Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([Mg]Cl)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:9][C:10]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20](F)[C:11]=1[C:12]([NH:14][C:15]([CH3:19])([CH3:18])[CH2:16][OH:17])=O.O.C(OCC)(=O)C>O1CCCC1>[CH:1]1([C:20]2[CH:21]=[C:22]([O:24][CH3:25])[CH:23]=[C:10]([F:9])[C:11]=2[C:12]2[O:17][CH2:16][C:15]([CH3:19])([CH3:18])[N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(F)c(C(=O)NC(C)(C)CO)c(F)c1
Reactant: Cl[Mg]C1CCCCC1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(F)c(C2=NC(C)(C)CO2)c(C2CCCCC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Cyclohexylmagnesium chloride (22 mL, 2M in diethyl ether, 44 mmol) was added slowly to an ice-cooled solution of the compound from preparation 2 (9.64 g, 40 mmol) in tetrahydrofuran (100 mL), and the solution then stirred at room temperature for 2 hours. Water (10 mL) was added, the mixture poured into ethyl acetate, and washed with a solution of ethylenediaminetetracetic acid disodium salt (24 g) in water (200 mL), then 1N sodium hydroxide solution (100 mL) and brine. The organic solution was dried (MgSO4) and evaporated under reduced pressure to afford the title compound as a colourless oil, 12.4 g.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH3:20])[C:13](=[O:21])[NH:12][C:11]=2[N:10]=[C:9]1[C:22]([CH3:25])([CH3:24])[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].CS([CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])(=O)=O>CN(C)C=O>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH3:20])[C:13](=[O:21])[N:12]([CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[C:11]=2[N:10]=[C:9]1[C:22]([CH3:24])([CH3:23])[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CCS(C)(=O)=O
Reactant: CCCn1c(=O)[nH]c2nc(C(C)(C)C)n(Cc3ccccc3)c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCn1c(=O)c2c(nc(C(C)(C)C)n2Cc2ccccc2)n(CCC(=O)OC)c1=O
Temperature: 95 °C

Procedure:
5.0 g (14.7 mmol) of 7-benzyl-8-(tert.-butyl)-1-n-propyl-xanthine are dissolved in 200 ml of dimethylformamide. After the addition of 5.36 g of K2CO3, 19.6 mmol of methyl 3-methanesulphonylpropionate are added at ambient temperature and the mixture is then heated to 90-100° C. After about 20 hours at constant temperature the solvent is distilled off in vacuo and the residue remaining is taken up in dichloromethane. The organic phase is washed with water, dried over MgSO4 and the solvent is distilled off in vacuo. The crude product remaining is purified by chromatography on silica gel (dichloromethane:methanol 97:3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH:16]([OH:18])[CH3:17])=[CH:10][CH:9]=1.FC(F)(F)C([O-])=O.[NH+]1C=CC=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16](=[O:18])[CH3:17])=[CH:10][CH:9]=1
Reactant: CC(O)CCc1ccc(-c2ccccc2Cl)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C([O-])C(F)(F)F
Agent: c1cc[nH+]cc1
Solvent: CS(C)=O
Product: CC(=O)CCc1ccc(-c2ccccc2Cl)cc1
Yield: 92 %

Procedure:
4-(2'-Chloro-4-biphenylyl)-2-butanone was prepared analogous to Example 42 from 4-(2'-chloro-4-biphenylyl)-2-butanol by oxidation with dimethyl sulfoxide in the presence of pyridinium trifluoroacetate and N,N'-dicyclohexyl-carbodiimide with a yield of 92% of theory. The colorless crystals melted at 34°-35°C after column-chromatographic purification on silicagel, using benzene/petroleum ether (ratio by volume = 2:1) as eluant, and recrystallization from petroleum ether and ethanol.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7](=[N:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+]>CCOCC>[CH3:17][CH:16]([CH3:18])[CH2:15][NH:14][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)CN=Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)CNCc1ccccc1
Yield: 90.6 %

Procedure:
To a stirred solution of lithium aluminum hydride (23 g, 606 mmol) in ether (115 ml) was added an ethereal solution (115 ml) of N-benzylidene-2-methyl-1-propanamine (72.1 g, 447 mmol) over a period of 45 minutes. It was then refluxed for one hour. The reaction mixture was cooled in an ice bath and while stirring vigorously, aqueous sodium hydroxide (20%, 120 ml) was added dropwise. The ether solution was separated, dried over magnesium sulfate and concentrated to dryness yielding 66.1 g of the title compound.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[N:8]([CH:9]2[CH2:15][CH:14]3[N:16]([CH2:17][CH2:18][C:19]4([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[C:7]2[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=2[N:5]=1.C(N(CC)CC)C.[O:42]1[CH:46]=[CH:45][CH:44]=[C:43]1[C:47](Cl)=[O:48]>ClCCl>[O:42]1[CH:46]=[CH:45][CH:44]=[C:43]1[C:47]([N:22]1[CH2:21][CH2:20][C:19]([CH2:18][CH2:17][N:16]2[C@H:14]3[CH2:13][CH2:12][C@@H:11]2[CH2:10][CH:9]([N:8]2[C:7]4[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=4[N:5]=[C:4]2[CH3:3])[CH2:15]3)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:24][CH2:23]1)=[O:48]
Reactant: O=C(Cl)c1ccco1
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2ccccc2)CCN(C(=O)c2ccco2)CC1
Reaction time: 0.5 h
Yield: 49.9 %

Procedure:
To a stirred solution of endo 2-methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole dihydrochloride II (0.35 g, 0.69 mmol) in dichloromethane (7 mL) and triethylamine (0.209 g, 2.07 mmol) was added 2-furoyl chloride (0.094 g, 0.72 mmol) at 0° C. The ice bath was then removed and the mixture allowed to stir for 30 min. The solvents were then removed in vacuo and the solid was added ethyl acetate and water. The insoluble precipitate was then filtered off and subsequently characterized as the desired product 19. Additional 0.18 g of the desired product 19 was obtained by extracting the organic layer with water (3×), drying with magnesium sulfate and evaporating solvents in vacuo. Following the SFC purification, on a portion of crude 19, 60 mg of the desired product 1-((1R,5S)-8-{2-[1-(2-furoyl)-4-phenylpiperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole 19 was obtained (calculated yield 86%). 1H NMR (400 MHz, CD3OD) δ 7.57 (1H, dist. d, J=1.1 Hz), 7.47 (1H, d, J=7.1 Hz), 7.43-7.29 (5H, m), 7.26-7.09 (3H, m), 6.89 (1H, d, J=3.6 Hz), 6.48 (1H, dd, J=1.8, 3.6 Hz), 4.08 (2H, m), 3.84 (2H, m), 2.60 (5H, m), 2.42 (3H, s), 2.30 (2H, m), 2.20 (2H, m), 2.05 (7H, m), 1.83 (2H, m). HRMS m/z (M+H)+Calc 523.3062; (M+H)+Obs 523.3073.
Reaction SMILES: Cl.C([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH:16]([OH:35])[CH2:17][O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:11][CH2:10]1)C1C=CC=CC=1.CO.O1CCCC1.[H][H]>C1(C)C=CC=CC=1.[Pd]>[OH:35][CH:16]([CH2:17][O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:15][N:12]1[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]1
Reactant: CCCCCCCCCCCCCCCCOCC(O)CN1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCOCC(O)CN1CCNCC1
Reaction time: 8 h

Procedure:
1-Benzyl-4-(2-hydroxy-3-n-hexadecyloxypropyl)-piperazine hydrochloride (8 g, 0.0146 mol) was dissolved in toluene (100 ml), methanol (100 ml) and tetrahydrofuran (700 ml) and divided into three 300 ml portions. Each portion was hydrogenated overnight at room temperature on a Parr shaker using a 10% palladium on carbon catalyst (2 g) and 50 p.s.i.g. hydrogen. The catalyst was filtered off and the filtrate evaporated under reduced pressure to a solid, which was triturated under acetone and filtered to give a total yield of product of 2.9 g (43%), mp 230° C. (dec).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH2:10][S:9]2(=[O:14])=[O:13])=[CH:4][CH:3]=1.[CH3:15][N:16]1[C:20]([C:21]#[N:22])=[CH:19][CH:18]=[C:17]1B(O)O.[F-].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:13]=[S:9]1(=[O:14])[CH2:10][CH2:11][CH2:12][N:8]1[C:5]1[CH:6]=[CH:7][C:2]([C:17]2[N:16]([CH3:15])[C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)=[CH:3][CH:4]=1
Reactant: Cn1c(C#N)ccc1B(O)O
Reactant: O=S1(=O)CCCN1c1ccc(Br)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [F-]
Product: Cn1c(C#N)ccc1-c1ccc(N2CCCS2(=O)=O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 9 %

Procedure:
2-(4-Bromophenyl)isothiazolidine 1,1-dioxide (0.56 g, 2.0 mmol), 1-methyl-5-cyano-2-pyrroleboronic acid (0.36 g, 2.4 mmol), KF (0.38 g, 6.6 mmol), and Pd2(dba)3 (48 mg, 0.05 mmol) were added to a 50 mL round bottom flask under nitrogen. The flask was sealed and purged with nitrogen for 5 minutes. THF (5 mL) was added and the mixture was purged with nitrogen. A solution of tri-t-butylphosphine (10% wt in hexanes) (0.3 mL, 0.1 mmol) was added via syringe and the mixture was stirred vigorously at 25° C. for 16 hours. The mixture was diluted with EtOAc, filtered through a plug of silica gel, washed with 200 mL of EtOAc and concentrated to give a crude brown/black semi-solid. Purification via Isco chromatography (the Redisep® column, silica, gradient 5%-100% ethyl acetate in hexane) afforded 5-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]-1-methyl-1H-pyrrole-2-carbonitrile as a white solid (54 mg).
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[N+:21]([C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27])([O-:23])=[O:22]>ClCCl.N1C=CC=CC=1>[N+:21]([C:24]1[CH:25]=[C:26]([NH:27][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:27][C:26]2[CH:28]=[CH:29][CH:30]=[C:24]([N+:21]([O-:23])=[O:22])[CH:25]=2)=[O:13])[CH:28]=[CH:29][CH:30]=1)([O-:23])=[O:22]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1cccc([N+](=O)[O-])c1)c1ccccc1SSc1ccccc1C(=O)Nc1cccc([N+](=O)[O-])c1
Yield: 24.9 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (2.00 g, 5.83 mmol) in 50 mL of dichloromethane and 3-nitroaniline (1.60 g, 11.6 mmol) in 13 mL of pyridine. The crude product was recrystallized once from ethanol-ether, then twice from acetonitrile-DMF-water to yield 0.79 g of the title compound, mp >270° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26](=[O:32])[CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:43])(=O)=O)=CC=1.Cl>O1CCCC1.CO>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26](=[O:32])[CH:27]([F:43])[CH2:28][C:29]([OH:31])=[O:30])=[CH:22][CH:21]=2)=[CH:18][CH:19]=1
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CC(F)C(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 9.8 %

Procedure:
To a stirred solution of diisopropylamine (0.295 mL, 0.0021 mol) in anhydrous tetrahydrofuran (10 mL) at room temperature under nitrogen was added in portions a 2.1 M solution of n-butyl lithium in hexanes (1.0 mL, 0.0021 mol), and the mixture cooled to −78° C. To the solution was added a solution of 4-(4′-chloro-biphenyl-4-yl)-4-oxo-butyric acid (0.288 g, 0.000997 mol) in THF (10 mL), and the mixture stirred for 1 hour. To the yellow solution was added dropwise a solution of N-fluorodibenzenesulfonamide (NFSI, 0.346 g, 0.00110 mol) in THF (10 mL), and the mixture stirred for 2 hours at −78° C. The mixture was allowed to warm to room temperature and stirred for 16 hours. The reaction was quenched with 1 M hydrochloric acid (1.1 mL, 0.0011 mol HCl), and the mixture was rotary evaporated to dryness. The residue was passed through a column of silica gel, eluting with dichloromethane-methanol (10:1 then 9:1) to give a gum. The gum was dissolved in methanol and acidified with additional 1 M hydrochloric acid (3.4 mL, 0.0034 mol HCl). The volatiles were rotary evaporated, and the resulting suspension was filtered. The filter cake was purified by chromatography on silica gel, eluting with dichloromethane-methanol (14:1) to give 0.030 g of (±)-4-(4′-chloro-biphenyl-4-yl)-3-fluoro-4-oxo-butyric acid as a white solid; mp 170-173° C.
Reaction SMILES: [C:1]([Li])([CH3:4])([CH3:3])[CH3:2].[CH:6]([O:9][B:10](OC(C)C)[O:11][CH:12]([CH3:14])[CH3:13])([CH3:8])[CH3:7]>C(OCC)C>[C:1]([B:10]([O:11][CH:12]([CH3:14])[CH3:13])[O:9][CH:6]([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [Li]C(C)(C)C
Reactant: CC(C)OB(OC(C)C)OC(C)C
Solvent: CCOCC
Product: CC(C)OB(OC(C)C)C(C)(C)C
Temperature: -78 °C

Procedure:
The reaction was conducted as described in Example 1 with tert-butyllithium (30.9 mL, 51 mmol) which was added to triisopropoxyborane (9.59 g, 51 mmol) in 51 mL ethyl ether cooled to -100° C. instead of -78° C. Solvents were removed at 0° C. and 15 mm Hg. The oil bath was maintained at 50° C. to furnish tert-butyldiisopropoxyborane: 8.44 g (45.3 mmol, 89%), bp 136-138 (754 mm Hg); proton NMR (neat) δ4.50 (septet, J=18 Hz, 2H), 1.12 (d, J=18 Hz, 12H), 0.95 (s, 9H); boron NMR (neat) δ+29.5 ppm (s).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:32])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([OH:31])[CH2:20][O:21][CH:22]2CC3C(=CC=CC=3)C2)[CH2:14][CH2:13]1.[CH3:33][O:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1CO>CC(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:32])[CH2:11][N:12]1[CH2:13][CH2:14][N:15]([CH2:18][CH:19]([OH:31])[CH2:20][O:21][CH2:22][C:36]2[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=2[O:34][CH3:33])[CH2:16][CH2:17]1
Reactant: Cc1cccc(C)c1NC(=O)CN1CCN(CC(O)COC2Cc3ccccc3C2)CC1
Reactant: COc1ccccc1CO
Solvent: CC(C)O
Product: COc1ccccc1COCC(O)CN1CCN(CC(=O)Nc2c(C)cccc2C)CC1

Procedure:
Compound 18 was prepared in a similar manner to compound 7, substituting the commercially available 2-methoxy-benzylalcohol for 2-propanol in part C. MS (M+1)=442.41
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][C:12]([NH:15][C:16]3[CH:33]=[CH:32][C:19]([O:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][CH:26]([C:29]([OH:31])=[O:30])[CH2:25][CH2:24]4)=[CH:18][CH:17]=3)=[N:13][CH:14]=2)=[CH:5][CH:4]=1.Cl[CH2:35][CH2:36]OC1C=CC(NC2N=CC(C3C=CC(OC)=CC=3)=CN=2)=CC=1.[I-].[Na+].N1CCC(C(OCC)=O)CC1>CN(C=O)C>[CH2:35]([O:30][C:29]([CH:26]1[CH2:25][CH2:24][N:23]([CH2:22][CH2:21][O:20][C:19]2[CH:32]=[CH:33][C:16]([NH:15][C:12]3[N:11]=[CH:10][C:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)=[CH:14][N:13]=3)=[CH:17][CH:18]=2)[CH2:28][CH2:27]1)=[O:31])[CH3:36]
Reactant: COc1ccc(-c2cnc(Nc3ccc(OCCN4CCC(C(=O)O)CC4)cc3)nc2)cc1
Reactant: COc1ccc(-c2cnc(Nc3ccc(OCCCl)cc3)nc2)cc1
Agent: CCOC(=O)C1CCNCC1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(CCOc2ccc(Nc3ncc(-c4ccc(OC)cc4)cn3)cc2)CC1
Temperature: 120 °C
Yield: 50 %

Procedure:
1-(2-{4-[5-(4-Methoxy-phenyl)-pyrimidin-2-ylamino]-phenoxy}-ethyl)-piperidine-4-carboxylic acid can be synthesized by the following procedure. To a solution of [4-(2-chloro-ethoxy)-phenyl]-[5-(4-methoxy-phenyl)-pyrimidin-2-yl]-amine (0.042 mmol) (from Example 5d) in DMF (1 ml) is added sodium iodide (0.050 mmol) and ethyl isonipecotate (0.084 mmol). The reaction is heated at 120° C. for 12 h. Purification by HPLC (ACN gradient 10-90%) affords 1-(2-{4-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-phenoxy}-ethyl)-piperidine-4-carboxylic acid ethyl ester (50%). MS (m/z) (M+1)+ 477.0. This solid is suspended in a 3:2:1=THF:MeOH:H2O solution (0.5 mL) and 6N LiOH (0.126 mmol) and stirred at rt for 12 h. The reaction mixture is diluted with DMF and purified by HPLC (ACN gradient 10-90%) to afford 1-(2-{4-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-phenoxy}-ethyl)-piperidine-4-carboxylic acid. MS (m/z) (M+1)+ 449.2.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][S:9][C:4]=2[CH:3]=1.[N+:13]([C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1)([O-:15])=[O:14].C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.C(O)C.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N+:13]([C:16]1[CH:21]=[C:20]([C:2]2[CH:12]=[CH:11][C:5]3[NH:6][C:7](=[O:10])[CH2:8][S:9][C:4]=3[CH:3]=2)[CH:19]=[CH:18][CH:17]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: O=C1CSc2cc(Br)ccc2N1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: O=C1CSc2cc(-c3cccc([N+](=O)[O-])c3)ccc2N1
Temperature: 25 °C

Procedure:
A solution of 7-bromo-4H-benzo[1,4]thiazin-3-one (2 g, 8.2 mmol), 3-nitrophenyl boronic acid (2.72 g, 16.4 mmol), potassium carbonate (6.85 g, 49.2 mmol), and tetrakis(triphenylphosphine) palladium(0) (0.95 g, 0.82 mmol) in dimethoxyethane (100 ml), ethanol (25 ml), and water (25 ml) was heated to reflux for 6 hours. After cooling to room temperature, the mixture was diluted with water and extracted with EtOAc (3×50 mL). The combined organic extracts were washed with water, then brine, dried (MgSO4) and evaporated to obtain crude 7-(3-nitro-phenyl)-4H-benzo[1,4]thiazin-3-one (0.15 g, 6%). Recrystallization of crude sample from EtOAc afforded the title compound: mp 290-292° C.; MS (EI) m/z 286 (M30).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:13]2[C@@H:22]3[C:23]([O:25][CH2:26][C@@H:21]3[C@@H:20]([OH:27])[C:19]3[CH:18]=[C:17]4[O:28][CH2:29][O:30][C:16]4=[CH:15][C:14]2=3)=[O:24])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Cl.C(=O)([O-])[O-].[Ca+2]>C(O)(=O)C>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C@H:13]2[C@H:22]3[C:23]([O:25][CH2:26][C@@H:21]3[C@@H:20]([OH:27])[C:19]3[CH:18]=[C:17]4[O:28][CH2:29][O:30][C:16]4=[CH:15][C:14]2=3)=[O:24])[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc([C@@H]2c3cc4c(cc3[C@H](O)[C@H]3COC(=O)[C@@H]23)OCO4)cc(OC)c1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CC(=O)O
Product: COc1cc([C@@H]2c3cc4c(cc3[C@H](O)[C@H]3COC(=O)[C@H]23)OCO4)cc(OC)c1OC

Procedure:
The first synthesis of podophyllotoxin, compound 6 (Scheme 2), was reported by Gensler and coworkers [J. Am. Chem. Soc., 76: 5894 (1954); J. Am. Chem. Soc., 76: 315 (1954)]. ##STR13## Stobbe condensation of 1-(3',4',5'-trimethoxybenzoyl)-3,4-methylenedioxybenzene 26 with ethyl succinate followed by saponification and hydrogenation gave the saturated dibasic acid 27. Conversion to the anhydride followed by intramolecular Friedel-Crafts acylation and then esterification gave the cyclic keto-ester 28. Condensation with ethyl formate followed by sodium borohydride reduction and saponification afforded the dihydroxy acid 29. Treatment with 10% aqueous sulfuric acid gave α-apopicropodophyllotoxin 30 which was converted to picropodophyllotoxin 15 by treatment with dry HCl in glacial acetic acid followed by aqueous calcium carbonate.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=2)=[O:20])=[CH:14][CH:13]=1.C(OC([N:40]1[CH2:47][CH2:46][CH2:45][C@H:41]1[C:42](O)=[O:43])=O)(C)(C)C>>[ClH:28].[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:19](=[O:20])[NH:18][C:15]2[CH:14]=[CH:13][C:12]([N:7]3[CH:6]=[N:5][C:4]4[C:8]3=[N:9][CH:10]=[N:11][C:3]=4[NH:2][C:42]([C@@H:41]3[CH2:45][CH2:46][CH2:47][NH:40]3)=[O:43])=[CH:17][CH:16]=2)=[CH:23][C:24]=1[C:29]([F:31])([F:32])[F:30]
Reactant: Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: Cl
Product: O=C(Nc1ccc(-n2cnc3c(NC(=O)[C@@H]4CCCN4)ncnc32)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1

Procedure:
The title compound can be synthesized from 1-[4-(6-aminopurin-9-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)urea hydrochloride and tert-butoxycarbonyl-L-proline by using the same method as in Example 96.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]2[C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>>[F:17][C:14]([F:15])([F:16])[C:13]([C:6]1[C:7]([CH3:12])=[N:8][C:9]2[C:4]([C:5]=1[C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1)=[CH:3][C:2]([N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1)=[CH:11][CH:10]=2)=[O:18]
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccc(S(C)(=O)=O)cc2)c1C(=O)C(F)(F)F
Reactant: C1CCNC1
Product: Cc1nc2ccc(N3CCCC3)cc2c(-c2ccc(S(C)(=O)=O)cc2)c1C(=O)C(F)(F)F
Reaction time: 16 h
Yield: 51 %

Procedure:
The title compound was prepared from 1-[6-Bromo-4-(4-methanesulfonyl-phenyl)-2-methyl-quinolin-3-yl]-2,2,2-trifluoro-ethanone [example 23] and pyrrolidine according to the procedure of example 25, except that the reaction time was of 16 h. Yield: 51%; MS: m/z=463 (M+H).
Reaction SMILES: [S:1]1[CH:5]=[C:4]2[C:6](O[C:9](=[O:10])[C:3]2=[CH:2]1)=[O:7].[CH2:11]([CH:13]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:14][CH2:15][C:16]1[C:22]([F:23])=[C:21]([F:24])[C:19]([NH2:20])=[C:18]([F:25])[C:17]=1[F:26])[CH3:12]>C1(C)C=CC=CC=1>[CH2:11]([CH:13]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:14][CH2:15][C:16]1[C:17]([F:26])=[C:18]([F:25])[C:19]([N:20]2[C:9](=[O:10])[C:3]3=[CH:2][S:1][CH:5]=[C:4]3[C:6]2=[O:7])=[C:21]([F:24])[C:22]=1[F:23])[CH3:12]
Reactant: CCCCC(CC)CCc1c(F)c(F)c(N)c(F)c1F
Reactant: O=C1OC(=O)c2cscc21
Solvent: Cc1ccccc1
Product: CCCCC(CC)CCc1c(F)c(F)c(N2C(=O)c3cscc3C2=O)c(F)c1F

Procedure:
A solution of thiophene-3,4-dicarboxylic anhydride (8.0 mmol) and 4-(3-ethylheptyl)-2,3,5,6-tetrafluoroaniline (8.5 mmol) in 125 ml of toluene is refluxed for 24 h. The crude product is collected by filtration of the cold reaction mixture. Another portion of product can be recovered by washing the filtrate with 5% hydrochloric acid and then evaporating the solvent. The target molecule is purified by recrystallization from toluene, dissolved in 150 ml of thionyl chloride and refluxed for 3 hrs. The reaction mixture is concentrated down, dried, and purified.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[NH:16][C:17](=[O:33])[CH2:18][C:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[CH:21]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=4)[CH:21]=3)[CH2:18][C:17](=[O:33])[NH:16][C:9]=2[CH:10]=1
Reactant: COc1ccc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccncc3)c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(c1)NC(=O)CC(c1cccc(-c3ccncc3)c1)=N2

Procedure:
The title compound was prepared from {4-methoxy-2-[3-oxo-3-(3-pyridin-4-yl-phenyl)-propionylamino]-phenyl}-carbamic acid tert-butyl ester (Example M34) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (160 mg).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][O:10][C:9]2=[O:18])[CH2:4][CH2:3]1.[Cl:19][C:20]1[CH:21]=[C:22]([N+:27]([O-:29])=[O:28])[CH:23]=[CH:24][C:25]=1F>>[Cl:19][C:20]1[CH:21]=[C:22]([N+:27]([O-:29])=[O:28])[CH:23]=[CH:24][C:25]=1[N:2]1[CH2:3][CH2:4][CH:5]([N:8]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][O:10][C:9]2=[O:18])[CH2:6][CH2:7]1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: O=C1OCc2ccccc2N1C1CCNCC1
Agent: Cl
Product: O=C1OCc2ccccc2N1C1CCN(c2ccc([N+](=O)[O-])cc2Cl)CC1

Procedure:
The product was prepared from 1-piperidin-4yl-1,4-dihydro-2H-3,1-benzoxazin-2-one hydrochloride (1.5 g) and 3-chloro-4-fluoronitrobenzene (1.23 g) using the method of example 115 step (ii). Yield 1.37 g.