Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].[C:4]([O:8][C:9]([N:11]([CH2:45][C@H:46]([OH:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([NH:28][S:29]([CH2:32][CH2:33][C:34]([O:36]C)=O)(=[O:31])=[O:30])=[O:27])=[C:22]([O:38][CH:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)[CH:21]=2)=[CH:16][CH:15]=1)=[O:10])([CH3:7])([CH3:6])[CH3:5].C([NH2:56])=O>>[NH2:56][C:34](=[O:36])[CH2:33][CH2:32][S:29]([NH:28][C:26]([C:23]1[CH:24]=[CH:25][C:20]([C:17]2[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][N:11]([CH2:45][C@H:46]([OH:53])[C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)[C:9](=[O:10])[O:8][C:4]([CH3:5])([CH3:6])[CH3:7])=[CH:15][CH:16]=2)=[CH:21][C:22]=1[O:38][CH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1)=[O:27])(=[O:30])=[O:31]
Reactant: NC=O
Reactant: COC(=O)CCS(=O)(=O)NC(=O)c1ccc(-c2ccc(CCN(C[C@H](O)c3ccccc3)C(=O)OC(C)(C)C)cc2)cc1OC1CCCCC1
Agent: C[O-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N(CCc1ccc(-c2ccc(C(=O)NS(=O)(=O)CCC(N)=O)c(OC3CCCCC3)c2)cc1)C[C@H](O)c1ccccc1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
Sodium methoxide (38.1 mg) was added to a solution of methyl 3-[[[[4′-[2-[(tert-butoxycarbonyl)[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-3-(cyclohexyloxy)-4-biphenylyl]carbonyl]amino]sulfonyl]propanoate (125 mg) in formamide (2.0 ml) at room temperature. The mixture was stirred for 1.5 hours at 60° C. The product was extracted with ethyl acetate. The combined extracts were washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography to give tert-butyl [2-[4′-[[[(3-amino-3-oxopropyl)sulfonyl]amino]carbonyl]-3′-(cyclohexyloxy)-4-biphenylyl]ethyl][(2R)-2-hydroxy-2-phenylethyl]carbamate (22.0 mg).
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][CH2:8][NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[C:15]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([C:24]#[N:25])[CH:14]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=3)[NH:13]2)=[O:11])[CH2:4][O:3]1.Cl>O1CCCC1>[OH:6][C@H:5]([CH2:4][OH:3])[CH2:7][CH2:8][NH:9][C:10]([CH:12]1[CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[C:15]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)([C:24]#[N:25])[CH:14]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=2)[NH:13]1)=[O:11]
Reactant: CC1(C)OC[C@H](CCNC(=O)C2NC(c3cccc(Cl)c3)C(C#N)(c3ccc(Cl)cc3)C2c2cccc(Cl)c2)O1
Agent: Cl
Solvent: C1CCOC1
Product: N#CC1(c2ccc(Cl)cc2)C(c2cccc(Cl)c2)NC(C(=O)NCC[C@H](O)CO)C1c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
To a solution of rac-(2R,3R,4R,5S)-3,5-bis-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethyl]-amide prepared in Example 42c (0.4 g, 0.66 mol) in tetrahydrofuran (10 mL) was added aqueous HCl solution (1N, 10 mL). The reaction mixture was stirred at room temperature for 2 h, then concentrated. Then the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, aqueous saturated NaHCO3, brine, dried over MgSO4, concentrated, dried under reduced pressure to give rac-(2R,3R,4R,5S)-3,5-bis-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.2 g, 89%).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[NH:18][C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([C:26]#[N:27])=[CH:21][CH:20]=3)[CH:12]=1>>[O:4]([CH2:3][CH2:2][N:18]1[C:19]2[C:24](=[CH:23][C:22]([C:26]#[N:27])=[CH:21][CH:20]=2)[CH:25]=[C:17]1[C:13]1[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: N#Cc1ccc2[nH]c(-c3cccnc3)cc2c1
Reactant: BrCCOc1ccccc1
Product: N#Cc1ccc2c(c1)cc(-c1cccnc1)n2CCOc1ccccc1

Procedure:
(2-Bromo-ethoxy)-benzene and 2-pyridin-3-yl-1H-indole-5-carbonitrile (Example 8) are processed according to the method described in Example 57 to give 1-(2-phenoxy-ethyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile. 1H NMR (400 MHz, MeOD) δ ppm 4.19 (t, J=5.2 Hz, 2H), 4.67 (t, J=5.1 Hz, 2H), 6.63 (d, J=7.8 Hz, 2H), 6.77 (s, 1H), 6.84 (t, J=7.5 Hz, 1H), 7.10-7.17 (m, 2H), 7.53 (dd, J=8.6, 1.8 Hz, 1H), 7.55-7.60 (m, 1H), 7.77 (d, J=8.6 Hz, 1H), 8.05 (s, 1H), 8.08-8.13 (m, 1H), 8.63 (dd, J=4.9, 1.6 Hz, 1H), 8.79 (d, J=1.5 Hz, 1H). HRMS (ESI) m/z 340.1453 [(M+H)+ Calcd for C22H18N3O: 340.1450].
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]([CH3:20])[C:12](=[O:21])[NH:11][N:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([N:11]2[N:10]=[C:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]([CH3:20])[C:12]2=[O:21])=[O:28])=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CN1C(=O)NN=C(c2ccccc2)c2ccccc21
Agent: [H-]
Agent: [Na+]
Product: CN1C(=O)N(C(=O)c2ccc(F)cc2)N=C(c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 9 h

Procedure:
To a suspension of NaH (70 mg of NaH was washed with hexane several times dispersed in 50% mineral oil) in 4ml of DNF is added a solution of 1,3-dihydro-5-phenyl-1-methyl-2H-1,3,4-benzotriazepine-2-one (251 mg) in 5 ml DMP under nitrogen atmosphere. After gas evolution ceased, 0.13 ml 4-fluorobenzoyl chloride is added and the mixture is stirred at room temperature overnight (about 12-6 hours). Solvent is removed in vacuo to a dryness and the residue is partitioned between ethylacetate and water. Organic layer is washed with aq.NaHCO3, water, then dried over MgSO4. After evaporation of solvent, the residue is recrystallized using methanol as a solvent. About 97mg of a product is obtained. TLC: (Silica gel - Chloroform/acetone=9:1, Rf.=0.52).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:28])[CH2:10][N:11]1[C:20](=[O:21])[C:19]2[N:18]([CH2:22][C:23]#[C:24][CH3:25])[C:17]([Br:26])=[N:16][C:15]=2[N:14]([CH3:27])[C:12]1=[O:13].B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:28])[CH2:10][N:11]1[C:20](=[O:21])[C:19]2[N:18]([CH2:22][C:23]#[C:24][CH3:25])[C:17]([Br:26])=[N:16][C:15]=2[N:14]([CH3:27])[C:12]1=[O:13]
Reactant: CC#CCn1c(Br)nc2c1c(=O)n(CC(=O)c1ccccc1OC)c(=O)n2C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC#CCn1c(Br)nc2c1c(=O)n(CC(=O)c1ccccc1O)c(=O)n2C

Procedure:
Prepared by treating 1-[2-(2-methoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine with boron tribromide in the presence of 4 Å molecular sieve in methylene chloride at 4° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:10]2[N:9]=[CH:8][N:7]=[C:6]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:5]=2[C:4]=1[NH2:22].[OH-].[Na+].[CH:25](O)=O>C(Cl)(Cl)Cl>[CH3:14][O:13][C:12]1[CH:11]=[C:10]2[C:5]3[C:6]([N:15]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:25]=[N:22][C:4]=3[C:3]=1[O:2][CH3:1])=[N:7][CH:8]=[N:9]2
Reactant: COc1cc2ncnc(Nc3ccccc3)c2c(N)c1OC
Reactant: O=CO
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: COc1cc2ncnc3c2c(c1OC)N=CN3c1ccccc1

Procedure:
A solution of 6,7-dimethoxy-N4-phenyl-quinazoline-4,5-diamine (80 mg, 0.27 mmol) (from Example 1, Step C, supra) in formic acid (5 mL) was heated at 110° C. for 2 hours. Aqueous NaOH solution was then added to the reaction mixture to a pH 10–12. The solution was diluted with chloroform (50 mL). The organic layer was separated, dried over Na2SO4, and concentrated. This residue was purified by chromatography using EtOAc/Et3N (1:0.04) as eluent to give the desired 8,9-dimethoxy-3-phenyl-3H-1,3,4,6-tetraaza-phenalene as a white solid. (Yield 45 mg, 54%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([NH:13][CH2:14][CH2:15][OH:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>ClCCl>[CH2:6]([N:13]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:14][CH2:15][O:16][S:2]([CH3:1])(=[O:4])=[O:3])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OCCNCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCN(Cc1ccccc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 59 %

Procedure:
Methanesulfonyl chloride (18.9 g, 0.1655 mol) was added dropwise at 0° C. to a solution of N-benzyl ethanolamine (10 g, 0.0662 mol, from step (i) above) and triethylamine (27.6 ml, 0.1987 mol) in dichloromethane (100 ml). The reaction mixture was stirred at RT for 3 h under nitrogen atmosphere and partitioned between water and dichloromethane. The organic layer was separated, washed with water and brine and dried over sodium sulfate. Thes solvent was evaporated under reduced pressure and the residue was purified by column chromatography over silica gel using 3% methanol in dichloromethane, as eluent to give the sub-title compound (12 g) as a solid.
Reaction SMILES: [CH2:1]([C:3]1([CH2:9][OH:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)[OH:2].[CH3:11][O:12][CH2:13][CH:14]=O.C1CCCCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH3:11][O:12][CH2:13][CH:14]1[O:10][CH2:9][C:3]2([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[CH2:1][O:2]1
Reactant: COCC=O
Reactant: OCC1(CO)CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCCCC1
Solvent: O
Product: COCC1OCC2(CCCCC2)CO1
Yield: 97 %

Procedure:
A mixture of 288 g (2 moles) of 1,1-dimethylolcyclohexane, 191 g (2.2 moles) of 85% strength methoxyacetaldehyde and 250 ml of cyclohexane was heated with 2 g of p-toluenesulfonic acid under a water separator until water no longer separated off. The resulting solution was washed with dilute sodium hydroxide solution, the solvent was stripped off under reduced pressure and the residue was subjected to fractional distillation under reduced pressure. 388 g (97% yield) of 3-methoxymethyl-2,4-dioxaspiro[5.5]undecane of boiling point 95° C./1 mbar were obtained.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[CH:11][C:12]([N+:29]([O-])=O)=[C:13]([CH:28]=1)[CH2:14][NH:15][CH2:16][CH2:17][C:18]([N:20]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[CH3:21])=[O:19])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S1C=CC=C1.[H][H]>[Pd].CO>[NH2:29][C:12]1[CH:11]=[CH:10][C:9]([C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:28][C:13]=1[CH2:14][NH:15][CH2:16][CH2:17][C:18]([N:20]([CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1)[CH3:21])=[O:19]
Reactant: [H][H]
Reactant: CN(C(=O)CCNCc1cc(C(=O)c2ccccc2)ccc1[N+](=O)[O-])C1CCCCC1
Agent: [Pd]
Solvent: c1ccsc1
Solvent: CO
Product: CN(C(=O)CCNCc1cc(C(=O)c2ccccc2)ccc1N)C1CCCCC1

Procedure:
A mixture of 3-(5-benzoyl-2-nitro-benzylamino)-N-cyclohexyl-N-methyl-propionamide (9 g, 0.02 mol), 10% palladium on carbon (2 g), and thiophene solution (2 mL) in MeOH (250 mL) was hydrogenated until 3 equivalents of hydrogen were consumed. The reaction mixture was filtered through Dicalite, and the filtrate was concentrated to yield a residue.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=1)[C:3]#[N:4].[C:12]([CH2:15][C:16](=O)[CH3:17])(=[O:14])[CH3:13]>C(O)C>[C:12]([C:15]1[C:3]([NH2:4])=[C:2]([C:5]2[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=2)[NH:1][C:16]=1[CH3:17])(=[O:14])[CH3:13]
Reactant: CC(=O)CC(C)=O
Reactant: Cc1cccc(C(N)C#N)c1
Solvent: CCO
Product: CC(=O)c1c(C)[nH]c(-c2cccc(C)c2)c1N

Procedure:
Starting from 2-amino-2-(m-tolyl)acetonitrile and acetylacetone, the open-chain intermediate compound is obtained, b.p. 170° C./0.02 mm Hg. The title compound is obtained in a 59% overall yield, m.p. 195°-7° C. (from ethanol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=O.Cl.[NH2:15][OH:16].C([O-])(=O)C.[Na+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[N:15][OH:16]
Reactant: NO
Reactant: COc1cccc2c1CCCC2=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1cccc2c1CCCC2=NO
Temperature: 25 °C
Yield: 97.7 %

Procedure:
In a mixture of 240 ml of ethanol and 80 ml of water were dispersed 50 g of 5-methoxytetralone, 20 g of hydroxylamine hydrochloride, and 56 g of sodium acetate, and the dispersion was heat-refluxed for 4 hours. After cooling to room temperature, the reaction mixture was poured into 400 ml of water. The precipitated crystals were collected by filtration and dried to obtain 53 g of 5-methoxytetralone oxime.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:7][C:8](OC)=O)[C:3](OC)=O.[NH2:12][CH2:13][CH2:14][OH:15]>>[CH3:1][C@H:2]1[CH2:7][CH2:8][N:12]([CH2:13][CH2:14][OH:15])[CH2:3]1
Reactant: NCCO
Reactant: COC(=O)C[C@H](C)C(=O)OC
Product: C[C@H]1CCN(CCO)C1

Procedure:
The title compound was synthesized as described in Intermediate 11 using (S)-dimethyl 2-methylsuccinate and 2-aminoethanol as starting materials. 1H NMR (CDCl3): δ 3.66 (t, 1H), 2.93 (dd, 1H), 2.81 (m, 1H), 2.73 (m, 1H), 2.66 (m, 1H), 2.63 (m, 1H), 2.29 (m, 1H), 2.18 (dd, 2H), 2.05 (m, 1H), 1.40 (m, 1H), 1.04 (d, 3H); MS: 130.2 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]1([C:13]2[S:14][CH:15]=[C:16]([C:18](OCC)=[O:19])[N:17]=2)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1>C1(C)C=CC=CC=1.C1COCC1>[N:7]1([C:13]2[S:14][CH:15]=[C:16]([CH2:18][OH:19])[N:17]=2)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1
Reactant: CCOC(=O)c1csc(N2CCOCC2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OCc1csc(N2CCOCC2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 61.1 %

Procedure:
A solution of 7.0 ml (7.0 mmol) of lithium aluminum hydride in toluene was diluted with 10 ml of THF, cooled to 0° C., and treated with a solution of 1.7 g (7.0 mmol) of ethyl 2-(4-morpholinyl)thiazole-4-carboxylate in 25 ml of THF. The resulting solution was stirred for 1 h, quenched cautiously with aqueous Rochelle's salts, diluted with chloroform, filtered, dried over Na2SO4, and concentrated in vacuo. Silica gel chromatography using 2-4% methanol in chloroform provided 856 mg (61%) of the desired compound, Rf 0.16 (4% methanol in chloroform). 1H NMR (CDCl3) δ2.44 (br, 1H), 3.46 (t, J=5 Hz, 4H), 3.81 (t, J=5 Hz, 1H), 4.55 (br s, 2H), 6.45 (s, 1H). Mass spectrum: (M+H)+ =200.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([CH:30]=C)[CH:28]=2)[C:5]2=[N:6][O:7][C:8]([C:9]3[O:13][N:12]=[C:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:10]=3[C:20]([F:23])([F:22])[F:21])=[C:4]2[CH2:3]1.C[N+]1([O-])CC[O:37]CC1.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[CH3:32][C:2]1([CH3:1])[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([CH:30]=[O:37])[CH:28]=2)[C:5]2=[N:6][O:7][C:8]([C:9]3[O:13][N:12]=[C:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:10]=3[C:20]([F:21])([F:23])[F:22])=[C:4]2[CH2:3]1
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=Cc1ccc2c(c1)C(C)(C)Cc1c-2noc1-c1onc(-c2ccccc2)c1C(F)(F)F
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)Cc2c(noc2-c2onc(-c3ccccc3)c2C(F)(F)F)-c2ccc(C=O)cc21
Temperature: 25 °C
Reaction time: 7 h
Yield: 94 %

Procedure:
To a mixture of 5,5-dimethyl-3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (Preparation 1E, 0.036 g, 0.082 mmol) and NMO in water (0.017 mL, 0.082 mmol) in THF (1.5 mL) at room temperature was added osmium tetroxide in water (0.013 mL, 1.65 μmol). The reaction mixture was stirred at room temperature for 7 hours. A solution of sodium periodate (0.026 g, 0.124 mmol) in water (1 mL) was added via syringe. The resulting cloudy reaction mixture was stirred overnight at room temperature concentrated under reduced pressure, and the residue was diluted with ethyl acetate (30 mL) and washed with water (15 mL). The organic layer was washed with brine and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded 5,5-dimethyl-3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde (0.034 g, 0.078 mmol, 94% yield) as a tan solid. The product had an HPLC ret. time=3.51 min. (condition A); LC/MS M+1=439.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[CH3:20])[CH2:9][C:10](O)=[O:11])=[CH:4][CH:3]=1.Cl.[CH3:22][NH:23][O:24][CH3:25]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[CH3:20])[CH2:9][C:10]([N:23]([O:24][CH3:25])[CH3:22])=[O:11])=[CH:4][CH:3]=1
Reactant: CNOC
Reactant: Cc1cc(F)ccc1C(CC(=O)O)c1ccc(Br)cc1
Agent: Cl
Product: CON(C)C(=O)CC(c1ccc(Br)cc1)c1ccc(F)cc1C

Procedure:
In analogy to example 74, step 4, from 3-(4-bromophenyl)-3-(4-fluoro-2-methylphenyl)-propanoic acid and N,O-dimethylhydroxylamine hydrochloride was prepared the title compound as a colorless oil, MS (ESI+): m/z=382.06 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20](O)=[O:21])=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.CN.[CH3:27][N:28](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:27][NH:28][C:20]([C:18]1[CH:17]=[CH:16][C:13]2[N:14]([CH3:15])[C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([F:1])[CH:24]=[CH:23][C:5]=4[N:6]=3)=[N:11][C:12]=2[CH:19]=1)=[O:21]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cn1c(Nc2nc3ccc(F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(F)cc3s1)n2C
Yield: 73.7 %

Procedure:
2-(6-Fluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylic acid methylamide (26 mg) was prepared by following General Procedure F using 2-(6-fluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylic acid (34 mg), methylamine (0.2 ml, 2.0 M solution in THF), HBTU (38 mg), and DIEA (0.1 ml). LCMS: m/z 357. 1H NMR (DMSO-d6, 400 MHz): δ 8.31 (m, 1H), 7.93 (d, 1H), 7.63 (d, 2H), 7.50-7.42 (m, 1H), 7.38-7.28 (m, 1H), 7.12 (t, 2H), 3.60 (s, 3H), and 2.78 (d, 3H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[CH:8]2>CO.[Pt]=O>[OH:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[NH:11][CH2:10][CH2:9][CH2:8]2
Reactant: OCc1cccc2cccnc12
Agent: O=[Pt]
Solvent: CO
Product: OCc1cccc2c1NCCC2
Yield: 97.5 %

Procedure:
8-Hydroxymethylquinoline (1.0 g) was dissolved in methanol (30 ml). Platinum oxide (0.25 g) was added thereto and the mixture was subjected to catalytic reduction at 3.5 kg/cm2, 40° C. After completion of the catalytic reduction, the catalyst was filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was recrystallized from ethyl acetate-n-hexane to give 8-hydroxymethyl-1,2,3,4-tetrahydroquinoline (1.0 g). Yellow needle crystals mp: 67°-68° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[NH:10][C@H:11]([CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]I)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:24][C:25]1[CH:37]=[CH:36][C:28]([O:29][CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:27][CH:26]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([O:8][C:9](=[O:23])[NH:10][C@H:11]([CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][N:33]1[CH2:32][CH2:31][CH:30]([O:29][C:28]2[CH:36]=[CH:37][C:25]([F:24])=[CH:26][CH:27]=2)[CH2:35][CH2:34]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC[C@H](CI)NC(=O)OCc1ccccc1
Reactant: Fc1ccc(OC2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC[C@H](CN1CCC(Oc2ccc(F)cc2)CC1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A solution of [(R)-1-(tert-butoxycarbonylamino-methyl)-2-iodo-ethyl]-carbamic acid benzyl ester (0.61 g, 1.2 mmol) and 4-(4-fluoro-phenoxy)-piperidine (0.24 g, 1.23 mmol) in dichloromethane (5 ml) is treated with triethylamine (0.335 ml, 2.46 mmol). The reaction mixture is stirred at ambient temperature for 5 days, the solvent evaporated and the residue partitioned between ethylacetate and saturated aqueous NaHCO3. The ethylacetate phase is washed with brine, dried over MgSO4 and evaporated. The crude product is purified by flash silica chromatography (elution with 4:1 hexane/ethylacetate) to afford {(R)-1-(tert-butoxycarbonylamino-methyl)-2-[4-(4-fluoro-phenoxy)-piperidin-1-yl]-ethyl}-carbamic acid benzyl ester [MH]+ 502.2.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)[OH:11].CCOC(C)=O>C(Cl)(Cl)Cl.CC(C)=O.[O-2].[O-2].[Mn+4]>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11]
Reactant: OC(c1ccc(Oc2nccnc2C2CCOCC2)cc1)c1nc2ccccc2[nH]1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C(c1ccc(Oc2nccnc2C2CCOCC2)cc1)c1nc2ccccc2[nH]1
Temperature: 50 °C
Reaction time: 0.67 h

Procedure:
A mixture of (1H-benzo[d]imidazol-2-yl)(4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)methanol (0.50 g, 1.24 mmol) in chloroform (7.5 mL) and acetone (4.00 mL) under nitrogen was treated with was treated with manganese dioxide (0.504 g, 6.21 mmol) in one portion. The reaction was heated to 50° C. After 40 minutes, the reaction was filtered through a pad of Celite™. The filtrate was washed (2×) with an aqueous saturated solution of sodium bicarbonate, with water and then brine. The organic layer was then dried with sodium sulfate and purified by column chromatography on silica gel using a gradient of 30 to 80% ethyl acetate in hexanes. The pure fractions were reduced under vacuum and the solid obtained was slurried in 1:1 EtOAc:ether, filtered and dried under vacuum to give (1H-benzo[d]imidazol-2-yl)(4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)methanone as a white solid. MS (ESI, pos. ion) m/z: 400.9 (M+1). IC50 (uM) +++++.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:15]2[C:10]3=[C:11]([C:16]4[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][C:21]=4[N:9]3[C:8]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=3)[CH:12]=[CH:13][CH:14]=2.Br[C:27]1[CH:28]=[CH:29][C:30]2[N:31]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:32]3[C:37]([C:38]=2[CH:39]=1)=[CH:36][CH:35]=[CH:34][CH:33]=3.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.O1CCOCC1>[CH3:1][C:2]1([CH3:25])[C:15]2[C:10]3=[C:11]([C:16]4[CH:17]=[C:18]([C:35]5[CH:34]=[CH:33][C:32]6[N:31]([C:40]7[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=7)[C:30]7[C:38]([C:37]=6[CH:36]=5)=[CH:39][CH:27]=[CH:28][CH:29]=7)[CH:19]=[CH:20][C:21]=4[N:9]3[C:8]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=3)[CH:12]=[CH:13][CH:14]=2
Reactant: CC1(C)c2ccccc2-n2c3ccc(B(O)O)cc3c3cccc1c32
Reactant: Brc1ccc2c(c1)c1ccccc1n2-c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)c2ccccc2-n2c3ccc(-c4ccc5c(c4)c4ccccc4n5-c4ccccc4)cc3c3cccc1c32

Procedure:
36 g (110 mmol) of 8,8-dimethyl-8H-indolo[3,2,1-de]acridine-3-boronic acid, 35 g (110 mmol) of 3-bromo-9-phenyl-9H-carbazole and 9.7 g (92 mmol) of sodium carbonate are suspended in 350 ml of toluene, of dioxane and 500 ml of water. 913 mg (3.0 mmol) of tri-o-tolylphosphine and 112 mg (0.5 mmol) of palladium(II) acetate are added to this suspension, and the reaction mixture is heated under reflux for 16 h. After cooling, the organic phase is separated off, filtered through silica gel, washed three times with 200 ml of water and subsequently evaporated to dryness. The residue is recrystallised from toluene and from CH2Cl2/isopanol and finally sublimed in a high vacuum.