Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:25]([F:33])[CH:24]=2)=[N:4][C:5]([C:8]2[CH2:13][CH2:12][CH:11]([CH2:14][O:15]CC3C=CC=CC=3)[CH2:10][CH:9]=2)=[CH:6][N:7]=1.CO>C1COCC1.[Pd]>[NH2:1][C:2]1[C:3]([C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:25]([F:33])[CH:24]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]2)=[CH:6][N:7]=1
Reactant: COC(=O)c1ccc(-c2nc(C3=CCC(COCc4ccccc4)CC3)cnc2N)cc1F
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2nc(C3CCC(CO)CC3)cnc2N)cc1F
Temperature: 25 °C
Reaction time: 14 h
Yield: 70.5 %

Procedure:
Methyl 4-(3-amino-6-(4-((benzyloxy)methyl)cyclohex-1-en-1-yl)pyrazin-2-yl)-2-fluorobenzoate (381 mg, 0.851 mmol) was dissolved in THF (5 mL) and then MeOH (15 mL) was added and then Pd—C (10% wet) (550 mg, 0.517 mmol) was added. The mixture was put under vacuum and purged with hydrogen and this cycle was repeated thrice and then finally under hydrogen overnight. After 14 h, LCMS indicated alkene saturation but only partial benzyl deprotection, and therefore another Pd—C (10% wet) (700 mg) was added and the mixture stirred at room temperature for another 5 h after which complete benzyl deprotection observed. The reaction mixture was filtered and concentrated in vacuo to afford 215.6 mg of the desired product as a mixture of diasteromers (cis/trans unspecified) (70%). LCMS (m/z): 360.2 (MH+), 0.71, 0.72 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:11](OC(=O)C)(=[O:13])[CH3:12].N1C=CC=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([CH3:10])[NH:9][C:11](=[O:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(N)C(=O)OC(C)(C)C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NN(C)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 41 %

Procedure:
To a solution of N-methylhydrazinecarboxylic acid tert-butyl ester (0.62 g, 4.20 mmol) in methylene chloride (10 ml) was added acetic acid anhydride (0.79 ml, 8.40) and pyridine (1.36 ml, 16.80 mmol) and the mixture was stirred overnight. Then methylene chloride (50 ml) was added and the mixture was washed with water (3×10 ml), dried (MgSO4), filtered and concentrated in vacuo to give 0.32 g (41%) of N'-acetyl-N-methylhydrazinecarboxylic acid tert-butyl ester as an oil.
Reaction SMILES: NCC1C=CC(NC2SC3CCCC4C=CC(F)=CC=4C=3N=2)=CC=1.[NH2:25][C:26]1[CH:40]=[CH:39][C:29]([CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:28][CH:27]=1.[C:41]([N:49]=[C:50]=[S:51])(=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C1COCC1>[C:41]([NH:49][C:50]([NH:25][C:26]1[CH:40]=[CH:39][C:29]([CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:37])[CH3:35])=[CH:28][CH:27]=1)=[S:51])(=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)cc1
Reactant: O=C(N=C=S)c1ccccc1
Agent: NCc1ccc(Nc2nc3c(s2)CCCc2ccc(F)cc2-3)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1ccc(NC(=S)NC(=O)c2ccccc2)cc1
Reaction time: 2 h
Yield: 99.9 %

Procedure:
To a stirred solution of N2-[4-(aminomethyl)phenyl]-9-fluoro-5,6-dihydro-4H-benzo-[6,7]cyclohepta[d][1,3]thiazol-2-amine-tert-butyl N-(4-aminobenzyl)carbamate (6.00 g, 27.0 mmol) in anhydrous THF (50 ml) was added benzoylisothiocyanate (4.43 g, 27.0 mmol). The solution was stirred for 2 hours and the solvent removed in vacuo to yield 100% (10.4 g) of the protected thiourea as a yellow solid: m.p. 161-163° C. 1H-NMR (CDCl3) δ 1.45 (9H, s), 4.33 (2H, d), 4.85 (1H, broad), 7.34 (2H, d), 7.60 (5H, m), 7.90 (2H, d), 9.13 (1H, s), 12.58 (1H, s); 386 (ESMS, MH+).
Reaction SMILES: [CH2:1]=[CH:2][C@@H:3]1[C@:20]2([CH3:21])[C@H:6]([C@H:7]3[C@H:17]([CH2:18][CH2:19]2)[C@:15]2([CH3:16])[C:10](=[CH:11][C:12](=[O:22])[CH2:13][CH2:14]2)[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1C=CC=CC=1.CCOCC>[CH2:1]=[CH:2][C@@H:3]1[C@:20]2([CH3:21])[C@H:6]([C@H:7]3[C@H:17]([CH2:18][CH2:19]2)[C@:15]2([CH3:16])[C:10](=[CH:11][C:12](=[O:22])[CH:13]=[CH:14]2)[CH2:9][CH2:8]3)[CH2:5][CH2:4]1
Reactant: C=C[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: c1ccccc1
Solvent: CCOCC
Product: C=C[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Yield: 22.1 %

Procedure:
Pregna-4,20-dien-3-one (1, 1.19 g. 3.99 mmol) was refluxed for 24 h with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ, 2.72 g, 12.1 mmol) in 40 ml of benzene under Argon. The cooled suspension was diluted with ether and washed with two 100 ml portions of 5% (w/w) sodium hydroxide, two 100 ml portions of water and once with 100 ml of brine. Ether (100 ml) was added to the resulting emulsion, which was dried over sodium sulfate and then filtered through a column of sodium sulfate (20 g). After washing the residue twice with 50 ml portions of ether the combined filtrates were concentrated under reduced pressure and then flash chromatographed (25% ethyl acetate/hexanes on silica gel) to give a slightly yellow crystalline solid (0.26 g, 0.88 mmol, 22%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:22][CH:21]([CH3:23])[N:11]2[C:12](=[O:20])[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[CH2:19][CH:10]2[CH2:9]1)C1C=CC=CC=1.[H][H]>[Pd].CO>[CH3:1][N:8]1[CH2:22][C@@H:21]([CH3:23])[N:11]2[C:12](=[O:20])[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[CH2:19][C@@H:10]2[CH2:9]1
Reactant: CC1CN(Cc2ccccc2)CC2Cc3ccccc3C(=O)N12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1CN(C)C[C@H]2Cc3ccccc3C(=O)N21
Temperature: 40 °C
Reaction time: 4 h
Yield: 16.3 %

Procedure:
1,2,3,4,11,11a-Hexahydro-2-benzyl-4-methyl-pyrazino[1,2-b]isoquinolin-6-one (from Isomer B, 12 mg, 0.04 mmol) and 10% palladium on carbon (5 mg) in MeOH (1 ml) was stirred under a balloon of hydrogen. The catalyst was filtered off and then fresh catalyst added. After stirring an additional 4 h at 40° C. under a balloon of hydrogen, the reaction was filtered through Celite® rinsing with methanol to afford 8 mg of crude product. Column purification (Chiralcel OD, 10% 1/1 MeOH/EtOH in hexanes) afforded pure (4R,11aR)-1,2,3,4,11,11a-hexahydro-2,4-dimethyl-pyrazino[1,2-b]isoquinolin-6-one (1.5 mg, 17% yield) MS (ESI) 231 (M+H). Further elution afforded (4S,1 aS)-1,2,3,4,11,11a-hexahydro-2,4-dimethyl-pyrazino[1,2-b]isoquinolin-6-one (1.6 mg, 18% yield) MS (ESI) 231 (M+H). Further elution also provided (4R,11aR)-1,2,3,4,11,11a-hexahydro-4-methyl-pyrazino[1,2-b]isoquinolin-6-one (2.4 mg, 29% yield) and (4S,11aS)-1,2,3,4,11,11a-hexahydro-4-methyl-pyrazino[1,2-b]isoquinolin-6-one (2.2 mg, 27% yield).
Reaction SMILES: C(Cl)(=O)C.C(O[C:10]([N:12](C)[CH:13]1[CH2:18][CH2:17][CH:16]([N:19]([CH2:34][C:35]2[CH:36]=[C:37]([C:43]3[CH:48]=[CH:47][N:46]=[C:45]([C:49]([O:51][CH3:52])=[O:50])[CH:44]=3)[CH:38]=[CH:39][C:40]=2[O:41][CH3:42])[C:20]([C:22]2[S:26][C:25]3[C:27]([F:32])=[CH:28][CH:29]=[C:30]([F:31])[C:24]=3[C:23]=2[Cl:33])=[O:21])[CH2:15][CH2:14]1)=O)(C)(C)C>CO>[Cl:33][C:23]1[C:24]2[C:30]([F:31])=[CH:29][CH:28]=[C:27]([F:32])[C:25]=2[S:26][C:22]=1[C:20]([N:19]([CH2:34][C:35]1[CH:36]=[C:37]([C:43]2[CH:48]=[CH:47][N:46]=[C:45]([C:49]([O:51][CH3:52])=[O:50])[CH:44]=2)[CH:38]=[CH:39][C:40]=1[O:41][CH3:42])[CH:16]1[CH2:17][CH2:18][CH:13]([NH:12][CH3:10])[CH2:14][CH2:15]1)=[O:21]
Reactant: COC(=O)c1cc(-c2ccc(OC)c(CN(C(=O)c3sc4c(F)ccc(F)c4c3Cl)C3CCC(N(C)C(=O)OC(C)(C)C)CC3)c2)ccn1
Solvent: CO
Solvent: CC(=O)Cl
Product: CNC1CCC(N(Cc2cc(-c3ccnc(C(=O)OC)c3)ccc2OC)C(=O)c2sc3c(F)ccc(F)c3c2Cl)CC1
Reaction time: 2 h

Procedure:
Acetyl chloride (5 mL) is added to anhydrous MeOH (10 mL) at 0° C. tert-Butyl carbamate 148 (247 mg, 0.35 mmol) is then treated with this solution and stirred 2 h. On removal of the solvents in vacuo, the reaction mixture is dissolved in DCM (25 mL) and extracted into 2 M HCl (4×10 mL). The combined HCl phases are washed with DCM (2×20 mL) then taken to pH 9 by careful addition of solid NaHCO3. The resultant aqueous suspension is then extracted into DCM (3×20 mL), the combined DCM phases dried (Na2SO4) and reduced in vacuo to afford the title compound.
Reaction SMILES: [NH2:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[I-].C([N+]1(C)[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]1)C>C(O)C.O>[C@@H:2]1([N:1]2[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CC[N+]1(C)CCC(=O)CC1
Reactant: N[C@H]1CCc2ccccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C1CCN([C@H]2CCc3ccccc32)CC1

Procedure:
(S)-1-Aminoindane (37 mmol) was dissolved in ethanol (65 ml). Potassium carbonate (3.7 mmol) and 1-ethyl-1-methyl-4-oxo-piperidinium iodide (56 mmol) dissolved in water (30 ml) were added and the mixture was refluxed for 30 mil. Water was added, ethanol was removed in vacuo and the residue was extracted with ethyl acetate. Organic phases were pooled, dried with sodium sulfate and concentrated. Chromatography on silica gel (ethyl acetate) yielded the desired product as an oil. 7.1 g (90%) of (S)-1-indan-1-yl-piperidine-4-one, MS: m/e=216.4 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][C@H:9]1[C@H:14]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:27][C@H:28]1[C:36]2[C:35]([N:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[N:34][CH:33]=[N:32][C:31]=2[C@@H:30]([OH:43])[CH2:29]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C@@H:14]([C@@H:9]2[CH2:10][O:11][CH2:12][CH2:13][N:8]2[C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[C:15]([N:40]2[CH2:41][CH2:42][N:37]([C:35]3[C:36]4[C@H:28]([CH3:27])[CH2:29][C@H:30]([OH:43])[C:31]=4[N:32]=[CH:33][N:34]=3)[CH2:38][CH2:39]2)=[O:17])=[CH:23][CH:22]=1
Reactant: C[C@@H]1C[C@H](O)c2ncnc(N3CCNCC3)c21
Reactant: CC(C)(C)OC(=O)N1CCOC[C@H]1[C@@H](C(=O)O)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1C[C@H](O)c2ncnc(N3CCN(C(=O)[C@@H](c4ccc(Cl)cc4)[C@@H]4COCCN4C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 60 h

Procedure:
(S)-2-((R)-4-(tert-Butoxycarbonyl)morpholin-3-yl)-2-(4-chlorophenyl)acetic acid (0.051 g, 0.143 mmol) was combined with (5R,7S)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (0.0440 g, 0.143 mmol), and then slurried in methylene chloride (1.4 mL). The suspension was treated with diisopropylethylamine (0.0749 mL, 0.430 mmol) and then with HBTU (0.0544 g, 0.143 mmol). The mixture was then stirred at ambient temperature for 60 hours. The reaction was quenched with 10% Na2CO3 and separated. The reaction mixture was washed with methylene chloride (3×), and the combined organics were then dried with Na2SO4 and concentrated in vacuo. The resulting residue was subjected to chromatography on SiO2 (Biotage 12M) eluting with methylene chloride (96 mL) then 0% to 5% MeOH/methylene chloride (500 mL) and 5% MeOH/methylene chloride (96 mL). The desired material eluted cleanly in approximately 1% MeOH/methylene chloride to yield (R)-tert-butyl 3-((S)-1-(4-chlorophenyl)-2-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-oxoethyl)morpholine-4-carboxylate as an oil. (81.2 mg, 99%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][CH2:13][C:14](=O)[CH3:15])[C:7]=1[F:17])[CH3:2].Cl.[Cl:20][C:21]1[C:22]([F:29])=[C:23]([NH:27]N)[CH:24]=[CH:25][CH:26]=1>>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:24]3[C:23](=[C:22]([F:29])[C:21]([Cl:20])=[CH:26][CH:25]=3)[NH:27][C:14]=2[CH3:15])[C:7]=1[F:17])[CH3:2]
Reactant: CCOC(=O)Cc1cccc(SCC(C)=O)c1F
Reactant: NNc1cccc(Cl)c1F
Agent: Cl
Product: CCOC(=O)Cc1cccc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)c1F

Procedure:
Prepared according to the procedure described in Example 2, Step 1, using the following starting materials: [2-Fluoro-3-(2-oxo-propylsulfanyl)-phenyl]-acetic acid ethyl ester and (3-chloro-2-fluoro-phenyl) hydrazine hydrochloride.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][N:9]=1.[C:17]([NH2:21])([CH3:20])([CH3:19])[CH3:18].[OH-].[Na+]>C1(C)C=CC=CC=1.CN(C=O)C>[C:17]([NH:21][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][C:8]([CH3:7])=[N:9][CH:10]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: Cc1ccc(C(=O)O)cn1
Reactant: CC(C)(C)N
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC(C)(C)C)cn1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
3.5 ml (40 mMol) Oxalylchloride and 57.4 □l (0.74 mMol) DMF were added to a suspension of 5.0 g (36.5 mMol) 6-methyl-nicotinic acid in 25 ml toluene and the system was heated to 40° C. for one hour. After diluting with 20 ml toluene and cooling to 0° C., 11.5 ml (109 mMol) tert.-butylamine were slowly added. After 30 minutes stirring at room temperature, 25 ml aqueous NaOH 2N were added and stirring pursued for 30 minutes. The phases were separated and the aqueous phase was extracted with toluene. The combined organic extracts were washed with water and brine, dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (eluent: ethyl acetate/n-heptan 1:1) to yield 5.4 g (77%) N-tert.-butyl-6-methyl-nicotinamide as a light beige solid of m.p. =103.5-104.8° C.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([NH2:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[CH2:9]1[CH2:15][S:12](=[O:14])(=[O:13])[O:11][CH2:10]1>O1CCCC1.O>[C:6]([C@@H:2]([NH:1][CH2:10][CH2:9][CH2:15][S:12]([OH:14])(=[O:13])=[O:11])[CH:3]([CH3:5])[CH3:4])(=[O:7])[NH2:8]
Reactant: CC(C)[C@H](N)C(N)=O
Reactant: O=S1(=O)CCCO1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@H](NCCCS(=O)(=O)O)C(N)=O
Temperature: 25 °C

Procedure:
To a solution of L-valinamide (1.57 g, 13.5 mmol) in tetrahydrofuran (20 mL) was slowly added 1,3-propane sultone (1.61 g, 12.9 mmol). The mixture was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid material was collected by filtration, washed with acetone (2×25 mL). The crude product was dissolved in water (60 mL) and treated with ion exchange resin Dowex Marathon C (strongly acidic, 15 g). The mixture was stirred for 15 minutes. The resin was removed by filtration. The filtrate was poured into EtOH (250 mL). The solid product, after the completion of the precipitation, was collected by filtration, and dried in vacuo, to afford compound EQ (1.6 g, 51%). 1H NMR (D2O, 500 MHz) δ ppm 3.63 (d, 1H), 3.05 (m, 2H), 2.85 (m, 2H), 2.05 (m, 4H), 0.93 (d, 3H), 0.88 (d, 3H). 13C NMR (D2O, 125 MHz) δ ppm 170.24, 65.92, 48.16, 46.31, 29.59, 21.31, 18.02, 17.07. [α]D=+10.5° (c=0.0027 in water), ES-MS 237 (M−1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH2:15][CH2:14]2)[N:5]2[C:10]=1[C:9]([NH2:11])=[N:8][CH:7]=[N:6]2.[CH2:25]([N:32]1[CH:40]=[C:39]2[C:34]([CH:35]=[C:36](B3OC(C)(C)C(C)(C)O3)[CH:37]=[CH:38]2)=[N:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([N:32]1[CH:40]=[C:39]2[C:34]([CH:35]=[C:36]([C:2]3[CH:3]=[C:4]([CH2:12][N:13]4[CH2:18][CH2:17][N:16]([C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH2:15][CH2:14]4)[N:5]4[C:10]=3[C:9]([NH2:11])=[N:8][CH:7]=[N:6]4)[CH:37]=[CH:38]2)=[N:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC1(C)OB(c2ccc3cn(Cc4ccccc4)nc3c2)OC1(C)C
Reactant: Nc1ncnn2c(CN3CCN(C(=O)C(F)(F)F)CC3)cc(Br)c12
Product: Nc1ncnn2c(CN3CCN(C(=O)C(F)(F)F)CC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Yield: 11 %

Procedure:
In a manner similar to the procedure described for step 3 of Example 83 and using 5-bromo-7-{[4-(trifluoroacetyl)piperazin-1-yl]methyl}pyrrolo[2,1-f][1,2,4]triazin-4-amine and 2-benzyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole as starting materials, 14 mg, (11%) of the desired product was isolated. 1H NMR (400 MHz, CD2Cl2) δ 8.05 (s, 1 H) 7.89 (s, 1 H) 7.74-7.81 (m, 2 H) 7.32-7.42 (m, 5 H) 7.24 (dd, 1 H) 6.71 (s, 1 H) 5.80 (br, 2 H) 5.62 (s, 2 H), 4.00 (s, 2 H) 3.59-3.71 (m, 4 H) 2.59-2.69 (m, 4 H). LC-MS [M+H]+=535.2, RT=2.51 min
Reaction SMILES: O1CCCC1.[CH3:6][CH2:7][CH:8]([OH:11])[CH2:9][CH3:10].[H-].[Na+].[Br:14][C:15]1[N:32]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:18]2[CH:19]=[N:20][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22](=[O:23])[C:17]=2[C:16]=1[CH2:41]Br>O>[Br:14][C:15]1[N:32]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:18]2[CH:19]=[N:20][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22](=[O:23])[C:17]=2[C:16]=1[CH2:41][O:11][CH:8]([CH2:9][CH3:10])[CH2:7][CH3:6]
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(CBr)c(Br)n2COCC[Si](C)(C)C)c1=O
Reactant: CCC(O)CC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCC(CC)OCc1c(Br)n(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
To 15 ml of dehydrated tetrahydrofuran solution containing 1.90 ml of 3-pentanol was added 0.38 g of sodium hydride (55% dispersed material in mineral oil) under cooling in ice-bath, and the mixture was stirred at room temperature for 3 hours. Then, 0.99 g (1.75 mmol) of 2-bromo-3-bromomethyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 25-(a) was added to the mixture, and the mixture was stirred at 45° C. for 2 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and then, concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=7:3 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 0.66 g of the title compound as a slightly yellowish oil. (Yield: 65%)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[C:31]1[CH:36]=[CH:35][NH:34][C:33](=[O:37])[CH:32]=1>>[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[C:31]1[CH:36]=[CH:35][N:34]([C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][C:7]=4[N:8]([CH3:11])[C:9]=3[CH:10]=2)[C:33](=[O:37])[CH:32]=1
Reactant: O=c1cc(-c2ccc(Cl)cc2Cl)cc[nH]1
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(Cl)cc5Cl)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Yield: 19.5 %

Procedure:
The compound was prepared from tert-butyl 7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (200 mg, 0.548 mmol) and 4-(2,4-dichlorophenyl)pyridine-2(1H)-one (132 mg, 0.548 mmol) according to the procedure in Example 1 (step c). Purification by flash column chromatography (silica gel, hexanes/EtOAc, 100:0 to 80:20 to 50:50 then 25:75) provided the title compound (56 mg, 20%) as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 7.56-7.52 (m, 2H), 7.47 (d, J=7.0 Hz, 1H), 7.39-7.32 (m, 3H), 7.10 (br s, 1H), 6.69 (s, 1H), 6.35 (d, J=5.7 Hz, 1H), 4.66 (s, 2H), 3.85 (br s, 2H), 3.65 (s, 3H), 2.84 (br s, 2H), 1.51 (s, 9H).
Reaction SMILES: [OH-].[K+].CO.[Cl:5][C:6]1[C:7]([O:17][CH3:18])=[C:8]([C:13]([Cl:16])=[CH:14][CH:15]=1)[C:9]([NH:11][OH:12])=[O:10].[CH3:19][O:20][C:21](=[O:24])[CH2:22]Br>C(Cl)Cl>[Cl:5][C:6]1[C:7]([O:17][CH3:18])=[C:8]([C:13]([Cl:16])=[CH:14][CH:15]=1)[C:9]([NH:11][O:12][CH2:22][C:21]([O:20][CH3:19])=[O:24])=[O:10]
Reactant: COc1c(Cl)ccc(Cl)c1C(=O)NO
Reactant: COC(=O)CBr
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CONC(=O)c1c(Cl)ccc(Cl)c1OC

Procedure:
To a solution of 2.15 g. of potassium hydroxide in 50 ml. of methanol was added 7.55 g. of 3,6-dichloro-2-methoxy benzohydroxamic acid followed by stirring until dissolution was obtained. To this solution was added dropwise 3.03 ml. methylbromoacetate in 25 ml. of methanol. The reaction mixture was refluxed for 2 hours and allowed to stir overnight at ambient temperature. To the reaction mixture was added 0.36 g. of additional potassium hydroxide and the mixture heated to reflux for 4 hours, then cooled, filtered, and the filtrate concentrated in vacuo to give a crude semi-solid product. This crude product was taken up in methylene chloride and washed with water, 5% aqueous NaHCO3, brine, then dried over MgSO4, filtered and evaporated in vacuo to give a viscuous oil. The oil crystallized from an ethyl acetate-hexane mixture to the title product as a white solid, m.p. 102°-105° C.
Reaction SMILES: [N:1]1[C:6](=[O:7])[NH:5][C:4](=[O:8])[N:3]2[CH2:9][CH2:10][CH2:11][CH2:12][C:2]=12.[F:13][C:14]1[CH:36]=[CH:35][C:17]([C:18]([CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([C:29]3C=CC=CC=3)[CH2:27]O)[CH2:22][CH2:21]2)=[O:19])=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH3:29][CH:26]([N:23]1[CH2:24][CH2:25][CH:20]([C:18](=[O:19])[C:17]2[CH:35]=[CH:36][C:14]([F:13])=[CH:15][CH:16]=2)[CH2:21][CH2:22]1)[CH2:27][N:5]1[C:4](=[O:8])[N:3]2[CH2:9][CH2:10][CH2:11][CH2:12][C:2]2=[N:1][C:6]1=[O:7]
Reactant: O=c1nc2n(c(=O)[nH]1)CCCC2
Reactant: O=C(c1ccc(F)cc1)C1CCN(C(CO)c2ccccc2)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(Cn1c(=O)nc2n(c1=O)CCCC2)N1CCC(C(=O)c2ccc(F)cc2)CC1

Procedure:
In the manner described in Example 1-2), 6,7,8,9-tetrahydro-2H-pyrido[1,2-a]-1,3,5-triazine-2,4(3H)-dione obtained in Example 1-1) and 4-(4-fluorobenzoyl)-1-(1-phenyl-2-hydroxyethyl)piperidine were condensed in N,N-dimmethylformamide in the presence of triphenylphosphine and diethyl azodicarboxylate to obtain the entitled compound as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2Cl)[C:7]=1[CH3:25])[CH3:2].C(OC(=O)CC1C2C(=CC=C(OC)C=2)NC=1C)C.[H-].[Na+].[Cl:47]C1C=C(C=CC=1)CCl>>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:47])[CH:19]=2)[C:7]=1[CH3:25])[CH3:2]
Reactant: CCOC(=O)Cc1c(C)n(Cc2ccccc2Cl)c2ccc(OC)cc12
Reactant: ClCc1cccc(Cl)c1
Agent: CCOC(=O)Cc1c(C)[nH]c2ccc(OC)cc12
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)Cc1c(C)n(Cc2cccc(Cl)c2)c2ccc(OC)cc12
Yield: 55 %

Procedure:
1-(2-Chlorophenylmethyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid ethyl ester. Using the procedure described in Example 1, Part F, 494 mg (2 mmol) of 5-methoxy-2-methyl-1H-indole-3-acetic acid ethyl ester was reacted with 80 mg (2 mmol) of 60% NaH/mineral oil and 0.25 mL (2 mmol) of meta-chlorobenzylchloride and after chromatography on silica (eluting with 33% EtOAc/hexane) and crystallizing from MeOH there was obtained 409 mg (55%) of 1-(3-chlorophenylmethyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid ethyl ester, mp, 79°-81° C.
Reaction SMILES: [C:1]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][CH3:16])[CH:9]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C([Li])CCC.C(Br)C[Br:24]>O1CCCC1>[C:1]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][CH3:16])[C:9]=1[Br:24])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: BrCCBr
Reactant: COc1cc(NC(=O)C(C)(C)C)ccc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1c(Cl)ccc(NC(=O)C(C)(C)C)c1Br
Temperature: 0 °C
Reaction time: 3 h
Yield: 5.7 %

Procedure:
To solution of N-pivaloyl-4-chloro-3-methoxyaniline (5.0 g, 21 mmol) in tetrahydrofuran (60 mL) at −60° C. was added n-butyl lithium (2.5M, 44 mmol). The solution was allowed to warm to 0° C. and stir for 3 hours. Ethylene dibromide (9.9 g, 53 mmol) was added and the solution stirred for 18 hours before being quenched with with ammonium chloride (saturated solution, 20 mL) and extracted with ethyl ether (2×50 mL). The combined extracts were washed with brine, dried (sodium sulfate) and concentrated. The residure was purified by chromatography (10% ethyl acetate/hexanes) to give N-pivaloyl-2-bromo-4-chloro-3-methoxyaniline (3.7 g, 1.2 mmol): LC/MS (m/z=320).