Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.Cl[C:8]([O:10][CH:11]([Cl:13])[CH3:12])=[O:9].[C:14]([O:19][CH2:20][CH2:21][OH:22])(=[O:18])[C:15]([CH3:17])=[CH2:16]>ClCCl>[C:8](=[O:9])([O:22][CH2:21][CH2:20][O:19][C:14](=[O:18])[C:15]([CH3:17])=[CH2:16])[O:10][CH:11]([Cl:13])[CH3:12]
Reactant: CC(Cl)OC(=O)Cl
Reactant: C=C(C)C(=O)OCCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=C(C)C(=O)OCCOC(=O)OC(C)Cl
Reaction time: 0.25 h
Yield: 74.4 %

Procedure:
Pyridine (0.89 ml, 11.00 mmol) is added dropwise to a solution of 1-chloroethyl chloroformate (1.20 ml, 11.00 mmol) and 2-hydroxyethyl methacrylate (1.22 ml, 10.00 mmol) in dichloromethane (12 ml) at 3° C. under a dry N2 atmosphere. After 15 min. at 3° C. and 17 hours at 20° C. the reaction mixture is transferred to a separating funnel with the aid of dichloromethane (10 ml). The reaction mixture is washed with hydrochloric acid (1.00M, 10 ml), saturated aqueous sodium hydrogen carbonate (10 ml) and water (2×10 ml). The organic phase is dried (MgSO4) and the solvent evaporated under reduced pressure to give 1.76 g (74%) of the title product. 1H NMR (60 MHz, CDCl3): δ 1.85 (3 H, d, J=6 Hz, CH3 --CH), 1.96 (3 H,d, J= 2 Hz, CH3 --C=), 5.55 (1 H, m, CH=), 6.10 (1 H, m, CH=), 6.38 (1 H, k, J=6 Hz, CH--CH3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[OH:39])[C:5]([N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[C@@H:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([O:26]C(=O)C(C)(C)C)[CH:20]=[CH:19][C:18]=2[CH2:17]1)=O.Cl[CH2:41][C:42]([N:44]([CH2:47][CH3:48])[CH2:45][CH3:46])=O>>[CH2:42]([N:44]([CH2:47][CH3:48])[CH2:45][CH2:46][O:39][C:38]1[CH:37]=[CH:36][C:4]([CH2:5][N:7]([CH:33]([CH3:35])[CH3:34])[C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=2[C@@H:16]2[CH2:25][CH2:24][C:23]3[CH:22]=[C:21]([OH:26])[CH:20]=[CH:19][C:18]=3[CH2:17]2)=[CH:3][C:2]=1[F:1])[CH3:41]
Reactant: CCN(CC)C(=O)CCl
Reactant: COc1ccc([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)c(F)c2)C(C)C)c1
Product: CCN(CC)CCOc1ccc(CN(c2cc(OC)ccc2[C@@H]2CCc3cc(O)ccc3C2)C(C)C)cc1F
Yield: 38.5 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(3-fluoro-4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (21 mg) and 2-chloro-N,N-diethylacetamide (12 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (8.1 mg) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2.[OH-].[K+].CO.Cl[CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][C:24]([C:33](=[O:35])[CH3:34])([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:23][CH2:22]1>CN(C)C=O>[C:33]([C:24]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:23][CH2:22][N:21]([CH2:20][CH2:19][CH2:18][O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]3)[CH2:26][CH2:25]1)(=[O:35])[CH3:34]
Reactant: O=c1ccc2cc(O)ccc2[nH]1
Reactant: CC(=O)C1(c2ccccc2)CCN(CCCCl)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(=O)C1(c2ccccc2)CCN(CCCOc2ccc3[nH]c(=O)ccc3c2)CC1
Temperature: 50 °C

Procedure:
1.65 Grams of 6-hydroxycarbostyril and 0.75 g of granular potassium hydroxide were mixed with 50 ml of methanol and concentrated under a reduced pressure to dryness. To the residue obtained was added 50 ml of dimethylformamide and mixed well, then 2.6 g of 1-(3-chloropropyl)-4-acetyl-4-phenylpiperidine was added and heated at 50° C. for 6 hours under stirring condition. The reaction mixture was concentrated under a reduced pressure to dryness and 20 ml of 5%-sodium hydrogencarbonate aqueous solution was added thereto and stirred. The insoluble matters were collected by filtration and washed with water. After dried the insoluble matters were recrystallized from ethanol to obtain 1.1 g of 6-[3-(4-acetyl-4-phenyl-1-piperidyl)propoxy]carbostyril as in the form of colorless prism-like crystals. Melting point: 192.5°-194° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][CH2:9][C@H:10]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][OH:12])([CH3:4])([CH3:3])[CH3:2].[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(N(CC)CC)C>ClCCl>[CH3:22][S:23]([O:12][CH2:11][C@@H:10]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:21])(=[O:25])=[O:24]
Reactant: CC(C)(C)OC(=O)NCC[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C

Procedure:
Preparation takes place in analogy to Example 84A from 250 mg (0.81 mmol) of tert-butyl{(3S)-3-[(tert-butoxycarbonyl)amino]-4-hydroxybutyl}carbamate (Example 89A) in 20 ml of dichloromethane with 110 mg (0.97 mmol) of methanesulfonyl chloride and 0.23 ml (1.6 mmol) of triethylamine. The product is reacted without further purification.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]2[C:27]3[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=3)[NH:21][C:20]=2[CH3:32])[CH2:13][CH2:12]1.C(Cl)Cl>CCOCC>[CH3:29][O:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][C:24]=1[O:30][CH3:31])[NH:21][C:20]([CH3:32])=[C:19]2[CH2:18][CH2:17][N:14]1[CH2:13][CH2:12][N:11]([NH:10][C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:9])[CH2:16][CH2:15]1
Reactant: COc1cc2[nH]c(C)c(CCN3CCN(N)CC3)c2cc1OC
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Solvent: CCOCC
Product: COc1cc2[nH]c(C)c(CCN3CCN(NC(=O)Nc4ccccc4)CC3)c2cc1OC
Reaction time: 2 h

Procedure:
3.5 g of phenylisocyanate are added dropwise to a stirred solution of 7.78 g of 3-[2-(4-aminopiperazin-1-yl)ethyl]-5,6-dimethoxy-2-methylindole in 100 ml. of dry methylene chloride while maintaining the reaction temperature below 35° C. After 2 hours, 50 ml. of ether are added, the product is filtered and washed with ether. The product is recrystallized from ethyl acetate to give a white solid, m.p. 170°-173° C. of 1-[1-(5,6-dimethoxy-2-methylindol-3-ylethyl)piperazin-4-yl]-3-phenylurea.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:15]1[C:16]([CH3:33])=[N:17][N:18]2[C:23]3[N:24]([CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29])[CH2:25][CH2:26][C:22]=3[C:21]([CH3:32])=[N:20][C:19]=12.O>N1C=CC=CC=1>[CH3:1][S:2]([N:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:6]=[C:7]1[C:15]1[C:16]([CH3:33])=[N:17][N:18]2[C:23]3[N:24]([CH:27]([CH2:28][CH3:29])[CH2:30][CH3:31])[CH2:25][CH2:26][C:22]=3[C:21]([CH3:32])=[N:20][C:19]=12)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCC(CC)N1CCc2c(C)nc3c(-c4nc5ccccc5[nH]4)c(C)nn3c21
Solvent: O
Solvent: c1ccncc1
Product: CCC(CC)N1CCc2c(C)nc3c(-c4nc5ccccc5n4S(C)(=O)=O)c(C)nn3c21
Reaction time: 1 h
Yield: 81.6 %

Procedure:
Methanesulfonyl chloride (12 mL, 0.16 mmol) was added to a soltution of 3-(1H-benzo[d]imidazol-2-yl)-8-(1-ethylpropyl)-2,5-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine (50 mg, 0.13 mmol) in pyridine (0.5 mL) at room temperature and the mixture was stirred for one hour. Water was added thereto, and the mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (50% ethyl acetate/hexane), to give the title compound (48 mg) as pale yellow crystals.
Reaction SMILES: C[Si](C)(C)[O:3][C:4]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5](=[O:10])[CH2:6][CH2:7][C:8]#[CH:9].O>CO>[CH:17]1([C:4]([OH:3])([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:5](=[O:10])[CH2:6][CH2:7][C:8]#[CH:9])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: C#CCCC(=O)C(O[Si](C)(C)C)(c1ccccc1)C1CCCCC1
Solvent: O
Solvent: CO
Product: C#CCCC(=O)C(O)(c1ccccc1)C1CCCCC1

Procedure:
1-(Trimethylsilyloxy)-1-cyclohexyl-1-phenylhex-5-yn-2-one is dissolved in methanol containing 1% concentrated hydrochloric acid at 25° C. Water is added and the solution transferred to a separatory funnel. The solution is washed with ether and the ether layer dried over sodium sulfate. Upon evaporation of the ether under vacuum and vacuum distillation of the crude product a pale yellow oil is isolated.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[N:7]=[CH:8][NH:9][C:10](=[O:11])[C:5]=2[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:3]1.C(=O)([O-])[O-].[K+].[K+].[F:24][C:25]([F:29])([F:28])[CH2:26]I>CN(C=O)C>[CH3:1][N:2]1[C:6]2[N:7]=[CH:8][N:9]([CH2:26][C:25]([F:29])([F:28])[F:24])[C:10](=[O:11])[C:5]=2[C:4]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:3]1
Reactant: Cn1cc(-c2ccccc2)c2c(=O)[nH]cnc21
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2ccccc2)c2c(=O)n(CC(F)(F)F)cnc21
Temperature: 90 °C
Yield: 61.3 %

Procedure:
To a stirring suspension of 7-methyl-5-phenyl-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (0.86 g, 3.82 mmol) in anhydrous DMF (30 ml) was added potassium carbonate (1.06 g, 7.64 mmol) and 1,1,1-trifluoro-2-iodoethane (0.564 ml, 5.73 mmol). The mixture was heated to 90° C. for 16 h. A further portion of potassium carbonate (1.06 g, 7.64 mmol) and 1,1,1-trifluoro-2-iodoethane (0.564 ml, 5.73 mmol) were added and the mixture heated to 90° C. for 24 h. The mixture was cooled and partitioned between brine/water (1:1, 300 ml) and ethyl acetate (75 ml). The aqueous portion was separated and extracted with ethyl acetate (3×75 ml). The combined organic fractions were washed with brine/water (1:1, 4×75 ml), dried (anhydrous sodium sulfate), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (gradient 0-30% ethyl acetate in cyclohexane) to afford the title compound (719 mg, 61%). LCMS RT=1.25 min, M+H+=308.0.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].O[CH2:7][CH2:8][CH:9]1[CH:15]=[CH:14][N:13]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:39])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[C:12]2[CH:40]=[CH:41][CH:42]=[CH:43][C:11]=2[S:10]1>C(N(CC)CC)C>[CH3:1][S:2]([CH2:7][CH2:8][CH:9]1[CH:15]=[CH:14][N:13]([S:16]([C:19]2[CH:20]=[CH:21][C:22]([NH:25][C:26](=[O:39])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[CH:23][CH:24]=2)(=[O:18])=[O:17])[C:12]2[CH:40]=[CH:41][CH:42]=[CH:43][C:11]=2[S:10]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(Nc1ccc(S(=O)(=O)N2C=CC(CCO)Sc3ccccc32)cc1)c1ccccc1-c1ccccc1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)CCC1C=CN(S(=O)(=O)c2ccc(NC(=O)c3ccccc3-c3ccccc3)cc2)c2ccccc2S1

Procedure:
Methanesulfonyl chloride (0.02 ml, 0.278 mM) was added to Compound 19 as prepared in Example 26 (0.151 g, 0.278 mM) and triethylamine (0.07 ml, 0.55 mM) following the procedure described in Example 29 to give the solid product. m/z (MH+) 623.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N+:4]([O-:8])[CH:5]=[CH:6][CH:7]=1.[N+:9]([O-])([OH:11])=[O:10].[OH-].[Na+]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:3]=[N+:4]([O-:8])[CH:5]=[CH:6][C:7]=1[N+:9]([O-:11])=[O:10]
Reactant: [O-][n+]1cccc(F)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1cc[n+]([O-])cc1F
Temperature: 120 °C
Reaction time: 3 h
Yield: 51 %

Procedure:
To a solution of 3-fluoropyridine N-oxide (3-2) (10.4 g, 90 mmol) in sulfuric acid (52 mL) stirring at 120° C. was added fuming nitric acid (21 mL) over 1 hour. After stirring at 120° C. for another 3 hours, the reaction mixture was cooled to ambient temperature and poured into 300 mL of ice. The pH of the solution was adjusted to pH 7 by addition of 20% sodium hydroxide, and extracted with chloroform. The organic layer was dried, filtered and concentrated. The residue was recrystallized from diethyl ether/hexane to give a pale yellow solid (7.5 g, 51%). 1H NMR (400 MHz, CDCl3): 8.05 (m, 2H), 8.22 (m, 1H)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[O-]CC.[Na+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)C>[CH2:9]([O:8][C:6](=[O:7])[C:5]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([NH:11][C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[C:4]([O:3][CH2:1][CH3:2])=[O:19])[CH3:10]
Reactant: CCOC(=O)C(NC(=O)OC(C)(C)C)C(=O)OCC
Reactant: BrCc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(Cc1ccccc1)(NC(=O)OC(C)(C)C)C(=O)OCC
Reaction time: 6 h

Procedure:
To diethyl[(tert-butoxycarbonyl)amino]propanedioate (5.56 mL, 21.79 mmol) in ethanol (30 ml) was added sodium ethoxide (9.76 ml, 26.2 mmol) followed by benzyl bromide (2.59 mL, 21.79 mmol). The mixture was stirred for 6 h, and the solvent was removed in vacuo. Saturated aqueous sodium hydrogen carbonate (50 mL) was added and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic fractions were washed with saturated aqueous brine (1×50 mL), dried with anhydrous sodium sulfate, filtered and the solvent removed in vacuo to afford the title compound as a colorless amorphous solid. LC/MS 366.1 (M+1).
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][C:4]([S:7]([C:10]2[NH:14][CH:13]=[N:12][C:11]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[H-].[Na+].[CH3:24][Si:25]([CH2:28][CH2:29][O:30][CH2:31]Cl)([CH3:27])[CH3:26].O>CN(C=O)C>[C:1]1([CH3:21])[CH:2]=[CH:3][C:4]([S:7]([C:10]2[N:14]([CH2:31][O:30][CH2:29][CH2:28][Si:25]([CH3:27])([CH3:26])[CH3:24])[CH:13]=[N:12][C:11]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Cc1ccc(S(=O)(=O)c2[nH]cnc2-c2ccccn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)c2c(-c3ccccn3)ncn2COCC[Si](C)(C)C)cc1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2-[5-(toluene-4-sulfonyl)-1H-imidazol-4-yl]-pyridine (Tetrahedron Lett. 1976, 285) (1.65 g, 5.51 mmol) in dry DMF (15 mL) was added NaH (60% in mineral oil, 0.36 g, 9.0 mmol) at room temperature under N2. After 30 minutes stirring, SEM-Cl (1.21 mL, 6.83 mmol) was added through a syringe. The slurry was further stirred at room temperature for 6 hours, and then poured into cold H2O (100 mL), extracted with dichloromethane (3×50 mL). Combined dichloromethane solution was washed with H2O (2×50 mL) and brine (50 mL). Flash silica gel chromatography (hexane to 2:1 hexane/ethyl acetate) afforded the 2-[5-(Toluene-4-sulfonyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-pyridin as a syrup intermediate in the forms of 1:1 regioisomers (1.89 g, 80%). 1H NMR δ −0.09 (s, 9H), 0.75 (t, 2H, J=7), 2.38 (s, 3H), 3.30 (t, 2H, J=7), 5.40 (s, 2H), 7.22 (d, 2H, J=8), 7.4 (t, 1H, J=6), 7.65–7.95 (m, 5 H), 8.70 (d, 1H, J=4) ppm; the other regio-isomer shows chemical shift at δ −0.02 (s, 9H), 0.8 (t, 2H, J=7), 2.41 (s, 3H), 3.41(t, 2H, J=7), 5.65 (s, 2H), 7.2–7.35 (m, 7.70–7.90 (m, 5H), 8.1 (d, 1H, J=8), 8.68 (d, 1H, J=4)ppm; (ESMS calcd for (C21H27N3O3SSI): 429.2; found: 430.4 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([O:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl:26][C:27]1[N:28]([CH2:35][C@@:36]2([CH3:39])[O:38][CH2:37]2)[CH:29]=[C:30]([N+:32]([O-:34])=[O:33])[N:31]=1>>[Cl:26][C:27]1[N:28]([CH2:35][C@:36]([OH:38])([CH3:37])[CH2:39][O:1][C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH2:9][CH2:10][CH:11]([O:14][C:15]4[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:23])[F:24])=[CH:17][CH:16]=4)[CH2:12][CH2:13]3)=[CH:6][CH:7]=2)[CH:29]=[C:30]([N+:32]([O-:34])=[O:33])[N:31]=1
Reactant: Oc1ccc(N2CCC(Oc3ccc(OC(F)(F)F)cc3)CC2)cc1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Product: C[C@](O)(COc1ccc(N2CCC(Oc3ccc(OC(F)(F)F)cc3)CC2)cc1)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 100 °C
Reaction time: 8 h

Procedure:
1-(4-hydroxyphenyl)-4-(4-trifluoromethoxyphenoxy)piperidine (2034 g) and 2-chloro-1-[(2R)-2-methyl-2,3-epoxypropyl]-4-nitroimidazole (1388 g) were heated with stirring for 8 hours at about 100° C. and crude 1-{4-[(2R)-3-(2-chloro-4-nitroimidazole-1-yl)-2-hydroxy-2-methylpropoxy]phenyl}-4-(4-trifluoromethoxyphenoxy)piperidine was obtained. At the point where this was cooled to 88° C., dimethylformamide (2.5 L) was added and dissolved therein. After leaving the mixture at room temperature for 13 hours, dimethylformamide (15.8 L) was further added and the mixture was cooled to −9° C. Sodium tert-butoxide (715 g) was gradually added thereto at not more than 0° C. over 3.5 hours. After stirring for further 15 minutes, the reaction mixture was poured into a mixture of water (41.2 L) and ethyl acetate (2.1 L) at room temperature. After stirring for an hour at 30° C., the precipitate was filtrated. Crystals were washed with water (9.2 L) and then with ethyl acetate (8.2 L) under reflux. Upon cooling to 5° C., the precipitate was filtrated. The precipitate washed with ethyl acetate (2.2 L), and dried by air blasting at 60° C. for 18 hours to obtain (2R)-2-methyl-6-nitro-2-{4-[4-(4-trifluoromethoxyphenoxy)piperidine-1-yl]phenoxymethyl}-2,3-dihydroimidazo[2,1-b]oxazole (1548 g; yield 50%).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.CC1(C)C(C)(C)OB([C:47]2[CH:55]=[CH:54][CH:53]=[C:52]3[C:48]=2[CH:49]=[CH:50][NH:51]3)O1.C(=O)([O-])[O-].[Na+].[Na+]>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>[NH:51]1[C:52]2[C:48](=[C:47]([C:2]3[C:10]4[C:9]([NH:11][C@H:12]([C:14]5[N:19]([C:20]6[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=6)[C:18](=[O:26])[C:17]6=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]6[N:15]=5)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=4[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=3)[CH:55]=[CH:54][CH:53]=2)[CH:49]=[CH:50]1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cccc5[nH]ccc35)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 69.9 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.17 mmol) was treated with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (196 mg, 0.81 mmol), sodium carbonate (86 mg, 0.81 mmols) and bis(triphenylphosphine)palladium(II) dichloride (24 mg, 0.03 mmol) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 30%, dichloromethane-ethyl acetate) to give 75 mg (65% yield) of the title compound. Purity 89%.
Reaction SMILES: [OH:1][C@H:2]([CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH2:3][N:4]1[CH2:9][CH2:8][C:7]2[NH:10][C:11]([CH:14]=O)=[C:12]([CH3:13])[C:6]=2[C:5]1=[O:16].[F:24][C:25]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=1[C:32]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:33]=1[CH2:34][C:35](=[O:41])[NH:36]2.N1CCCCC1>C(O)C>[F:24][C:25]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=1[C:32]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:33]=1/[C:34](=[CH:14]/[C:11]1[NH:10][C:7]3[CH2:8][CH2:9][N:4]([CH2:3][C@H:2]([OH:1])[CH2:17][N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)[C:5](=[O:16])[C:6]=3[C:12]=1[CH3:13])/[C:35](=[O:41])[NH:36]2
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2F)N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(C[C@H](O)CN1CCOCC1)CC2
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4F)c32)[nH]c2c1C(=O)N(C[C@H](O)CN1CCOCC1)CC2
Temperature: 25 °C
Yield: 73 %

Procedure:
(R)-5-(2-Hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde if (50 mg, 0.156 mmol), 4-(2,3-difluoro-phenyl)-1,3-dihydro-indol-2-one 3d (34.3 mg, 0.14 mmol) and piperidine (7.7 μL, 0.078 mmol) were dissolved in 0.3 mL of ethanol under stirring at room temperature. The reaction system was stirred at 80° C. in an oil bath in dark for 2 hours. The reaction was completed until TLC showed the disappearance of starting materials, and the oil bath was removed. The reaction system was naturally cooled down to room temperature to precipitate solids. The resulting solids were filtered to give the title compound 2-[(Z)-4-(2,3-difluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-[(R)-2-hydroxy-3-morpholin-4-yl-propyl]-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one 3 (56 mg, yield 73%) as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[NH:5][C:4](=[O:11])[C:3]=1[N+:12]([O-:14])=[O:13].[NH3:15]>CO>[NH2:15][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[NH:5][C:4](=[O:11])[C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: N
Reactant: CC(C)c1cc(Cl)c([N+](=O)[O-])c(=O)[nH]1
Solvent: CO
Product: CC(C)c1cc(N)c([N+](=O)[O-])c(=O)[nH]1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
A mixture of 4-chloro-6-isopropyl-3-nitro-1H-pyridin-2-one (700 mg, 3.23 mmol) in 6-7 μL of 7 N NH3 in MeOH is stirred at 100° C. in a sealed tube for 1.5 h. After cooling, the reaction mixture is concentrated in vacuo. The residue is suspended in H2O, filtered, washed with H2O, and dried, yielding 4-amino-6-isopropyl-3-nitro-1H-pyridin-2-one. 1H NMR (DMSO-d6, 300 MHz) δ 10.96 (br s, 1H), 8.15 (br s, 2H), 5.70 (d, J=0.9 Hz, 1H), 2.58 (sept, J=6.9 Hz, 1H), 1.11 (d, J=6.9 Hz, 6H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1.[OH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][C:10]=1[C:25](OCC)=[O:26]>C1(C)C=CC=CC=1>[OH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:11][C:10]=1[C:25]([NH:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1)=[O:26]
Reactant: Cc1cc(N)no1
Reactant: CCOC(=O)C1=C(O)c2ccccc2N(c2ccccc2)C1
Solvent: Cc1ccccc1
Product: Cc1cc(NC(=O)C2=C(O)c3ccccc3N(c3ccccc3)C2)no1
Yield: 54.1 %

Procedure:
A solution of 2.0 g of 3-amino-5-methylisoxazole and 5.5 g of 1,2-dihydro-4-hydroxy-1-phenyl-3-quinolinecarboxylic acid, ethyl ester in 260 ml of toluene was refluxed for 10 hours in a soxhlet apparatus containing 10 g of 4Å molecular sieves. Evaporation of the volatiles afforded a residue which was purified by means of high pressure liquid chromatography (silica gel: 3:1 ethyl acetate-hexane as the eluent) to yield 3.5 g (51%) of 1,2-dihydro-4-hydroxy-N-(5-methyl-3-isoxazolyl)-1-phenyl-3-quinolinecarboxamide. Recrystallization from dichloromethane afforded the analytical sample, m.p. 148°-150° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:17][CH3:18]>CC(C)=O.C(OCC)(=O)C>[Cl:9][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH2:1])[C:7]=1[O:8][CH2:17][CH3:18]
Reactant: CCI
Reactant: Nc1ncnc(Cl)c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCOc1c(N)ncnc1Cl
Temperature: 50 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
A reaction mixture of 4-amino-6-chloro-pyrimidin-5-ol (1000.0 mg; 6.8 mmol; 1.0 eq.), cesium carbonate (2686.3 mg; 8.24 mmol; 1.2 eq.), and iodoethane (1285.9 mg; 8.24 mmol; 1.2 eq.) in acetone (10 ml) was stirred at 50° C. overnight. The reaction solution was diluted with ethyl acetate (50 ml), washed with water, then brine, dried and concentrated. The residue was treated with ether, stirred for 30 min, filtered, collected white off solid as title compound (1165 mg in yield 98%).