzylamino-1-[4-(1,2,4-triazol-1-yl)benzoyl]piperidine as a white powder.
Reaction SMILES: [Br:1][C:2]1[C:3]([Br:15])=[C:4]([Br:14])[C:5]([Br:13])=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]=12.[CH2:16]([CH2:18][NH2:19])[OH:17].O>C1(C)C(C)=CC=CC=1>[OH:17][CH2:16][CH2:18][N:19]1[C:8](=[O:10])[C:7]2=[C:2]([Br:1])[C:3]([Br:15])=[C:4]([Br:14])[C:5]([Br:13])=[C:6]2[C:11]1=[O:12]
Reactant: O=C1OC(=O)c2c(Br)c(Br)c(Br)c(Br)c21
Reactant: NCCO
Solvent: O
Solvent: Cc1ccccc1C
Product: O=C1c2c(Br)c(Br)c(Br)c(Br)c2C(=O)N1CCO

Procedure:
To a suspension of 464 gm (1 mole) of tetrabromophthalic anhydride in 1.2 liters of xylene was added 61 gm (1 mole) of ethanolamine. The solution was heated and refluxed with a Dean-Stark water separator until the theoretical amount of water separated. The mixture was cooled, diluted with hexane, and filtered. The resulting 413 gm of an off-white solid was washed with hexane and dried at 100° C. This material is used as is for subsequent reactions without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][S:9][C:10]=1[NH:11][CH:12]1[CH2:14][CH2:13]1)=[O:5])C.[Li+:15].[OH-]>C1COCC1.CO>[CH:12]1([NH:11][C:10]2[S:9][CH:8]=[N:7][C:6]=2[C:4]([O-:5])=[O:3])[CH2:13][CH2:14]1.[Li+:15]
Reactant: CCOC(=O)c1ncsc1NC1CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C([O-])c1ncsc1NC1CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
198 mg of 5-cyclopropylamino-thiazole-4-carboxylic acid ethyl ester (0.93 mmol) were dissolved in a 3:1 mixture of THF/methanol (2 ml) and 1.4 ml of a 1N LiOH-solution were added. The reaction mixture was stirred at RT for 3 days, then concentrated in vacuo and the remaining residue was dried. This gave 191 mg of a yellow solid containing the crude title compound (contaminated with excess of lithium hydroxide) that was used in the following step without further purification. MS (ISP) 182.9 (M−H)−.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.Cl.[CH3:11][O:12][NH2:13].C(N(CC)CC)C>CO>[CH3:11][O:12][N:13]=[CH:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([I:1])[CH:3]=1
Reactant: CON
Reactant: O=Cc1cccc(I)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CON=Cc1cccc(I)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 3-iodo benzaldehyde (1 g, 4.3 mmol) in methanol (25 ml), O-methyl hydroxyl amine hydrochloride (0.54 g, 6.5 mmol) was added followed by triethyl amine (0.9 ml, 6.5 mmol). The reaction mixture was stirred at ambient temperature for 4 hours. Reaction mixture was concentrated under vacuum; residual mass was diluted with water (50 ml) and extracted with ethyl acetate (3×30 ml). Ethyl acetate layer was washed with water (2×30 ml) followed by brine solution, dried over anhydrous sodium sulfate and evaporated to obtain 3-Iodo-benzaldehyde O-methyl-oxime (crude), which was dissolved in glacial acetic acid (10 ml), followed by addition of sodium cyanoborohydride (0.54 g, 8.6 mmol) portion wise at 15° C. The mixture was stirred for 12 hrs at room temperature. Excess acetic acid was removed by distillation. Resulting reaction mass was basified with 10% aq. NaOH solution at 10-15° C. Aqueous layer was extracted with EtOAc (3×30 ml). The combined organic layer was washed with brine (2×30 ml) and dried over sodium sulfate. Organic layer was concentrated under vacuum to give crude mass, which was purified by chromatography to afford 1 g (89% of theory) of N-(3-Iodo-benzyl)-O-methyl-hydroxylamine