Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([O:18][CH2:19][C:20]2[C:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:22][O:23][C:24]=2[CH3:25])=[N:4][C:5]([CH3:17])=[C:6]([CH:16]=1)[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)=[O:8].C([O-])=O.[NH4+]>CO.C1COCC1.[Pd]>[CH3:17][C:5]1[N:4]=[C:3]([O:18][CH2:19][C:20]2[C:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:22][O:23][C:24]=2[CH3:25])[CH:2]=[CH:16][C:6]=1[C:7]([NH:9][CH:10]1[CH2:11][CH2:12][O:13][CH2:14][CH2:15]1)=[O:8]
Reactant: Cc1nc(OCc2c(-c3ccccc3)noc2C)c(Br)cc1C(=O)NC1CCOCC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc(OCc2c(-c3ccccc3)noc2C)ccc1C(=O)NC1CCOCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 19.2 %

Procedure:
To a solution of 5-bromo-2-methyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-nicotinamide (150 mg, 0.37 mmol) in methanol (3 mL) and THF (3 mL) was added under an argon atmosphere palladium on charcoal (10%, 20 mg) and ammonium formate (70 mg, 1.12 mmol). The reaction mixture was stirred for 6 h at ambient temperature. Filtration over Hyflo® and washing with THF afforded the title compound (29 mg, 20%) which was obtained as a light brown semi-solid. MS: m/e=408.3 [M+H]+.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1([CH3:23])[CH2:11][O:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH3:22])=[N:8]1.[Br:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Br>O1CCCC1>[Br:24][C:25]1[CH:26]=[C:27]([CH2:28][CH2:22][C:13]2[CH:14]=[C:15]([C:18]([F:21])([F:19])[F:20])[CH:16]=[CH:17][C:12]=2[C:9]2[O:10][CH2:11][C:7]([CH3:23])([CH3:6])[N:8]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: Cc1cc(C(F)(F)F)ccc1C1=NC(C)(C)CO1
Reactant: BrCc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)COC(c2ccc(C(F)(F)F)cc2CCc2cccc(Br)c2)=N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
n-Butyllithium (1.6 ml of a 2.5M solution in hexanes) was added to the product of step (ii) (0.59 g) in tetrahydrofuran (15 ml) at -65° C. After 1.5 hours 3-bromobenzyl bromide (1.0 g) in tetrahydrofuran (6 ml) was added. The reaction was stirred at room temperature for 2 hours, partitioned between brine and ethyl acetate, dried (MgSO4) and evaporated under reduced pressure. Purification was by chromatography eluting with 10% ethyl acetate in isohexane. Yield 0.44 g.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][NH2:10].O=[C:12]([CH2:17][CH3:18])[C:13]([O:15][CH3:16])=[O:14]>C(O)C>[CH3:16][O:15][C:13](=[O:14])/[C:12](=[N:10]\[NH:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Br:1])/[CH2:17][CH3:18]
Reactant: NNc1ccc(Cl)cc1Br
Reactant: CCC(=O)C(=O)OC
Solvent: CCO
Product: CC/C(=N/Nc1ccc(Cl)cc1Br)C(=O)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.5 %

Procedure:
A stirred solution of (2-bromo-4-chloro-phenyl)-hydrazine (step A) (1.98 g, 8.94 mmol) in ethanol (6.5 ml) was cooled to 0° C. and a solution of commercially available methyl 2-ketobutyrate (1.08 g, 1.04 ml, 9.3 mmol) in ethanol (2 ml) was added drop wise at 0° C. for 15 min. After the mixture was allowed to stir at room temperature for 3 h it was evaporated. The crude material (3.01 g) was purified by flash chromatography on silica gel (heptane/ethyl acetate 0-20%) to yield (Z)-2-[(2-bromo-4-chloro-phenyl)-hydrazono]-butyric acid methyl ester (2.67 g, 94%) as a light yellow solid, MS (ISP) m/z=321.3 [(M+H)+], mp 67° C.
Reaction SMILES: [CH3:1][N:2]([C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=1)[NH2:11])[C:3]1[NH:7][N:6]=[N:5][N:4]=1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[CH2:34]1[CH2:39][CH:38]([C:40]2([NH:53][C:54](NC3C=CC=C(NC4NN=NN=4)C=3)=[O:55])[N:46]=[CH:45][C:44]3[CH:47]=[CH:48][CH:49]=[CH:50][C:43]=3[N:42]([CH3:51])[C:41]2=[O:52])[CH2:37][CH2:36][CH2:35]1>O1CCCC1>[CH2:36]1[CH2:37][CH:38]([C@@:40]2([NH:53][C:54]([NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[C:8]([N:2]([CH3:1])[C:3]4[NH:7][N:6]=[N:5][N:4]=4)[CH:9]=3)=[O:55])[N:46]=[CH:45][C:44]3[CH:47]=[CH:48][CH:49]=[CH:50][C:43]=3[N:42]([CH3:51])[C:41]2=[O:52])[CH2:39][CH2:34][CH2:35]1
Reactant: CN1C(=O)C(NC(=O)Nc2cccc(Nc3nnn[nH]3)c2)(C2CCCCC2)N=Cc2ccccc21
Reactant: CN(c1cccc(N)c1)c1nnn[nH]1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1C(=O)[C@@](NC(=O)Nc2cccc(N(C)c3nnn[nH]3)c2)(C2CCCCC2)N=Cc2ccccc21
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 145 %

Procedure:
To a cooled (0° C.) and stirred milky solution of 3-[N-methyl-N-(tetrazol-5-yl)amino]aniline (230 mg) in anhydrous tetrahydrofuran (30 ml) was added solid triphosgene (120 mg) in one portion, under a nitrogen atmosphere. After 5 minutes of stirring, anhydrous triethylamine (505 μl) was added dropwise and the mixture was allowed to warm to 17° C. over 15 minutes. The reaction mixture was recooled to 0° C. and a solution of Intermediate 3 (225 mg) in anhydrous tetrahydrofuran (5 ml) was added dropwise via cannula over 4 minutes. After being stirred at 0° C. for 15 minutes, the mixture was allowed to warm to room temperature and stirred for a further 2 hours before a white precipitate was removed by filtration and the solvent was evaporated under reduced pressure. The remaining residue was partitioned between ethyl acetate (200 ml) and 10% aqueous citric acid (2×40 ml) and the organic phase was then washed with brine (1×40 ml), dried (Na2SO4) and concentrated to a yellow solid. Flash chromatography (silica gel, dichloromethane-methanol, 90:10) afforded the title compound (336 mg) as a solid; mp 222°-225° C. (methanol; decomposition); [α]D23 +15.9° (c=0.71, dimethylformamide); the spectroscopic properties (1H-NMR and MS spectra) of this material were identical to those described for its racemate (Example 3). (Found: C, 61.92; H, 5.87; N, 25.96. C25 H29N9O2 requires: C, 61.59; H, 6.00; N, 25.86%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:26]=[CH:25][C:24]([NH:27]C(=O)C)=[CH:23][C:11]=3[C:12](=[O:22])[C:13]=2[O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.[ClH:31]>C(Cl)(Cl)Cl.CO>[ClH:31].[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][C:11]=3[C:12](=[O:22])[C:13]=2[O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1ccc2oc(-c3ccc(O)cc3)c(OCc3ccccc3)c(=O)c2c1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Nc1ccc2oc(-c3ccc(O)cc3)c(OCc3ccccc3)c(=O)c2c1
Yield: 82 %

Procedure:
Prepared analogously to Example 5c, starting from 2-(4-hydroxyphenyl)-3-benzyloxy-6-acetamido-4H-1-benzopyran-4-one. Yield: 82%; TLC (9/1 Chloroform/Methanol) Rf: 0.71 Elem. anal. C29H23NO4*HCl; theory C, 71.68; H, 4.98; N, 2.88. found C, 71.35; H, 4.76; N, 3.03. 1H-NMR (d6-DMSO): 8.02 (d, 2H), 7.8-7.7 (m, 2H), 7.55-7.25 (m, 11H), 7.18 (d, 2H), 5.22 (s, 2H), 5.08 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]2[CH2:16][C:11]3[C:12]4[C:13]2=[C:4]([CH2:5][CH2:6][C:7]=4[CH:8]=[CH:9][CH:10]=3)[CH:3]=1.C1(Cl)C(Cl)=C(Cl)C(=O)C(=O)C=1Cl>C1(C)C(C)=CC=CC=1>[CH:3]1[C:4]2[CH2:5][CH2:6][C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[CH2:16][C:14]([C:13]=2[C:12]=34)=[CH:15][CH:2]=1
Reactant: Brc1cc2c3c(c1)Cc1cccc(c1-3)CC2
Agent: O=C1C(=O)C(Cl)=C(Cl)C(Cl)=C1Cl
Solvent: Cc1ccccc1C
Product: c1cc2c3c(c1)Cc1cccc(c1-3)CC2
Yield: 111 %

Procedure:
2-bromo-8,9-dihydro-4H-cyclopenta[def]phenanthrene (4.45 g, 16.4 mmol) in a 250 ml round bottom flask was dissolved with xylene, and o-chloranil (4.3 g) was added thereto at room temperature. The reaction mixture was heated and refluxed in an oil bath for 72 hours. After the reaction was terminated, the reaction solution was cooled and concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: n-hexane) to give a compound 1 (3.5 g, 79%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[CH:22][N:21]=1>>[F:29][CH:27]([F:28])[O:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:16]2[CH:11]([C:4]3[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:12][CH2:13][CH2:14][C:15]2=[O:17])=[N:21][CH:22]=1
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1
Reactant: FC(F)Oc1ccc(CBr)nc1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc(OC(F)F)cn1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)piperidin-2-one with 2-(bromomethyl)-5-(difluoromethoxy)pyridine. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions B): tR=0.82 min.; [M+H]+: 393.28 g/mol.
Reaction SMILES: [Cl:1][C:2]([Cl:12])=[CH:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1.[C:13]([N:17]1[C:22](=[O:23])[C:21]([Cl:24])=[C:20]([SH:25])[CH:19]=[N:18]1)([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:13]([N:17]1[C:22](=[O:23])[C:21]([Cl:24])=[C:20]([S:25][CH2:8][C:7]2[CH:10]=[CH:11][C:4]([CH:3]=[C:2]([Cl:12])[Cl:1])=[CH:5][CH:6]=2)[CH:19]=[N:18]1)([CH3:16])([CH3:14])[CH3:15]
Reactant: ClC(Cl)=Cc1ccc(CBr)cc1
Reactant: CC(C)(C)n1ncc(S)c(Cl)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)n1ncc(SCc2ccc(C=C(Cl)Cl)cc2)c(Cl)c1=O

Procedure:
1.2 g of 4-(2,2-dichloroethenyl)-benzyl bromide and 0.8 g of 2-tert.-butyl-4-chloro-5-mercapto-3(2H)-pyridazinone are added to a suspension of 0.7 g of potassium carbonate in 10 cc of dimethylformamide.
Reaction SMILES: [CH3:1][CH:2]1[CH:27]2[O:28][C:26]2([CH3:29])[CH:25]([OH:30])[CH2:24][C:22](=[O:23])[N:21]([CH3:31])[C:14]2=[C:15]([Cl:20])[C:16]([O:18][CH3:19])=[CH:17][C:12](=[CH:13]2)[CH2:11][C:10]([CH3:32])=[CH:9][CH:8]=[CH:7][CH:6]([O:33][CH3:34])[C:5]2([OH:39])[NH:35][C:36]([O:38][CH:3]1[CH2:4]2)=[O:37].C([Li])CCC.ClC(OCCCCCCCC)=[O:47]>C1COCC1>[CH3:1][CH:2]1[CH:27]2[O:28][C:26]2([CH3:29])[CH:25]([OH:30])[CH2:24][C:22](=[O:23])[N:21]([CH3:31])[C:14]2=[C:15]([Cl:20])[C:16]([O:18][CH3:19])=[CH:17][C:12](=[CH:13]2)[CH2:11][C:10]([CH3:32])=[CH:9][CH:8]=[CH:7][CH:6]([O:33][CH3:34])[C:5]2([OH:39])[NH:35][C:36]([O:38][CH:3]1[CH2:4]2)=[O:37].[CH3:5][CH2:4][CH:3]([O:38][C:36](=[O:37])[O-:47])[CH2:2][CH2:27][CH2:26][CH2:25][CH3:24]
Reactant: CCCCCCCCOC(=O)Cl
Agent: COc1cc2cc(c1Cl)N(C)C(=O)CC(O)C1(C)OC1C(C)C1CC(O)(NC(=O)O1)C(OC)/C=C/C=C(\C)C2
Agent: COc1cc2cc(c1Cl)N(C)C(=O)CC(O)C1(C)OC1C(C)C1CC(O)(NC(=O)O1)C(OC)C=CC=C(C)C2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCC(CC)OC(=O)[O-]
Reaction time: 0.25 h

Procedure:
In 6.0 ml of dry THF is dissolved 163 mg of maytansinol and under nitrogen gas streams and at -20° C., the solution is treated with 10 molar equivalents of 15% n-butyllithium (n-hexane solution). Then, 556 mg of n-octyl chloroformate is added and the mixture is stirred for 15 minutes. Thereafter, at 0° C., the organic layer is extracted with 1.0 ml of saturated sodium chloride and 20 ml of THF. The organic layer is dried, after which the solvent is distilled off. The residue is purified by silica gel chromatography to obtain 58 mg of maytansinol 3-n-octylcarbonate. Thin layer chromatography on silica gel (Merck HPTLC): Rf=0.61 (developing solvent: chloroform-methanol=95:5),
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH2:28][CH2:29][CH:30]1[O:34][N:33]([CH2:35][CH3:36])[C:32](=[O:37])[CH2:31]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:26])([F:25])[F:27])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:28][CH2:29][CH:30]4[O:34][N:33]([CH2:35][CH3:36])[C:32](=[O:37])[CH2:31]4)=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCN1OC(CN)CC1=O
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Product: CCN1OC(CNC(=O)c2ccc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc2C)CC1=O
Yield: 15.9 %

Procedure:
4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid (0.3 g) (prepared according to WO 2009/080250) was coupled with the amine obtained in Step D (0.12 g) as described in Example 12, Step C to afford the title product as a beige solid (62 mg, mixture of diasteroisomers). LCMS (Method F) 2.02 min, M+H 542/544.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.[F:34][C:35]1[CH:36]=[C:37]([CH2:41][C:42](O)=[O:43])[CH:38]=[CH:39][CH:40]=1.Cl.CN(C)CCCN=C=NCC>CC#N>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:42](=[O:43])[CH2:41][C:37]3[CH:38]=[CH:39][CH:40]=[C:35]([F:34])[CH:36]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: O=C(O)Cc1cccc(F)c1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(Cc1cccc(F)c1)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.17 h
Yield: 67.6 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.70 g, 2.2 mmol) in CH3CN (60 ml), was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.82 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzenetriazole (0.35 g, 2.6 mmol) and 3-fluorophenylacetic acid (0.37 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.62 g, 3.2 mmol). After stirring at room temperature overnight, the mixture was concentrated in vacuo, and the residue was dissolved in CH2Cl2 (50 mL). The CH2Cl2 solution was then washed with water (2×30 mL) and brine (30 mL), and dried over MgSO4. Solvent was removed in vacuo, and the resulting oil was purified by ISCO silica gel flash chromatography (eluent: 40% EtOAc in CH2Cl2 for 5 min then increase to 80% EtOAc in CH2Cl2 over 20 min.) to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-2-(3-fluoro-phenyl)-acetamide as a white solid (0.63 g, 69%): mp, 192-194° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=3.0 min (98%); 1H NMR (DMSO-d6): δ 2.03-2.08 (m, 1H), 2.52-2.63 (m, 2H), 2.84-2.91 (m, 1H), 3.57 (s, 2H), 4.73 (d, J=5.9 Hz, 2H), 5.12-5.18 (dd, J=5, 12 Hz, 1H), 7.03-7.14 (m, 3H), 7.31-7.39 (m, 1H), 7.63-7.67 (m, 1H), 7.78-7.81 (m, 2H), 8.69 (t, J=6.0 Hz, 1H), 11.14 (s, 1H). 13C NMR (DMSO-d6) δ: 21.94, 30.90, 37.86, 41.67, 48.82, 113.08, 113.35, 115.69, 115.98, 121.91, 125.19, 125.22, 127.13, 129.98, 130.09, 131.51, 133.22, 134.67, 138.77, 138.87, 139.03, 160.38, 163.60, 166.88, 167.41, 169.78, 170.06, 172.73. Anal Calcd for C22H18FN3O5: C, 62.41; H, 4.29; N, 9.92; F, 4.49. Found: C, 62.55; H, 4.04; N, 9.80; F, 4.36.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][C:28]([F:32])([F:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([C:38]3[CH:39]=[C:34]([CH3:33])[CH:35]=[CH:36][CH:37]=3)[C:18]([C:23]([N:25]3[CH2:26][CH2:27][C:28]([F:31])([F:32])[CH2:29][CH2:30]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cccc(B(O)O)c1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cccc(-n2c(C(=O)N3CCC(F)(F)CC3)cc3cc(C(=O)N4CCN(C5CCCC5)CC4)ccc32)c1
Yield: 81 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 8), 3-methylphenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a white foam (81%).
Reaction SMILES: [NH2:1][C:2]1[C:14]([N+:15]([O-])=O)=[C:13]2[C:5]([C:6]3[C:11]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:12]2)[CH2:10][CH2:9][C:8](=[O:22])[C:7]=3[CH3:23])=[CH:4][C:3]=1[F:24].CC([O-])=O.[K+]>C(O)C.[Pd]>[NH2:1][C:2]1[C:14]([NH2:15])=[C:13]2[C:5]([C:6]3[C:11]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:12]2)[CH2:10][CH2:9][C:8](=[O:22])[C:7]=3[CH3:23])=[CH:4][C:3]=1[F:24]
Reactant: CCCCC12CCC(=O)C(C)=C1c1cc(F)c(N)c([N+](=O)[O-])c1C2
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCO
Product: CCCCC12CCC(=O)C(C)=C1c1cc(F)c(N)c(N)c1C2
Temperature: 25 °C
Reaction time: 3.25 h
Yield: 72.3 %

Procedure:
A sample of 7-amino-9a-butyl-6-fluoro-4-methyl-8-nitro-1,2,9,9a-tetrahydro-3H-fluoren-3-one (106 mg, 0.32 mmol) was dissolved in ethanol (13 mL) with slight warming. After cooling to room temperature, the solution was treated with KOAc (31 mg, 32 mmol) and 10% palladium on carbon (31 mg), and the resulting mixture was stirred under an atmosphere of hydrogen for 3.25 hours. The mixture was filtered through a pad of silica gel, washing the product off with 5% MeOH in CH2Cl2. The filtrate and washings were evaporated under vacuum. The residue was purified by preparative layer chromatography on a 0.1×20×20 cm silica gel GF plate, developing with 1:1 hexanes-EtOAc. The major UV visible band was eluted with 5% MeOH in CH2Cl2, the eluant was concentrated under vacuum, and the residue was lyophilized from benzene to afford 7,8-diamino-9a-butyl-6-fluoro-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (70 mg, 72%) as an amorphous solid.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([C:21](=[O:25])[C:22]([O-])=[O:23])[C:17]=3[CH:26]=2)[C:3]1=[O:27].CO[CH2:30][CH2:31]O>O>[OH:25][C:21]1([C:18]2[C:17]3[CH:26]=[C:13]([N:4]4[C:5](=[O:12])[CH:6]=[C:7]([C:8]([F:11])([F:9])[F:10])[N:2]([CH3:1])[C:3]4=[O:27])[CH:14]=[CH:15][C:16]=3[S:20][N:19]=2)[C:22](=[O:23])[NH:4][C:3]([C:31]2[CH:30]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[N:2]1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C(=O)C(=O)[O-])c3c2)c1=O
Reactant: COCCO
Solvent: O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C4(O)N=C(c5ccccc5)NC4=O)c3c2)c1=O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 14.6 %

Procedure:
A mixture of 5-[3-,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazole-3-glyoxylate (0.620 g, 1.50 mmol), phenyl amidine hydrochloride (0.258 g, 1.65 mmol) and 2-methoxyethanol is stirred 40 minutes at reflux, cooled to room temperature and poured into water. The resultant yellow precipitate is filtered and saved. The filtrate is extracted four times with methylene chloride; the combined organic layers are concentrated in vacuo and the residue is triturated with ether to afford a yellow solid. The yellow solids are combined and chromatographed on silica gel with methylene chloride-methanol to afford the title compound as a solid (0.110 g, 14.6%, mp 139-141° C.) which is identified by NMR spectral analysis.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]([CH2:18][C:19]3[CH:39]=[CH:38][C:22]([CH2:23][O:24][C:25]4[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]([O:35]C)=[O:34])=[C:27]([CH3:37])[CH:26]=4)=[CH:21][C:20]=3[O:40][CH:41]([CH3:43])[CH3:42])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>CO.O1CCCC1.C(OCC)(=O)C>[C:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:9]([CH2:18][C:19]3[CH:39]=[CH:38][C:22]([CH2:23][O:24][C:25]4[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[C:27]([CH3:37])[CH:26]=4)=[CH:21][C:20]=3[O:40][CH:41]([CH3:43])[CH3:42])[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CCc1ccc(OCc2ccc(Cn3nc(-c4ccccc4)cc3-c3ccccc3)c(OC(C)C)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(OCc2ccc(Cn3nc(-c4ccccc4)cc3-c3ccccc3)c(OC(C)C)c2)ccc1CCC(=O)O
Temperature: 50 °C
Reaction time: 2 h
Yield: 76.4 %

Procedure:
To a mixed solution of methyl 3-[4-({4-[(3,5-diphenyl-1H-pyrazol-1-yl)methyl]-3-isopropoxybenzyl}oxy)-2-methylphenyl]propanoate (0.20 g, 0.35 mmol) in methanol (2 mL) and tetrahydrofuran (4 mL) was added 1 N aqueous sodium hydroxide solution (0.70 mL, 0.70 mmol), and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was neutralized with 1 N hydrochloric acid, and diluted with ethyl acetate. The mixture washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC (gradient cycle A). The obtained oil was diluted with ethyl acetate, and neutralized with saturated aqueous sodium hydrogencarbonate, and the mixture washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (0.15 g, yield 77%) as a colorless oil. MS (ESI+): 561 (M+H).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH2:25][C@@H:26]5[CH2:30][CH2:29][CH2:28][NH:27]5)[CH:20]=4)[N:15]=[CH:14]3)[CH:7]=2)[CH2:3][CH2:2]1.[CH2:32]=O>C(O)=O>[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH2:25][C@@H:26]5[CH2:30][CH2:29][CH2:28][N:27]5[CH3:32])[CH:20]=4)[N:15]=[CH:14]3)[CH:7]=2)[CH2:2][CH2:3]1
Reactant: C=O
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(OC[C@@H]3CCCN3)cc2c1=O
Solvent: O=CO
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(OC[C@@H]3CCCN3C)cc2c1=O

Procedure:
N-Cyclopropyl-4-methyl-3-[4-oxo-6-[(2S)-pyrrolidin-2-ylmethoxy]quinazolin-3(4H)-yl]benzamide (0.15 g) and 38% aqueous formaldehyde (0.284 ml) were stirred in formic acid (3 ml) at 90° C. for 16 hours and then concentrated. The residue was partitioned between ethyl acetate and saturated aqueous NaHCO3 solution. The organic layer was washed with brine, dried (magnesium sulfate) and concentrated. Purification by column chromatography on a silica column eluting with 10% methanol/ethyl acetate followed by 10% methanol/ethyl acetate+1% aqueous ammonia solution to give the title compound (0.12 g) as a white foam solid; NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.70 (m, 2H), 1.70 (m, 3H), 1.99 (m, 1H), 2.14 (s, 3H), 2.22 (m, 1H), 2.39 (s, 3H), 2.62 (m, 1H), 2.85 (m, 1H), 2.96 (m, 1H), 3.99 (m, 1H), 4.09 (m, 1H), 7.52 (m, 2H), 7.60 (s, 1H), 7.73 (d, 1H), 7.83 (s, 1H), 7.91 (d, 1H), 8.19 (s, 1H), 8.42 (d, 1H); Mass Spectrum: M+H+ 433.
Reaction SMILES: Cl.[C:2]([O:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].CN1CCOCC1.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.[O:37]([C:44]1[CH:49]=[CH:48][C:47]([S:50][C:51]2([CH2:57][C:58](O)=[O:59])[CH2:56][CH2:55][O:54][CH2:53][CH2:52]2)=[CH:46][CH:45]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.Cl>C(Cl)Cl>[C:2]([O:6][NH:7][C:58](=[O:59])[CH2:57][C:51]1([S:50][C:47]2[CH:48]=[CH:49][C:44]([O:37][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)=[CH:45][CH:46]=2)[CH2:52][CH2:53][O:54][CH2:55][CH2:56]1)([CH3:5])([CH3:4])[CH3:3]
Reactant: O=C(O)CC1(Sc2ccc(Oc3ccccc3)cc2)CCOCC1
Reactant: CC(C)(C)ON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)ONC(=O)CC1(Sc2ccc(Oc3ccccc3)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.5 %

Procedure:
O-(tert-Butyl)hydroxylamine hydrochloride (9.57 g), 4-methylmorpholine (15.64 ml), hydroxybenzotriazole (6.87 g), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (19.5 g) was added to a solution of 2-[4-(4-phenoxyphenylthio)-tetrahydropyran-4-yl]acetic acid (17.5 g) in methylene chloride (200 ml). After stirring for 3 hours at room temperature, 0.5 M hydrochloric acid (200 ml) was added to the mixture, and the mixture extracted with methylene chloride. The solvent was removed from the combined extracts under reduced pressure. Silica gel chromatography of the residue and elution with 35%-80% ethyl acetate/hexane gave N-tert-butoxy-2-[4-(4-phenoxyphenylthio)-tetrahydropyran-4-yl]-acetamide (15.3 g) as an oil, which can be used in the next reaction without further purification.