Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH:4]=[CH:5][NH:6]3)=[CH:15][CH:14]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Brc1cccc2[nH]ccc12
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cccc3[nH]ccc23)cc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 82.9 %

Procedure:
To a mixture of 4-bromoindole (1.96 g, 10 mmol), and 4-methoxyphenylboronic acid (1.52 g, 10 mmol) in THF (34 mL)) were added Palladium catalyst Pd(PPh3)4 (347 mg, 0.3 mmol) and the freshly prepared sodium hydroxide solution (1.20 g, 30 mmol in 14 mL water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 70° C. oil bath for 16 hours. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed by brine, dried over Na2SO4, and concentrated. The crude product was purified by a silica gel column eluting with hexanes—EtOAc (9:1) to provide 1.85 g (83%) of the product 4-(4-Methoxy-phenyl)-1H-indole as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.Cl.[CH3:15]O>>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([O:11][CH3:15])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=CC(=O)O)cc1
Reactant: CO
Agent: Cl
Product: COC(=O)C=Cc1ccc(OC)cc1

Procedure:
p-Methoxycinnamic acid was dissolved in refluxing methanol containing a catalytic amount of hydrogen chloride to form methyl p-methoxycinnamate. The yield of purified ester was 85%, m.p. 88°-89° (lit. 90°; Dictionary of Organic Compounds, II, Sir Ian Heilbron, ed., p. 600 (1946)): λmaxCCl4 3.32, 3.38 and 3.52 (CH1 --OCH3), 5.81 (C=O), 6.1 and 10.15 (CH-CH, trans), 7.95 and 8.5--8.6 (ester)μ. The NMR (δ) supported the expected structure: 6.13-7.78 (series of multiples, aromatic and vinyl), 3.86 (--CO2CH3), and 3.78 (Ar--O--CH3).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([CH:13]([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:21]([O:23]CC)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.CCCCCC>[CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([CH:13]([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:21]([OH:23])=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2C
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC1OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Yield: 96 %

Procedure:
Saponification of intermediate 14, ethyl 3-benzyloxy-9-methyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate, (0.225 g, 0.65 mmol) as described in the preparation of intermediate 7 gave 0.198 g (96% yield) of the title acid as white crystals; mp 167–168° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ ppm: 1.68 (3H, d, J=6.6 Hz, CH3), 3.93 (2H, m, CH2), 4.12–4.21 (1H, m, CH), 4.27–4.35 (1H, m, CH), 4.70 (1H, q, J=6.6 Hz, OCH), 5.53 (2H, ABq, JAB=11.1 Hz, OCH2), 7.39 (3H, m, aromatics), 7.55 (2H, m, aromatics). MS (ESI+) m/z 317 [M+H+]. Anal. Calcd for C16H16N2O5: C, 60.75; H, 5.10; N, 8.86. Found: C 60.65; H, 5.05; N, 8.72.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([CH3:13])[C@@H:10](O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([N:17](CC)CC)C.CS(Cl)(=O)=O.O>ClCCl>[CH2:1]([N:8]1[CH2:12][C@@H:11]([CH3:13])[C@@H:10]([C:15]#[N:17])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: C[C@H]1CN(Cc2ccccc2)C[C@@H]1O
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccccc2)C[C@@H]1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(3R,4S)-1-Benzyl-3-hydroxy-4-methylpyrrolidine (4.00 g) was dissolved in dichloromethane (40 mL). While the solution was chilled in a dry ice/acetone bath, triethylamine (3.06 mL) was added, followed by dropwise addition of methanesulfonyl chloride (1.70 mL) and stirring for 1 hour. Subsequently, water (40 mL) was added and the mixture was allowed to warm to room temperature. The dichloromethane layer was separated and the aqueous layer was extracted with dichloromethane (40 mL). The dichloromethane layers were combined, washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was dissolved in N,N-dimethylformamide (120 mL), followed by the addition of tetrabutylammonium cyanide (5.53 g) and sodium cyanide (2.05 g) and stirring at 80° C. for 13 hours. Subsequently, the reaction mixture was concentrated under reduced pressure. Water (50 mL) was then added to the resulting residue and the mixture was extracted with diethyl ether (2×200 mL). The diethyl ether layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=4:1) to give (3R,4S)-1-benzyl-4-methyl-3-pyrrolidinecarbonitrile as a brown oil (3.32 g).
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][CH2:37][CH2:38]Br)[CH:30]=2)=[CH:24][CH:23]=1)[C:9]1[C:10]([CH3:20])=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][CH2:37][CH2:38][N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[CH:30]=2)=[CH:24][CH:23]=1)[C:9]1[C:10]([CH3:20])=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCCCBr)c2)cc1
Reactant: C1COCCN1
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCCCN3CCOCC3)c2)cc1

Procedure:
The product from Example 72D and morpholine were processed as described in Example 72E to provide the title compound. 1H NMR (300 MHz, CDCl3) δ7.10-7.30 (m, 11 H), 6.86 (d, 2 H), 6.63 (d, 1 H), 6.55 (m, 2 H), 6.33 (t, 1 H), 4.31 (s, 2 H), 4.28 (s, 2 H), 4.00 (m, 6 H), 3.65 (m, 2 H), 3.25 (m, 2 H), 2.95 (m, 2 H), 2.85 (s, 3 H), 2.25 (m, 2 H), 2.17 (s, 3 H); MS (ESI+) m/z 616 (M+H)+.
Reaction SMILES: [C:1]1([NH:7][N:8]=[C:9]([CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:26])[CH3:25])[CH2:20][CH2:19]2)[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2F)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[H][H].O>CN(C)C=O>[C:24]([N:21]1[CH2:22][CH2:23][CH:18]([C:9]2[C:10]3[C:15](=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=2)[CH2:19][CH2:20]1)(=[O:26])[CH3:25]
Reactant: CC(=O)N1CCC(C(=NNc2ccccc2)c2ccc(F)cc2F)CC1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N1CCC(c2nn(-c3ccccc3)c3cc(F)ccc23)CC1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 84.7 %

Procedure:
To a stirred solution of 3.0 g of 1-acetyl-4-(2,4-difluorobenzoyl)piperidine phenylhydrazone in 30 ml of dimethylformamide, under nitrogen, was added 0.44 g of a 50% oil dispersion of sodium hydride. The reaction mixture was heated, and at about 40° C. a vigorous evolution of hydrogen occurred. The temperature was then raised to 80° C. and held there for 1.5 hrs. The reaction mixture was poured into water and the aqueous suspension was extracted with ethyl acetate. The ethyl acetate extracts were washed with water, dried over anhydrous magnesium sulfate and concentrated to yield an oil. The oil was combined with the oil from another experiment and a total of 13.5 g of material was chromatographed on a Water's Prep LC 500. Two silica gel columns were utilized and dichloromethane-methanol (3%) was used as the eluent. The appropriate fractions were evaporated. The residue was recrystallized twice from isopropyl alcohol-water (one charcoal treatment) to yield 2.4 g (18%) of product, mp 126°-128° C.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1F)=O.[NH2:14][NH2:15].CCOC(C)=O>C(O)CO>[CH3:1][C:2]1[C:4]2[C:5](=[CH:6][CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=2)[NH:15][N:14]=1
Reactant: CC(=O)c1cc([N+](=O)[O-])ccc1F
Reactant: NN
Solvent: OCCO
Solvent: CCOC(C)=O
Product: Cc1n[nH]c2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.5 %

Procedure:
A solution of 2-fluoro-5-nitroacetophenone (1.57 g, 8.6 mmol) in ethylene glycol (50 mL) was added hydrazine (0.29 g, 9.0 mmol) was stirred for 2 h at room temperature and then heated at 165° C. for 24 h. The reaction mixture was cooled to room temperature, poured over EtOAc (100 mL), and extracted with H2O (2×100 mL). The organic layers was dried over Na2SO4 and the solvent was removed in vacuo. The crude product was purified by silica gel chromatography to afford a light yellow solid (0.8 g, 53%) Rf=0.2 (EtOAc/hexane, 1/3). 1H NMR CDCl3 δ 8.63 (s, 1H), 8.23 (d, 2H, J=3 Hz), 7.46 (d, 1H, J=3 Hz), 2.60 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[C:8]1(B2OC(C)(C)C(C)(C)O2)[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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>[C:8]1([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1
Reactant: Brc1cccnc1
Reactant: CC1(C)OB(C2=CCCCC2)OC1(C)C
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: C1=C(c2cccnc2)CCCC1
Yield: 90.9 %

Procedure:
A solution of 3-bromopyridine (0.38 g, 2.40 mmol), 2-cyclohex-1-en-1-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.50 g, 2.40 mmol), tetrakis(triphenylphosphine)palladium (0) (0.14 g, 0.12 mmol) and cesium carbonate (1.72 g, 5.29 mmol) in 1,4-dioxane (8.0 mL) and water (4.0 mL) was stirred at 90° C. for 4 hours. After allowing to cool, the reaction solution was subjected to extraction with ethyl acetate (50 mL), and the organic layer was dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with column chromatography (hexane/ethyl acetate=2:1) to yield the title compound (347.3 mg, 99%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])=[O:9])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35].O>C(Cl)Cl>[CH2:37]([O:36][C:34](=[O:35])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8](=[O:9])[C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])[CH:7]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(NC(=O)OCc2ccccc2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Compound 494 (0.06 g, 0.16 mmol) was suspended in dry CH2Cl2 (1.5 mL) under an argon atmosphere in a screw cap vessel. K2CO3 (0.044 g, 0.32 mmol) was added followed by benzyl chloroformate (0.046 mL, 0.032 mmol). The suspension was stirred for 18 h at room temperature. H2O and CH2Cl2 were added and the phases were separated. The water phase was washed with CH2Cl2 (×2) and the combined organic phases were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 1:4 as the eluent. This afforded the title compound as yellow oil. 13C NMR (CD3OD) δ 198.3, 161.0 (dd), 157.8 (dd), 155.8, 151.1, 141.1, 138.0, 136.2, 135.0, 132.8, 132.7, 129.5, 129.1, 129.0, 128.7, 127.3 (dd), 126.0 (dd), 122.3, 120.6, 116.7, 112.9, 112.6 (dd), 105.7 (dd), 67.6, 19.7
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12](=[O:30])[N:13]([CH2:15][CH2:16][O:17][C:18]3[C:27]4[C:22](=[CH:23][C:24]([O:28][CH3:29])=[CH:25][CH:26]=4)[N:21]=[CH:20][CH:19]=3)[CH:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].C(N(CC)CC)C.[C:38](Cl)(=[O:44])[O:39][CH2:40][CH:41]([CH3:43])[CH3:42]>C(Cl)Cl>[CH3:29][O:28][C:24]1[CH:23]=[C:22]2[C:27]([C:18]([O:17][CH2:16][CH2:15][N:13]3[C:12](=[O:30])[CH:11]=[CH:10][C:9]([C:4]4[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([NH:1][C:38](=[O:44])[O:39][CH2:40][CH:41]([CH3:43])[CH3:42])[CH:3]=4)=[CH:14]3)=[CH:19][CH:20]=[N:21]2)=[CH:26][CH:25]=1
Reactant: CC(C)COC(=O)Cl
Reactant: COc1ccc2c(OCCn3cc(-c4ccc(C)c(N)c4)ccc3=O)ccnc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2c(OCCn3cc(-c4ccc(C)c(NC(=O)OCC(C)C)c4)ccc3=O)ccnc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 70.1 %

Procedure:
To a solution of 5-(3-amino-4-methylphenyl)-1-(2-(7-methoxyquinolin-4-yloxy)ethyl)pyridin-2(1H)-one (0.10 g, 0.25 mmol) in 10 mL of CH2Cl2 at rt was added triethylamine (0.083 ml, 0.60 mmol) followed by isobutyl chlorocarbonate (0.048 ml, 0.37 mmol). The reaction was stirred at rt for 4 hours and was then concentrated in vacuo. The residue was dissolved in 50 mL of EtOAc and the resulted organic phase was washed with 20 mL of satd. NaHCO3 followed by 20 mL of brine. The organic solution was dried over Na2SO4 and concentrated in vacuo. The residue was washed with 50% hex/EtOAc to give white solid as desired product (0.0879 g, 70% yield). MS (ESI pos. ion) m/z (MH+): 502.1. Calc'd Exact Mass for C29H31N3O5: 501.23.
Reaction SMILES: [C:1]([CH:6]([CH2:10]C#C)[C:7](=O)[CH3:8])([O:3][CH2:4][CH3:5])=O.C(=O)(O)O.[NH2:17][C:18]([NH2:20])=[NH:19].CC(C)=O>CS(C)=O>[CH3:8][C:7]1[C:6]2[CH:10]=[C:4]([CH3:5])[O:3][C:1]=2[N:17]=[C:18]([NH2:20])[N:19]=1
Reactant: N=C(N)N
Reactant: C#CCC(C(C)=O)C(=O)OCC
Agent: O=C(O)O
Solvent: CS(C)=O
Solvent: CC(C)=O
Product: Cc1cc2c(C)nc(N)nc2o1
Yield: 8.3 %

Procedure:
A mixture of 4.0 g 3-carbethoxy-5-hexyn-2-one and 2.4 g guanidine carbonate was heated in 6 ml dimethylsulfoxide under a nitrogen atmosphere at 110°-120° for 2 hours. The solution was then cooled, acetone added and the solid collected then rinsed with water to afford 0.27 g of 4,6-dimethylfuro[2,3-d]pyrimidin-2-amine: m.p. 263°-265°. The above filtrates were diluted further with water and the deposited solid was collected and dried to give 0.44 g of 2-amino-6-methyl-5-(2-propynyl)-4(3H)pyrimidinone, m.p. 245°-249°. Absorptions at 2.1 (triplet), 2.55 (singlet), and 3.45 (doublet) ppm in the nuclear magnetic resonance spectrum (60 MHz) indicated the title compound.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[C:8]1([C:14]2[N:15]=[C:16]([CH:25]3[NH:29][C:28](=[O:30])[CH2:27][CH2:26]3)[O:17][C:18]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Br[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40]>Cl>[C:8]1([C:14]2[N:15]=[C:16]([CH:25]3[CH2:26][CH2:27][C:28](=[O:30])[N:29]3[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40])[O:17][C:18]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C1CCC(c2nc(-c3ccccc3)c(-c3ccccc3)o2)N1
Reactant: COC(=O)CCCCCCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCN1C(=O)CCC1c1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 81 %

Procedure:
NaH (820 mg of a 50% dispersion, 17 mmol) was covered with DMF (80 mL) and 5-(4,5-diphenyl-2-oxazolyl)-2-pyrrolidinone (4.00 g, 13 mmol) added. The mixture was stirred at about 120° C. for about 15 minutes, cooled to room temperature and methyl 8-bromooctanoate (3.42 g, 14.5 mmol) added. The mixture was heated at about 110° C. for about 1 hour, cooled, diluted with 1N HCl and extracted with Et2O (3 times). The combined extracts were washed with H2O (3 times), dried over Na2SO4 and the solvent evaporated. The residual oil was chromatographed on a column of silica gel using Et2O as eluent to afford methyl 2-(4,5-Diphenyl-2-oxazolyl)-5-oxo-l-pyrrolidineoctanoate (4.85 g, 80%) as an oil. IR (Film) 1740 (CO2CH3), 1695 (N.CO) cm-1 ; 1H NMR (CDCl3) δ1.18-1.60 (10H, m, CH2), 2.20 (2H, t, J=7 Hz, CH2CO2CH3), 2.30-2.55 (3H, m, CH2 of ring), 2.73 (1H, m, CH2 of ring), 3.00 (2H, m, NCH2 of side chain), 3.61 (3H, s, CO2CH3), 4.86 (1H, m, CHN of ring), 7.25-7.40 (6H, m, aromatic H) , 7.50-7.70 (4H, m, aromatic H), MS m/z 461 (MH+).
Reaction SMILES: [CH3:1]CCCCC.[H-].[Na+].[Br:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[CH3:19])[C:13]([OH:15])=[O:14]>CN(C=O)C.CCOC(C)=O>[Br:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[CH3:19])[C:13]([O:15][CH3:1])=[O:14]
Reactant: Cc1ccc(C(=O)O)cc1Br
Reactant: CCCCCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C)c(Br)c1
Temperature: 25 °C
Yield: 63 %

Procedure:
To a mixture of hexane washed 60% disp. NaH (2.28 g, 57 mmol) in DMF (250 mL), 0 C., was added 3-bromo-4-methylbenzoic acid (10.03 g, 46.6 mmol) After 30 min, the reaction was warmed to room temperature, diluted with EtOAc (1.25 L) and washed with H2O (5×250 mL). The organic layer was MgSO4 dried and concentrated. The residue was chromatographed (˜375 g silica, 10% EtOAc/CH2Cl2) to give the desired product as a solid (16.68 g, 63%); IR(CHCl3): 1260, 1294, 1437, 1721 cm−1; NMR(300 MHz, CDCl3): 2.46 (s, 3H); 3.92 (s, 3H); 7.31 (d, 1H, J=7.8 Hz); 7.88 (d, 1H, J=7.8 Hz); 8.21 (s, 1H); MS(FD): 228.0.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][N:13]=[C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]([C:25]3[CH:26]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[C:38]=4[Cl:44])[C:27]([C:33]([O:35][CH3:36])=[O:34])=[C:28]([CH3:32])[NH:29][C:30]=3[CH3:31])=[O:24])[CH:11]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H].C>C(O)C.[Ni].C(OCC)(=O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][N:13]=[C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]([C:25]3[CH:26]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[C:38]=4[Cl:44])[C:27]([C:33]([O:35][CH3:36])=[O:34])=[C:28]([CH3:32])[NH:29][C:30]=3[CH3:31])=[O:24])[CH:11]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCCCOc2cc(-c3ccc([N+](=O)[O-])cc3)[nH]n2)C1c1cccc(Cl)c1Cl
Reactant: [H][H]
Agent: [Ni]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCCCOc2cc(-c3ccc(N)cc3)[nH]n2)C1c1cccc(Cl)c1Cl
Yield: 54 %

Procedure:
12.86 g (20 mmole) of 1,4-dihydro-2,6-dimethyl-4-(2,3-dichlorophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-(5-p-nitrophenyl-3-pyrazolyloxy)hexyl ester (Example 60) was dissolved in 100 ml of ethanol, to which was added 5 ml of Raney nickel, and catalytic hydrogenation was effected at room temperature and atmospheric pressure, thereby 1350 ml (60 mmole) of hydrogen was absorbed. The Raney nickel was filtered off from the reaction mixture, and the filtrate was concentrated under reduced pressure to obtain a pale yellow oily residue. This residue was purified by chromatography on a silica gel column using a mixed solution of chloroform-methanol (the ratio by volume of 3:1) as an eluent, and the fractions containing the intended compound were concentrated under reduced pressure to obtain a pale yellow oily residue. This residue was dissolved in ethyl acetate, and after adding 5 g of activated charcoal, stirred well, and filtered. The filtrate was concentrated to dryness under reduced pressure to obtain 6.63 g (yield 54.0%) of the 1,4-dihydro-2,6-dimethyl-4 -(2,3-dichlorophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-(5-p-aminophenyl-3-pyrazolyloxy)hexyl ester as a pale yellow powder.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH:4]1[CH2:18][OH:19])[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3.[H][H].Cl>O.CO.[Pd]>[NH2:1][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH:4]1[CH2:18][OH:19])[NH:11][C:10](=[O:16])[CH2:9][CH2:8]3
Reactant: [H][H]
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CN)C2CO
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: Cc1cc2c(c3c1NC(=O)CC3)OC(CN)C2CO
Yield: 77.3 %

Procedure:
(2RS,3SR)-2-Aminomethyl-3-hydroxymethyl-5-methyl-2,3,6,7-tetrahydrofuro-[2,3-f]quinoline-7-one (550.0 mg, 2.12 mmol) was dissolved in water (50 ml). To the solution, 10% palladium-on-carbon (500 mg) was added, followed by stirring at 80° C. for 2 hours in the atmosphere of hydrogen. The reaction mixture was filtered, and the filtrate was condensed under reduced pressure, and the residue was dissolved in methanol. HCl--methanol solution was added thereto to convert the mixture to a hydrochloric acid salt. The salt was condensed, and recrystallized from methanol--ether. As a result, 430.1 mg of the title compound was obtained as colorless powdery crystals (78.2%).
Reaction SMILES: P(Cl)(Cl)Cl.[NH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[Cl:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=1>N1C=CC=CC=1>[Cl:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:5][CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[O:20])=[CH:17][CH:16]=1
Reactant: NCCN1CCOCC1
Reactant: O=C(O)c1ccc(Cl)cc1
Solvent: ClP(Cl)Cl
Solvent: c1ccncc1
Product: O=C(NCCN1CCOCC1)c1ccc(Cl)cc1
Temperature: 90 °C

Procedure:
2.8 G. of phosphorus trichloride in 20 ml. of pyridine are added to 5.2 g. of N-(2-aminoethyl)-morpholine in 80 ml. of pyridine at -5° C. over a period of 15 minutes, with stirring. The mixture is stirred for 30 minutes at -5° C. and 90 minutes at room temperature. Then, 3.1 g. of p-chlorobenzoic acid are added and the mixture is heated for 3 hours at 90° C. This mixture is evaporated to dryness and the residue is evaporated twice more with 100 ml. of toluene each time. The solid residue is taken up in 100 ml. of methylene chloride and 100 ml. of ice-water and the mixture is rendered basic with 3-N sodium hydroxide solution. The phases are separated and the methylene chloride extract is washed with water, dried over sodium sulfate and evaporated. The residue is recrystallized from isopropanol and 1.3 g. of p-chloro-N-(2-morpholinoethyl)-benzamide are obtained, which is identical to the product obtained in Example 1.
Reaction SMILES: [OH:1][C@@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@H:4]([CH3:8])[CH2:3]1.CCN(C(C)C)C(C)C.[CH3:34][N:35]([CH3:41])[C@@H:36]1[CH2:40][CH2:39][NH:38][CH2:37]1>>[OH:1][C@@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:38]4[CH2:39][CH2:40][C@@H:36]([N:35]([CH3:41])[CH3:34])[CH2:37]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@H:4]([CH3:8])[CH2:3]1
Reactant: C[C@H]1CCC[C@@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Reactant: CN(C)[C@@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CCC[C@@](O)(CNC(=O)c2c(Cl)ccc3nc(N4CC[C@@H](N(C)C)C4)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid ((1S,3S)-1-hydroxy-3methyl-cyclohexylmethyl)-amide, DIPEA and (R)-3-dimethylamino-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 4.16 (s, 1H), 4.00 (t, 2H), 3.80 (t, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.22 (s, 6H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27 (t, 1H), 1.07 (t, 1H), 0.83 (d, 3H). m/z: 446 [M+H]