Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([CH3:11])[CH:3]=1.B.C1COCC1>C1COCC1.O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Agent: B
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Br)ccc1CO
Temperature: 0 °C
Reaction time: 3 h
Yield: 89.3 %

Procedure:
4-Bromo-2-methyl-benzoic acid (9.88 g, 45.9 mmol) was dissolved in THF (100 ml), and the solution was cooled to 0° C. To this solution, a solution of 1M BH3.THF (91.89 ml, 91.89 mmol) was added at 0° C., and the solution was vigorously stirred for 3 hours at room temperature. The reaction mixture was diluted with cold water (20 mL), washed with a saturated solution of NaHCO3, then extracted with ether 3 times (300 mL). The combined organic ether was washed with brine (250 mL), dried over MgSO4, and concentrated in Vacuo. The residue was purified via flash column chromatography (25% to 55% EtOAc in Hexane) to give white solid (8.24 g, 90% yield). 1H NMR (400 MHz, CDCl3) δ: 2.32 (2H, s) 4.64 (1H, d, J=5.81 Hz) 7.20-7.26 (2H, m) 7.30-7.36 (1H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=1)[NH:8][CH2:7][CH2:6]2.[C:28]1(=O)[CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH:28]1([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]2[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: COc1ccc2c(c1)CCNC2Cc1ccc(OCc2ccccc2)cc1
Reactant: O=C1CCCC1
Product: COc1ccc2c(c1)CCN(C1CCCC1)C2Cc1ccc(OCc2ccccc2)cc1
Yield: 83.3 %

Procedure:
The title compound was prepared as described in Example 14. C, using 6-methoxy-1-[4-(phenylmethoxy)benzyl]-1,2,3,4-tetrahydroisoquinoline (0.5 g, 1.39 mmol) and cyclopentanone (0.951 g, 11.3 mmol) to provide the title compound (0.495 g, 83% yield): ES-MS (m/z) 428 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]2[S:14][CH2:13][C:12]3([CH2:18][CH2:17][CH2:16][CH2:15]3)[NH:11]2)=[C:5]([CH2:19][CH3:20])[CH:4]=1)#[N:2].Br[CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]2[S:14][CH2:13][C:12]3([CH2:15][CH2:16][CH2:17][CH2:18]3)[N:11]2[CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[C:5]([CH2:19][CH3:20])[CH:4]=1)#[N:2]
Reactant: CCc1cc(C#N)ccc1N=C1NC2(CCCC2)CS1
Reactant: CCC(Br)CC
Product: CCc1cc(C#N)ccc1N=C1SCC2(CCCC2)N1C(CC)CC

Procedure:
1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 4-cyano-2-ethylphenyl isothiocyanate according to Method C1e to give 2-(4-cyano-2-ethylphenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with 3-bromopentane according to Method D2b to give 2-(4-cyano-2-ethylphenylimino)-1-(3-pentyl)-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.C(N(CC)CC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:33][C@@H:34]1[CH2:38][CH2:37][O:36][CH2:35]1>O1CCOCC1>[CH2:11]([O:10][C:8]([C:7]1[C:2]([NH:33][C@@H:34]2[CH2:38][CH2:37][O:36][CH2:35]2)=[N:3][C:4]([S:13][CH3:14])=[N:5][CH:6]=1)=[O:9])[CH3:12]
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: N[C@@H]1CCOC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc(SC)nc1N[C@@H]1CCOC1

Procedure:
A solution of ethyl 4-chloro-2-methylthio-5-pyrimidinecarboxylate (897 mg, 3.86 mmol) (Aldrich) and triethylamine (1.2 mL, 870 mg, 8.49 mmol) (Aldrich) in dioxane (20 mL) was treated with (R)-3-aminotetrahydrofuran p-toluene-sulfonic acid salt (1.0 g, 3.86 mmol) (Fluka). The mixture was stirred at reflux for 1 hour, then cooled and partitioned between brine and ethyl acetate. The organic layer was dried over sodium sulfate, filtered, concentrated and the residue was purified by chromatography with a silica gel column using a 0–100% ethyl acetate in hexanes gradient to give (R)-2-methylsulfanyl-4-(tetrahydrofuran-3-ylamino)-pyrimidine-5-carboxylic acid ethyl ester as a colorless viscous oil. (Yield 1.0 g, 92%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]([CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:30][CH:29]=2)([CH2:13][O:14]C(=O)C2C=CC=CC=2[N+]([O-])=O)[CH2:11][O:10][C:9]1([CH3:43])[CH3:42])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+]>CO.C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:12]([CH2:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:32][CH:33]=2)([CH2:13][OH:14])[CH2:11][O:10][C:9]1([CH3:43])[CH3:42])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C(CCc2ccc(OCc3ccccc3)cc2)(COC(=O)c2ccccc2[N+](=O)[O-])COC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C(CO)(CCc2ccc(OCc3ccccc3)cc2)COC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
To a solution of 4-[2-(4-benzyloxy-phenyl)-ethyl]-2,2-dimethyl-4-(2-nitro-benzoyloxymethyl)-oxazolidine-3-carboxylic acid tert-butyl ester (80 mg, 0.13 mmol) in methanol (1 ml) and THF (1 ml) is added K2CO3 (1.5 mg, 0.076 eq), the reaction mixture is stirred overnight at room temperature. The reaction mixture is concentrated to dryness and 4-[2-(4-benzyloxy-phenyl)-ethyl]-4-hydroxymethyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (51 mg, 85%) is isolated as a white solid after flash chromatography (Ethyl acetate/Hexane (1/4)).
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](Br)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:25]([N:27]2[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28]2)=[O:26])=[O:8])[CH2:5][CH2:4]1)#[N:2].[Cl:34][C:35]1[CH:40]=[C:39](B(O)O)[CH:38]=[CH:37][N:36]=1>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([C:39]4[CH:38]=[CH:37][N:36]=[C:35]([Cl:34])[CH:40]=4)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:25]([N:27]2[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28]2)=[O:26])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(Br)cc3Cl)C[C@H]2C(=O)N2CCC(F)(F)C2)CC1
Reactant: OB(O)c1ccnc(Cl)c1
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(-c4ccnc(Cl)c4)cc3Cl)C[C@H]2C(=O)N2CCC(F)(F)C2)CC1

Procedure:
The title compound was prepared in analogy to example 196 using (1R,2R,4R)-4-(2-chloro-4-bromo-benzenesulfonyl)-2-(3,3-difluoro-pyrrolidine-1-carbonyl)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (Example 187 step 4) and 2-chloropyridine-4-boronic acid. Light brown solid (58%). MS (EI): 597.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14]CC)=[O:13])[CH:10]=2)[NH:5][CH:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH:23][S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH2:3]1.O.[OH-].[Li+].[OH-].[Na+]>C(O)C.O>[C:27]1([S:24]([NH:23][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH:4]2[CH2:3][C:2]([CH3:1])([CH3:33])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:12]([OH:14])=[O:13])[CH:10]=3)[NH:5]2)(=[O:26])=[O:25])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1ccccc1NS(=O)(=O)c1ccccc1)N2
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1(C)CC(c2ccccc2NS(=O)(=O)c2ccccc2)Nc2ccc(C(=O)O)cc21
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a stirred solution of ethyl 4,4-dimethyl-2-(2-(phenylsulfonamido)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (crude 0.62 mmol) in ethanol was added a solution of lithium hydroxide monohydrate (129 mg, 3.08 mmol) and sodium hydroxide (50 mg, 1.23 mmol) in water (1.5 mL) at room temperature. The reaction mixture was stirred at 85° C. overnight. The reaction mixture was concentrated in vacuo. The residue was diluted with water, adjusted pH=3˜4 by 1M aqueous hydrochloric acid, extracted with ethyl acetate. The combined organic layer was washed by brine, dried over anhydrous sodium sulfate, concentrated in vacuo. The residue was purified by HPLC to give 2-(2-benzenesulfonylamino-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid. LC/MS m/e obsd. (ESI+) [(M+H)+] 437.30.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:15]3=[CH:16][C:17]4[O:21][CH2:20][O:19][C:18]=4[CH:22]=[C:14]3[O:13][CH2:12]1)[C:5](=[O:11])[NH:6]2.[CH3:23][N:24]([CH3:34])[C:25]1[N:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.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>[CH3:23][N:24]([CH3:34])[C:25]1[N:30]=[CH:29][C:28]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[C:4]2([C:15]4=[CH:16][C:17]5[O:21][CH2:20][O:19][C:18]=5[CH:22]=[C:14]4[O:13][CH2:12]2)[C:5](=[O:11])[NH:6]3)=[CH:27][CH:26]=1
Reactant: CN(C)c1ccc(B(O)O)cn1
Reactant: O=C1Nc2cccc(Br)c2C12COc1cc3c(cc12)OCO3
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: CN(C)C=O
Product: CN(C)c1ccc(-c2cccc3c2C2(COc4cc5c(cc42)OCO5)C(=O)N3)cn1
Yield: 53.8 %

Procedure:
To a suspended mixture of 4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (1.00 g, 2.78 mmol), 6-(dimethylamino)pyridin-3-ylboronic acid (0.69 g, 4.17 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.32 g, 0.28 mmol) in N,N-dimethylformamide (30 mL) was added aqueous 2 M sodium carbonate (2.8 mL, 5.6 mmol). The reaction mixture was refluxed for 3 h. The solid was filtered and washed with ethyl acetate (40 mL). The filtrate was concentrated in vacuo to dryness. The residue was purified by column chromatography with ethyl acetate in hexanes (20% to 50% gradient) to afford 4′-[6-(dimethylamino)pyridin-3-yl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.60 g, 54%) as a white powder: mp>245° C. (ethyl acetate); 1H NMR (300 MHz, DMSO-d6) δ10.69 (s, 1H), 7.59 (d, J=2.4 Hz, 1H), 7.29 (dd, J=7.8, 7.8 Hz, 1H), 6.93 (d, J=7.8 Hz, 1H), 6.79-6.74 (m, 2H), 6.40-6.35 (m, 3H), 5.95 (d, J=19.9 Hz, 2H), 4.52 (d, J=9.3 Hz, 1H), 4.36 (d, J=9.3 Hz, 1H), 2.99 (s, 6H); 13C NMR (75 MHz, DMSO-d6) δ 178.8, 157.9, 155.5, 148.1, 146.6, 142.2, 141.5, 137.0, 136.8, 129.8, 128.9, 124.4, 121.9, 121.2, 109.0, 104.2, 102.5, 101.3, 93.1, 77.5, 58.2, 37.6; MS (ES+) m/z 402.3 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]([O:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=2)=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:26]1([C:32]2[N:33]=[CH:34][NH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12](=[O:13])[O:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N:35]3[CH:36]=[C:32]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:33]=[CH:34]3)=[CH:19][CH:18]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: c1ccc(-c2c[nH]cn2)cc1
Reactant: Cc1ccc(S(=O)(=O)NC(=O)OCCc2ccc(B(O)O)cc2)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NC(=O)OCCc2ccc(-n3cnc(-c4ccccc4)c3)cc2)cc1
Temperature: 25 °C
Yield: 44.9 %

Procedure:
A mixture of 4-{2-[({[(4-Methylphenyl)sulfonyl]amino}carbonyl)oxy]ethyl}phenylboronic acid (100 mg, 0.28 mmol), 4-phenylimidazole (40 mg, 0.28 mmol), Copper(II) acetate (50 mg, 0.28 mmol), triethylamine (115 μL, 0.83 mmol), molecular sieves 4A (100 mg), and dichloromethane (4 mL) was stirred at room temperature for 1 week. Insoluble materials were removed by Celite pad, the filtrate was diluted with dichloromethane, and washed with water. The combined organic phase was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by TLC with dichloromethane/methanol (10:1) to afford 58 mg (46%) of the title compound as white solids: MS (ESI) m/z 462 [M+H]+, 460 [M−H]−, 1H-NMR (DMSO-d6) δ 2.35 (3H, s), 2.88 (2H, t, J=6.5 Hz), 4.23 (2H, t, J=6.5 Hz), 7.22-7.43 (7H, m), 7.62 (2H, d, J=8.3 Hz), 7.74 (2H, d, J=8.3 Hz), 7.86 (2H, d, J=7.3 Hz), 8.26 (1H, s), 8.32 (1H, s).
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[O:20][CH3:21])=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([CH3:24])=[CH:6][C:7]([CH3:23])([CH3:22])[NH:8]2.[CH3:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[S:31])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[C:3]([CH2:2][O:32][C:30](=[S:31])[C:29]3[CH:33]=[CH:34][C:26]([CH3:25])=[CH:27][CH:28]=3)=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7]([CH3:22])([CH3:23])[CH:6]=[C:5]3[CH3:24])=[C:14]([O:20][CH3:21])[CH:15]=1
Reactant: Cc1ccc(C(O)=S)cc1
Reactant: COc1cc(F)ccc1-c1ccc2c(c1CCl)C(C)=CC(C)(C)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(F)ccc1-c1ccc2c(c1COC(=S)c1ccc(C)cc1)C(C)=CC(C)(C)N2
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 48.4 %

Procedure:
5-Chloromethyl-6-(4-fluoro-2-methoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 5-2, 50.0 mg, 0.145 mmol), 4-methylthiobenzoic acid (73.2 mg, 0.435 mmol), and potassium carbonate (80.2 mg, 0.580 mmol) were suspended in anhydrous N,N-dimethylformamide (1 mL), and the reaction mixture was stirred at 80° C. for 2.5 hours. Ethyl acetate (100 mL) was added to the reaction mixture, and the whole was washed with water (100 mL) and saturated brine (100 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (32.4 mg) as a colorless amorphous product. (Yield 47%)
Reaction SMILES: Br[CH2:2][C:3]#[N:4].[S:5]1[CH2:9][CH2:8][NH:7][C:6]1=[O:10]>CN(C=O)C>[O:10]=[C:6]1[N:7]([CH2:2][C:3]#[N:4])[CH2:8][CH2:9][S:5]1
Reactant: O=C1NCCS1
Reactant: N#CCBr
Solvent: CN(C)C=O
Product: N#CCN1CCSC1=O

Procedure:
Preparation took place in analogy to Example IV a from bromoacetonitrile and 2-thiazolidinone. The substance was employed as DMF-containing crude product in the next reaction.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:24]([CH3:25])=[CH:23][C:12]([CH2:13][C@@H:14]([CH2:19][C:20]([O-])=[O:21])[C:15]([O:17][CH3:18])=[O:16])=[CH:11][C:10]=1[O:26][CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:28]1[CH2:33][CH2:32][CH:31]([N:34]2[CH2:40][CH2:39][C:38]3[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=3[NH:36][C:35]2=[O:45])[CH2:30][CH2:29]1.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.C(#N)C.C1COCC1>[CH2:1]([O:8][C:9]1[C:24]([CH3:25])=[CH:23][C:12]([CH2:13][C@@H:14]([CH2:19][C:20](=[O:21])[N:28]2[CH2:29][CH2:30][CH:31]([N:34]3[CH2:40][CH2:39][C:38]4[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=4[NH:36][C:35]3=[O:45])[CH2:32][CH2:33]2)[C:15]([O:17][CH3:18])=[O:16])=[CH:11][C:10]=1[O:26][CH3:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Reactant: COC(=O)[C@H](CC(=O)[O-])Cc1cc(C)c(OCc2ccccc2)c(OC)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CC#N
Product: COC(=O)[C@H](CC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1)Cc1cc(C)c(OCc2ccccc2)c(OC)c1

Procedure:
Prepared analogously to Example 12d from 5.80 g (15.6 mmol) 1-methyl (S)-2-(4-benzyloxy-3-methoxy-5-methyl-benzyl)-succinate and 4.20 g (17.13 mmol) 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, using 3.43 g (17.9 mmol) (3-dimethylamino-propyl)-ethyl-carbodiimide and 2.38 g (19.5 mmol) 4-dimethylamino-pyridine for the coupling and 130 mL acetonitrile and 50 mL THF as solvent.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.C([Li])CCC.[CH2:17]1[O:27][C:20]2([CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]2)[O:19][CH2:18]1>C1COCC1.CCOCC>[CH3:10][N:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([C:23]2([OH:26])[CH2:24][CH2:25][C:20]3([O:27][CH2:17][CH2:18][O:19]3)[CH2:21][CH2:22]2)=[N:7][CH:6]=1)[CH3:11]
Reactant: CN(C)Cc1ccc(Br)nc1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(C)Cc1ccc(C2(O)CCC3(CC2)OCCO3)nc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 53.8 %

Procedure:
1-(6-Bromopyridin-3-yl)-N,N-dimethylmethanamine (1.15 g, 5.4 mmol) was dissolved in 30 mL of THF and 80 mL of anhydrous ether. After the solution was cooled to −78° C., 2.60 mL of n-butyllithium (2.5 M, 6.40 mmol) was slowly dropped through a syringe in 10 min. After being stirred at −78° C. for 30 minutes, 1,4-cyclohexanedione mono-ethylene ketal (1.01 g, 6.4 mmol) was added. The reaction mixture was allowed to warm up to room temperature during two hours and then quenched by addition of 10 mL of water. The mixture was extracted twice using EtOAc. The combined extracts were dried and concentrated. After flash column using 20-40% methanol in EtOAc and 0.5% NH4OH, 0.85 g oil was obtained (54% yield), MS: (M+H)+ 293.2.0.
Reaction SMILES: [CH:1]1[N:5]2[C@H:6]3[C@H:11]([NH:12][C:13]4([CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]4)[C:4]2=[CH:3][CH:2]=1)[CH2:10][CH2:9][CH2:8][CH2:7]3.O1CCOCC1>Cl>[CH:1]1[N:5]2[C@H:6]3[C@H:11]([NH:12][C:13]4([CH2:14][CH2:15][NH:16][CH2:17][CH2:18]4)[C:4]2=[CH:3][CH:2]=1)[CH2:10][CH2:9][CH2:8][CH2:7]3
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)N[C@@H]1CCCC[C@H]1n1cccc12
Agent: Cl
Solvent: C1COCCO1
Product: c1cc2n(c1)[C@@H]1CCCC[C@H]1NC21CCNCC1
Reaction time: 2 h

Procedure:
trans-tert-Butyl 5a′,6′,7′,8′,9′,9a′-hexahydro-5′H-spiro[piperidine-4,4′-pyrrolo[1,2-a]quinoxaline]-1-carboxylate (0.311 g, 0.901 mmol) was suspended in hydrogen chloride in dioxane (2.0 mL of 4.0 M, 8.0 mmol). The reaction mixture was allowed to stand for 2 hours. The reaction mixture was then evaporated to dryness to give trans-5a′,6′,7′,8′,9′,9a′-hexahydro-5′H-spiro[piperidine-4,4′-pyrrolo[1,2-a]quinoxaline]. ESI-MS m/z calc. 245.2, found 246.3 (M+1)+; Retention time: 0.32 minutes (3 min run).
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[S:4][CH2:3]1.[CH2:14]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([CH2:30][CH2:31][CH2:32][CH2:33][C:34](=O)[C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:26][CH2:25]1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[CH2:14]([O:21][C:22]([N:24]1[CH2:25][CH2:26][CH:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH:34]([NH:1][C@@H:2]2[C:8](=[O:9])[NH:7][C:6]3[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=3[S:4][CH2:3]2)[C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:28][CH2:29]1)=[O:23])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)C(=O)CCCCC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: N[C@H]1CSc2ccccc2NC1=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(CCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@H]1CSc2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 38.6 %

Procedure:
A mixture of 3(R)-amino-2,3-dihydro-1,5-(5H)-benzothiazepin-4-one (1.0 g), ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-oxohexanoate (6.0 g), acetic acid (0.37 g), molecular sieves 3A (3.0 g) and ethanol (25 ml) is stirred at room temperature for 20 minutes. To the stirred mixture is added dropwise a solution of sodium cyanoborohydride (0.66 g) in ethanol (20 ml) over a period of 5 hours. After the reaction mixture is concentrated under reduced pressure, the residue is diluted with a mixture of ethyl acetate (80 ml) and water (100 ml). After the insoluble substance is removed by filtration, the ethyl acetate layer is washed with diluted hydrochloric acid, water and sodium bicarbonate solution successively, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to yield 3(R)-[5-(1-benzyloxycarbonyl-4-piperidyl)-1-ethoxycarbonylpentyl]amino-2,3-dihydro-1,5(5H)-benzothiazepin-4-one (1.1 g) as a colorless oil.
Reaction SMILES: C(N(CC)CC)C.Cl.[Cl:9][CH2:10][CH2:11][CH2:12][NH2:13].[C:14]([C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:23]=[O:24])=[CH:18][CH:17]=1)#[N:15]>C(Cl)Cl>[Cl:9][CH2:10][CH2:11][CH2:12][NH:13][C:23]([NH:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]#[N:15])=[CH:17][CH:18]=1)=[O:24]
Reactant: N#Cc1ccc(N=C=O)cc1
Reactant: NCCCCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc(NC(=O)NCCCCl)cc1
Yield: 53.7 %

Procedure:
Triethylamine (13.8 g; 137 mmole) was slowly added to a mixture of 3-chloropropylamine hydrochloride (17.8 g; 137 mmole), 4-cyanophenyl isocyanate (19.7 g; 137 mmole), and methylene chloride (200 ml). The resulting solution was stirred until the mild exothermic reaction had subsided and the solvent was removed in vacuo. The product was dissolved in ether, washed with water, dried, and part of the ether removed. The colorless crystals which precipitated out were filtered and dried to give 1-(3-chloropropyl)-3-(4-cyanophenyl)urea (17.5 g; 54% yield). A small portion of the product was recrystallized from water/acetone to give pure product, m.p. 95°-97° C.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:32][CH3:33])=[C:28]([OH:31])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:34]([C@@H:36]1[O:38][CH2:37]1)Cl>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:32][CH3:33])=[C:28]([O:31][CH2:34][C@H:36]5[CH2:37][O:38]5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1O
Reactant: ClC[C@H]1CO1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OC[C@H]1CO1
Yield: 8.9 %

Procedure:
1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-hydroxy-7-methoxyquinazolin-4-yloxy)phenyl)urea (320 mg, 0.712 mol) and (R)(−)epichlorohydrin (288 μL, 3.56 mmol) were reacted using the same procedure as described before from Example 111A to afford (R)-1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(oxiran-2-ylmethoxy)quinazolin-4-yloxy)phenyl)urea (160 mg, 44%). LC-MS (ESI) m/z 506 (M+H)+.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH2:10]([O:18][C:19]1[C:20](=O)[NH:21][C:22]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:27][CH:26]=2)=[N:23][CH:24]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(=O)(O)[O-].[Na+]>ClCCl>[F:7][C:20]1[C:19]([O:18][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:24][N:23]=[C:22]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:27][CH:26]=2)[N:21]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CCCCCCCCOc1ccc(-c2ncc(OCCCCCCCC)c(=O)[nH]2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCCCOc1ccc(-c2ncc(OCCCCCCCC)c(F)n2)cc1
Reaction time: 8 h

Procedure:
A solution of 0.7 ml of diethylaminosulfurtrifluoride (DAST) in 10 ml of dichloromethane is added in the course of 10 minutes, at 0° C., to a suspension of 2.1 g of 5-octyloxy-2-(4-octyloxyphenyl)pyrimidin-4-one (prepared, for example, in accordance with Boller et al., Z. Naturf. 33b, 433 (1978)) in 30 ml of dichloromethane. After 8 h at 40° C., aqueous sodium bicarbonate solution is added. After chromatography and recrystallization from acetonitrile, the organic phase yields 0.7 g of colorless crystals.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17](Cl)(=[O:20])[CH:18]=[CH2:19].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[C:17]([C:8]1[CH:9]=[CH:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:20])[CH:18]=[CH2:19]
Reactant: C=CC(=O)Cl
Reactant: c1ccc(-c2cccc3ccccc23)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C=CC(=O)c1ccc2ccccc2c1-c1ccccc1
Yield: 125.2 %

Procedure:
1-phenylnaphthalene (204 mg), acryloyl chloride (200 mg), and aluminium chloride (290 mg) were reacted in dichloromethane (1.5 mL) at from −40° C. to room temperature for 2 hours. The resultant was treated in the same manner as described in Example 1 to obtain the title compound (323 mg).