Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[C:23]([O:27][C:28]([N:30]1[CH2:34][CH2:33][CH:32]([OH:35])[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].C1CCN2C(=NCCC2)CC1.[H-].[Na+]>CN(C=O)C>[C:23]([O:27][C:28]([N:30]1[CH2:34][CH2:33][CH:32]([O:35][C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[CH:9][C:10]=2[F:16])[CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(OC3CCN(C(=O)OC(C)(C)C)C3)c(F)cc2c1=O
Temperature: 25 °C
Yield: 58.6 %

Procedure:
To a mixture of 233 mg of ethyl 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate, 168 mg of 1-t-butoxycarbonyl-3-hydroxypyrrolidine, 170 mg of DBU and 5 xl of DMF was added 36 mg of 55% sodium hydride while the former was stirred at room temperature. After the resultant mixture was stirred for 1 hour at room temperature, the reaction mixture was concentrated to dryness under reduced pressure. After chloroform and 10% citric acid were added to the residue and the resultant mixture was shaken thoroughly, the resulting chloroform layer was collected and then successively washed with a 5% aqueous solution of sodium hydrogencarbonate and saturated saline. The chloroform solution was dried over anhydrous sodium sulfate and then concentrated. The residue was purified by chromatography on silica gel (chloroform/methanol: 100:1), whereby 210 mg of ethyl 7-(1-t-butoxycarbonyl-3-pyrrolidinyloxy)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate was obtained.
Reaction SMILES: [I-].[CH:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:4])[CH3:3].CC(C)([O-])C.[K+].[Br:30][C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[C:33]([CH3:39])[CH:32]=1>>[Br:30][C:31]1[CH:38]=[CH:37][C:34]([CH:35]=[C:2]([CH3:4])[CH3:3])=[C:33]([CH3:39])[CH:32]=1
Reactant: Cc1cc(Br)ccc1C=O
Reactant: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Product: CC(C)=Cc1ccc(Br)cc1C

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 23 (23d) using isopropyltriphenylphosphonium iodide (7.2 g, 17 mmol), potassium t-butoxide (2.0 g, 18 mmol), and 4-bromo-2-methylbenzaldehyde (2.4 g, 12 mmol) that was obtained in Example 27 (27b). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (0:10 to 6:94) as the eluent to afford the title compound (2.2 g) in a yield of 84% as a colourless oily product.
Reaction SMILES: [CH3:1][Si:2]([CH3:11])([CH3:10])[C:3]1[O:7][CH:6]=[C:5]([CH:8]=[O:9])[CH:4]=1.B(F)(F)F.CCOCC.[CH3:21][C:22]([CH:29]=[CH2:30])=[CH:23][O:24][Si](C)(C)C>C(Cl)Cl>[OH:9][CH:8]([C:5]1[CH:4]=[C:3]([Si:2]([CH3:11])([CH3:10])[CH3:1])[O:7][CH:6]=1)[CH2:30][CH:29]=[C:22]([CH3:21])[CH:23]=[O:24]
Reactant: C[Si](C)(C)c1cc(C=O)co1
Reactant: C=CC(C)=CO[Si](C)(C)C
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C=O)=CCC(O)c1coc([Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 5-trimethylsilyl-3-furaldehyde (0.382 g., 2.27 mmol) in dry methylene chloride (15 ml) at -50° under argon was added dropwise boron trifloride etherate (0.28 ml, 2.3 mmol). This addition was followed by the dropwise addition of 2-methyl-1-trimethylsilyloxy-1,3-butadiene (0.356 g., 2.3 mmol). The solution was stirred at -50° to -60° for 18 hours, quenched by the addition of several ml saturated sodium bicarbonate solution, warmed to room temperature and poured into methylene chloride. The organic portion was washed once with saturated bicarbonate solution, once with water, once with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give a yellow oil which consisted of several components by TLC. The mixture was applied to a chromatography column (silica) and eluted with 30% ethyl acetate/hexane. Eluted last was the desired alcohol, which was concentrated to give a yellow gum.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][C:3](=[O:7])[C:2]1=[O:8].C[Si](C([Si](C)(C)C)C(N)=O)(C)C.C(#N)C.[C:24]1([C:30](Cl)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O>[C:24]1([C:30]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[N:1]2[CH2:6][CH2:5][NH:4][C:3](=[O:7])[C:2]2=[O:8])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1NCCNC1=O
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: CC#N
Solvent: O
Product: O=C1NCCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.4 %

Procedure:
A mixture of 2,3-piperazinedione (11.4 g, 100 mmol), bistrimethylsilylacetamide (55.7 g, 270 mmol) and 150 ml of acetonitrile was heated under reflux for one hour. Within 30 minutes, triphenylmethylchloride (22.2 g, 80 mmol) was added dropwise and the mixture was again refluxed for two hours. After stirring overnight at room temperature, 21.6 ml of water was added to the clear solution. The resulting precipitate (3.13 g) was filtered off and the filtrate concentrated in vacuo. The residue was triturated with water and dried to yield 25.5 g of crude title compound which was recrystallized from ethanol. Yield of pure product: 12.19 g, melting point 230°-235° C.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Cl:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.CCOC(C)=O>[Cl:11][C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=1)[O:18][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1ccc(C#N)c(F)c1
Reactant: Oc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1ccc(C#N)c(Oc2cccc(Cl)c2)c1
Temperature: 80 °C

Procedure:
To a solution of 2-fluoro-4-methylbenzonitrile (356mg, 3.96 mmol) and 3-chlorophenol (439 μL, 4.16 mmol) in 10 mL of DMSO was added Cs2CO3 (2.58 g, 7.92 mmol). The solution was heated at 80° C. for 4 h. The solution was diluted with EtOAc and was washed with Sat. NaHCO3 solution, water, and brine. The organics were dried (MgSO4), filtered, and concentrated in vacuo to give the title compound without further purification.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][C:7]([CH3:10])=[CH:6][CH2:5]1)(=[O:3])[CH3:2].S(=O)(=O)(O)O.C(O)C.[CH2:19](O)[CH:20]=[CH2:21]>>[CH3:10][C:7]1[CH2:8][CH2:9][CH:4]([C:1](=[O:3])[CH2:2][CH2:21][CH:20]=[CH2:19])[CH2:5][CH:6]=1
Reactant: C=CCO
Reactant: CC(=O)C1CC=C(C)CC1
Agent: O=S(=O)(O)O
Solvent: CCO
Product: C=CCCC(=O)C1CC=C(C)CC1
Temperature: 190 °C
Yield: 31.5 %

Procedure:
Execution: 4-acetyl-1-methyl-cyclohexene 1) was placed in the flask and mixed with the sulphuric acid/ethanol mixture 2) at room temperature for about 0.5 hours while being stirred and in conditions that exclude moisture. Component 3) was then added during the course of about 1 hour. The allyl alcohol (component 4) was added portion by portion. The mixture produced in this way was transferred to a steel autoclave insert and heated to 190° C. for 5 hours under 20 bar nitrogen. The GC control showed that the educt had been reduced down to 2% and that 31.5% main product had formed.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[OH:63][N:64]1[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:67]1[CH2:68][CH2:69][N:64]([OH:63])[CH2:65][CH2:66]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: ON1CCNCC1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2cc(C(=O)N3CCN(O)CC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 4-hydroxy-piperazine in DMSO at ambient temperature.
Reaction SMILES: NC1C2C(=[O:16])C3C(=CC=CC=3)C(=O)C=2C=CC=1.[NH2:18][C:19]1[C:32]2[C:31](=[O:33])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24](=[O:34])[C:23]=2[C:22](Br)=[CH:21][C:20]=1[Br:36].B(O)(O)O>S(=O)(=O)(O)O>[NH2:18][C:19]1[C:32]2[C:31](=[O:33])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24](=[O:34])[C:23]=2[C:22]([OH:16])=[CH:21][C:20]=1[Br:36]
Reactant: Nc1cccc2c1C(=O)c1ccccc1C2=O
Reactant: Nc1c(Br)cc(Br)c2c1C(=O)c1ccccc1C2=O
Agent: O=S(=O)(O)O
Agent: OB(O)O
Product: Nc1c(Br)cc(O)c2c1C(=O)c1ccccc1C2=O

Procedure:
Further, German Offenlegungsschrift No. 28 17 890 discloses a one-vessel process and starting from 1-aminoanthraquinone, which is first converted by bromination into 1-amino-2,4-dibromoanthraquinone, which is in turn, without being isolated, reacted in sulfuric acid, in the presence of boric acid, to give 1-amino-2-bromo-4-hydroxyanthraquinone. The process is simple to perform and affords the desired product in good yield. The shortcoming of this process is, however, that the mixture of dilute sulfuric acid and boric acid formed during working up cannot be easily regenerated. For example, glassy residues are obtained and it is often necessary to neutralise the waste sulfuric acid, e.g. with calcium carbonate or slaked lime. In addition, the 1-amino-2-bromo-4-hydroxyanthraquinone obtained by this process is contaminated by compounds that are brominated in the 3-position. Such impurities result in changes in shade during the dye synthesis, i.e. standard shade dyes are not obtained.
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].[OH-].[Na+].[Cl:7][CH2:8][CH2:9][N:10]([CH2:34][CH2:35][Cl:36])[P:11]([N:27]([CH2:31][CH2:32][Cl:33])[CH2:28][CH2:29][Cl:30])(=[O:26])[O:12][CH2:13][CH2:14]OS(C1C=CC(Br)=CC=1)(=O)=O>CO>[Cl:36][CH2:35][CH2:34][N:10]([CH2:9][CH2:8][Cl:7])[P:11]([N:27]([CH2:28][CH2:29][Cl:30])[CH2:31][CH2:32][Cl:33])(=[O:26])[O:12][CH2:13][CH2:14][S:1][CH2:2][CH2:3][OH:4]
Reactant: OCCS
Reactant: O=P(OCCOS(=O)(=O)c1ccc(Br)cc1)(N(CCCl)CCCl)N(CCCl)CCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=P(OCCSCCO)(N(CCCl)CCCl)N(CCCl)CCCl
Temperature: 0 °C
Reaction time: 12 h
Yield: 54.9 %

Procedure:
2-mercaptoethanol (400 μL, 5.7 mmol) was dissolved in methanol (8 mL), and NaOH in methanol, (3.56 mL of 4M, 14.25 mmol) was added. The solution was cooled to 0° C. and 2-(4-bromobenzenesulfonyloxy)ethyl N,N,N′,N′-tetrakis(2-chloroethyl)phosphorodiamidate (8.35 mL of 0.82M solution in toluene, 6.84 mmol) was added, and the reaction mixture allowed to warm to room temperature. After 12 hours, the mixture was filtered, neutralized to pH 7 with 1M aqueous H3PO4, and concentrated under vacuum to a thick syrup. This syrup was diluted with isopropyl acetate (200 mL), and washed with water (3×200 mL). The isopropyl acetate layer was dried over MgSO4, filtered, and concentrated under vacuum to give a clear oil. This oil was purified on a 30 mm×150 mm silica gel column using a gradient of 70:30 ethyl acetate/hexanes to 100% ethyl acetate to give 2-{[2-(hydroxy)ethyl]thio}ethyl N,N,N′,N′-tetrakis(2-chloroethyl)phosphorodiamidate as a clear oil (1.41 g, 55% yield). 1H NMR (CDCl3): δ 1.64 (bs, 1H), 2.76 (t, 2H, J=5.9 Hz), 2.84 (t, 2H, J=6.3 Hz), 3.40-3.47 (m, 8H), 3.62-3.69 (m, 8H), 3.76 (t, 2H, J=5.9 Hz), 4.18-4.23 (m, 2H); 31P NMR (CDCl3): δ 17.58.
Reaction SMILES: [OH:1][CH:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12](=[O:14])[CH3:13])=[CH:9][CH:10]=2)[C:5]([CH3:16])([CH3:15])[CH2:4][CH2:3]1.[CH3:17][O:18][CH2:19]Cl.C(N(CC)CC)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[CH3:17][O:18][CH2:19][O:1][CH:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12](=[O:14])[CH3:13])=[CH:9][CH:10]=2)[C:5]([CH3:16])([CH3:15])[CH2:4][CH2:3]1
Reactant: COCCl
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)CCC2O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCOC1CCC(C)(C)c2cc(C(C)=O)ccc21
Yield: 61.7 %

Procedure:
A solution of (+/−) 1-hydroxy-6-acetyl-1,2,3,4-tetrahydro-4,4-dimethyl-naphthalene (Compound D25, 24.8 mg, 0.11 mmol), chloromethyl methyl ether (0.12 mmol), triethyl amine (0.02 ml, 0.13 mmol) and catalytic amount of tetrabutylammonium bromide in 2 ml of CH2Cl2 was stirred at room temperature for 5 h. Purification by column chromatography (silica) with ethyl acetate/hexane (1/10) afforded the title compound as an oil (17.8 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].[CH3:19][NH:20][NH2:21]>>[CH3:19][NH:20][NH:21][C:6]1[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]([C:15]([F:18])([F:17])[F:16])=[C:2]([Cl:1])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c1Cl
Reactant: CNN
Product: CNNc1c([N+](=O)[O-])cc(C(F)(F)F)c(Cl)c1[N+](=O)[O-]

Procedure:
The product was obtained by reacting 2,4-dichloro-3,5-dinitrobenzotrifluoride with methylhydrazine and found to melt at 136°-137° C.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:12]=[C:11]([CH2:13]O)[CH:10]=[CH:9][N:8]=2)=[O:6])[CH2:3][CH2:2]1.S(Cl)([Cl:17])=O>>[Cl:17][CH2:13][C:11]1[CH:10]=[CH:9][N:8]=[C:7]([C:5]([NH:4][CH:1]2[CH2:3][CH2:2]2)=[O:6])[CH:12]=1
Reactant: O=C(NC1CC1)c1cc(CO)ccn1
Reactant: O=S(Cl)Cl
Product: O=C(NC1CC1)c1cc(CCl)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.5 g (13.01 mmol) of N-cyclopropyl-4-(hydroxymethyl)pyridine-2-carboxamide (Example 52A) and 11.76 g (98.84 mmol) of thionyl chloride were combined and stirred at RT overnight. The reaction mixture was concentrated using a rotary evaporator. The residue was dissolved in ethyl acetate and washed once with saturated aqueous sodium bicarbonate solution. The organic phase was dried over magnesium sulfate, filtered and concentrated using a rotary evaporator. The residue was purified by column chromatography on silica gel 60 (mobile phase: cyclohexane/ethyl acetate 2/1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:25]=[C:24]2[C:20](/[C:21](=[CH:27]/[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=3[F:35])/[C:22](=[O:26])[NH:23]2)=[CH:19][CH:18]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[NH:8][CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:21]2([C:20]3[C:24](=[CH:25][C:17]([Cl:16])=[CH:18][CH:19]=3)[NH:23][C:22]2=[O:26])[CH:27]1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=1[F:35])=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Reactant: O=C1Nc2cc(Cl)ccc2/C1=C/c1cccc(Cl)c1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of [3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester (2 g, 9.4 mmol) prepared in Example 1 and E/Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-indol-2-one (2.3 g, 7.5 mmol) prepared in Example 2 in dichloromethane (30 mL) were added triethyl amine (2.8 mL, 20 mmol) and AgF (1.1 g, 8.7 mmol). The mixture was stirred at room temperature for 3 h. The mixture was concentrated, and the residue was partitioned between ethyl acetate and brine. The organic layer was separated, washed with water, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:3, 1:2) to give as rac-(2′R,3′S,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid tert-butyl ester a white foam (1.9 g, 49%)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=O.[C:18]([O:24][CH2:25][CH3:26])(=[O:23])[CH2:19][C:20]([CH3:22])=O.O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:20]([CH3:22])[C:19]([C:18]([O:24][CH2:25][CH3:26])=[O:23])=[C:9]2[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccc(F)cc1
Reactant: CCOC(=O)CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1c(C)nc2ccc(Cl)cc2c1-c1ccc(F)cc1
Temperature: 25 °C
Yield: 73.9 %

Procedure:
To a solution of (2-amino-5-chlorophenyl)-(4-fluorophenyl)methanone (10.0 g) in 100 mL of toluene was added 8.3g (1.6 equivalents) of ethyl acetoacetate and 0.30 g of p-toluenesulfonic acid. The resulting mixture was heated to reflux with azeotropic removal of water. After one and one-half hours, the mixture was cooled to room temperature and concentrated under vacuum. The crude product was purified by flash chromatography over silica gel to give 10.18 g of 6-chloro-4-(4-fluorophenyl)-2-methyl-3-quinolinecarboxylic acid, ethyl ester as an off-white solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:20])[C:7]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[CH:8][O:9]2)=[CH:4][CH:3]=1.[CH2:21]([CH:23]1[O:25][CH2:24]1)Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:7]2[C:6](=[O:20])[C:5]3[C:10](=[CH:11][C:2]([O:1][CH2:21][CH:23]4[CH2:24][O:25]4)=[CH:3][CH:4]=3)[O:9][CH:8]=2)=[CH:13][CH:14]=1
Reactant: ClCC1CO1
Reactant: COc1ccc(-c2coc3cc(O)ccc3c2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2coc3cc(OCC4CO4)ccc3c2=O)cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 7-hydroxy-3-(4-methoxyphenyl)chromen-4-one (0.86 g, 3.21 mmol), epichlorohydrin (1.25 ml, 16 mmol) and potassium carbonate (0.89 g, 6.42 mmol) in dimethylformamide (20 ml) was stirred at 80° C. for 3 hours. After removing solvent under reduced pressure, water was added to the residue, and the precipitate filtered off and washed with water. The crude product was purified by chromatography on silica gel, eluting with ethyl acetate/hexanes. (1:4 to 2:3), to afford 3-(4-methoxyphenyl)-7-(oxiran-2-ylmethoxy)chromen-4-one.
Reaction SMILES: [C:1]([OH:5])(=O)[CH:2]=[CH2:3].Cl.[CH3:7][N:8]1[CH2:14][C:13]2[CH:15]=[C:16](/[CH:19]=[CH:20]/[C:21](O)=O)[CH:17]=[N:18][C:12]=2NC(=O)[CH2:9]1.CNCC1C2C(=CC=CC=2)N(C)C=1>>[CH3:17][N:18]([CH2:12][C:13]1[C:15]2[C:9](=[CH:21][CH:20]=[CH:19][CH:16]=2)[N:8]([CH3:7])[CH:14]=1)[C:1](=[O:5])[CH:2]=[CH2:3]
Reactant: C=CC(=O)O
Reactant: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: CNCc1cn(C)c2ccccc12
Agent: Cl
Product: C=CC(=O)N(C)Cc1cn(C)c2ccccc12
Yield: 58 %

Procedure:
According to the procedure of Example 1 (a), except substituting acrylic acid for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, and substituting methyl-(1-methyl-1H-indol-3-ylmethyl)amine for the methyl-(1-propyl-napthalen-2-ylmethyl)anine, the title compound (1.51 g, 58%) was prepared as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 7.71-7.50 (s, 1H), 7.34-7.21 (m, 2H), 7.15-6.90 (m, 2H), 6.80-6.53 (m, 1H), 6.45-6.35 (s, 1H), 5.72-5.67 (m, 1H), 4.80-4.75 (m, 2H), 3.77 (s, 3H), 3.05-2.99 (m, 3H).
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5]([NH2:6])=[N:4][C:2]1=[O:3].CN([Si:17]([CH3:20])([CH3:19])[CH3:18])C(=O)C(F)(F)F>ClCCl>[CH3:18][Si:17]([N:6]([Si:17]([CH3:20])([CH3:19])[CH3:18])[C:5]1[CH:7]=[CH:8][NH:1][C:2](=[O:3])[N:4]=1)([CH3:20])[CH3:19]
Reactant: Nc1cc[nH]c(=O)n1
Reactant: CN(C(=O)C(F)(F)F)[Si](C)(C)C
Solvent: ClCCl
Product: C[Si](C)(C)N(c1cc[nH]c(=O)n1)[Si](C)(C)C
Temperature: 0 °C

Procedure:
A bis-trimethylsilylcytosine solution was prepared by suspending 5.78 g of cytosine in 20 ml of dichloromethane and adding 20.57 ml of N-methyl-N-trimethylsilyltrifluoroacetamide in 10 ml of dichloromethane and cooling the resulting solution to 0° C.
Reaction SMILES: O[CH2:2][C:3]1[NH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:19]=[C:18]4[N:20]([CH2:24][CH2:25][CH:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)[C:21](=[O:23])[NH:22][C:17]4=[N:16][CH:15]=3)=[CH:10][CH:9]=2)[N:4]=1.O=C1NC2=NC=C(C3C=CC(C(=N)OCC)=CC=3)N=C2[N:34]1CCC1CCOCC1.OCC(NN)=O.C(N(CC)CC)C>C(O)C>[NH2:34][CH2:2][C:3]1[NH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:19]=[C:18]4[N:20]([CH2:24][CH2:25][CH:26]5[CH2:27][CH2:28][O:29][CH2:30][CH2:31]5)[C:21](=[O:23])[NH:22][C:17]4=[N:16][CH:15]=3)=[CH:10][CH:9]=2)[N:4]=1
Reactant: O=c1[nH]c2ncc(-c3ccc(-c4n[nH]c(CO)n4)cc3)nc2n1CCC1CCOCC1
Reactant: CCOC(=N)c1ccc(-c2cnc3[nH]c(=O)n(CCC4CCOCC4)c3n2)cc1
Agent: NNC(=O)CO
Solvent: CCO
Solvent: CCN(CC)CC
Product: NCc1nc(-c2ccc(-c3cnc4[nH]c(=O)n(CCC5CCOCC5)c4n3)cc2)n[nH]1
Temperature: 110 °C
Reaction time: 16 h
Yield: 49 %

Procedure:
6-(4-(5-(Hydroxymethyl)-1H-1,2,4-triazol-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one. Ethyl 4-(2-oxo-3-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzimidate (See Example 195. B) (0.250 g, 0.63 mmol) in ethanol (20 mL) was treated with 2-hydroxyacetohydrazide (0.17 g, 1.9 mmol) and triethylamine (0.26 mL, 1.9 mmol), and the resulting reaction mixture was stirred in a sealed tube at 110° C. for 16 h. The cooled reaction solvent removed under reduced pressure. The resulting material was purified using reverse-phase semi-preparatory HPLC (15-50% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min). Fractions containing clean product were passed through a Phenomenex Strata-X-C ion exchange column to remove TFA. The column was washed successively with water, methanol, and then 5% ammonium hydroxide in methanol. The product came off with the 5% ammonium hydroxide in methanol eluent and was concentrated on a rotary evaporator. The residue was triturated with ethyl ether in hexane to make a fine powder and dried under vacuum at 50° C. to give the desired product (0.130 g, 49%) as a white solid. MS (ESI) m/z 422.3 [M+1]+
Reaction SMILES: [Br:1][C:2]1[C:7]2[N:8]([CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:9](Cl)=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:22]=1[NH2:23].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[C:7]2[N:8]([CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:9]([NH:23][C:22]3[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:21]=3[Cl:20])=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)CCCn1c(Cl)nc2cccc(Br)c21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1C
Product: CCOC(=O)CCCn1c(Nc2ccc(Cl)cc2Cl)nc2cccc(Br)c21
Temperature: 150 °C
Reaction time: 3 h
Yield: 75.3 %

Procedure:
A mixture of ethyl 4-(7-bromo-2-chloro-1H-benzimidazol-1-yl)butanoate (1.57 g, 4.54 mmol), 2,4-dichloroaniline (2.21 g, 13.6 mmol), p-toluenesulfonic acid monohydrate (930 mg, 4.89 mmol) and xylene (8.0 mL) was stirred at 150° C. for 3 hr. The mixture was neutralized with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 5-30% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound as a colorless solid (1.61 g, 3.42 mmol, 75%).