Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@H:15]3[C:19]([CH3:21])([CH3:20])[C@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.[F:23][C:24]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:25]=1[CH2:26]Br>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@H:15]3[C:19]([CH3:21])([CH3:20])[C@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[N:10]1[CH2:26][C:25]1[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:24]=1[F:23]
Reactant: CC1(C)[C@H]2CC[C@]1(C)c1[nH]n(-c3ccc(F)cc3Cl)c(=O)c12
Reactant: Fc1ccc(CBr)c(F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Product: CC1(C)[C@H]2CC[C@]1(C)c1c2c(=O)n(-c2ccc(F)cc2Cl)n1Cc1ccc(F)cc1F
Temperature: 80 °C
Yield: 58.6 %

Procedure:
A mixture of (4R,7S)-2-(2-chloro-4-fluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 43; 150 mg, 0.47 mmol), tetrabutylammonium iodide (174 mg, 0.47 mmol) and 2,4-difluorobenzyl bromide (240 μL, 1.9 mmol) in dimethylformamide (3 mL) was heated at 80° C. overnight. The solvent was evaporated and dichloromethane (50 mL) was added. The solution was washed with water (2×20 mL), saturated aqueous sodium thiosulfate (20 mL), and brine (20 mL), dried (magnesium sulfate), filtered, concentrated, purified by chromatography, eluting with 50-60% ethyl acetate/petroleum ether, and dried under high vacuum overnight to give (4R,7S)-2-(2-chloro-4-fluoro-phenyl)-1-(2,4-difluoro-benzyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (123 mg, 59%) as a light brown solid. APCI(+)-MS (M+H) 447.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1.[CH3:19][S-:20].[Na+].[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([S:20][CH3:19])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Reactant: C[S-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4,6-dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine (the product of example 1 step ii) (1.54 g) in THF (50 mL) was added sodium methanethiolate (0.39 g). The mixture was allowed to warm to room temperature and stirring continued for 2 h. Saturated ammonium chloride was added and the resulting mixture extracted with EtOAc. The combined organic extracts were washed with saturated aqueous sodium chloride, dried (MgSO4), filtered and evaporated to give the subtitle compound as a pale yellow solid. Yield: 1.51 g.
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][C@@H:9]([CH2:40][O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:10]([NH:12][C@@H:13]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1)[C:14]([NH:16][C@@H:17]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:18]([C@@:20]1([CH3:23])[CH2:22][O:21]1)=[O:19])=[O:15])=[O:11].[O:49]1[CH2:54][CH2:53][N:52]([CH2:55][C:56](O)=[O:57])[CH2:51][CH2:50]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:42]([O:41][CH2:40][C@H:9]([NH:8][C:56](=[O:57])[CH2:55][N:52]1[CH2:53][CH2:54][O:49][CH2:50][CH2:51]1)[C:10]([NH:12][C@@H:13]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1)[C:14]([NH:16][C@@H:17]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:18]([C@@:20]1([CH3:23])[CH2:22][O:21]1)=[O:19])=[O:15])=[O:11])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: O=C(O)CN1CCOCC1
Reactant: COc1ccc(C[C@H](NC(=O)[C@@H](N)COCc2ccccc2)C(=O)N[C@@H](Cc2ccccc2)C(=O)[C@@]2(C)CO2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc(C[C@H](NC(=O)[C@H](COCc2ccccc2)NC(=O)CN2CCOCC2)C(=O)N[C@@H](Cc2ccccc2)C(=O)[C@@]2(C)CO2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 32.7 %

Procedure:
To (S)-2-amino-3-(benzyloxy)-N-((S)-3-(4-methoxyphenyl)-1-(((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)amino)-1-oxopropan-2-yl)propanamide TFA salt (2.94 mmol assumed) was added 2-morpholinoacetic acid (647 mg, 4.46 mmol), HATU (1.86 g, 4.91 mmol), and DMF (5 mL). The mixture was cooled to 0° C. and DIEA (3.10 mL, 17.8 mmol) was added. The reaction mixture was stirred at ambient temperature for 30 min then quenched with sodium bicarbonate (sat.), extracted with ethyl acetate (2×), dried with sodium sulfate, filtered, and concentrated. Purification by column chromatography (3:1 DCM/ethyl acetate+0-10% methanol) provided (S)-3-(benzyloxy)-N-((S)-3-(4-methoxyphenyl)-1-(((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)amino)-1-oxopropan-2-yl)-2-(2-morpholinoacetamido)propanamide (660 mg, 28% over 5 steps) as an amorphous colorless solid. MS (EI) for C38H46N4O8, found 687.4 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[O:6][C@@H:5]2[CH2:7][CH2:8][C@H:9](O)[C@@H:4]2[O:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:31][C:32]1[C:37]2[N:38]=[CH:39][NH:40][C:36]=2[C:35]([F:41])=[CH:34][N:33]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][C:2]1([CH3:11])[O:6][C@@H:5]2[CH2:7][CH2:8][C@@H:9]([N:40]3[C:36]4[C:35]([F:41])=[CH:34][N:33]=[C:32]([F:31])[C:37]=4[N:38]=[CH:39]3)[C@@H:4]2[O:3]1.[CH3:1][C:2]1([CH3:11])[O:6][C@@H:5]2[CH2:7][CH2:8][C@@H:9]([N:38]3[C:37]4[C:32]([F:31])=[N:33][CH:34]=[C:35]([F:41])[C:36]=4[N:40]=[CH:39]3)[C@@H:4]2[O:3]1
Reactant: Fc1ncc(F)c2[nH]cnc12
Reactant: CC1(C)O[C@H]2[C@@H](O)CC[C@H]2O1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C)O[C@H]2[C@H](n3cnc4c(F)cnc(F)c43)CC[C@H]2O1
Product: CC1(C)O[C@H]2[C@H](n3cnc4c(F)ncc(F)c43)CC[C@H]2O1
Temperature: 0 °C
Reaction time: 14 h

Procedure:
(3 aS,4S,6aR)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (1-3) (4.3 g, 27.2 mmol, 1 equiv) was dissolved in dry THF (136 mL). Triphenylphosphine (10.7 g, 40.8 mmol, 1.5 equiv) was added, followed by 4,7-difluoro-1H-imidazo[4,5-c]pyridine (1-4, 5.1 g, 32.6 mmol, 1.2 equiv). The mixture was cooled to 0° C. and DIAD (7.9 mL, 40.8 mmol, 1.5 equiv) was added dropwise. The resulting mixture was stirred at ambient temperature for 14 hours and then heated to 50° C. for an additional 72 hours. The solvent was removed at reduced pressure and the yellow residue was purified via flash chromatography on 2-330 g silica gel columns (gradient elution 0 to 100% ethyl acetate in hexanes) to yield 1-[(3aS,4R,6aR)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-4,7-difluoro-1H-imidazo[4,5-c]pyridine (1-6) and 3-((3aS,4R,6aR)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-4,7-difluoro-3H-imidazo[4,5-c]pyridine (1-5) as a 1:1 regioisomeric mixture. 1H NMR (1-6) (500 MHz, CDCl3): δ 7.85 (m, 2H); 5.00 (brs, 1H); 4.90 (t, J=5.6 Hz, 1H); 4.82 (t, J=7.3 Hz, 1H); 2.56 (m, 1H); 2.04-2.19 (m, 3H); 1.55 (s, 3H); 1.34 (s, 3H). LRMS rn/z (M+H) 296.0 found, 296.1 required. 1H NMR (1-5) (500 MHz, CDCl3): δ 7.92 (s, 1H); 7.82 (m, 1H); 5.00 (brs, 1H); 4.90 (t, J=5.6 Hz, 1H); 4.82 (t, J=7.3 Hz, 1H); 2.56 (m, 1H); 2.04-2.19 (m, 3H); 1.55 (s, 3H); 1.34 (s, 3H). LRMS m/z (M+H) 296.0 found, 296.1 required.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[NH:12][C:11](=[O:21])[C@:10]([CH2:23][CH:24]([OH:27])[CH2:25][OH:26])([CH3:22])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.CO[C:30](OC)([CH3:32])[CH3:31].CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[NH:12][C:11](=[O:21])[C@:10]([CH2:23][CH:24]3[CH2:25][O:26][C:30]([CH3:32])([CH3:31])[O:27]3)([CH3:22])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(C)(C)OC
Reactant: C[C@]1(CC(O)CO)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)NC1=O
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CN(C)C=O
Product: CC1(C)OCC(C[C@@]2(C)C[C@H](c3cccc(Cl)c3)[C@@H](c3ccc(Cl)cc3)NC2=O)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2,3-dihydroxypropyl)-3-methylpiperidin-2-one (Example 102, Step A) (4.900 g, 12.00 mmol) and 2,2-dimethoxypropane (14.76 mL, 120 mmol) in N,N-dimethylformamide (34 mL) at room temperature was added CSA (0.279 g, 1.200 mmol) and the reaction mixture was allowed to stir for 1 hr at room temperature. The reaction was quenched with sodium bicarbonate (100 mL) and EtOAc (100 mL). The layers were separated and the organic layer was washed three times with sat. sodium carbonate (100 mL). The aqueous layers were combined and were extracted with EtOAc (200 mL). The organic layers were combined, washed with sat. aq. NaCl solution, dried with sodium sulfate, filtered, and concentrated under reduced pressure to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:16][CH2:15][CH2:14][C:13]3[C:12](=[NH:17])[NH:11][C:10](=N)[C:9]2=3)=[CH:4][CH:3]=1.Cl.[CH2:20]([C:22]1[CH:34]=[CH:33][C:25]([NH:26][C:27]2[S:28][CH2:29][C:30](=[NH:32])[N:31]=2)=[CH:24][CH:23]=1)[CH3:21].N=C1C2CCCCC=2C(=N)N1.Cl.N=C1NC(=N)CS1>>[NH:17]=[C:12]1[C:13]2[CH2:14][CH2:15][CH2:16][CH:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:9]=2[C:10](=[C:29]2[S:28][C:27]([NH:26][C:25]3[CH:24]=[CH:23][C:22]([CH2:20][CH3:21])=[CH:34][CH:33]=3)=[N:31][C:30]2=[NH:32])[NH:11]1
Reactant: CCc1ccc(NC2=NC(=N)CS2)cc1
Reactant: N=C1NC(=N)C2=C1CCCC2c1ccc(Cl)cc1
Agent: Cl
Agent: N=C1CSC(=N)N1
Agent: N=C1NC(=N)C2=C1CCCC2
Product: CCc1ccc(NC2=NC(=N)C(=C3NC(=N)C4=C3C(c3ccc(Cl)cc3)CCC4)S2)cc1

Procedure:
Proceeding in a manner similar to that described above in Example 10, part A but substituting equivalent amounts of 4-(p-chlorophenyl)-4,5,6,7-tetrahydro-1,3-diiminoisoindoline and 2-(p-ethylanilino)-4-imino-2-thiazoline hydrochloride for 4,5,6,7-tetrahydro-1,3-diiminoisoindoline and 2,4-diiminothiazolidine hydrochloride, there is obtained as the product 1-imino-4-(p-chlorophenyl)-4,5,6,7-tetrahydro-3-[2-(p-ethylanilino)-4-imino-2-thiazolin-5-ylidene]isoindoline.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[CH:5]=O.[F:15][C:16]1[CH:34]=[CH:33][C:19]([CH:20]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:18][CH:17]=1.C(O)=O.[C:38]([OH:45])(=[O:44])/[CH:39]=[CH:40]/[C:41]([OH:43])=[O:42]>C(O)C>[C:38]([OH:45])(=[O:44])/[CH:39]=[CH:40]/[C:41]([OH:43])=[O:42].[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[CH2:5][N:30]1[CH2:29][CH2:28][N:27]([CH:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:19]2[CH:18]=[CH:17][C:16]([F:15])=[CH:34][CH:33]=2)[CH2:32][CH2:31]1
Reactant: COc1ccc(C=O)c(OC)c1OC
Reactant: Fc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: O=CO
Product: COc1ccc(CN2CCN(C(c3ccccc3)c3ccc(F)cc3)CC2)c(OC)c1OC
Temperature: 25 °C
Yield: 32.7 %

Procedure:
2,3,4-Trimethoxybenzaldehyde (7.85 g; 40.0 millimoles) and 10.8 g (39.9 millimoles) of 4-fluorobenzhydrylpiperazine (see German OLS 1929330) were melted in an oil bath at 120° C., and 2.3 ml (61.0 millimoles) of formic acid was added dropwise. The mixture was stirred under heat for 1 hour, and allowed to cool to room temperature. Then, 50 ml of an ethanol solution containing 5.0 g (43.1 millimoles) of fumaric acid was added, and the precipitated crystals were collected by filtration. Recrystallization of the crystals from ethanol gave 7.4 g (yield 32.7%) of 1-(2,3,4-trimethoxybenzyl)-4-(4-fluorobenzhydryl)piperazine fumarate as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[S:8][C:9]([CH2:11]Br)=[N:10][C:5]2=[CH:4][CH:3]=1.[F:13][C:14]1[C:22]([OH:23])=[CH:21][CH:20]=[C:19]([F:24])[C:15]=1[C:16]([NH2:18])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[N:7]=[C:6]2[S:8][C:9]([CH2:11][O:23][C:22]3[C:14]([F:13])=[C:15]([C:19]([F:24])=[CH:20][CH:21]=3)[C:16]([NH2:18])=[O:17])=[N:10][C:5]2=[CH:4][CH:3]=1
Reactant: BrCc1nc2ccc(Br)nc2s1
Reactant: NC(=O)c1c(F)ccc(O)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1c(F)ccc(OCc2nc3ccc(Br)nc3s2)c1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 77 %

Procedure:
To a solution of 5-bromo-2-bromomethyl-thiazolo[5,4-b]pyridine (2.0 g, 6.493 mmol) in 10 ml of anhydrous DMF was added 2,6-Difluoro-3-hydroxy-benzamide (1.01 g, 5.84 mmol) and potassium carbonate (3.09 g, 22.72 mmol). The reaction mixture was stirred at 25° C. for 24 h under nitrogen atmosphere. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (60-120 M) using ethyl acetate/hexane (50:50) as the eluent to provide the title compound (1.80 g, 69%). 1H NMR (DMSO-d6, 400 MHz): δ 5.72 (s, 2H), 7.12 (t, J=7.60 Hz, 1H), 7.39 (m, 1H), 7.90 (br s, 1H), 8.18 (br s, 1H) and 8.80 (m, 2H). MS ES+ (402.08), HPLC (method I) Rt=15.50 min.
Reaction SMILES: [CH:1]1([CH:4]([O:6][C:7]2[CH:8]=[C:9]([CH2:13]O)[CH:10]=[CH:11][CH:12]=2)[CH3:5])[CH2:3][CH2:2]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)(Cl)(Cl)[Cl:35]>>[Cl:35][CH2:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([O:6][CH:4]([CH:1]2[CH2:3][CH2:2]2)[CH3:5])[CH:8]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC(Oc1cccc(CO)c1)C1CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(Oc1cccc(CCl)c1)C1CC1
Temperature: 78 °C

Procedure:
[3-(1-cyclopropylethoxy)phenyl]methanol (0.418 g, 2.17 mmol) in carbon tetrachloride (8.70 ml) was added triphenylphosphine resin (1.14 g, 4.35 mmol). The reaction was refluxed overnight with minimal stirring at 78° C. The next day the mixture was filtered through a fritted funnel and washed with dichloromethane. The filtrate was concentrated and no purification was necessary.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:31]=[CH:30][C:6]([C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([CH3:29])=[C:14]([NH:16][C:17]3[N:22]=[C:21]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)[CH:20]=[CH:19][N:18]=3)[CH:15]=2)=[O:8])=[CH:5][CH:4]=1.N1C=CC=CC=1.[NH2:38][N:39]1[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]1>O1CCCC1>[CH3:45][N:42]1[CH2:43][CH2:44][N:39]([NH:38][CH2:2][C:3]2[CH:31]=[CH:30][C:6]([C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([CH3:29])=[C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=5)[CH:20]=[CH:19][N:18]=4)[CH:15]=3)=[O:8])=[CH:5][CH:4]=2)[CH2:40][CH2:41]1
Reactant: Cc1ccc(NC(=O)c2ccc(CCl)cc2)cc1Nc1nccc(-c2cccnc2)n1
Reactant: CN1CCN(N)CC1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)c2ccc(CNN3CCN(C)CC3)cc2)cc1Nc1nccc(-c2cccnc2)n1
Reaction time: 0.5 h
Yield: 74.3 %

Procedure:
N-[5-(4-chloromethylbenzoylamino)-2-methylphenyl]-4-(3-pyridyl)-2-pyrimidine-amine (1 g, 2.33 mmol) was dissolved in tetrahydrofuran (20 ml), pyridine (360 μl, 4.66 mmol) was added thereto, and the mixture was stirred for 30 minutes. 1-Amino-4-methylpiperazine (418 μl, 3.49 mmol) was added, and the mixture was refluxed for 12 hours and filtered. The filtrate was concentrated, subjected to column chromatography (eluent: chloroform:methanol=3:1(v/v)), concentrated again, and then crystallized from dimethylether to give 4-(4-methylpiperazin-1-ylaminomethyl)-N-[4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-yl)aminophenyl]benzamide (880 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH:13]=O)[C:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[O:32][CH:33]=[CH:34][CH:35]=4)[O:28][C:29]=3[CH3:30])=[C:19]([O:36][CH3:37])[CH:18]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OP([CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48])(OCC)=O)C.CN(C)C=O.[H-].[Na+]>O>[CH2:1]([N:8]1[CH:12]=[C:11](/[CH:13]=[CH:46]/[C:47]([O:49][CH2:50][CH3:51])=[O:48])[C:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[O:32][CH:33]=[CH:34][CH:35]=4)[O:28][C:29]=3[CH3:30])=[C:19]([O:36][CH3:37])[CH:18]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: COc1cc(COc2nn(Cc3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C/c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Reaction time: 15 h
Yield: 87.7 %

Procedure:
To a mixture of 1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1H-pyrazole-4-carbaldehyde (1.50 g), ethyl diethylphosphonoacetate (0.74 g) and N,N-dimethylformamide (30 mL) was added sodium hydride (60% in oil, 0.14 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give ethyl (2E)-3-{1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1H-pyrazol-4-yl}-2-propenoate as colorless crystals (1.50 g, yield 88%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 147-148° C.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:3]=1[C:4](=[O:13])[NH:5][S:6]2(=[O:8])=[O:7].[CH:14]([Li])(CC)[CH3:15].C(I)C>C1COCC1.C1CCCCC1>[CH2:1]([C:2]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:3]=1[C:4](=[O:13])[NH:5][S:6]2(=[O:8])=[O:7])[CH2:14][CH3:15]
Reactant: Cc1cccc2c1C(=O)NS2(=O)=O
Reactant: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Solvent: CCI
Product: CCCc1cccc2c1C(=O)NS2(=O)=O
Yield: 89 %

Procedure:
Following a procedure similar to that described in Preparation 16A, 10 g (0.051 mol) of 4-methylsaccharin in THF was reacted with 86 ml (0.10 mol) of a 1.18M solution of s-butyl lithium in cyclohexane and the resulting solution treated with 4.5 ml (0.050 mol) of ethyl iodide to give 10.15 g (89%) of 4-propylsaccharin, which, on reaction with 5.32 ml (0.056 mol) of chloromethyl phenyl sulfide in toluene in the presence of tetrabutylammonium bromide, afforded a crude mixture from which was isolated by flash chromatography on silica gel 2-phenylthiomethyl-4-propylsaccharin as an oil, 1.8 g (0.0052 mol) of which, on reaction with 1.25 ml (0.016 mol) of sulfuryl chloride in MDC, afforded 0.94 g (66%) of 2-chloromethyl-4-propylsaccharin.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:7][O:8][C:9]=1[CH3:10])=O.[NH2:17][C:18]1[C:23]([OH:24])=[CH:22][CH:21]=[CH:20][N:19]=1>>[CH3:10][C:9]1[O:8][N:7]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]=1[C:3]1[N:17]=[C:18]2[C:23]([OH:24])=[CH:22][CH:21]=[CH:20][N:19]2[CH:2]=1
Reactant: Nc1ncccc1O
Reactant: Cc1onc(-c2ccccc2)c1C(=O)CBr
Product: Cc1onc(-c2ccccc2)c1-c1cn2cccc(O)c2n1
Yield: 4 %

Procedure:
As described for Example 2, 4-(bromoacetyl)-5-methyl-3-phenylisoxazole (commercially available) (140 mg, 0.5 mmol) was converted, using 2-amino-3-hydroxypyridine instead of 2-amino-3-methylpyridine, to the title compound (6 mg, 4%) which was obtained as a yellow foam. MS: m/e=292.1 [M+H]+.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.[Cl:15][C:16]1[N:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19].[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26]1>>[Cl:15][C:16]1[C:17]([C:18]([N:6]2[CH:7]([C:27]3[C:28]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[NH:25][CH:26]=3)[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)=[O:19])=[CH:21][CH:22]=[CH:23][N:24]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: c1ccc2c(c1)cnc1ccccc12
Reactant: O=C(Cl)c1cccnc1Cl
Product: O=C(c1cccnc1Cl)N1c2ccccc2-c2ccccc2C1c1c[nH]c2ccccc12

Procedure:
(2-Chloro-pyridin-3-yl)-[6-(1H-indol-3-yl)-6H-phenanthridin-5-yl]-methanone was prepared from phenanthridine, 2-chloronicotinoyl chloride, and indole according to GP 2. Yield, 55%. 1H-NMR (DMSO-d6): δ=6.18 (s, br., 1H), 6.37 (d, J=7.9 Hz, 1H), 6.79 (t, J≈7 Hz, 1H), 7.01-7.17 (m, 4H), 7.23-7.30 (m, 1H), 7.36-7.62 (m, 5H), 7.88 (s, br., 1H), 7.94 (d, J=7.7 Hz, 1H), 8.07 (d, J=7.1 Hz, 1H), 8.37 (d, J=4.6 Hz, J=1.3 Hz, 1H), 10.72 (s, 1H); (+)-ESI-MS: m/z=436 [M(35Cl)+H]+, 319 [M(35Cl)-indole+H]+.
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[CH:13]=[C:12]([CH2:14][OH:15])[CH:11]=[CH:10][N:9]=1.BrC1C=C(C)C=CN=1.[F:24][C:25]([F:52])([F:51])[C:26]1[CH:27]=[C:28]([NH:36][C:37]([N:39]2[CH2:44][CH2:43][N:42]([C:45]3[C:49](Cl)=[N:48][S:47][N:46]=3)[CH2:41][CH2:40]2)=[O:38])[CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1>C(O)(C)(C)C>[F:52][C:25]([F:24])([F:51])[C:26]1[CH:27]=[C:28]([NH:36][C:37]([N:39]2[CH2:44][CH2:43][N:42]([C:45]3[C:49]([O:15][CH2:14][C:12]4[CH:11]=[CH:10][N:9]=[C:8]([Br:7])[CH:13]=4)=[N:48][S:47][N:46]=3)[CH2:41][CH2:40]2)=[O:38])[CH:29]=[C:30]([C:32]([F:33])([F:35])[F:34])[CH:31]=1
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(c2nsnc2Cl)CC1
Reactant: OCc1ccnc(Br)c1
Agent: CC(C)(C)[O-]
Agent: Cc1ccnc(Br)c1
Agent: [K+]
Solvent: CC(C)(C)O
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(c2nsnc2OCc2ccnc(Br)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of potassium t-butoxide (0.070 g, 0.63 mmol) and t-butanol (0.5 mL) was added dropwise with stirring (2-bromo-pyridin-4-yl)-methanol (0.078 g, 0.42 mmol, prepared in the similar fashion as Example 16a from 2-Bromo-4-methyl-pyridine), followed by 4-(4-chloro-[1,2,5]thiadiazol-3-yl)-piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-phenyl)-amide (0.100 g, 0.21 mmol; prepared in Example 10b). The mixture was stirred at room temperature overnight. LC/MS analysis indicated formation of the desired product. The mixture was concentrated in vacuo, and the crude product was purified on preparative HPLC to afford N-[3,5-bis(trifluoromethyl)phenyl]-4-(4-{[(2-bromopyridin-4-yl)methyl]oxy}-1,2,5-thiadiazol-3-yl)piperazine-1-carboxamide (13 mg, 10% yield). 1H NMR (CDCl3) 8.40 (s, 1H), 7.95 (s, 2H), 7.45 (s, 2H), 7.25 (m, 1H), 6.6 (s, 1H), 5.45 (m, 2H), 3.6 (m, 4H), 1.6 (m, 4H) ppm.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:7][C:8]1[CH:9]=[C:10]([CH:14]2[C:19]([C:20]([O:22]CC3C=CC=CC=3)=O)=[C:18]([CH3:30])[NH:17][C:16]([O:31]C)=[N:15]2)[CH:11]=[CH:12][CH:13]=1.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>C(OCC)(=O)C>[C:3]1([CH:4]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:5][CH2:6][NH:1][C:20]([C:19]2[CH:14]([C:10]3[CH:11]=[CH:12][CH:13]=[C:8]([Cl:7])[CH:9]=3)[N:15]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:16](=[O:31])[NH:17][C:18]=2[CH3:30])=[O:22])[CH:14]=[CH:19][CH:18]=[CH:30][CH:2]=1
Reactant: CCOC(=O)Cl
Reactant: COC1=NC(c2cccc(Cl)c2)C(C(=O)OCc2ccccc2)=C(C)N1
Reactant: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)N1C(=O)NC(C)=C(C(=O)NCCC(c2ccccc2)c2ccccc2)C1c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10 ml of pyridine was added to a mixture of 512 mg (1.38 mmol) of benzyl 4-(3-chlorophenyl)-2-methoxy-6-methyl-1,4-dihydropyrimidine-5-carboxylate and 180 mg (1.66 mmol) of ethyl chloroformate, and they were stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, then washed with water and saturated aqueous sodium chloride solution and concentrated under reduced pressure. The product was dissolved in a mixture of 5 ml of methanol and 5 ml of THF. 3 N hydrochloric acid was added to the obtained solution, and they were stirred at room temperature for 10 minutes. After the concentration under reduced pressure, the reaction mixture was diluted with ethyl acetate and then washed with 1 N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=10/1 to 1/1) to obtain the crude title compound.