Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)C.[CH2:4]([CH:6]1[CH2:15][CH:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([OH:16])[CH2:13]2)[CH2:8][N:7]1[CH2:19][C:20]1[CH:25]=[C:24](OC)[C:23](OC)=[C:22]([O:30][CH3:31])[CH:21]=1)[CH3:5]>C1COCC1.[Pd]>[CH2:4]([CH:6]1[CH2:15][CH:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([OH:16])[CH2:13]2)[CH2:8][N:7]1[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:30][CH3:31])[CH:21]=1)[CH3:5]
Reactant: CCC1CC2CC(O)=C(OC)C=C2CN1Cc1cc(OC)c(OC)c(OC)c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCC1CC2CC(O)=C(OC)C=C2CN1Cc1cccc(OC)c1

Procedure:
Pd/C (10%, 30.3 mg), THF (2.0 mL) and ethanol (2.0 mL) were reacted with 263 (292, 0.7 mmol) in THF (4.0 mL) as described for the synthesis of 264. The residue was purified by flash column chromatography using Flashmaster (SiO2: 5 g, hexane 100% to hexane/ethyl acetate 60:40). The title compound was obtained as yellow oil (211 mg, 92%). 1H NMR (400 MHz, CDCl3) δ 0.98 (3H, t, J 7.2, CH2CH3), 1.42 (1H, sept, J 7.1, one of CH2CH3), 1.69 (1H, sept, J 6.8, one of CH2CH3), 2.52 (1H, dd, J 16.4, 6.3, one of ArCH2CH), 2.80 (1H, dd, J 16.4, 5.1, one of ArCH2CH), 2.86-2.90 (1H, m, CHN), 3.58-3.73 (4H, m, 2×ArCH2N), 3.80 (6H, s, 2×OCH3), 6.42 (1H, s, CH), 6.64 (1H, s, CH), 6.79 (1H, dd, J 8.0, 2.2, CH), 6.92-6.98 (2H, m, 2×CH), 7.22 (1H, t, J 7.8, CH). 13C NMR (100 MHz, CDCl3) δ 11.1, 23.0, 29.5, 50.9, 55.0, 55.1, 55.9, 58.5, 108.8, 112.3, 114.1, 114.6, 121.1, 125.3, 126.7, 129.1, 141.5, 143.9, 144.9, 159.6. LC/MS (ES+) tr 1.13 min; m/z 328.10 ((M+H)+, 100%); MeOH/H2O 95:5 (1.0 mL/min), HPLC tr 2.86 min (>99%); CH3CN/H2O 90:10 (1.0 mL/min).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)[C:4]([O:6][CH3:7])=[O:5].[CH:13]([O:15][CH2:16][CH3:17])=[CH2:14]>C(OCC)(=O)C.P(Cl)(Cl)(Cl)=O>[CH2:13]([O:15][CH2:16][CH2:17][O:1][N:2]=[C:3]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)[C:4]([O:6][CH3:7])=[O:5])[CH3:14]
Reactant: C=COCC
Reactant: COC(=O)C(=NO)c1cccs1
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOCCON=C(C(=O)OC)c1cccs1
Reaction time: 0.33 h
Yield: 100 %

Procedure:
To a stirred mixture of methyl 2-hydroxyimino-2-(thien-2-yl)acetate syn-isomer (3.98 g.) and ethyl vinyl ether (2.5 mls) in ethyl acetate (25 mls) was added phosphorous oxychloride (2 drops). After 20 mins. at 50° the ethyl acetate was washed with saturated sodium bicarbonate solution, dried over sodium sulphate and evaporated to an oil, giving methyl 2-(1-ethoxy)ethoxyimino-2-(thien-2-yl)acetate (syn-isomer) (5.7 g; 100%) λmax. (EtOH) 289 nm (ε 11,700), τ (CDCl3 ; 60 MHz) 2.61 (multiplet; thienyl H5), 2.82 to 2.97 (multiplet; thienyl H3 and H4), 4.64 (quartet, J5 Hz; ##STR57## 6.06 (singlet, --COOCH3), 6.24 (quartet, J 7 Hz, OCH2), 8.56 (doublet J 5 Hz; CH--CH3), 8.79 (triplet, J 7 Hz; O.CH2CH3).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][C:14]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:15]=3[C:16]#[N:17])=[CH:10][CH:11]=2)[CH:6]=[N:5]1)(=O)C.Cl.[OH-].[Na+].O>CO>[NH:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][C:14]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:15]=3[C:16]#[N:17])=[CH:10][CH:11]=2)[CH:6]=[N:5]1
Reactant: CC(=O)n1ncc2cc(Oc3ccc(F)cc3C#N)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: N#Cc1cc(F)ccc1Oc1ccc2[nH]ncc2c1
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 91.2 %

Procedure:
2-(1-Acetyl-1H-indazol-5-yloxy)-5-fluorobenzonitrile (369.4 mL, 221.7 mmol) in 370 mL MeOH was treated with 1.0 N HCl (243.8 mL, 243.8 mmol) at ambient temperature. The brown suspension was warmed to 70° C. for 28 hours and then cooled to 0° C. Sodium hydroxide (254.9 mL, 254.9 mmol) was added, followed by water (400 mL). The reaction was stirred at 0° C. for 15 minutes and then filtered. The solids were washed with water (1.5 and dried under high vacuum at 40° C. for 72 hours to provide 51.2 g of the desired product as a tan solid (91% yield for steps 2 and 3).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1([C:26](Cl)=[O:27])[C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2>>[S:4]1[CH:5]=[CH:6][CH:7]=[C:3]1[CH2:2][NH:1][C:26]([C:13]1([CH2:12][CH2:11][CH2:10][CH2:9][Br:8])[C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:27]
Reactant: NCc1cccs1
Reactant: O=C(Cl)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: O=C(NCc1cccs1)C1(CCCCBr)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 2-(aminomethyl)-thiophene and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([O-:13])=O)[S:10][C:3]=12.[Li+].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:11]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH:8]=2)=[O:13])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Agent: [Li+]
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc3nccc(Cl)c3s2)CC1

Procedure:
The title compound was prepared from lithium 7-chloro-thieno[3,2-b]pyridine-2-carboxylate and piperazine-1-carboxylic acid tert-butyl ester by a procedure analogous to Example 1B. MS: 383 (MH+); HPLC Rf: 5.69; HPLC purity: 99%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[N:6]([CH:8]=[C:9]([C@@H:11]3[CH2:13][C@@H:12]3[C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]=3)[N:10]=2)[N:7]=1.Br[C:31]1[CH:43]=[CH:42][C:34]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[C:33]([F:44])[CH:32]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[N:6]([C:8]([C:31]3[CH:43]=[CH:42][C:34]([C:35]([O:37][C:38]([CH3:41])([CH3:39])[CH3:40])=[O:36])=[C:33]([F:44])[CH:32]=3)=[C:9]([C@@H:11]3[CH2:13][C@@H:12]3[C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]=3)[N:10]=2)[N:7]=1
Reactant: Clc1cc(N2CCOCC2)c2nc([C@@H]3C[C@@H]3c3ccc4ccccc4n3)cn2n1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1F
Product: CC(C)(C)OC(=O)c1ccc(-c2c([C@@H]3C[C@@H]3c3ccc4ccccc4n3)nc3c(N4CCOCC4)cc(Cl)nn23)cc1F

Procedure:
Compound 79d (100 mg, 0.246 mmol) was coupled with tert-butyl 4-bromo-2-fluorobenzoate (102 mg, 0.370 mmol) using the procedures described in Example 20, Step A to afford compound 81a. Mass Spectrum (LCMS, ESI pos.): Calcd. for C33H31ClFN5O3: 600.2 (M+H). found: 600.2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13]([OH:20])=[C:14]([Cl:19])[CH:15]=3)[O:10][CH:9]=2)=[CH:4][CH:3]=1.C1N2CN3CN(C2)CN1C3.Cl.O.[C:33](O)(=[O:35])C>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17](=[O:18])[C:16]3[C:11](=[C:12]([CH:33]=[O:35])[C:13]([OH:20])=[C:14]([Cl:19])[CH:15]=3)[O:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: O=c1c(-c2ccc(Br)cc2)coc2cc(O)c(Cl)cc12
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: O
Product: O=Cc1c(O)c(Cl)cc2c(=O)c(-c3ccc(Br)cc3)coc12
Temperature: 100 °C

Procedure:
3-(4-Bromo-phenyl)-6-chloro-7-hydroxy-chromen-4-one (0.35 g, 1 mmol) and hexamethylene tetramine (0.14 g, 1 mmol) were dissolved in glacial acetic acid (20 ml) and heated overnight at 100° C. Warm 6M HCl (10 ml) was added and the mixture heated for a further hour before being poured in to water. The precipitate formed was filtered, washed and dried to provide the pure desired product as a pale brown solid.
Reaction SMILES: ClCC([O:5][C:6]1[CH:14]=[CH:13][C:12]2[N:11]([CH3:15])[C:10]3[C:16](=O)[CH2:17][CH2:18][C:9]=3[C:8]=2[CH:7]=1)=O.CC([O-])=O.[Na+].Cl.[NH2:26][OH:27]>CCO.O>[OH:27][N:26]=[C:16]1[C:10]2[N:11]([CH3:15])[C:12]3[CH:13]=[CH:14][C:6]([OH:5])=[CH:7][C:8]=3[C:9]=2[CH2:18][CH2:17]1
Reactant: NO
Reactant: Cn1c2c(c3cc(OC(=O)CCl)ccc31)CCC2=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cn1c2c(c3cc(O)ccc31)CCC2=NO

Procedure:
7-Chloroacetyloxy-1,4-dihydro-4-methylcyclopent[b]indol-3(2H)-one (8.0 g) was suspended in EtOH (200 ml) and a solution of NaOAc (15.6 g) in water (25 ml) and a solution of hydroxylamine hydrochloride (8.0 g) in water (25 ml) were added and the mixture was refluxed for 3 hours. The mixture was concentrated in vacuo and the residue was recrystallized from 95% EtOH to provide 3-hydroxyimino-4-methyl-1,2,3,4-tetrahydrocyclopent[b]indol-7-ol as an off-white solid. The oxime was dissolved in tetrahydrofuran (100 ml), and thereafter acetic anhydride (8.1 g) and 4-dimethylaminopyridine (400 mg) were added and the mixture was stirred under nitrogen at ambient temperature overnight. The mixture was concentrated in vacuo, CH2Cl2 (100 ml) was added and the solution was washed successively with water (50 ml), 5% NaHCO3 (50 ml) and water (50 ml). After drying (Na2SO4), the solvent was removed in vacuo and the product recrystallized from EtOH to provide 3-acetyloximino-4-methyl-1,2,3,4-tetrahydrocyclopent[b]indol-7-yl acetate (1.7 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:32]([F:35])([F:34])[F:33])[O:14][N:13]=[C:12]([C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]([C:25]([NH:27][CH2:28][CH2:29][S:30][CH3:31])=[O:26])=[CH:17][CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].ClC1C=C(C2(C(F)(F)F)ON=C(C3C4C(=CC=CC=4)C(C(NCCS(C)(=[N:66][C:67](=[O:72])[C:68]([F:71])([F:70])[F:69])=O)=O)=CC=3)C2)C=C(Cl)C=1.FC(F)(F)C(N)=O.C(OI(C1C=CC=CC=1)OC(=O)C)(=O)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:32]([F:33])([F:34])[F:35])[O:14][N:13]=[C:12]([C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]([C:25]([NH:27][CH2:28][CH2:29][S:30]([CH3:31])=[N:66][C:67](=[O:72])[C:68]([F:71])([F:70])[F:69])=[O:26])=[CH:17][CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8]
Reactant: CS(=O)(CCNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12)=NC(=O)C(F)(F)F
Reactant: CSCCNC(=O)c1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Agent: CC(=O)OI(OC(C)=O)c1ccccc1
Agent: NC(=O)C(F)(F)F
Solvent: ClCCl
Product: CS(CCNC(=O)c1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)c2ccccc12)=NC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
To a stirred suspension of 4-[4,5-dihydro-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-(methylthio)ethyl]-1-naphthalenecarboxamide (prepared analogously as described for the compound of Example 3, Step A) (200 mg), 2,2,2-trifluoroacetamide (80 mg), MgO (57 mg), and Rh2(OAc)4 (4 mg) in dichloromethane (4 mL) was added PhI(OAc)2 (172 mg) at room temperature. The resulting mixture was stirred overnight at room temperature, then filtered through a short pad of Celite® diatomaceous filter aid, and rinsed with ethyl acetate. The filtrate was concentrated, and the residue was purified by column chromatography on silica gel using hexanes/ethyl acetates (1:1 to 1:4) as eluent to afford the title compound as a semisolid (70 mg, 30% yield).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([C:16]([O:18]CC)=[O:17])=[C:5]2[C@@H:4]2[CH2:21][CH2:22][CH2:23][N:3]12.[OH-].[Na+].Cl>C(O)C.O>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([C:16]([OH:18])=[O:17])=[C:5]2[C@@H:4]2[CH2:21][CH2:22][CH2:23][N:3]12
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1ccccc1-2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ncn2c1[C@@H]1CCCN1C(=O)c1ccccc1-2

Procedure:
A solution of 12.45 g (0.04 mol) of ethyl (S)-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate and 1.6 g (0.04 mol) of sodium hydroxide in 100 ml of ethanol and 25 ml of water is heated to boiling under reflux for 30 minutes. Subsequently, 40 ml of 1 N hydrochloric acid are added thereto and the mixture is evaporated to half of the volume. The crystals which thereby precipitate are filtered off under suction, washed with water and dried. There is obtained (S)-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylic acid of decomposition point 225°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:27]4[CH:28]=[CH:29][C:24]([CH3:23])=[CH:25][CH:26]=4)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Br)c3O2)cc1
Reactant: Cc1ccc(B(O)O)cc1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(-c2cccc3c2OC(COS(=O)(=O)c2ccc(C)cc2)C3)cc1
Yield: 85 %

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (11.2 g, 29.22 mmol) with 4-methylphenylboronic acid (5.96 g, 43.84 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (1.15 g, 1.46 mmol), and potassium carbonate (10.10 g, 73.07 mmol) generally according to the procedure described for Intermediate 37 provided 9.8 g (85%) of (±)-[7-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. mp 145-147° C.; Anal. calcd. for C23H22O4S: C, 70.03; H, 5.62. Found: C, 69.91; H, 5.7.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][CH:23]([CH3:29])[NH:24]2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][CH:23]([CH3:29])[N:24]2[C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: CC1Cc2c(F)cccc2N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC1Cc2c(F)cccc2N1C(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Yield: 52.6 %

Procedure:
The product is prepared by following the procedure described in example 1c using 0.2 g of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 127 mg of (+)-4-fluoro-2-methyl-2,3-dihydro-1H-indole [reference example 8c, step 6c] and 0.20 g of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 123 μl of pyridine and 3.5 ml of N,N-dimethylformamide. 0.15 g of (−)-2-{2-[4-fluoro-2-methyl-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}-6-(morpholin-4-yl)pyrimidin-4(3H)-one is thus obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH2:10][C:9]([C:13]([OH:15])=[O:14])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1>CO>[C:1]1([N:7]2[C:11](=[O:12])[C:10](=[CH:21][C:20]3[CH:23]=[CH:24][C:17]([OH:16])=[CH:18][CH:19]=3)[C:9]([C:13]([OH:15])=[O:14])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: O=C(O)C1=NN(c2ccccc2)C(=O)C1
Solvent: CO
Product: O=C(O)C1=NN(c2ccccc2)C(=O)C1=Cc1ccc(O)cc1
Temperature: 25 °C

Procedure:
204 g (1 mole) of 1-phenyl-3-carboxy-2-pyrazolin-5-one and 122 g (1 mole) of p-hydroxybenzaldehyde were dissolved in 1000 ml of methanol. After a few minutes of refluxing the dye started crystallizing and after 1 h of boiling the reaction mixture was cooled to room temperature. The dye was filtered with suction and rinsed with methanol.
Reaction SMILES: [NH:1]1[CH2:10][CH2:9][CH2:8][C:7]2[N:6]=[CH:5][C:4]3[CH:11]=[CH:12][CH:13]=[CH:14][C:3]=3[C:2]1=2.[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>[OH-].[K+]>[C:15]([N:1]1[CH2:10][CH2:9][CH2:8][C:7]2[N:6]=[CH:5][C:4]3[CH:11]=[CH:12][CH:13]=[CH:14][C:3]=3[C:2]1=2)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1ccc2c3c(ncc2c1)CCCN3
Reactant: O=C(Cl)c1ccccc1
Agent: [K+]
Agent: [OH-]
Product: O=C(c1ccccc1)N1CCCc2ncc3ccccc3c21
Yield: 86.8 %

Procedure:
A stirred solution of 1,2,3,4-tetrahydrobenzo[c]-1,5-naphthyridine (4.6 g) and KOH-dried pyridine (50 ml) was treated dropwise over one minute with benzoyl chloride (8.4 g). A crystalline precipitate formed. The stirred suspension was heated (steam bath) for 1.25 hours and the resultant solution was then stirred overnight at ambient temperature during which a crystalline precipitate formed. The mixture was decanted into water (200 ml), basified with 10% sodium hydroxide solution and extracted with dichloromethane. The dried (Na2SO4) organic phase was filtered and evaporated to dryness (7.47 g of crystalline solid). Recrystallization from toluene afforded 6.25 g of crystals, m.p. 208.5°-210.5° C. An aliquot of the material (4.81 g) was further purified by preparative HPLC (silica gel, eluted with ethyl acetate). The appropriate fractions were concentrated and the residue was recrystallized from toluene (100 ml) to give 4.14 g of crystals, m.p. 208°-210° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[CH3:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[O:27][C:26]([C:31](O)=[O:32])=[CH:25][C:24]2=[O:34]>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:31]([C:26]1[O:27][C:28]2[C:23]([C:24](=[O:34])[CH:25]=1)=[CH:22][C:21]([CH3:20])=[CH:30][CH:29]=2)=[O:32]
Reactant: Cc1ccc2oc(C(=O)O)cc(=O)c2c1
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Product: Cc1ccc2oc(C(=O)Nc3ccc(N4CCC(N5CCCC5C)C4)cc3C)cc(=O)c2c1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 6-methyl-4-oxo-4H-chromene-2-carboxylic acid. MS: 446.4 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[CH2:20][N:8]2[C:9](=[O:19])[CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:12]=[C:7]2[N:6]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([NH:27][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:22]=2)[CH2:5]1.[CH3:36][C:37]([CH3:39])=O.ClCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH:37]([NH:1][CH2:2][CH2:3][CH:4]1[CH2:20][N:8]2[C:9](=[O:19])[CH:10]=[C:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:12]=[C:7]2[N:6]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([NH:27][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:22]=2)[CH2:5]1)([CH3:39])[CH3:36]
Reactant: CC(C)=O
Reactant: NCCC1CN(c2ccnc(NCCc3ccccc3)n2)c2nc(-c3ccccc3)cc(=O)n2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)NCCC1CN(c2ccnc(NCCc3ccccc3)n2)c2nc(-c3ccccc3)cc(=O)n2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 7-(2-Amino-ethyl)-9-(2-phenethylamino-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one (70 mg, 0.15 mmol), acetone (0.02 mL), dichloromethane (0.5 mL) and methanol (0.5 mL) was added sodium triacetoxyborohydride (38 mg, 0.18 mmol) Reaction stirred for 2 h at room temperature. Solvents removed under vacuum. Residue partitioned between dichloromethane and 5% sodium bicarbonate. Organics purified on silica to afford a white solid. M+1=510. 1NMR (CDCl3) d (6H, 1.17 ppm), m (2H, 1.68 ppm), m (1H, 2.32 ppm), m (3H, 2.78 ppm), t (2H, 2.94 ppm), m (1H, 3.55 ppm), dd (2H, 3.70 ppm), d (1H, 4.40 ppm), dd (1H, 4.53 ppm), m (1H, 5.10 ppm), s (1H, 6.60 ppm), m (3H, 7.24 ppm), m (2H, 7.32 ppm), m (3H, 7.44 ppm), m (2H, 7.90 ppm) d (1H, 8.18 ppm).
Reaction SMILES: [Li+].[Cl-].C(COC)OC.Br[C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[C:12]#[N:13].[C:18]1([CH3:26])[CH:23]=[CH:22][C:21]([Mg]Cl)=[CH:20][CH:19]=1>O1CCCC1>[C:18]1([CH3:26])[CH:23]=[CH:22][C:21]([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[C:12]#[N:13])=[CH:20][CH:19]=1
Reactant: N#Cc1ccccc1Br
Reactant: Cc1ccc([Mg]Cl)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: COCCOC
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of MnCl2 (0.25 g, 1.98 mmol) and LiCl (0.17 g, 3.955 mmol) in a mixture of 2 ml of anhydrous tetrahydrofuran and 0.38 ml of dimethoxyethane (3.955 mol) is stirred at room temperature until, after approximately 30 minutes, a homogeneous medium is obtained. The PdCl2/dppp complex (0.0023 g, 0.1 mol %) and the o-bromobenzonitrile (0.72 g, 3 955 mmol) are then added and then a solution of p-tolylmagnesium chloride in tetrahydrofuran (1.80N, 2.86 ml, 5.14 mmol) is added over 30 minutes. After stirring for 30 minutes, the reaction mixture is treated as described in Example 4. The o-(p-tolyl)benzonitrile is thus obtained with a yield of isolated product of 95%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH:16]2[CH2:18][CH2:17]2)=[C:4]([OH:19])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[N:26]1([C:32](Cl)=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>C(C(C)=O)C(C)C>[N:26]1([C:32]([O:19][C:4]2[CH:3]=[C:2]([Cl:1])[N:7]=[N:6][C:5]=2[O:8][C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH:16]2[CH2:18][CH2:17]2)=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Reactant: O=C(Cl)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1OC(=O)N1CCOCC1
Yield: 98.2 %

Procedure:
To 6.50 g (23.5 mmol) of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol were added 39 g of methyl isobutyl ketone and 3.57 g (25.9 mmol) of potassium carbonate, and the resultant mixture was stirred at 50° C. To the mixture was added dropwise 3.87 g (25.9 mmol) of morpholinecarbonyl chloride over one hour. The reaction mixture was subjected to reaction at 50° C. for 4 hours. After completion of the reaction, the resultant opaque mixture was subjected to filtration, and washed with methyl isobutyl ketone, and then the resultant organic phase was quantitatively determined by an HPLC internal standard analysis method, which showed that 9.00 g of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl morpholine-4-carboxylate (yield: 98%) was obtained.
Reaction SMILES: CC1C=C(N2CCN(CCOC3C=CC=CC=3)C2=O)SC=1C(O)=O.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41]([OH:43])=O)=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1.[S:48]1[CH:52]=[CH:51][N:50]=[C:49]1[CH2:53][NH2:54]>>[F:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41]([NH:54][CH2:53][C:49]4[S:48][CH:52]=[CH:51][N:50]=4)=[O:43])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:46][CH:47]=1
Reactant: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: NCc1nccs1
Agent: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1nccs1
Yield: 48 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with thiazol-2-ylmethanamine, the title compound was obtained as a colorless solid in 48% yield: 1H NMR (300 MHz, CDCl3) δ 7.72 (d, J=3.3 Hz, 1H), 7.31-7.23 (m, 3H), 7.07-6.99 (m, 2H), 6.50 (t, J=5.4 Hz, 1H), 6.12 (s, 1H), 4.90 (d, J=5.4 Hz, 2H), 4.43 (s, 2H), 3.84-3.75 (m, 2H), 3.47-3.39 (m, 2H), 2.50 (s, 3H); MS (ES+) m/z 453.1 (M+23).