Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[CH:19]=3)[N:16]=[C:15]([C:25]([OH:27])=O)[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.ClC1C=C(C2N(C3C=NC=CC=3)N=C(C([N:49]3[CH2:54][CH2:53][NH:52][C:51](=[O:55])[CH2:50]3)=O)C=2)C=C(F)C=1.O=C1CNCCN1>>[Cl:24][C:20]1[CH:19]=[C:18]([N:17]2[C:13]([C:4]3[CH:5]=[C:6]([O:8][C:9]([F:10])([F:11])[F:12])[CH:7]=[C:2]([F:1])[CH:3]=3)=[CH:14][C:15]([C:25]([N:49]3[CH2:54][CH2:53][NH:52][C:51](=[O:55])[CH2:50]3)=[O:27])=[N:16]2)[CH:23]=[CH:22][N:21]=1
Reactant: O=C(O)c1cc(-c2cc(F)cc(OC(F)(F)F)c2)n(-c2ccnc(Cl)c2)n1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3cccnc3)n2)CCN1
Agent: O=C1CNCCN1
Product: O=C1CN(C(=O)c2cc(-c3cc(F)cc(OC(F)(F)F)c3)n(-c3ccnc(Cl)c3)n2)CCN1

Procedure:
40 mg (0.08 mmol) of the compound of Example 35A is reacted analogously to the synthesis of the compound of Example 4 with 8 mg (0.08 mmol) of 2-oxopiperazine. 27 mg (71% of theory) of the title compound is obtained.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][C:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[N:7]([C:14]2[N:19]=[C:18]([NH2:20])[C:17]([NH2:21])=[CH:16][N:15]=2)[N:6]=1.Cl[C:27]([O:29][CH3:30])=[O:28].C(OCC)(=O)C>N1C=CC=CC=1>[NH2:20][C:18]1[C:17]([NH:21][C:27](=[O:28])[O:29][CH3:30])=[CH:16][N:15]=[C:14]([N:7]2[C:8]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[C:5]([CH2:4][C:3]3[CH:22]=[CH:23][CH:24]=[CH:25][C:2]=3[F:1])=[N:6]2)[N:19]=1
Reactant: Nc1cnc(-n2nc(Cc3ccccc3F)c3ncccc32)nc1N
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)Nc1cnc(-n2nc(Cc3ccccc3F)c3ncccc32)nc1N
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Under argon, 330 mg (0.98 mmol) of the compound from example 12A were initially charged in pyridine (12 ml), the mixture was cooled to 0° C. and 84 μl (108 mmol) of methyl chloroformate were then added dropwise. The reaction mixture was stirred further at RT overnight, and ethyl acetate was then added. The organic phase was washed twice with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated. The residue was separated by preparative RP-HPLC (acetonitrile:water (+0.1% formic acid) gradient), giving 241 mg (62% of theory) of the target compound as a colorless solid.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.[CH3:13][C:14]([CH3:25])([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:15](OC)=[O:16].C(O)(=O)C>C1COCC1.O>[CH3:13][C:14]([CH3:25])([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:15](=[O:16])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: CCCCCCC(C)(C)C(=O)OC
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCC(C)(C)C(=O)CP(=O)(OC)OC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
Dimethyl methylphosphonate (7.6 g, 0.061 mol) was dissolved in 70 ml anhydrous THF under argon atmosphere. To the mixture stirred at -78° C. was added dropwise n-butyl lithium (1.44N, 42.4 ml, 0.061 mol). After 30 minutes, methyl 2,2-dimethyloctanoate (4.5 g, 0.024 mol) was further added dropwise. After being stirred for 30 minutes the mixture was warmed to room temperature. To the mixture cooled with ice bath were added 3.8 ml of acetic acid and 10 ml of water. After concentration of the reaction mixture, 20 ml of water was added to the residue and the mixture was extracted with ethyl acetate (50 ml×2). The ethyl acetate layers were washed with water (20 ml×1) and with brine (20 ml×1), dried over anhydrous sodium sulfate, and concentrated. Distillation of the residue gave dimethyl 3,3-dimethyl-2-oxononanylphosphonate (5.34 g, 0.0192 mol, 79%, b.p. 137° -140° C./0.6 mmHg). The structure of this product was confirmed by the following data.
Reaction SMILES: [Li][CH3:2].[CH3:3][O:4][C:5]1[CH:16]=[CH:15][C:8]([CH2:9][C@@H:10]([CH2:13][CH3:14])[CH:11]=O)=[C:7]([CH:17]=[CH2:18])[CH:6]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:11]([C@@H:10]([CH:13]=[CH2:14])[CH2:9][C:8]1[CH:15]=[CH:16][C:5]([O:4][CH3:3])=[CH:6][C:7]=1[CH:17]=[CH2:18])[CH3:2]
Reactant: C=Cc1cc(OC)ccc1C[C@H](C=O)CC
Reactant: [Li]C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1cc(OC)ccc1C[C@H](C=C)CC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
MeLi (32 mL, 51 mmol, 1.6 M in diethyl ether) is added to a suspension of methyltriphenylphosphonium bromide (27.8 g, 77.8 mmol) in THF (100 mL) at 0° C. The mixture is stirred at 0° C. for 30 min. Then a solution of (R)-2-(4-Methoxy-2-vinylbenzyl)-butyraldehyde (6.12 g) in THF (50 mL) is added. The mixture is stirred at 0° C. for 1 h. The mixture is partitioned between EtOAc and aq. NH4Cl. The organic extract is dried with MgSO4, concentrated and purified to give the title compound as an oil: 1H NMR (CDCl3) δ 0.85 (t, J=7.3 Hz, 3H), 1.23-1.28 (m, 1H), 1.42-1.47 (m, 1H), 2.09-2.14 (m, 1H), 2.56-2.69 (m, 2H), 3.81 (s, 3H), 4.85 (d, J=17 Hz, 1H), 4.93 (dd, J=2, 10 Hz, 1H), 5.27 (dd, J=1, 11 Hz, 1H), 5.50-5.65 (m, 2H), 6.74 (dd, J=3, 8 Hz, 1H), 6.94 (dd, J=11, 17 Hz, 1H), 6.99 (d, J=8 Hz, 1H), 7.02 (d, J=3 Hz, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:47]=[CH:46][C:7]([O:8][C:9]2[C:14]([F:15])=[C:13]([F:16])[C:12]([C:17]3[C:22]([F:23])=[C:21]([F:24])[C:20]([O:25][C:26]4[CH:31]=[CH:30][C:29]([C:32]([O:34]CC5C=CC=CC=5)=[O:33])=[CH:28][CH:27]=4)=[C:19]([F:42])[C:18]=3[F:43])=[C:11]([F:44])[C:10]=2[F:45])=[CH:6][C:5]=1[O:48]CC1C=CC=CC=1)([O-])=O.[H][H]>O1CCCC1.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:47]=[CH:46][C:7]([O:8][C:9]2[C:10]([F:45])=[C:11]([F:44])[C:12]([C:17]3[C:22]([F:23])=[C:21]([F:24])[C:20]([O:25][C:26]4[CH:27]=[CH:28][C:29]([C:32]([OH:34])=[O:33])=[CH:30][CH:31]=4)=[C:19]([F:42])[C:18]=3[F:43])=[C:13]([F:16])[C:14]=2[F:15])=[CH:6][C:5]=1[OH:48]
Reactant: O=C(OCc1ccccc1)c1ccc(Oc2c(F)c(F)c(-c3c(F)c(F)c(Oc4ccc([N+](=O)[O-])c(OCc5ccccc5)c4)c(F)c3F)c(F)c2F)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2c(F)c(F)c(-c3c(F)c(F)c(Oc4ccc(C(=O)O)cc4)c(F)c3F)c(F)c2F)cc1O
Reaction time: 72 h

Procedure:
49.9 g of 4-(4-nitro-3-benzyloxyphenoxy)-4'-(4-benzyloxycarbonylphenoxy)octafluorobiphenyl prepared in this way (0.065 mol) are dissolved in 400 ml of a mixture of tetrahydrofuran and ethyl acetate (volume ratio 1:1), and 5 g of Pd/C (palladium/carbon) are added to the solution. The mixture is then hydrogenated at room temperature in an autoclave with vigorous stirring using hydrogen at a pressure of 1 bar; after 3 days, the reaction is terminated. The yellow-beige solution is evaporated to half in a rotary evaporator and left to stand overnight at room temperature, during which the reaction product precipitates in crystalline form. The reaction product is then collected and dried for 48 hours under nitrogen at 40° C./10 mbar in a vacuum drying cabinet.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8]([C:17]([O:19]C)=[O:18])[C:9]2[C:14]([CH3:15])=[N:13][N:12]([CH3:16])[C:10]=2[N:11]=1.Cl>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8]([C:17]([OH:19])=[O:18])[C:9]2[C:14]([CH3:15])=[N:13][N:12]([CH3:16])[C:10]=2[N:11]=1
Reactant: COC(=O)c1cc(-c2ccco2)nc2c1c(C)nn2C
Agent: Cl
Product: Cc1nn(C)c2nc(-c3ccco3)cc(C(=O)O)c12
Yield: 79 %

Procedure:
Synthesized using the procedure for 1 except ester 37 was used as the starting material. After the work up and acidifying the aqueous layer with 1N HCl, solid precipitated which was filtered off and dried on high vacuum to provide the title compound (203 mg, 79%) as a beige solid. 100% pure by HPLC. 1H NMR (400 MHz, DMSO-d6) δ 13.91 (s, 1H), 7.91 (s, 1H), 7.85 (s, 1H), 7.33 (d, J=2.9 Hz, 1H), 6.72-6.67 (m, 1H), 3.98 (s, 3H), 2.55 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 166.91, 152.73, 152.00, 147.61, 145.67, 140.08, 135.59, 113.13, 112.56, 111.40, 109.74, 33.82, 15.92. ESI MS: m/z 258.0 (M+H)+.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1.F[C:12]1[CH:21]=[C:20]2[C:15]([C:16](=[O:22])[NH:17][CH:18]=[N:19]2)=[CH:14][CH:13]=1>C1COCC1>[N:8]1[CH:9]=[CH:10][C:5]([CH2:4][O:3][C:12]2[CH:21]=[C:20]3[C:15]([C:16](=[O:22])[NH:17][CH:18]=[N:19]3)=[CH:14][CH:13]=2)=[CH:6][CH:7]=1
Reactant: O=c1[nH]cnc2cc(F)ccc12
Reactant: OCc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1[nH]cnc2cc(OCc3ccncc3)ccc12
Temperature: 120 °C
Yield: 73.7 %

Procedure:
Sodium hydride (0.72 g of a 60% suspension in mineral oil, 18 mmol) was added to a solution of 4-hydroxymethylpyridine (4 g, 36 mmol) in THF (30 ml) and the mixture heated at reflux for 15 minutes. 7-Fluoro-3,4-dihydroquinazolin-4-one (1 g, 6 mmol), (J. Chem. Soc. section B 1967, 449), was added, the THF was removed by evaporation, and the mixture was heated at 120° C. for 30 minutes. The mixture was allowed to cool, diluted with water (40 ml) and was adjusted to pH8 with concentrated hydrochloric acid. The resulting precipitate was collected by filtration, washed with water, then ether and dried under vacuum to give 7-(4-pyridylmethoxy)-3,4-dihydroquinazolin-4-one (1.12 g, 71%). 1H NMR Spectrum (DMSOd6) 5.35(s, 2H); 7.15-7.22(m, 2H); 7.5(d, 2H); 8.05(d, 1H); 8.07 (s, 1H); 8.6(d, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([CH3:8])=[C:3]1[C:9](=[O:13])[CH2:10][C:11]#[N:12].[C:14]1([N:20]=[C:21]=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([CH3:8])=[C:3]1[C:9](=[O:13])[CH:10]([C:21](=[O:22])[NH:20][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11]#[N:12]
Reactant: Cc1cc(C)n(C)c1C(=O)CC#N
Reactant: O=C=Nc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cc(C)n(C)c1C(=O)C(C#N)C(=O)Nc1ccccc1
Reaction time: 8 h

Procedure:
To the suspension of 1.0 g of 1,3,5-trimethyl-β-oxo-2-pyrrolpropionitrile in 30 ml of dry toluene and 0.7 g of anhydrous triethylamine, 0.75 g of phenylisocyanate are added while stirring. The mixture is warmed for 5 minutes at the steam cone and allowed to stand at room temperature overnight. It is filtered, the residue taken up in methanol and the solution acidified with N hydrochloric acid. The precipitate formed is collected, dissolved in N aqueous sodium hydroxide, re-precipitated with 5 N hydrochloric acid and washed with water, to yield the 1,3,5-trimethyl-β-oxo-α-phenylcarbamoyl-2-pyrrolpropionitrile melting at 172°-174°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:18]=3[CH2:19][CH2:20][N:21](C(OC(C)(C)C)=O)[CH2:22]4)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].Cl>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:18]=3[CH2:19][CH2:20][NH:21][CH2:22]4)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)Oc1ccc(-c2noc(-c3cccc4c3CCN(C(=O)OC(C)(C)C)C4)n2)cc1Cl
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(-c2noc(-c3cccc4c3CCNC4)n2)cc1Cl
Yield: 72.5 %

Procedure:
To a solution of tert-butyl 5-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.403 g, 0.858 mmol) in dioxane (17.15 ml) was added a 4N solution of HCl in dioxane (3.86 ml, 15.44 mmol). After about 15 h the reaction mixture was filtered. The resulting solid was partitioned between EtOAc and sat NaHCO3. The organic layer was separated, dried (MgSO4) filtered and concentrated in vacuo to provide 3-(3-chloro-4-isopropoxyphenyl)-5-(1,2,3,4-tetrahydroisoquinolin-5-yl)-1,2,4-oxadiazole (0.230 g, 73%) as a colorless solid. LCMS (Table 1, Method c) Rt=2.00 min, m/z 372 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:9][CH:8]=[CH:7][N:6]=1)=O.[BH4-].[Na+].CO>C1COCC1.CCOC(C)=O>[C:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][CH:11]([C:10]2[C:5]([CH2:3][OH:2])=[N:6][CH:7]=[CH:8][CH:9]=2)[CH2:12][CH2:13]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: COC(=O)c1ncccc1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2cccnc2CO)CC1
Temperature: 0 °C
Yield: 49.9 %

Procedure:
A solution of 3′,4′,5′,6′-tetrahydro-2′H-[3,4]bipyridinyl-2,1′-dicarboxylic acid 1′-t-butyl ester 2-methyl ester (1.9 g, 5.9 mmol, 1.0 eq.) in THF (50 mL) was maintained under nitrogen. To the mixture was added NaBH4 (1.1 g, 29.5 mmol, 5.0 eq.), followed by the dropwise addition of MeOH (15 mL), while stirring at 0° C. The resulting solution was stirred for 30 minutes at room temperature. The resulting solution was diluted with EtOAc (150 mL). The resulting mixture was washed with a saturated solution of NH4Cl (1×100 mL), then with saturated aqueous NaCl (2×100 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with EtOAc/PE (1:1) to yield the title compound (860 mg) as a white solid. MS m/z: [M+H]+ calcd for C16H25N2O3, 293. found 293.
Reaction SMILES: [CH3:1][S:2]([C:4]1[S:8][C:7]([N:9]=[C:10]=[O:11])=[N:6][N:5]=1)=[O:3].[CH2:12]([C:15]([NH:21][CH2:22][CH:23]=[O:24])([CH2:18][CH2:19][CH3:20])[C:16]#[CH:17])[CH2:13][CH3:14]>C1C=CC=CC=1>[CH2:18]([C:15]([N:21]([CH2:22][CH:23]=[O:24])[C:10]([NH:9][C:7]1[S:8][C:4]([S:2]([CH3:1])=[O:3])=[N:5][N:6]=1)=[O:11])([CH2:12][CH2:13][CH3:14])[C:16]#[CH:17])[CH2:19][CH3:20]
Reactant: CS(=O)c1nnc(N=C=O)s1
Reactant: C#CC(CCC)(CCC)NCC=O
Solvent: c1ccccc1
Product: C#CC(CCC)(CCC)N(CC=O)C(=O)Nc1nnc(S(C)=O)s1

Procedure:
A mixture of 5-methylsulfinyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the diethyl acetal of 2-(1,1-dipropylprop-2-ynylamino)acetaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the diethyl acetal of 2-[1-(1,1-dipropylprop-2-ynyl)-3-(5-methylsulfinyl-1,3,4-thiadiazol-2-yl)ureido]acetaldehyde.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[C:4]([Cl:10])[C:3]=1[CH3:11].[OH-].[Na+]>[Zn]>[Cl:10][C:4]1[C:3]([CH3:11])=[CH:2][CH:7]=[C:6]([Cl:8])[C:5]=1[OH:9]
Reactant: Cc1c(Br)cc(Cl)c(O)c1Cl
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Product: Cc1ccc(Cl)c(O)c1Cl
Temperature: 100 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
Zn powder (9.84 g, 150 mmol) was added to a solution of 4-bromo-2,6-dichloro-3-methylphenol (4.92 g, 19.22 mmol) in 10% NaOH (50 ml, 125 mmol). The reaction mixture was stirred for 1 h at 100° C. and then cooled down to RT. The Zn powder was filtered off and the filtrate was acidified with 10% HCl and extracted with CH2Cl2. The combined organic extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel eluted with 0-5% EtOAc in hexane to give the title compound as a colorless oil (2.98 g, 88%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.14 (1H, d) 6.76 (1H, d) 5.83 (1H, s) 2.34 (3H, s). LCMS: m/z 175 (M−1).
Reaction SMILES: C(OC(N1CCCCC1[CH2:14][NH:15][N:16]1[CH2:21][CH2:20][N:19]([S:22]([C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[C:30]([Cl:35])[CH:31]=3)[CH:26]=2)(=[O:24])=[O:23])[CH2:18][C:17]1=[O:36])=O)(C)(C)C.Cl.C(O[CH2:42][CH3:43])(=O)C>CO>[ClH:35].[Cl:35][C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][CH:29]=1)[CH:26]=[C:25]([S:22]([N:19]1[CH2:20][CH2:21][N:16]([N:15]([CH3:14])[CH:43]3[CH2:42][CH2:21][NH:16][CH2:17][CH2:18]3)[C:17](=[O:36])[CH2:18]1)(=[O:24])=[O:23])[CH:34]=[CH:33]2
Reactant: CC(C)(C)OC(=O)N1CCCCC1CNN1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1=O
Reactant: CCOC(C)=O
Agent: Cl
Solvent: CO
Product: CN(C1CCNCC1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A suspension of 1-{[1-(tert-butoxycarbonyl)piperidinyl]methylamino}-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone (10.42 g) in methanol (40 ml) was combined with a 4N solution of hydrochloric acid in ethyl acetate (20 ml) and stirred at room temperature for 5 hours. The reaction mixture was combined with ethyl acetate (50 ml) and the crystals precipitated were collected by filtration, dried to obtain the title compound (9.21 g) as colorless crystals.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([NH2:12])[S:8][C:9]=1[CH:10]=O)=O.O.[NH2:14][NH2:15].C(O)(=O)C>C(O)C.CO>[NH2:12][C:7]1[S:8][C:9]2[CH:10]=[N:15][NH:14][C:3](=[O:2])[C:5]=2[N:6]=1
Reactant: NN
Reactant: COC(=O)c1nc(N)sc1C=O
Solvent: CCO
Solvent: O
Solvent: CO
Product: Nc1nc2c(=O)[nH]ncc2s1
Temperature: 25 °C

Procedure:
The compound (788 mg) obtained in Step 3 was suspended in ethanol (7.8 ml), and hydrazine monohydrate (243 μl) and acetic acid (780 μl) were added, with stirring at room temperature. The mixture was stirred overnight at a bath temperature of 100° C. and returned to room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained crude crystals were suspended in methanol, collected by filtration and dried to give the title compound (690 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]2[C:14]3[C:21]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)=[C:20]([C:29]4[CH:34]=[CH:33][C:32](Br)=[CH:31][CH:30]=4)[O:19][C:15]=3[N:16]=[CH:17][N:18]=2)[CH:7]=1>ClCCl.C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:36])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]2[C:14]3[C:21]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)=[C:20]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[O:19][C:15]=3[N:16]=[CH:17][N:18]=2)[CH:7]=1
Reactant: COC(=O)COc1cccc(Nc2ncnc3oc(-c4ccc(Br)cc4)c(-c4ccc(F)cc4)c23)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)COc1cccc(Nc2ncnc3oc(-c4ccccc4)c(-c4ccc(F)cc4)c23)c1
Temperature: 25 °C

Procedure:
Dissolve 115 mg (0.21 mmol) of 3-{[6-(4-bromophenyl)-5-(4-fluorophenyl)furo[2,3-d]pyrimidin-4-yl]amino}phenoxy acetic acid methyl ester in 5 ml of dichloromethane and 5 ml of ethyl acetate, and add 22 mg of 10% palladium on activated carbon under argon. Stir the mixture under a hydrogen atmosphere of 3 bar gauge at RT until the starting material has been converted completely. Filter off the catalyst, concentrate the resulting filtrate under reduced pressure and chromatograph the residue on silica gel (eluent: dichloromethane/ethyl acetate 10:1). 27.9 mg (28.3% of theory) of the target compound are obtained as a colourless solid.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([NH:11][C:12]3[NH:16][N:15]=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.N12CCCN=C1CCCCC2.[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH:43]([C:49](=O)[CH2:50][CH2:51][CH3:52])[C:44](OCC)=[O:45])=[CH:38][C:37]=1[CH3:54])#[N:29].C(OCC)(=O)C>CCN(C1C=CC=CC=1)CC.O>[O:4]1[C:5]2([CH2:6][CH2:7][CH:8]([N:11]3[C:44](=[O:45])[C:43]([CH2:42][C:39]4[CH:40]=[CH:41][C:36]([C:31]5[C:30]([C:28]#[N:29])=[CH:35][CH:34]=[CH:33][CH:32]=5)=[C:37]([CH3:54])[CH:38]=4)=[C:49]([CH2:50][CH2:51][CH3:52])[N:16]4[N:15]=[CH:14][CH:13]=[C:12]34)[CH2:9][CH2:10]2)[O:1][CH2:2][CH2:3]1
Reactant: c1cc(NC2CCC3(CC2)OCCO3)[nH]n1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)c(C)c1)C(=O)OCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)c1ccccc1
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)c(C)c2)c(=O)n(C2CCC3(CC2)OCCO3)c2ccnn12
Yield: 72.4 %

Procedure:
A solution of N-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrazol-5-amine (0.59 g), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.080 mL) and ethyl 2-[(2′-cyano-2-methylbiphenyl-4-yl)methyl]-3-oxohexanoate (1.5 g) in diethylaniline (3 mL) was stirred at 180° C. for 2 hr. The mixture was allowed to cool, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (1.0 g, 74%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([CH:12]=O)[N:11]=[C:4]2[N:3]=1.[CH:14]1([C:19]2([CH2:27][CH2:28][C:29]3[CH:34]=[C:33]([CH2:35][CH3:36])[C:32]([OH:37])=[C:31]([CH2:38][CH3:39])[CH:30]=3)[O:24][C:23](=[O:25])[CH2:22][C:21](=[O:26])[CH2:20]2)[CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH:14]1([C:19]2([CH2:27][CH2:28][C:29]3[CH:34]=[C:33]([CH2:35][CH3:36])[C:32]([OH:37])=[C:31]([CH2:38][CH3:39])[CH:30]=3)[O:24][C:23](=[O:25])[C:22]([CH2:12][C:10]3[N:11]=[C:4]4[N:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]4[N:9]=3)=[C:21]([OH:26])[CH2:20]2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Cc1cc(C)n2nc(C=O)nc2n1
Reactant: CCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc(CC)c1O
Product: CCc1cc(CCC2(C3CCCC3)CC(O)=C(Cc3nc4nc(C)cc(C)n4n3)C(=O)O2)cc(CC)c1O

Procedure:
The title compound was prepared analogously to Example A(224) where 5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was used in place of 6-methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde and 6-cyclopentyl-6-[2-(3,5-diethyl-4-hydroxyphenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dione (Example A(235)) was used in place of 6-cyclopentyl-6-{2-[4-hydroxy-3-(2,2,2-trifluoroethyl)phenyl]ethyl}dihydro-2H-pyran-2,4(3H)-dione in that example. 1H NMR (DMSO): δ 1.15 (t, J=7.54 Hz, 6H), 1.30-1.80 (brm, 8H), 2.00-2.20 (brm, 5H), 2.43 (q, J=19.06 Hz 4H), 2.60 (s, 3H), 2.80 (brm, 7H), 3.34 (m, 3H), 6.70 (s, 2H), 6.99 (s, 1H). Anal. Calcd. For C30H38O4N4, C, 69.47; H, 7.38; N, 10.80. Found: C, 69.45; H, 7.35; N, 10.75.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O=[C:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10][CH2:9]1.[BH4-].[Na+].O1CCN([C@H]2CC[C@H](NC(=O)[O-])CC2)CC1>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].CO>[O:4]1[CH2:5][CH2:6][N:1]([C@@H:8]2[CH2:9][CH2:10][C@H:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])[CH2:12][CH2:13]2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Reactant: C1COCCN1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: O=C([O-])N[C@H]1CC[C@H](N2CCOCC2)CC1
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N2CCOCC2)CC1

Procedure:
To a mixture of morpholine (4.08 ml) and tert-butyl 4-oxocyclohexylcarbamate (10 g) stirred for 24 hours at room temperature in titanium(IV) isopropoxide (27.5 ml), methanol (10 ml) was added followed by careful addition of sodium borohydride (3.55 g). The reaction mixture was quenched with water, extracted with ether (2×100 mL), dried over magnesium sulfate, filtered and concentrated. The crude product was purified by FC (silica gel 200 g, 30%-100% acetone/hexanes) providing two products, the title compound and trans 4-morpholinocyclohexylcarbamate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH3:13])[CH:16]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COc1cccc(O)c1
Reactant: COC(=O)c1cc(Cl)ccc1F
Product: COC(=O)c1cc(Cl)ccc1Oc1cccc(OC)c1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 67 from methyl 5-chloro-2-fluorobenzoate and 3-methoxyphenol: 1H-NMR (CDCl3) δ 7.89 (1H, d, J=2.8 Hz), 7.41 (1H, dd, J=8.4, 2.8 Hz), 7.24–7.19 (1H, m), 6.95 (1H, d, J=8.4 Hz), 6.67–6.64 (1H, m), 6.53–6.49 (2H, m), 3.83 (3H, s), 3.78 (3H, s).