Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[CH:14]=[N:13][C:12]([NH:15][CH3:16])=[N:11][C:10]1=[O:17].Cl.C(NC(N)=O)(=N)N>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[CH:14]=[N:13][CH:12]([NH:15][CH3:16])[NH:11][C:10]1=[O:17]
Reactant: CNc1ncn(-c2c(C)cccc2Cl)c(=O)n1
Agent: Cl
Agent: N=C(N)NC(N)=O
Solvent: CO
Product: CNC1N=CN(c2c(C)cccc2Cl)C(=O)N1
Reaction time: 1.5 h

Procedure:
The reaction mixture was stirred for 1.5 hours after which an aliquot of the reaction product which had been dissolved in MeOH showed there to be one major spot with Rf equal to that of 1-(2-chloro-6-methylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one and two minor spots of very small Rf, one at the origin and one of the same Rf as the starting material amidinourea hydrochloride. The reaction mixture was allowed to stir an additional 0.5 hour and the solid was filtered to yield 1-(2-chloro-6-methylphenyl)-4-methylaminodihydro-1,3,5-triazin-2-one, (EtOAc:MeOH; 9:1). It has the same two impurities as the crude reaction mixture. 7.7 g of the crude mixture was recrystallized from absolute EtOH; melting point 257.5°-258.5° C.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:16](=[O:17])[CH2:15][C:14]([CH3:19])([CH3:18])[CH2:13][C:12]2=[O:20])=[CH:7][CH:6]=1)=[O:3].[CH3:21][O:22][C:23]1[CH:35]=[CH:34][C:26]([CH2:27][N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:25][CH:24]=1>>[CH3:18][C:14]1([CH3:19])[CH2:15][C:16](=[O:17])[N:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:31]3[CH2:30][CH2:29][N:28]([CH2:27][C:26]4[CH:34]=[CH:35][C:23]([O:22][CH3:21])=[CH:24][CH:25]=4)[CH2:33][CH2:32]3)=[O:3])=[CH:6][CH:7]=2)[C:12](=[O:20])[CH2:13]1
Reactant: CC1(C)CC(=O)N(c2ccc(OC(=O)Cl)cc2)C(=O)C1
Reactant: COc1ccc(CN2CCNCC2)cc1
Product: COc1ccc(CN2CCN(C(=O)Oc3ccc(N4C(=O)CC(C)(C)CC4=O)cc3)CC2)cc1

Procedure:
The title compound was prepared from 4-(4,4-dimethyl-2,6-dioxo-piperidin-1-yl)-phenyl chloroformate and 1-(4-methoxybenzyl)-piperazine, preparative HPLC (Method C) (54%, white crystals). HPLC-MS m/z=466.3 (M+1), Rt: 2.26 min.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1)=[O:5].C(N(CC)CC)C.[NH:27]1[C:31]2=[CH:32][NH:33][C:34]3[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=3[CH2:36][N:30]2[CH:29]=[CH:28]1>C(Cl)Cl>[N:27]1[CH:28]=[CH:29][N:30]2[CH2:36][C:35]3[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=3[N:33]([C:11]([C:10]3[CH:14]=[CH:15][C:7]([NH:6][C:4](=[O:5])[C:3]4[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=4[CH3:1])=[CH:8][CH:9]=3)=[O:12])[CH2:32][C:31]=12
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: C1=CN2Cc3ccccc3NC=C2N1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3nccn3Cc3ccccc32)cc1
Temperature: 0 °C
Reaction time: 0.05 h

Procedure:
To a mixture of 1.37 g (5 mmol) of 4-[(2-methylbenzoyl)amino]benzoyl chloride in 15 ml of methylene chloride, cooled to 0° C. is added 1.5 ml of triethylamine. After stirring for 3 minutes, 5 mmol of 10, 1-dihydro-5H-imidazo[2,1-c][1,4]benzodiazepine in 5 ml of methylene chloride is added. The cooling bath is removed and after about 30 minutes a complete solution is obtained. The reaction mixture is allowed to stir at room temperature for 1 hour and the volatiles are concentrated in vacuo. The residue is dissolved in 100 ml of ethyl acetate and washed with water, 2N citric acid, and brine. The solution is dried with Na2 SO4 and the volatiles concentrated in vacuo to give the desired product as a solid.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:14](=[O:16])[CH3:15])[N:4]2[C:8]3[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:7]=3[S:6][C:5]=12.[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([CH:25]=O)=[CH:23][CH:24]=1>>[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([CH:25]=[CH:15][C:14]([C:3]2[N:4]3[C:5]([S:6][C:7]4[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]=43)=[N:1][CH:2]=2)=[O:16])=[CH:23][CH:24]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CC(=O)c1cnc2sc3c(n12)CCCCC3
Product: COc1ccc(C=CC(=O)c2cnc3sc4c(n23)CCCCC4)cc1

Procedure:
1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-ethanone (Formula N-4), 0.44 g, and anisaldehyde (0.5 mL) were condensed according to non-critical variations in PREPARATION 15 to produce 3-(4-Methoxyphenyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-2-propene-1-one, 0.65 g, (Formula N-5, X=4-methoxy), m.p. 180-187°.
Reaction SMILES: [N:1]1([CH:10]([NH:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[C:11](O)=[O:12])C2C=CC=CC=2N=N1.C(Cl)(=O)C(Cl)=O.[NH2:31][C:32]1[C:37]([CH2:38][O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])=[CH:36][CH:35]=[CH:34][C:33]=1[C:47]([C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([F:55])[CH:50]=1)=O.CN1CCOCC1.N.CO.C(O)(=O)C.C([O-])(=O)C.[NH4+]>C1COCC1.O.CN(C=O)C>[CH2:18]([O:17][C:15](=[O:16])[NH:14][CH:10]1[C:11](=[O:12])[NH:31][C:32]2[C:37]([CH2:38][O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])=[CH:36][CH:35]=[CH:34][C:33]=2[C:47]([C:49]2[CH:54]=[CH:53][CH:52]=[C:51]([F:55])[CH:50]=2)=[N:1]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(NC(C(=O)O)n1nnc2ccccc21)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(C(=O)c2cccc(F)c2)c1N
Agent: CC(=O)[O-]
Agent: N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1cccc2c1NC(=O)C(NC(=O)OCc1ccccc1)N=C2c1cccc(F)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 62.7 %

Procedure:
To a solution of 2-(1H-benzo[d][1,2,3]triazol-1-yl)-2-(((benzyloxy)carbonyl)amino)acetic acid (608 mg, 1.864 mmol) in THF (7 mL) cooled at 0° C. was added oxalyl chloride (0.157 mL, 1.789 mmol), followed by DMF (0.02 mL). The resulting mixture was stirred at 0° C. for 1.5 h. Then a solution of Intermediate 37F (268 mg, 0.745 mmol) and 4-methylmorpholine (0.246 mL, 2.236 mmol) in THF (3 mL) were slowly added. After the addition, the reaction mixture was warmed to room temperature and stirred for 1 h. Next, 7N ammonia in MeOH (4 mL, 28.0 mmol) was added and the mixture was stirred at room temperature overnight. The resulting mixture was concentrated and the residue was treated with EtOAc and water. The organic layer was separated, and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with 1N NaOH, sat NaHCO3 and brine and then dried over MgSO4, filtered and concentrated. The residue was then dissolved in acetic acid (1.5 mL, 26.2 mmol), and treated with ammonium acetate (287 mg, 3.73 mmol). The mixture was stirred at 40° C. for 2 h. The reaction mixture was then treated with water and extracted with EtOAc. The combined extracts were washed with water, saturated NaHCO3, and brine and then dried and concentrated. The crude material was purified by flash chromatography (SiO2, 12 g column, EtOAc/hexane=0-40%) to afford Intermediate 37G (256 mg, 63%). HPLC: RT=3.61 min (CHROMOLITH® SpeedROD column 4 6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 220 nm), MS(ES): m/z=548.5 [M+H+].
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:40][C:41]([N:43]1[CH2:47][CH2:46][CH2:45][CH2:44]1)=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:40][CH2:41][N:43]2[CH2:47][CH2:46][CH2:45][CH2:44]2)=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=C(CCl)N1CCCC1
Product: CCN(Cc1ccc(OCCN2CCCC2)c(F)c1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 92.2 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 2-chloro-1-pyrrolidin-1-ylethanone (14 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (23 mg) was obtained.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][O:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][S:14]([CH:17]=[CH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:16])=[O:15])[C:8]=1[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1.Cl[C:33]1[N:38]=[CH:37][CH:36]=[CH:35][N:34]=1>C1COCC1>[N:34]1[CH:35]=[CH:36][CH:37]=[N:38][C:33]=1[O:3][CH2:4][CH2:5][O:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][S:14]([CH:17]=[CH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:15])=[O:16])[C:8]=1[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1
Reactant: Clc1ncccn1
Reactant: Cc1ccc(-c2c(NS(=O)(=O)C=Cc3ccccc3)ncnc2OCCO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(NS(=O)(=O)C=Cc3ccccc3)ncnc2OCCOc2ncccn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.9 %

Procedure:
To sodium hydride (26 mg, 55-65% in mineral oil) was added THF (10 ml) followed by the addition of 2-phenyl-ethenesulfonic acid [6-(2-hydroxy-ethoxy)-5-p-tolyl-pyrimidin-4-yl]-amide (100 mg). The mixture was stirred for 1 h at rt. Then 2-chloro-pyrimidine (46 mg) was added and stirring continued for 19 h at 80° C. The solvent was evaporated and diethylether (20 ml) was added to the residue. The precipitate was filtered off and washed with diethylether, dissolved in water and acidified by citric acid. The precipitate was filtered off and the crude material was purified by chromatography over silicagel with hexane/EtOAc=1/1 to give 2-phenyl-ethenesulfonic acid {6-[2-(pyrimidin-2-yloxy)-ethoxy]-5-p-tolyl-pyrimidin-4-yl}-amide (23.7 mg); tR=4.85 (LC); [M+H]+=490.27 (ES+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:21])[CH2:11][O:12][CH:13]([CH2:19]O)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:6][CH:5]=1)[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([C@H:10]2[CH2:11][O:12][C@H:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:19][O:21]2)=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCCCCC(CO)OCC(O)c1ccc(OCC)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCC[C@@H]1CO[C@@H](c2ccc(OCC)cc2)CO1

Procedure:
One boils a solution of 29.6 g. 1-p-ethoxyphenyl-4-hydroxymethyl-3-oxa-nonan-1-ol (obtainable by reaction of p-ethoxyphenacyl bromide with 2-hydroxyheptanoic acid ethyl ester to give 2-p-ethoxyphenacyloxyheptanoic acid ethyl ester and reduction with LiAlH4) and 1 g. p-toluenesulphonic acid in 400 ml. toluene for 1 hour with water separator, washes with NaHCO3 solution, dries, evaporates and obtains trans-2-p-ethoxyphenyl-5-pentyl-1,4-dioxane.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([Li])CCC.CN(C)[CH:26]=[O:27]>C1COCC1.[Cl-].[NH4+]>[O:12]([C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH:26]=[O:27])[CH:3]=2)[N:8]=[CH:7][CH:6]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Brc1ccc2nccc(Oc3ccccc3)c2c1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=Cc1ccc2nccc(Oc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 26.9 %

Procedure:
To a solution of 6-bromo-4-phenoxy-quinoline (1.12 g, 3.73 mmol) in THF (15 mL) was added dropwise a 2.5M solution of n-butyllithium in hexanes (1.64 mL, 4.10 mmol, 1.1 equiv.) at −70° C. During the addition, the color of the solution was turned into brown and this solution was stirred for 20 min at this temperature. Then, a neat dimethylformamide (0.576 mL, 7.46 mmol) was added dropwise. After addition, the mixture was allowed to warm to room temperature and stirred for 2 h. Then, the mixture was diluted with saturated ammonium chloride solution and the two layers were separated. The aqueous layer was extracted with ethyl acetate (2×75 mL). The combined organic extracts were washed with brine solution and dried over anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent under the vacuum gave the crude residue which was purified by using a Biotage silica gel column chromatography to afford 0.250 g (27% yield) of 4-phenoxy-quinoline-6-carbaldehyde as a white solid: mp 112-115° C.; EI-HRMS m/e calcd for C16H11NO2 (M+) 249.0790, found 249.0787.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH:11]([C@@H:24]1[O:29][CH2:28][C@@H:27]([OH:30])[CH2:26][CH2:25]1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[CH:11]([CH:24]1[O:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O[C@H]1CC[C@H](C(c2ccccc2)c2ccccc2)OC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C1CCC(C(c2ccccc2)c2ccccc2)OC1
Reaction time: 0.25 h
Yield: 90.1 %

Procedure:
Into a solution of DMSO (0.13 g, 1.64 mmol) in methylene chloride (5 ml) at −78° C. was added a solution of oxalyl chloride (0.11 g, 0.82 mmol) in methylene chloride (1 ml) in a dropwise manner A solution of trans-2-diphenylmethyl-tetrahydropyran-5-ol 11 (0.2 g, 0.75 mmol) in methylene chloride (2 ml) was added next. The reaction was continued for 15 minutes, triethylamine (0.38 g, 3.73 mmol) was next added portion wise and the reaction mixture was allowed to come to room temperature for over a period of 30 minutes. Additional methylene chloride (10 ml) was added, and washed with sat. aqueous NaHCO3, brine, and then dried over anhydrous Na2SO4. Removal of the solvent and purification by flash chromatography (SiO2, Hexane/Ethyl Acetate 8.5:1.5) gave 2-diphenylmethyl-dihydro-pyran-5-one 12 (0.18 g, 91%) as a liquid.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.CO.[Si]([O:27][C@H:28]1[CH2:39][C:38](=[O:40])[O:37][C@H:36](/[C:41](/[CH3:45])=[CH:42]/[CH:43]=[CH2:44])[C@@H:35]([CH3:46])[CH:34]=[CH:33][C@@H:32]2[O:47][C@H](C3C=CC=CC=3)[O:49][C@:31]2([CH3:56])[CH2:30][CH2:29]1)(C(C)(C)C)(C)C.O>C(OCC)(=O)C>[OH:27][C@@H:28]1[CH2:29][CH2:30][C@:31]([OH:49])([CH3:56])[C@@H:32]([OH:47])[CH:33]=[CH:34][C@H:35]([CH3:46])[C@@H:36](/[C:41](/[CH3:45])=[CH:42]/[CH:43]=[CH2:44])[O:37][C:38](=[O:40])[CH2:39]1
Reactant: C=C/C=C(\C)[C@H]1OC(=O)C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@]2(C)O[C@@H](c3ccccc3)O[C@H]2C=C[C@@H]1C
Agent: C=C/C=C(\C)[C@H]1OC(=O)C[C@H](O)CC[C@@](C)(O)[C@@H](O)/C=C/[C@@H]1C
Agent: C=C/C=C(\C)[C@H]1OC(=O)C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@]2(C)O[C@@H](c3ccccc3)O[C@H]2/C=C/[C@@H]1C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: C=C/C=C(\C)[C@H]1OC(=O)C[C@H](O)CC[C@@](C)(O)[C@@H](O)C=C[C@@H]1C
Temperature: 25 °C
Reaction time: 96 h

Procedure:
Pyridinium p-toluene sulfonate (68.2 mg, 271 μmol) was added to a methanol (1.22 ml) solution of (2S,3aS,4E,6S,7S,11R,13aR)-11-{[tert-butyl(dimethyl)silyl]oxy}-6,13a-dimethyl-7-[(1E)-1-methylbuta-1,3-dien-1-yl]-2-phenyl-3a,6,7,10,11,12,13,13a-octahydro-9H-[1,3]dioxolo[4,5-f]oxacyclododecin-9-one (36.0 mg, 0.07 mmol) and the reaction solution was stirred at room temperature for four days. Distilled water (1 ml) was added to the reaction solution, and the reaction solution was diluted with ethyl acetate and washed with distilled water and brine sequentially, and after dried over anhydrous sodium sulfate, the drying agent was filtered off and the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Merck, commercial name Silica Gel 60, 230-400 mesh; hexane:diethyl ether=1:3) to obtain the title compound (18.3 mg) as a white solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([O:31]C(C)(C)C)=[O:30])[C:26]([CH2:36][CH2:37][CH2:38][O:39][C:40]3[CH:45]=[CH:44][C:43]([N:46]4[C:50]5=[N:51][CH:52]=[N:53][C:54]([NH:55][CH2:56][CH2:57][CH2:58][N:59]([CH3:61])[CH3:60])=[C:49]5[CH:48]=[N:47]4)=[CH:42][CH:41]=3)=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12].C([SiH](CC)CC)C.[C:69]([OH:75])([C:71]([F:74])([F:73])[F:72])=[O:70]>C(Cl)Cl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([OH:31])=[O:30])[C:26]([CH2:36][CH2:37][CH2:38][O:39][C:40]3[CH:45]=[CH:44][C:43]([N:46]4[C:50]5=[N:51][CH:52]=[N:53][C:54]([NH:55][CH2:56][CH2:57][CH2:58][N:59]([CH3:61])[CH3:60])=[C:49]5[CH:48]=[N:47]4)=[CH:42][CH:41]=3)=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12].[C:69]([OH:75])([C:71]([F:74])([F:73])[F:72])=[O:70]
Reactant: CN(C)CCCNc1ncnc2c1cnn2-c1ccc(OCCCc2ccc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)OC(C)(C)C)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCCNc1ncnc2c1cnn2-c1ccc(OCCCc2ccc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)O)cc1

Procedure:
Compound 92A (90 mg, 0.107 mmol) and triethylsilane (37.4 mg, 0.322 mmol) in DCM (1 ml) was treated with TFA (3 ml, 38.9 mmol) for 4 h. The mixture was concentrated and the residue was purified by reverse phase HPLC (mobile phase: 0%-60% acetonitrile in 0.1% TFA aqueous solution during 70 min) to provide the title compound as a TFA salt: 1H NMR (400 MHz, DMSO-D6) δ ppm 12.82 (1H, s), 9.37 (1H, s), 8.55 (1H, t) 8.34 (1H, d), 8.03 (1H, d), 7.96-8.01 (2H, m), 7.79 (1H, d), 7.55-7.63 (2H, m), 7.44-7.50 (2H, m), 7.39-7.43 (1H, m), 7.35 (2H, t), 7.05-7.09 (2H, m), 6.97 (1H, d), 4.93 (2H, s), 3.99 (2H, q), 3.87 (2H, t), 3.43-3.70 (2H, m), 3.12-3.18 (2H, m), 2.99 (2H, t), 2.82-2.87 (2H, m), 2.80 (6H, s), 1.91-2.05 (4 FI, m). LCMS (APCI) 783 (M+H).
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH:14]([NH:17][C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)C.[H-].C([Al+]CC(C)C)C(C)C.CCCCCC.CO.[Cl-].[Na+]>ClCCl>[CH2:21]([O:20][C:18]([NH:17][CH:14]1[CH2:13][CH2:12][N:11]([C:8]2[CH:7]=[CH:6][C:5]([CH:4]=[O:3])=[CH:10][CH:9]=2)[CH2:16][CH2:15]1)=[O:19])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)c1ccc(N2CCC(NC(=O)OCc3ccccc3)CC2)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: CO
Solvent: ClCCl
Solvent: CCCCCC
Product: O=Cc1ccc(N2CCC(NC(=O)OCc3ccccc3)CC2)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
The 4-(4-benzyloxycarbonylaminopiperidin-1-yl)-benzoic acid ethyl ester (13.6 g, 35.6 mmol) obtained in Example 7 (2) was dissolved in dichloromethane (150 ml), and a diisobutylaluminum hydride-hexane solution (91 ml, 89.0 mmol) was added thereto, followed by stirring at −78° C. for 1 hour. Methanol was added to the reaction mixture, and then saturated sodium chloride was added thereto, followed by stirring. After the insoluble material was filtered with Celite, the solvent was evaporated from the filtrate under reduced pressure. The obtained residue was dissolved in dichloroethane (180 ml), and manganese dioxide (38.0 g) was added thereto, followed by stirring at 60° C. for 21 hours. After the insoluble material was filtered with Celite, the solvent was evaporated from the filtrate under reduced pressure, thereby obtaining 4-(4-benzyloxycarbonylaminopiperidin-1-yl)-benzaldehyde (7.0 g, 58%) as a white solid.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:12][CH3:13])=[C:7](B(O)O)[CH:8]=1)=[O:2].I[C:15]1[CH:16]=[C:17]([C:21]2[O:22][CH:23]=[N:24][N:25]=2)[CH:18]=[CH:19][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:13][O:12][C:6]1[C:7]([C:19]2[CH:20]=[CH:15][CH:16]=[C:17]([C:21]3[O:22][CH:23]=[N:24][N:25]=3)[CH:18]=2)=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=1
Reactant: COc1ccc(C=O)cc1B(O)O
Reactant: Ic1cccc(-c2nnco2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1ccc(C=O)cc1-c1cccc(-c2nnco2)c1
Temperature: 25 °C
Yield: 54.5 %

Procedure:
A mixture of 5-formyl-2-methoxyphenyl boronic acid (414 mg, 2.29 mmol), the above product, 2-(3-iodo-phenyl)-[1,3,4]oxadiazole, (626 mg, 2.29 mmol), aqueous 2N K2CO3 (3.4 mL, 3 equivalents), Pd(PPh3)2Cl2 (50 mg, 0.068 mmol) in DME (15 mL) was stirred at room 80° C. for 7 hours. Reaction mixture was cooled to r.t., then it was diluted with ethyl acetate (45 mL) and washed with water, brine and dried over Na2SO4. After removal of solvent, 700 mg of crude was obtained. Purification by column chromatography gave 350 mg of the product (Yield: 55%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31](O)=[O:32])[C:25]=1[CH3:34])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH:49]1([NH:52][CH2:53][C@@H:54]2[C@@H:58]([OH:59])[CH2:57][CH2:56][NH:55]2)[CH2:51][CH2:50]1>CN(C=O)C>[CH:49]1([NH:52][CH2:53][C@@H:54]2[C@@H:58]([OH:59])[CH2:57][CH2:56][N:55]2[C:31](=[O:32])[CH2:30][C:26]2[C:25]([CH3:34])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])(=[O:11])=[O:12])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])[CH2:51][CH2:50]1
Reactant: O[C@H]1CCN[C@@H]1CNC1CC1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)N1CC[C@H](O)[C@H]1CNC1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.7 %

Procedure:
A mixture of {5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-acetic acid (250 mg, 0.48 mmol), HOBt (78 mg, 1.2 eq.), EDC (110 mg, 1.2 eq.), TEA (0.17 mL, 2.5 eq.) and (2R,3S)-2-cyclopropylaminomethyl-pyrrolidin-3-ol (300 mg, 4 eq.) in DMF (10 mL) was stirred at rt for overnight. The reaction was concentrated, washed with water, sodium bicarbonate and brine, dried and concentrated. The residue was purified on a silica gel column to give 100 mg of the titled compound as a yellow solid.
Reaction SMILES: [Na].[CH3:2][N:3]1[C:11]2[N:10]=[C:9]3[N:12]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[C:13](=[O:17])[CH:14]=[C:15]([OH:16])[N:8]3[C:7]=2[C:6](=[O:26])[N:5]([CH3:27])[CH2:4]1.Br[CH2:29][CH:30]=[C:31]([CH3:33])[CH3:32]>C(O)C>[CH3:2][N:3]1[C:11]2[N:10]=[C:9]3[N:12]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[C:13](=[O:17])[C:14]([CH2:29][CH:30]=[C:31]([CH3:33])[CH3:32])=[C:15]([OH:16])[N:8]3[C:7]=2[C:6](=[O:26])[N:5]([CH3:27])[CH2:4]1
Reactant: CN1CN(C)c2nc3n(Cc4ccc(F)cc4)c(=O)cc(O)n3c2C1=O
Reactant: CC(C)=CCBr
Agent: [Na]
Solvent: CCO
Product: CC(C)=CCc1c(O)n2c3c(nc2n(Cc2ccc(F)cc2)c1=O)N(C)CN(C)C3=O
Temperature: 25 °C
Reaction time: 90 h

Procedure:
Dissolve 1.48 g (0.0644 mole) of sodium metal in 450 ml of ethanol (2B; anhydrous). Add 23.0 g (0.0644 mole) of 2,3-dihydro-1,3-dimethyl-9-(4-fluorobenzyl)-6-hydroxy-pyrimido[2,1-f]purine-4,8(1H,9H)-dione. Stir the resultant suspension under a nitrogen atmosphere for 0.5 hour, then add 9.60 g (0.0644 mole) of 1-bromo-3-methyl-2-butene. Stir the mixture at room temperature for 90 hours under a nitrogen atmosphere. Filter off the white solids, and remove solvent from the filtrate under reduced pressure. Dissolve the residue in 150 ml of chloroform, add 125 ml of 3N hydrochloric acid and shake the mixture. Separate the layers, and extract the aqueous phase with two 50-ml volumes of chloroform. Dry the combined extracts over anhydrous magnesium sulfate, filter off the drying agent, and remove solvent from the filtrate under reduced pressure. Chromatograph the residual glassy solid on silica gel, eluting with ethyl acetate(3)-hexanes(1). Triturate the product thus obtained with hexane (125 ml per gram) and filter to obtain the title compound as a solid (mp 188°-188.5° C.).