Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:9]1[CH2:16][CH:15]2[CH:11]([CH2:12][NH:13][CH2:14]2)[CH2:10]1)=[O:8].Cl[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=1>>[C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:9]1[CH2:10][CH:11]2[CH:15]([CH2:14][N:13]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)[CH2:12]2)[CH2:16]1)=[O:8]
Reactant: Cc1cccc(Cl)n1
Reactant: O=C(c1ccccc1-c1ccccc1)N1CC2CNCC2C1
Product: Cc1cccc(N2CC3CN(C(=O)c4ccccc4-c4ccccc4)CC3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 17 and 2-chloro-6-methyl-pyridine. MS (ESI) mass calcd. for C25H25N43O, 383.5; m/z found, 384.3 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.O=C(Cl)[O:25][C:26](Cl)(Cl)Cl.[CH2:31]([NH:35][CH3:36])[CH2:32][CH2:33][CH3:34]>>[CH2:31]([N:35]([CH3:36])[C:26]([N:17]1[CH2:16][CH2:15][C:12]2([C:11](=[O:20])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:19][CH2:18]1)=[O:25])[CH2:32][CH2:33][CH3:34]
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CCCCNC
Product: CCCCN(C)C(=O)N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O

Procedure:
This material was prepared in analogy to example 251 step B) from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one, diphosgene and butyl-methyl-amine. MS (ESI): 428.4 (MH+).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C@@H:10]1[CH2:19][CH2:18][C:17]2[CH:16]=[C:15]([O:20]C(=O)C(C)(C)C)[CH:14]=[CH:13][C:12]=2[CH2:11]1)[CH3:2].C(OC(=O)[NH:33][C:34]([CH3:46])([CH3:45])[CH2:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([CH:43]=O)=[CH:39][CH:38]=1)(C)(C)C>>[NH2:33][C:34]([CH3:45])([CH3:46])[CH2:35][O:36][C:37]1[CH:38]=[CH:39][C:40]([CH2:43][CH2:2][CH2:1][NH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C@@H:10]2[CH2:19][CH2:18][C:17]3[CH:16]=[C:15]([OH:20])[CH:14]=[CH:13][C:12]=3[CH2:11]2)=[CH:41][CH:42]=1
Reactant: CC(C)(COc1ccc(C=O)cc1)NC(=O)OC(C)(C)C
Reactant: CCNc1ccccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CC(C)(N)COc1ccc(CCCNc2ccccc2[C@@H]2CCc3cc(O)ccc3C2)cc1
Yield: 29 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylaminophenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (30 mg) and tert-butyl[2-(4-formylphenoxy)-1,1-dimethylethyl]carbamate (125 mg) according to an analogous synthetic method to Example 238 and purified by LC-MS, the title compound (11 mg) was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:7]=[CH:6][O:5][CH:4]=1)#[N:2].C[O-].[Na+].[C:11](O)(=[O:13])C>CO>[O:5]1[CH:6]=[CH:7][C:3]([C:1](=[NH:2])[O:13][CH3:11])=[CH:4]1
Reactant: N#Cc1ccoc1
Reactant: CC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=N)c1ccoc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-cyanofuran (3.76 g, 40.1 mmol) was dissolved in methanol (30 ml), and sodium methoxide (0.1 g, 1.9 mmol) was added. The mixture was stirred at room temperature for 18 hours. After the reaction was completed, acetic acid (0.14 g, 2.3 mmol) was added to neutralize the reaction solution, and the solution was concentrated under reduced pressure. Diethyl ether was added to the concentrated residue, and insolubles were removed by filtration. The filtrate was concentrated under reduced pressure to give the crude product of methyl 3-furancarboximidate as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19]O)=[CH:15][CH:14]=3)[CH:10]=[CH:9][C:8]2=[O:21])=[CH:4][CH:3]=1.C1C(=O)N([Br:31])C(=O)C1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][Br:31])=[CH:15][CH:14]=3)[CH:10]=[CH:9][C:8]2=[O:21])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=c1ccc(-c2ccc(CO)cc2)cn1Cc1ccc(Cl)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=c1ccc(-c2ccc(CBr)cc2)cn1Cc1ccc(Cl)cc1
Yield: 67.1 %

Procedure:
According to Scheme 25 Step 3: To a solution of 1-(4-chlorobenzyl)-5-(4-(hydroxymethyl)phenyl)pyridin-2(1H)-one (1 eq, 3.07 mmol, 1.00 g, Example 35 Step 1) in THF (8 mL) were added NBS (1.22 eq, 3.74 mmol, 0.67 g) and PPh3 (1.20 eq, 3.68 mmol, 0.97 g) at −20° C. for 4 hours. After evaporation of the solvent, the crude product was purified by silica gel chromatography (AIT Flashsmart prepacked column 50 g SiO2) using CH2Cl2/MeOH 98/2 to afford 1-(4-chlorobenzyl)-5-(4-(bromomethyl)phenyl)pyridin-2(1H)-one (2.06 mmol, 0.80 g, 67%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:12]([C:13](=[O:30])[CH2:14][NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][C:26]([O:28]C)=[O:27])[CH:20]=2)=[O:17])[CH:11]([C:31](=[O:40])[N:32]([CH3:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:10][CH:9]1[C:41]([O:43]C)=[O:42].[OH-].[K+]>O.CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:12]([C:13](=[O:30])[CH2:14][NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][C:26]([OH:28])=[O:27])[CH:20]=2)=[O:17])[CH:11]([C:31](=[O:40])[N:32]([CH3:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:10][CH:9]1[C:41]([OH:43])=[O:42]
Reactant: COC(=O)Cc1cccc(NC(=O)NCC(=O)N2C(C(=O)N(C)c3ccccc3)CC(C(=O)OC)C2c2ccccc2F)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(C(=O)C1CC(C(=O)O)C(c2ccccc2F)N1C(=O)CNC(=O)Nc1cccc(CC(=O)O)c1)c1ccccc1
Yield: 47.7 %

Procedure:
A The reaction is carried out in a way analogous to that described in Example 3, but from 1.1 g of methyl (2RS,4RS,5SR)-5-(2-fluorophenyl)-1-{2-[3-(3-(methoxycarbonylmethyl)phenyl)ureido]acetyl}-2-(methylphenylcarbamoyl)pyrrolidine-4-carboxylate and 0.21 g of potassium hydroxide in a mixture of 20 cm3 of distilled water and 40 cm3 of methanol. After treatment, there is obtained 0.5 g of (2RS,4SR,5SR)-5-(2-fluorophenyl)-1-{2-[3-(3-(carboxymethyl)phenyl)ureido]acetyl}-2-(methylphenylcarbamoyl)pyrrolidine-4-carboxylic acid, melting at 164° C.
Reaction SMILES: BrC[C:3]1[C:11]2N=[CH:9][N:8]([C:12](OC(C)(C)C)=O)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH3:19][N:20](C(C(OCC)=O)C(OCC)=O)C.[CH2:33]([N:36](C(C(OCC)=O)C(OCC)=O)CCC)[CH2:34][CH3:35]>>[CH3:12][N:8]([CH3:9])[CH:7]1[CH2:6][CH:5]=[C:4]2[CH:19]=[N:20][N:36]3[C:3]2=[C:11]1[CH2:35][CH:34]=[CH:33]3
Reactant: CCCN(CCC)C(C(=O)OCC)C(=O)OCC
Reactant: CCOC(=O)C(C(=O)OCC)N(C)C
Reactant: CC(C)(C)OC(=O)n1cnc2c(CBr)cccc21
Product: CN(C)C1CC=c2cnn3c2=C1CC=C3

Procedure:
This compound was prepared by following the procedure of Example 18, but substituting methyl 7-(bromomethyl)-1H-indazole-1-carboxylate for t-butyl 4-(bromomethyl)-1H-benzimidazole-1-carboxylate and diethyl (dimethylamino)malonate for diethyl (dipropylamino)malonate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][NH:14]C(OC(C)(C)C)=O)=[C:7]([Cl:22])[CH:6]=1.CC1CCCCC1.C(=O)([O-])[O-].[Na+].[Na+]>FC(F)(F)C(O)=O.C(OCC)(=O)C>[ClH:22].[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][NH2:14])=[C:7]([Cl:22])[CH:6]=1
Reactant: COC(=O)Cc1ccc(SCCNC(=O)OC(C)(C)C)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CC1CCCCC1
Product: COC(=O)Cc1ccc(SCCN)c(Cl)c1
Product: Cl
Reaction time: 2 h

Procedure:
50 mg (0.144 mmol) of 3-chloro-4-[2-[[(1,1-dimethylethoxy)carbonyl]-amino]-ethylthio]benzeneacetic acid methyl ester are dissolved in 322 μl of trifluoroacetic acid. Agitation is performed for 2 hours at ambient temperature. The trifluoroacetic acid is eliminated by coevaporation with methylcyclohexane. The evaporation residue is dissolved in ethyl acetate and neutralisation takes place by addition of a solution of sodium carbonate at 10%. The organic phase is dried on magnesium sulfate, filtration takes place and concentration under reduced pressure. The expected product is obtained in the form of an orange oil with a quantitative yield.
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:30]=[CH:29][CH:28]=[CH:27][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16](OS(C(F)(F)F)(=O)=O)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:31]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)=[O:32].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O>[CH2:1]([C:8]1[O:9][C:10]2[CH:30]=[CH:29][CH:28]=[CH:27][C:11]=2[C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([C:36]2[CH:37]=[CH:38][C:33]([CH:31]=[O:32])=[CH:34][CH:35]=2)=[CH:17][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Oc1ccc(-c2c(Cc3ccccc3)oc3ccccc23)cc1)C(F)(F)F
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: O=Cc1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 87.5 %

Procedure:
To a stirred solution of the triflate (from example 10) (9.35 g, 21.6 mmol) and tetrakis-(triphenylphosphine)palladium(0) (750 mg, 0.65 mmol) in toluene (70 mL) was added a solution of 4-formylphenylboronic acid (4.06 g, 27.05 mmol) in ethanol (20 mL) and 2N sodium carbonate (21.6 mL, 43.2 mmol). The resulting suspension was stirred at 100° C. for 4 hrs (TLC control). The reaction was cooled, diluted with water (50 mL) and extracted with diethyl ether (3×100 mL). The combined extract was washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting brown solid was redissolved in tetrahydrofuran (50 mL). 2N Hydrochloric acid (10 mL) was added and the resulting solution was stirred at room temperature for 1 hour, and then diluted with water (50 mL) and extracted with diethyl ether (3×100 mL). The combined extract was washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification of the product by flash column chromatography, using 20% ethyl acetate in heptane as eluent, afforded the title compound as a white solid (7.34 g, 88%).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].Br[CH2:21][C:22]#[C:23][C:24]([CH3:27])([CH3:26])[CH3:25].C([O-])([O-])=O.[K+].[K+]>>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:21][C:22]#[C:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: CC(C)(C)C#CCBr
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)C#CCN1C(=O)C(C)(C)c2cc(N)c([N+](=O)[O-])cc21
Yield: 23.1 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (10.5 g) is alkylated using 1-bromo-4,4-dimethyl-pent-2-yne (7 g; 40 mmol) and K2CO3 (5.52 g; 40 mmol) at 40° C. for 16 h. After aqueous work-up and purification by RP chromatography the pure material (3.9 g) is de-acetylated in MeOH (250 ml) using DBU (3.58 g) at reflux. After aqueous work-up 5-amino-1-(4,4-dimethyl-pent-2-ynyl)-3,3-dimethyl-6-nitro-1,3-dihydro-indol-2-one (2.9 g) is obtained and used without further purification.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([O:13]C)=O)[C:4]=2[NH:3]1.[CH2:15]([Mg]Br)[CH3:16].[CH2:19](OCC)[CH3:20].Cl>O1CCCC1.CO>[CH2:19]([C:11]([C:10]1[C:4]2[NH:3][C:2](=[O:1])[NH:6][C:5]=2[CH:7]=[CH:8][CH:9]=1)([OH:13])[CH2:15][CH3:16])[CH3:20]
Reactant: COC(=O)c1cccc2[nH]c(=O)[nH]c12
Reactant: CC[Mg]Br
Reactant: CCOCC
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CCC(O)(CC)c1cccc2[nH]c(=O)[nH]c12
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 79 %

Procedure:
To a suspension of methyl 2-oxo-2,3-dihydro-1H-benzimidazole-4-carboxylate (35.9 g, 189 mmol) in tetrahydrofuran (700 mL) was added dropwise 3M solution of ethylmagnesium bromide in diethyl ether (374 mL, 1.12 mol), and the mixture was refluxed for 3 hr. After cooling, methanol (70 mL) was added dropwise at 0° C., and 1 N hydrochloric acid (1300 mL) was added at 0° C. The mixture was stirred at room temperature for 40 min, and the organic layer was separated and concentrated in vacuo. The aqueous layer was extracted with ethyl acetate (400 mL×2). The combined organic layer was concentrated in vacuo. The resulting solid was suspended in diisopropyl ether (70 mL)-water (10 mL)-ethyl acetate (40 mL), and the mixture was refluxed for 30 min. After cooling to room temperature, the resulting solid was collected by filtration and washed with diisopropyl ether to give the title compound (33.0 g, 150 mmol, 79%) cas a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[NH2:15][C:16]1[CH:24]=[C:23]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19]>>[NH2:15][C:16]1[CH:24]=[C:23]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:22]=[CH:21][C:17]=1[C:18]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:4]=1)=[O:19]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(N)c1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: CS(=O)(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(N)c1

Procedure:
2.2 g of methyl 4-(methylsulfonyl)-2-nitrobenzoate was reacted via Procedure C to afford methyl 2-amino-4-(methylsulfonyl)benzoate. 500 mg of methyl 2-amino-4-(methylsulfonyl)benzoate was hydrolyzed via Procedure M to give 2-amino-4-(methylsulfonyl)benzoic acid. 100 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 2-amino-4-(methylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield 2-amino-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide. MS (Q1) 402.0 (M)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[S:5][C:4]2[CH:13]=[C:14]([C:17](OC)=O)[CH:15]=[CH:16][C:3]1=2.[NH3:21]>CO>[C:17]([C:14]1[CH:15]=[CH:16][C:3]2[C:2](=[O:1])[CH2:8][C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[S:5][C:4]=2[CH:13]=1)#[N:21]
Reactant: N
Reactant: COC(=O)c1ccc2c(c1)Sc1ccccc1CC2=O
Solvent: CO
Product: N#Cc1ccc2c(c1)Sc1ccccc1CC2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Stir 5 gm. of methyl 10,11-dihydro-11-oxodibenzo[b,f]thiepin-3-carboxylate in 500 ml. of methanol saturated with ammonia gas for 24 hours at room temperature. Evaporate the reaction mixture to dryness. Reflux the residue in 200 ml. of methylene chloride containing 10 gm. of phosphorous oxychloride for eight hours. Cool the reaction mixture to room temperature and shake several times with water. Separate the organic layer, dry over magnesium sulfate and evaporate to dryness to obtain the title product.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]1[S:10][C:9]([C:11]2[NH:15][C:14]3[CH:16]=[CH:17][CH:18]=[C:19]([C:20]([NH2:22])=[O:21])[C:13]=3[N:12]=2)=[CH:8][CH:7]=1.C=O.[C:25]([BH3-])#N.[Na+]>CO.O>[CH3:25][N:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]1[S:10][C:9]([C:11]2[NH:15][C:14]3[CH:16]=[CH:17][CH:18]=[C:19]([C:20]([NH2:22])=[O:21])[C:13]=3[N:12]=2)=[CH:8][CH:7]=1
Reactant: [BH3-]C#N
Reactant: NC(=O)c1cccc2[nH]c(-c3ccc([C@H]4CCCN4)s3)nc12
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN1CCC[C@@H]1c1ccc(-c2nc3c(C(N)=O)cccc3[nH]2)s1
Reaction time: 8 h

Procedure:
A solution of EXAMPLE 16D (50 mg) in methanol (20 mL) was treated with 37 wt % formaldehyde in water (114 μL) and stirred overnight. Sodium cyanoborohydride (315 mg) was added, and the solution was stirred for 3 hours and concentrated. The concentrate was dissolved in methanol and TFA, and purified by HPLC (Zorbax C-8, 0.1% TFA/acetonitrile/water). 1H NMR (CD3OD) δ 2.30 (m, 2H), 2.47 (m, 1H), 2.74 (m, 1H), 2.94 (s, 3H), 3.31-3.40 (m, 1H), 3.88 (m, 1H), 4.81 (m, 1H), 7.40 (t, J=7.7 Hz, 1H), 7.51 (d, J=3.7 Hz, 1H), 7.73 (d, J=7.6 Hz, 1H), 7.86 (d, J=4.0 Hz, 1H), 7.95 (d, J=7.6 Hz, 1H).
Reaction SMILES: O[C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[C:9](O)[CH:10]=3)[C:5](=[O:18])[C:4]=2[CH:3]=1.ClC1C=CC=CC=1.Cl.[CH2:27]([N:29]([CH2:33][CH3:34])[CH2:30][CH2:31]Cl)[CH3:28].[OH-:35].[K+]>C(Cl)(Cl)Cl.O>[CH2:27]([N:29]([CH2:33][CH3:34])[CH2:30][CH2:31][O:35][C:10]1[C:11]2[C:12](=[O:16])[C:13]3[C:4](=[CH:3][CH:2]=[CH:15][CH:14]=3)[C:5](=[O:18])[C:6]=2[CH:7]=[CH:8][CH:9]=1)[CH3:28]
Reactant: O=C1c2ccc(O)cc2C(=O)c2ccc(O)cc21
Reactant: CCN(CC)CCCl
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: Clc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCN(CC)CCOc1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 0 °C
Reaction time: 24 h

Procedure:
In addition to the methods given in Examples 1 and 2, the following method has also proven useful. To a mixture of 114g (0.6 mole) of 2,6-dihydroxyanthraquinone and 1.2 liters of chlorobenzene was added a solution of 412g (2.4 moles) 2-diethylaminoethyl chloride hydrochloride in 350 ml. of water. With efficient stirring, a solution of 264g (4.0 moles) of potassium hydroxide pellets (85%) in 350 ml. of water was added. The resulting mixture was heated with continued stirring on a steam bath for about 24 hours, then cooled by adding about 500 g of ice. 400 ml. chloroform was added. The lower organic layer was separated and washed several times with water, then dried with anhydrous magnesium sulfate. After filtration, the solvents were removed under reduced pressure in a rotary evaporator. The residue was recrystallized from a mixture of methanol and chloroform as described in Example 1 to give 2,6-bis 2-(diethylamino)ethoxy anthraquinone base, M.P. 178-181° C. The base can be converted to the dihydrochloride salt as described in Example 1.
Reaction SMILES: C1([CH2:6][CH2:7][NH:8][C:9]([C:11]2[C:12](=[O:30])[C:13]3[CH:27]=[N:26][C:25](SC)=[N:24][C:14]=3[N:15]3[C:23]=2[S:22][C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]3=2)=[O:10])CCCC1.[N:31]1([C:37](=[O:39])[CH3:38])[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.C[N:41]1[C:45](=O)[CH2:44][CH2:43][CH2:42]1>>[N:41]1([CH2:6][CH2:7][NH:8][C:9]([C:11]2[C:12](=[O:30])[C:13]3[CH:27]=[N:26][C:25]([N:34]4[CH2:35][CH2:36][N:31]([C:37](=[O:39])[CH3:38])[CH2:32][CH2:33]4)=[N:24][C:14]=3[N:15]3[C:23]=2[S:22][C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]3=2)=[O:10])[CH2:45][CH2:44][CH2:43][CH2:42]1
Reactant: CN1CCCC1=O
Reactant: CC(=O)N1CCNCC1
Reactant: CSc1ncc2c(=O)c(C(=O)NCCC3CCCC3)c3sc4ccccc4n3c2n1
Product: CC(=O)N1CCN(c2ncc3c(=O)c(C(=O)NCCN4CCCC4)c4sc5ccccc5n4c3n2)CC1

Procedure:
A solution of 2-methylsulfanyl-5-oxo-5H-7-thia-1,3,11b-triaza-benzo[c]fluorene-6-carboxylic acid (2-cyclopentyl-ethyl)-amide (25 mg, 0.057 mmol) and 1-(piperazin-1-yl)ethanone (75 mg, 0.585 mmol) in NMP (1.0 mL) was heated for 20 min at 200° C. in a microwave. The crude reaction mixture was purified by reverse phase HPLC. MS (m/z): 520 (MH+).
Reaction SMILES: Br[C:2]([C:5](=[O:7])[CH3:6])=[CH:3]O.[C:8]([CH2:11][NH:12][C:13](=[O:15])[CH3:14])(=[S:10])[NH2:9]>CC(C)=O>[C:5]([C:2]1[S:10][C:8]([CH2:11][NH:12][C:13](=[O:15])[CH3:14])=[N:9][CH:3]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)C(Br)=CO
Reactant: CC(=O)NCC(N)=S
Solvent: CC(C)=O
Product: CC(=O)NCc1ncc(C(C)=O)s1
Yield: 30.1 %

Procedure:
A mixture of 2-bromo-1-hydroxy-3-oxo-1-butene (9.61 g) and N-[(thiocarbamoyl)methyl]acetamide (7.70 g) in acetone (100 ml) was refluxed for one hour with stirring. The resulting precipitate was collected by filtration and chromatographed on silica gel eluting with a mixture of chloroform and methanol (20:1, V/V) to give 5-acetyl-2-(acetylaminomethyl)thiazole (3.48 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.[Br:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:21])=[C:17]([CH:20]=1)[CH:18]=O.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>C(#N)C.C(OCC)(=O)C.C=C(C)C>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]2[C:7](=[CH:8][CH:9]=1)[NH:10][CH:18]([C:17]1[CH:20]=[C:13]([Br:12])[CH:14]=[CH:15][C:16]=1[CH3:21])[CH2:3][C:4]2([CH3:9])[CH3:5])=[O:11]
Reactant: Cc1ccc(Br)cc1C=O
Reactant: COC(=O)c1ccc(N)cc1
Agent: C=C(C)C
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1ccc2c(c1)C(C)(C)CC(c1cc(Br)ccc1C)N2
Temperature: 85 °C
Reaction time: 16 h
Yield: 73.1 %

Procedure:
To a stirred solution of 4-amino-benzoic acid methyl ester (8.25 g, 50 mmol) and 5-bromo-2-methyl-benzaldehyde (12 g, 60 mmol) in acetonitrile (200 mL) were added isobutene (14 mL, 0.2 mmol) and ytterbium(III) trifluoromethanesulfonate (Yb(OTf)3) (4.65 g, 7.5 mmol). The resulting mixture was stirred at 85° C. for 16 h in sealed tube. The mixture was diluted with ethyl acetate (300 mL) and washed with water (100 mL×2) and brine (100 mL×2) and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 10-50% ethyl acetate in petroleum ether) to afford 2-(5-bromo-2-methyl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (7.1 g, 35%) as a light yellow solid: MS (ESI) M+1=402.0.
Reaction SMILES: OC[CH2:3][C:4]1[C:9](=O)[N:8]2[N:11]=[CH:12][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:7]2[NH:6][C:5]=1[CH3:19].P(Cl)(Cl)([Cl:22])=O.C(N(CC)CC)C.C(=O)([O-])O.[Na+].[CH:37]([Cl:40])(Cl)Cl>>[Cl:22][C:9]1[N:8]2[N:11]=[CH:12][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:7]2[N:6]=[C:5]([CH3:19])[C:4]=1[CH2:3][CH2:37][Cl:40]
Reactant: CCOC(=O)c1cnn2c(=O)c(CCO)c(C)[nH]c12
Reactant: ClC(Cl)Cl
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnn2c(Cl)c(CCCl)c(C)nc12
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 84.6 %

Procedure:
To 0.34 g (1.28 mmol) of ethyl 6-(2-hydroxyethyl)-5-methylpyrazolo[1,5-a]pyrimidin-7(4H)-one-3-carboxylate were successively added 0.4 ml (d=1.645, 4.29 mmol) of phosphorus oxychloride and 0.36 ml (d=0.726, 2.59 mmol) of triethylamine. The mixture was then stirred for 2 hours and 15 minutes in an oil bath heated to 100° C. under a nitrogen atmosphere. Thereafter, the reaction mixture was cooled with ice water and dissolved in 10 ml of chloroform, and the solution was poured into 30 ml of ice water. After the pH of the mixture was adjusted to about 6 with a saturated aqueous solution of sodium hydrogencarbonate, and the thus-treated mixture was fully shaken, the organic layer was separated. The water layer was further extracted with chloroform (10 ml×2). After all the organic layers were put together and dried over anhydrous sodium sulfate, the solvent was distilled off. The residue was subjected to column chromatography on silica gel (chloroform) to obtain 0.33 g (yield: 84.6%) of the intended product.
Reaction SMILES: [N:1]([C:4]1[C:5]([Cl:11])=[N:6][CH:7]=[CH:8][C:9]=1[I:10])=[N+]=[N-].[C:12]1([P:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1COCC1.[N-]=[N+]=[N-]>O>[Cl:11][C:5]1[C:4]([N:1]=[P:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:9]([I:10])[CH:8]=[CH:7][N:6]=1
Reactant: [N-]=[N+]=Nc1c(I)ccnc1Cl
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [N-]=[N+]=[N-]
Solvent: C1CCOC1
Solvent: O
Product: Clc1nccc(I)c1N=P(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 92 %

Procedure:
3-azido-2-chloro-4-iodopyridine (7 g, 25 mmol) and triphenylphosphine (8.5 g, 32 mmol) was stirred in 100 mL 1:1 mixture of THF and water until azide starting material disappears in TLC. After that most of the THF was removed under vacuum. Crude product was partitioned between brine and ethylacetate. Organic layer was isolated, dried over anhd. Na2SO4 and purified by silica gel column chromatography using 5-40% ethyl acetate and hexanes as eluent. 2-chloro-4-iodo-N-(triphenylphosphoranylidene)pyridin-3-amine (12 g, 23 mmol, 93% yield) was isolated as crystalline white solid.