Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[N:8][C:9]([NH:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=[O:5])C.[NH2:27][CH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[O:31]1[CH2:32][CH2:33][CH:28]([NH:27][C:4]([C:6]2[N:7]=[N:8][C:9]([NH:12][CH2:13][C:14]3[C:15]([C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)=[N:16][O:17][C:18]=3[CH3:19])=[CH:10][CH:11]=2)=[O:5])[CH2:29][CH2:30]1
Reactant: NC1CCOCC1
Reactant: CCOC(=O)c1ccc(NCc2c(-c3ccc(F)cc3)noc2C)nn1
Product: Cc1onc(-c2ccc(F)cc2)c1CNc1ccc(C(=O)NC2CCOCC2)nn1
Yield: 62 %

Procedure:
As described for example 81, 6-{[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-pyridazine-3-carboxylic acid ethyl ester (89 mg, 0.25 mmol) was converted, using 4-aminotetrahydropyran instead of aminomethylcyclopropane, to the title compound (64 mg, 62%) which was obtained as a white foam. MS: m/e=412.5 [M+H]+.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)\[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.O[C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.O>[CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)\[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:22]2[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=2)=[CH:9][CH:8]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: CO/N=C(\COc1ccc(CO)cc1)c1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CO/N=C(\COc1ccc(COc2ccc(C=O)cc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 36 %

Procedure:
To a stirring solution of (4-{[(2Z)-2-(methoxyimino)-2-phenylethyl]oxy}phenyl)methanol (10 g, 37 mmol) and 4-hydroxybenzaldehyde (4.5 g, 37 mmol) in THF (100 mL) was added triphenylphosphine (12.2 g, 46.5 mmol) and Diisopropyl azodicarboxylate (11.2 g, 55 mmol) at 0° C., then stirred at RT for 12 h. RM diluted with water and extracted with ethyl acetate. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated to pale brown oil. Crude was purified by column (100-200 silica) using 8% ethyl acetate to get the titled compound as white solid (5 g, Yield: 36.2%). 1H NMR (300 MHz, CDCl3): δ 9.81 (s, 1H), 7.74-7.77 (d, 2H), 7.58-7.61 (m, 2H), 7.24-7.29 (m, 5H), 6.97-6.99 (d, 2H), 6.85-6.87 (d, 2H), 5.13 (s, 2H), 4.98 (s, 2H), 3.98 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([NH2:23])([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-])=O)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[C].[Pd]>[C:1]([O:5][C:6]([NH:8][C:9]([NH2:23])([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH2:20])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(N)(Cc1ccccc1[N+](=O)[O-])C(=O)O
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC(N)(Cc1ccccc1N)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
(±)-2-tert-Butoxycarbonylamino-3-(2-nitrophenyl)-amin opropionic acid (325 mg) was dissolved in methanol (50 mL), followed by the addition of 10% palladium carbon (50 mg). The resulting mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure, whereby (±)-2-tert-butoxycarbonylamino-3-(2-aminophenyl)-aminopropi onic acid was obtained. It was suspended in toluene (30 mL) The suspension was refluxed for 3 hours while removing water by a Dean-Stark extractor. The resultant mixture was concentrated under reduced pressure. After the residue was purified by silica gel colomn chromatography (chloroform:methanol=20:1), diisopropyl ether was added thereto for crystallization. Crystals so precipitated were then collected by filtration, whereby the title compound (210 mg) was obtained. Yield: 76%.
Reaction SMILES: [F:1][C:2]1([F:24])[C:6]([F:8])([F:7])[C:5]2[CH:9]=[CH:10][CH:11]=[C:12]([CH2:13][CH:14]3[CH2:23][CH2:22][C:17]4(OCC[O:18]4)[CH2:16][CH2:15]3)[C:4]=2[O:3]1.O>C(O)(=O)C>[F:24][C:2]1([F:1])[C:6]([F:7])([F:8])[C:5]2[CH:9]=[CH:10][CH:11]=[C:12]([CH2:13][CH:14]3[CH2:15][CH2:16][C:17](=[O:18])[CH2:22][CH2:23]3)[C:4]=2[O:3]1
Reactant: FC1(F)Oc2c(CC3CCC4(CC3)OCCO4)cccc2C1(F)F
Solvent: CC(=O)O
Solvent: O
Product: O=C1CCC(Cc2cccc3c2OC(F)(F)C3(F)F)CC1

Procedure:
This compound is prepared in a manner analogous to that of Step D of Example 2, using 6.2 grams (0.018 mole) of 8-(2,2,3,3-tetrafluoro-2,3-dihydrobenzofuran-7-ylmethyl)-1,4-dioxaspiro[4.5]decane and 25 mL of water in 100 mL of acetic acid, yielding 4-(2,2,3,3-tetrafluoro-2,3-dihydrobenzofuran-7-ylmethyl)cyclohexanone.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[CH2:3][CH2:4][NH:5][C:6]1[N:15]=[C:14]2[C:9]([C:10](=[O:29])[C:11]([C:24]([O:26]CC)=[O:25])=[CH:12][N:13]2[CH2:16][C@@H:17]2[CH2:21][CH2:20][CH2:19][N:18]2[CH2:22][CH3:23])=[CH:8][C:7]=1[I:30].C1COCC1.[Li+].[OH-]>CO>[CH3:31][N:2]([CH3:1])[CH2:3][CH2:4][NH:5][C:6]1[N:15]=[C:14]2[C:9]([C:10](=[O:29])[C:11]([C:24]([OH:26])=[O:25])=[CH:12][N:13]2[CH2:16][C@@H:17]2[CH2:21][CH2:20][CH2:19][N:18]2[CH2:22][CH3:23])=[CH:8][C:7]=1[I:30]
Reactant: CCOC(=O)c1cn(C[C@@H]2CCCN2CC)c2nc(NCCN(C)C)c(I)cc2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCN1CCC[C@H]1Cn1cc(C(=O)O)c(=O)c2cc(I)c(NCCN(C)C)nc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(S)-ethyl 7-(2-(dimethylamino)ethylamino)-1-((1-ethylpyrrolidin-2-yl)methyl)-6-iodo-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (Intermediate 40) was then taken up in methanol (2 mL) and THF (5 mL) and 1 ml of 2N LiOH was added and stirred at room temperature for 30 min. The solvent was removed in vacuo to give (S)-7-(2-(dimethylamino)ethylamino)-1-((1-ethylpyrrolidin-2-yl)methyl)-6-iodo-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid as a light brown solid, material, which will be carried forward without further purification.
Reaction SMILES: [H][H].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]=[CH:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)[CH:4]=1>[Pd]>[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:19][CH:20]=2)[CH:4]=1
Reactant: [H][H]
Reactant: COC(=O)c1ccc(C=Cc2cccnc2)cc1
Agent: [Pd]
Product: COC(=O)c1ccc(CCc2cccnc2)cc1
Yield: 93.7 %

Procedure:
Hydrogen gas was slowly bubbled through a vigorously stirred mixture of methyl 4-(2-(3-pyridyl)ethenyl)benzoate (952 mg, 3.98 mmol) and 10% palladium on carbon (95 mg) at room temperature for 4 h. The reaction mixture was filtered through Kieselguhr which was then washed with excess ethyl acetate. The combined organics were evaporated under reduced pressure to give methyl 4-(2-(3-pyridyl)ethyl)benzoate (900 mg, 94%) as an oil which crystallised on standing.
Reaction SMILES: [NH2:1][C:2]1([CH2:18][OH:19])[C:15]2[C:10](=[N:11][CH:12]=[C:13]([Br:16])[CH:14]=2)[O:9][C:8]2[C:3]1=[CH:4][C:5]([I:17])=[CH:6][CH:7]=2.Br[CH2:21][C:22]#[N:23].CC(C)([O-])C.[Li+]>C1COCC1>[NH2:1][C:2]1([CH2:18][O:19][CH2:21][C:22]#[N:23])[C:15]2[C:10](=[N:11][CH:12]=[C:13]([Br:16])[CH:14]=2)[O:9][C:8]2[C:3]1=[CH:4][C:5]([I:17])=[CH:6][CH:7]=2
Reactant: NC1(CO)c2cc(I)ccc2Oc2ncc(Br)cc21
Reactant: N#CCBr
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CCOCC1(N)c2cc(I)ccc2Oc2ncc(Br)cc21
Yield: 51.2 %

Procedure:
A solution of (5-amino-3-bromo-7-iodo-5H-chromeno[2,3-b]pyridin-5-yl)methanol (10.00 g, 23.09 mmol) and bromoacetonitrile (12.06 mL, 173 mmol) in 25 mL THF was heated to 40° C. Lithium tert-butoxide [1N in THF (173 mL, 173 mmol)] was added drop wise via addition funnel over 5 hours. After completed addition, the reaction mixture was concentrated. The residue was purified by column chromatography [0-80% (95:5 EtOAc/MeOH)/heptane] to yield 2-((5-amino-3-bromo-7-iodo-5H-chromeno[2,3-b]pyridin-5-yl)methoxy)acetonitrile (5.58 g, 11.82 mmol, 51.2% yield).
Reaction SMILES: C(C1N(CC2COC(C)(C)O2)C2C(C=1)=CC([NH:14][C:15]([C:17]1([C:20]3[CH:30]=[CH:29][C:23]4[O:24][C:25]([F:28])([F:27])[O:26][C:22]=4[CH:21]=3)[CH2:19][CH2:18]1)=[O:16])=CC=2)(C)(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.O>[F:28][C:25]1([F:27])[O:24][C:23]2[CH:29]=[CH:30][C:20]([C:17]3([C:15]([NH2:14])=[O:16])[CH2:19][CH2:18]3)=[CH:21][C:22]=2[O:26]1
Reactant: CC1(C)OCC(Cn2c(C(C)(C)C)cc3cc(NC(=O)C4(c5ccc6c(c5)OC(F)(F)O6)CC4)ccc32)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: NC(=O)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Temperature: 80 °C
Yield: 163.8 %

Procedure:
To a stirred solution of N-(2-tert-butyl-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-indol-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (1.28 g, 2.43 mmol) in methanol (34 mL) and water (3.7 mL) was added para-toluenesulfonic acid-hydrate (1.87 g, 9.83 mmol). The reaction mixture was stirred and heated at 80° C. for 25 minutes. The solvent was evaporated under reduced pressure. The crude product was dissolved in ethyl acetate. The organic layer was washed with saturated aqueous NaHCO3 (2×10 mL) and brine (2×10 mL). The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/hexane=13/7) to give N—((R)-2-tert-butyl-1-2,3-dihydroxypropyl)-1H-indol-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (0.96 g, 81%). 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J=2 Hz, 1H), 7.31 (dd, J=2, 8 Hz, 1H), 7.27 (dd, J=2, 8 Hz, 1H), 7.23 (d, J=8 Hz, 1H), 7.14 (d, J=8 Hz, 1H), 7.02 (br s, 1H), 6.96 (dd, J=2, 8 Hz, 1H), 6.23 (s, 1H), 4.35 (dd, J=8, 15 Hz, 1H), 4.26 (dd, J=4, 15 Hz, 1H), 4.02-3.95 (m, 1H), 3.60 (dd, J=4, 11 Hz, 1H), 3.50 (dd, J=5, 11 Hz, 1H), 1.75 (q, J=8 Hz, 3H), 1.43 (s, 9H), 1.14 (q, J=8 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11]C)=O)=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.[CH3:13][NH2:14]>CO>[NH2:1][C:2]1[C:3]([C:9]([NH:14][CH3:13])=[O:11])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: CN
Reactant: COC(=O)c1nc(Br)cnc1N
Solvent: CO
Product: CNC(=O)c1nc(Br)cnc1N
Temperature: 25 °C
Yield: 88 %

Procedure:
An ice-cooled solution of 50 g of methyl 3-amino-6-bromo-pyrazine-2-carboxylate in 500 mL of MeOH was saturated with methylamine gas. The reaction was then heated at 85° C. in a sealed, stainless steel Parr pressure vessel for 2 h, and cooled to room temperature, and then on an ice water bath. The mixture was concentrated to an oil on a rotary evaporator under reduced pressure. The crude oil was dissolved in EtOAc and washed with water, dried (Na2SO4), filtered, and concentrated to give 43.9 g (88.0% yield) of product as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.[CH3:45][CH:46]1[CH:51]([CH3:52])[CH2:50][CH2:49][CH2:48][CH:47]1[NH2:53]>CN(C=O)C>[CH3:45][CH:46]1[CH:51]([CH3:52])[CH2:50][CH2:49][CH2:48][CH:47]1[NH:53][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:3]2[CH:4]=[C:5]([C:8]3[O:9][C:10]([CH3:13])=[N:11][N:12]=3)[CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:15][CH:16]=1)=[O:21]
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: CC1CCCC(N)C1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NC4CCCC(C)C4C)cc3)c2)o1
Reaction time: 18 h

Procedure:
2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid (11.3 mg, 0.034 mmol), HOBT (6.0 mg, 0.044 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (8.0 mg, 0.042 mmol) and 2,3-dimethylcyclohexylamine (0.34 mmol) were mixed in DMF (0.7 ml) and the reaction left at room temperature for 18 h. The DMF was evaporated under vacuum and the residue partitioned between DCM (0.4 ml) and water (0.4 ml). The organic phase was washed with aqueous sodium hydroxide (0.5M, 0.2 ml) and the DCM evaporated under vacuum. The residue was purified by mass directed HPLC to give N-(2,3-dimethylcyclohexyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1B(O)O.C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH3:10])[NH:9][C:13]1[C:12]([F:11])=[CH:17][CH:16]=[CH:15][C:14]=1[F:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1c(F)cccc1F
Reactant: CN(N)C(=O)OC(C)(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CN(Nc1c(F)cccc1F)C(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 9.5 %

Procedure:
A mixture of N-methyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 1; 1.00 g, 6.8 mmol), 2,6-difluorophenylboronic acid (Aldrich; 1.07 g, 6.8 mmol), copper(II) acetate (1.24 g, 6.8 mmol) and triethylamine (960 μL, 6.8 mmol) in 1,2-dichloroethane (15 mL) was heated in an oil bath at 50° C. overnight. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 120 g column, eluting with 20-25% ethyl acetate/hexanes, to give N′-(2,6-difluoro-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester (167 mg, 9%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[C:4]([F:24])[CH:3]=1.[Br:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[N:33]1[C:38]([CH3:39])=[CH:37][CH:36]=[C:35]([C:40](O)=[O:41])[C:34]1=[O:43].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Br:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[N:33]1[C:38]([CH3:39])=[CH:37][CH:36]=[C:35]([C:40]([NH:1][C:2]2[CH:23]=[CH:22][C:5]([O:6][C:7]3[CH:8]=[CH:9][C:10]4[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]5[CH2:21][CH2:20]5)=[O:18])[N:15]=4)[CH:12]=3)=[C:4]([F:24])[CH:3]=2)=[O:41])[C:34]1=[O:43]
Reactant: Cc1ccc(C(=O)O)c(=O)n1-c1ccc(F)cc1Br
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c(F)c2)c(=O)n1-c1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 72 h
Yield: 53.5 %

Procedure:
A mixture of N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (150 mg, 0.459 mmol), 1-(2-bromo-4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (146 mg, 0.448 mmol), HATU (262 mg, 0.689 mmol), N,N-diisopropylethylamine (160 μl, 0.919 mmol) and N,N-dimethylformamide (3 mL) was stirred at room temperature for 3 days. After dilution with ethyl acetate, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, 30 g, ethyl acetate/hexane=2/98→100/0) and preparative HPLC (acetonitrile/water=40/60→50/50, containing 0.1% trifluoroacetic acid) to give the title compound (152 mg, 52%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:7][CH2:6][CH:5]([C:8]2[CH:9]=[C:10]([N:20]3[CH2:25][C@H:24]([CH3:26])[O:23][C@H:22]([CH3:27])[CH2:21]3)[CH:11]=[CH:12][C:13]=2[N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH2:4][CH2:3]1.Br[CH2:30][CH:31]1[CH2:34][CH2:33][CH2:32]1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.CN(C)C=O>[CH:31]1([CH2:30][N:17]2[CH2:16][CH2:15][N:14]([C:13]3[CH:12]=[CH:11][C:10]([N:20]4[CH2:25][C@H:24]([CH3:26])[O:23][C@H:22]([CH3:27])[CH2:21]4)=[CH:9][C:8]=3[CH:5]3[CH2:4][CH2:3][C:2]([CH3:28])([CH3:1])[CH2:7][CH2:6]3)[CH2:19][CH2:18]2)[CH2:34][CH2:33][CH2:32]1
Reactant: C[C@@H]1CN(c2ccc(N3CCNCC3)c(C3CCC(C)(C)CC3)c2)C[C@H](C)O1
Reactant: BrCC1CCC1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(c2ccc(N3CCN(CC4CCC4)CC3)c(C3CCC(C)(C)CC3)c2)C[C@H](C)O1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of the cis-4-[3-(4,4-dimethylcyclohexyl)-4-piperazin-1-ylphenyl]-2,6-dimethylmorpholine (30 mg, 0.0778 mmol) produced in Example (61b), bromomethylcyclobutane (23 mg, 0.156 mmol), potassium carbonate (22 mg, 0.156 mmol) and dimethylformamide (1 mL) was stirred for 1 hour at an external temperature of 80° C. Then, bromomethylcyclobutane (23 mg, 0.156 mmol) was further added and stirring was continued for 2 hours under the same conditions. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with ethyl acetate. The separated organic layer was washed with water and brine in that order, and then the solvent was distilled off by nitrogen stream. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give cis-4-[4-(4-cyclobutylmethylpiperazin-1-yl)-3-(4,4-dimethylcyclohexyl)phenyl]-2,6-dimethylmorpholine as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:16][C:17]([C:19]1[CH:24]=[C:23]([Br:25])[CH:22]=[CH:21][C:20]=1[OH:26])=[O:18]>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[Br:25][C:23]1[CH:22]=[CH:21][C:20]([O:26][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[C:19]([C:17](=[O:18])[CH3:16])[CH:24]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: CC(=O)c1cc(Br)ccc1O
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccc(Br)cc3C(C)=O)c2cc1OC
Temperature: 160 °C
Reaction time: 4 h
Yield: 47.3 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (113 mg), 5-bromo-2-hydroxyacetophenone (550 mg), and 4-dimethylaminopyridine (311 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 160° C. for 4 hr. The reaction solution was cooled to room temperature, and the solvent was then removed therefrom by distillation under the reduced pressure. Chloroform was added to the residue, and the organic layer was washed with a 1 N aqueous potassium hydroxide solution and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform and by thin layer chromatography using acetone-hexane to give the title compound (96.2 mg, yield 47%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:11]2([CH2:14][NH:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]([F:29])([F:28])[O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][N:25]=[C:26]=[O:27]>>[C:1]([O:5][C:6]([N:8]1[C:11]2([CH2:12][N:13]([C:26](=[O:27])[NH:25][CH2:24][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[O:17][C:16]([F:29])([F:15])[F:28])[CH2:14]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC12CNC2
Reactant: O=C=NCc1ccccc1OC(F)(F)F
Product: CC(C)(C)OC(=O)N1CCC12CN(C(=O)NCc1ccccc1OC(F)(F)F)C2

Procedure:
In analogy to the experimental procedure of example 8) 1,6-diaza-spiro[3.3]heptane-1-carboxylic acid tert-butyl ester instead of 1-benzyl-1,6-diaza-spiro[3.3]heptane was converted using 1-trifluoromethoxy-2-isocyanatomethyl-benzene instead of (3-isocyanato-propyl)-benzene into the title compound which was used directly in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5](O)=[O:6].[OH:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([N:33]2[CH2:34][CH2:35][N:30]([CH2:29][CH2:28][OH:27])[CH2:31][CH2:32]2)=[O:6])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Reactant: OCCN1CCNCC1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(C(=O)N2CCN(CCO)CC2)cc1Cl

Procedure:
50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to N-(2-hydroxyethyl)piperazine via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(4-(2-hydroxyethyl)piperazine-1-carbonyl)benzamide. MS (Q1) 499 (M)+.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[Cl-].[Cl-].[Cl-].[Al+3]>O1CCCC1.CN(C=O)C>[C:1]1([S:7][C:8]2[CH:9]=[C:10]3[C:11]([CH2:14][CH2:15][CH2:16][C:17]3=[O:19])=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CCCc1ccc(Sc2ccccc2)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C1CCCc2ccc(Sc3ccccc3)cc21
Reaction time: 1 h
Yield: 54.3 %

Procedure:
4-(4-Phenylsulfanyl-phenyl)-butyric acid (5.0 g, 18.4 mmol) was dissolved in 50 mL tetrahydrofuran (THF). Oxalyl chloride (1.8 mL, 20 mmol) and one drop of DMF were added, and the reaction mixture was stirred for 1 hour, and then evaporated to dryness under reduced pressure. The resulting residue was dissolved in 40 mL of 1,2-dichloroethane, and aluminum trichloride (0.85 g, 25 mmol) was added all at once. The reaction mixture was stirred for 1 hour, and quenched by addition of 2% HCl. This aqueous mixture was extracted twice with 100 mL of EtOAc, and the combined organic layers were dried (MgSO4) and evaporated to yield 2.54 g (10 mmol, 55.5%) of 7-phenylsulfanyl-3,4-dihydro-2H-naphthalen-1-one as a gummy residue. MS: 255 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH2:17][C:18]3[N:19]=[C:20]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:21][C:22]=3[CH3:23])=[CH:14][C:13]=2[CH:30]=1)[C:5]([OH:7])=[O:6])[CH3:2].C(O[C@H](C(N1[C@@H](CC2C=CC=CC=2)COC1=O)=O)CC1C=CC2OC(CC3N=C(C4C=CC=CC=4)OC=3C)=CC=2C=1)C.[OH-].[Li+]>O1CCCC1>[CH2:1]([O:3][C@H:4]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH2:17][C:18]3[N:19]=[C:20]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:21][C:22]=3[CH3:23])=[CH:14][C:13]=2[CH:30]=1)[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCO[C@@H](Cc1ccc2oc(Cc3nc(-c4ccccc4)oc3C)cc2c1)C(=O)O
Agent: CCO[C@@H](Cc1ccc2oc(Cc3nc(-c4ccccc4)oc3C)cc2c1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCO[C@H](Cc1ccc2oc(Cc3nc(-c4ccccc4)oc3C)cc2c1)C(=O)O
Temperature: 0 °C

Procedure:
(S)-2-Ethoxy-3-{2-[(5-methyl-2-phenyl-4-oxazolyl) methyl]benzofuran-5-yl}propanoic acid. 5-{(S)-2-Ethoxy-3-[(S)-4-benzyl-2-oxo-3-oxazolidinyl]-3-oxopropyl}-2-[(5-methyl-2-phenyl-4-oxazolyl) methyl]benzofuran (0.15 g, 0.26 mmol) was dissolved in tetrahydrofuran (5 ml). The solution was cooled to 0° C. and 0.5N lithium hydroxide (1.1 ml, 0.52 mmol) was added. After 15 minutes the bulk of the ethanol was removed, the residue was acidified with 1N HCl, diluted with water and extracted with ethyl acetate (3X). The combined extracts were washed with brine, dried over sodium sulfate and concentrated. The product was purified by flash chromatography (hexanes/ethyl acetate/acetic acid, 10:10:1) then recrystallized from hexanes/ethyl acetate and obtained as a white solid (48 mg, m.p. 129° C., [α]D =-12.5° (c 0.99, CDCl3)).