Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[C:11]3=[N:12][C:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[C:19]([CH3:31])[CH:18]=4)=[N:14][CH:15]=[C:10]3[CH2:9][NH:8][C:7]2=[O:32])[CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)([O-])C.[K+]>CS(C)=O.COC(C)(C)C.CCCCCC>[CH:1]1([N:6]2[C:11]3=[N:12][C:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[C:19]([CH3:31])[CH:18]=4)=[N:14][CH:15]=[C:10]3[CH:9]=[N:8][C:7]2=[O:32])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCN(CC)CCOc1ccc(Nc2ncc3c(n2)N(C2CCCC2)C(=O)NC3)cc1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCCCCC
Solvent: COC(C)(C)C
Product: CCN(CC)CCOc1ccc(Nc2ncc3cnc(=O)n(C4CCCC4)c3n2)cc1C
Yield: 24.3 %

Procedure:
Prepared from 70 mg (0.16 mmol) of 1-cyclopentyl-7-{3-methyl-4-[2-(diethylamino)ethoxy]phenylamino}-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one and 72 mg (0.58 mmol) of potassium tert-butoxide in 3.0 mL of DMSO. The crude semi-solid residue is dissolved in a mixture of tert-butyl methyl ether and hexane. The solution is allowed to evaporate slowly to less than 1 mL, then diluted with 2 mL of 1:3 diethyl ether/hexane. The precipitated solids are collected and dried to give 17 mg (24%) of the title compound: mp>95° C. (dec).
Reaction SMILES: [CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[NH:10][CH:9]=[N:8][C:7]=2[N:6]([CH2:14][CH3:15])[C:4]1=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:22][C:23]1[CH:38]=[CH:37][C:26]([C:27]([C:29]2[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=2)=[O:28])=[CH:25][CH:24]=1>CN(C=O)C.O>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([C:27]([C:29]2[CH:36]=[CH:35][C:32]([CH2:33][N:10]3[C:11]4[C:12](=[O:13])[N:3]([CH2:1][CH3:2])[C:4](=[O:5])[N:6]([CH2:14][CH3:15])[C:7]=4[N:8]=[CH:9]3)=[CH:31][CH:30]=2)=[O:28])=[CH:37][CH:38]=1
Reactant: CCn1c(=O)c2[nH]cnc2n(CC)c1=O
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(=O)c2c(ncn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)n(CC)c1=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 54.5 %

Procedure:
To a solution of 1,3-diethylxanthine (190 mg), a synthetic process for which is described in Journal of American Chemical Society, 75, 114 (1953), in DMF (5 ml) were added potassium carbonate (189 mg) and 4-(4-chlorobenzoyl)benzyl bromide (282 mg) and the mixture was stirred at room temperature for 17 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=1:1) and recrystallized (ether-hexane) to provide the title compound as colorless powder (217 mg, 54%).
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[F:9][C:10](I)([F:12])[F:11].OO>S([O-])([O-])(=O)=O.[Fe+2].CS(C)=O>[F:9][C:10]([F:12])([F:11])[C:7]1[C:5](=[O:6])[NH:4][C:2](=[O:3])[NH:1][CH:8]=1
Reactant: O=c1cc[nH]c(=O)[nH]1
Reactant: FC(F)(F)I
Agent: [Fe+2]
Agent: O=S(=O)([O-])[O-]
Agent: OO
Solvent: CS(C)=O
Product: O=c1[nH]cc(C(F)(F)F)c(=O)[nH]1
Temperature: 45 °C
Reaction time: 0.33 h
Yield: 94 %

Procedure:
0.11 g (1.0 mmol) of uracil was weighed and placed in a 50 ml two-neck flask equipped with a magnetic rotor and the atmosphere in the flask was replaced with argon. The following materials were added thereinto: 2.0 ml of a 1N dimethyl sulfoxide solution, 1.0 ml of a 2.1 mol/l dimethyl sulfoxide solution of trifluoromethyl iodide, 0.2 ml of a 30% hydrogen peroxide aqueous solution and 0.3 ml of a 1.0 mol/l aqueous solution of iron (II) sulfate. The mixture was stirred at 40 to 50° C. for 20 minutes and then the resulting solution was cooled to room temperature. Formation of 5-trifluoromethyl uracil (19F-NMR yield: 94%) was confirmed by 19F-NMR with 2,2,2-trifluoroethanol as an internal standard. 5-Trifluoromethyluracil was obtained as a white solid (0.17 g, yield: 93%) by preparative thin-layer chromatography.
Reaction SMILES: [CH:1]([C:4]1[CH:31]=[CH:30][C:7]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([OH:29])=[C:13]3[C:22]=2[C:21](=[O:23])[C:20]2[C:19]([OH:24])=[CH:18][CH:17]=[C:16]([N+:25]([O-:27])=[O:26])[C:15]=2[C:14]3=[O:28])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[S:32](Cl)([C:35]1[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=1)(=[O:34])=[O:33].CN(C)C>ClCCl>[CH:1]([C:4]1[CH:31]=[CH:30][C:7]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([O:29][S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])=[C:13]3[C:22]=2[C:21](=[O:23])[C:20]2[C:19]([O:24][S:32]([C:35]4[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=4)(=[O:34])=[O:33])=[CH:18][CH:17]=[C:16]([N+:25]([O-:27])=[O:26])[C:15]=2[C:14]3=[O:28])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)c1ccc(Nc2ccc(O)c3c2C(=O)c2c(O)ccc([N+](=O)[O-])c2C3=O)cc1
Agent: CN(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Oc2ccc(Nc3ccc(C(C)C)cc3)c3c2C(=O)c2c([N+](=O)[O-])ccc(OS(=O)(=O)c4ccc(C)cc4)c2C3=O)cc1
Yield: 95.9 %

Procedure:
A 1.2 g of 8-(4′-isopropylanilino)-1,5-dihydroxy-4-nitroanthraquinone and a 1.4 g of tosyl chloride were dissolved in 20 ml of dichloromethane, and a 1.0 ml of trimethylamine was added to the solution and allowed to react for 12 hours at room temperature under stirring. The reaction solution was extracted with adequate amounts of ethyl acetate and 1N-hydrochloric acid to separate into two layers. The extracted organic layer was dried with magnesium sulfate and concentrated. The obtained product was purified by silica gel chromatography to give a 2.0 g of 8-(4′-isopropylanilino)-4-nitro-1,5-bis(p-toluenesulfonyloxy)anthraquinone in a 94% yield.
Reaction SMILES: P([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])(O)(O)=O.[H-].[Na+].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1>O1CCCC1>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18](/[CH:19]=[CH:5]\[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:17][CH:16]=1
Reactant: CCOC(=O)CP(=O)(O)O
Reactant: COc1ccc(C=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C\c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99.7 %

Procedure:
To a 500 mL RB flask fitted with magnetic stirrer was charged with 160 mL of tetrahydrofuran. To the stirred solvent was added ethyl phosphonoacetate (16.5 g, 73.6 mmol) under argon atmosphere. The reaction mixture was cooled to 0° C. and sodium hydride (2.65 g, 110 mmol) was added portion wise, stirred for 15 minutes at the same temperature. Then 4-methoxybenzaldehyde (5 g, 36.0 mmol) in tetrahydrofuran (30 mL) was added drop wise. The reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was quenched with water at 0° C. by slow addition, stirred for 10 minutes. The layers were separated; ethyl acetate (50 mL) was added to the aqueous layer and extracted the layers. The organic layer was washed with brine solution (50 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as pale yellow semi-solid (7.4 g, yield: 98.76%). 1H NMR (300 MHz, CDCl3): δ 7.54-7.60 (d, 1H), 7.39-7.42 (d, 2H), 6.82-6.85 (d, 2H), 6.21-6.26 (d, 1H), 4.15-4.22 (q, 2H), 3.76 (s, 3H), 1.24-1.28 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=[O:22])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].CCN(CC)CC.FC(F)(F)C(O[C:36]1[C:41]([F:42])=[C:40]([F:43])[C:39]([F:44])=[C:38]([F:45])[C:37]=1[F:46])=O.O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([O:23][C:36]2[C:37]([F:46])=[C:38]([F:45])[C:39]([F:44])=[C:40]([F:43])[C:41]=2[F:42])=[O:22])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11]
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(CC(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc1NC(=O)Nc1ccccc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To a stirred mixture of 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetic acid (1.30 g, 4.136 mmol), Et3N (0.63 mL, 4.549 mmol) in DMF (20 mL) was added pentafluorophenyl trifluoroacetate at 0° C. The resulting mixture was stirred at room temp for 1 hr. The mixture was poured into water (60 mL) and precipitate was collected with suction. The crude solid was washed with 0.1N HCl, H2O, n-hexane, and dried at 40° C. to afford 1.91 g (96%) pentafluorophenyl 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetate as a pale brownish crystalline powder. IR (KBr) 1785, 1224, 1216 cm−1; 1H-NMR (400 MHz, CDCl3) δ2.29 (s, 3H), 3.76 (s, 3H), 3.90 (s, 2H), 6.49 (s, 1H), 6.81 (d, J=1.5 Hz, 1H), 6.91 (dd, J=1.5, 8.3 Hz, 1H), 7.15 (t, J=7.3 Hz, 3H), 7.24 (m, 1H), 7.50 (d, J=7.8 Hz, 1H), 8.17 (d, J=7.8 Hz, 1H); MS (FAB) m/z 481 (M++1); Anal. Calcd. for C30H33N3O5S.1/4H2O: C, 57.51; H, 3.57; N, 5.83. Found: C, 57.40; H, 3.75; N, 5.68.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:6][N:7]1[C:11]([C:12](=[O:29])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[N:18]([N:20]=[C:21]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)[N:22]=3)[CH:19]=2)=[C:10]([C:30](O)=[O:31])[CH:9]=[N:8]1>>[CH3:6][N:7]1[C:11]([C:12]([NH:13][C:14]2[CH:15]=[CH:16][C:17]3[N:18]([N:20]=[C:21]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)[N:22]=3)[CH:19]=2)=[O:29])=[C:10]([C:30]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:31])[CH:9]=[N:8]1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccc2nc(-c3cccnc3)nn2c1
Reactant: C1CCNC1
Product: Cn1ncc(C(=O)N2CCCC2)c1C(=O)Nc1ccc2nc(-c3cccnc3)nn2c1

Procedure:
Using pyrrolidine and 1-methyl-5-(2-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid, the title compound was prepared in the same manner as described for example 2. White solid (53 mg, 33%). Mp.: 251° C. MS: m/z=417.3 (M+H+).
Reaction SMILES: [OH-].[Na+].[C:3]([NH:6][CH2:7][C:8]1[N:13]=[C:12]([C:14]2[N:15]=[C:16]([NH:19][C:20]([NH:22]C(=O)C3C=CC=CC=3)=[S:21])[S:17][CH:18]=2)[CH:11]=[CH:10][CH:9]=1)(=[O:5])[CH3:4]>O.CO>[C:3]([NH:6][CH2:7][C:8]1[N:13]=[C:12]([C:14]2[N:15]=[C:16]([NH:19][C:20]([NH2:22])=[S:21])[S:17][CH:18]=2)[CH:11]=[CH:10][CH:9]=1)(=[O:5])[CH3:4]
Reactant: CC(=O)NCc1cccc(-c2csc(NC(=S)NC(=O)c3ccccc3)n2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=O)NCc1cccc(-c2csc(NC(N)=S)n2)n1
Reaction time: 1 h
Yield: 91 %

Procedure:
A solution of sodium hydroxide (0.8 g) in water (8 ml) was added to a suspension of 4-(6-acetylaminomethylpyridin-2-yl)-2-(3-benzoylthioureido)thiazole (8.0 g) in methanol (80 ml) and the mixture was stirred at 50°-60° C. for 1 hour. Following evaporation in vacuo, the residue was mixed with water and the mixture was adjusted to pH 7.5 with 6N-hydrochloric acid. The mixture was extracted with the mixture of tetrahydrofuran and ethyl acetate and extract layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo to give 4-(6-acetylaminomethylpyridin-2-yl)-2-thioureidothiazole (5.44 g).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[CH2:12][CH2:13][OH:14]>[Pt].C1COCC1>[NH2:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[C:4]([CH2:12][CH2:13][OH:14])[CH:5]=1
Reactant: O=[N+]([O-])c1ccc(CO)c(CCO)c1
Agent: [Pt]
Solvent: C1CCOC1
Product: Nc1ccc(CO)c(CCO)c1
Reaction time: 2 h

Procedure:
Pt-C (50% water wet, 200 mg) was added to a THF (40 mL) solution of 2-(2-hydroxymethyl-5-nitrophenyl)-ethanol (1.0 g, 5 mmol) and the mixture was hydrogenated at 50 psi for 2 hrs. NMR showed complete reaction to form 2-(5-amino-2-hydroxymethyl-phenyl)-ethanol (compound (14) in Scheme 3).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([CH3:10])=[CH2:9])=[CH:6][C:5]([NH2:11])=[C:4]([O:12][CH3:13])[CH:3]=1>CO.[Ni]>[Cl:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][C:5]([NH2:11])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: C=C(C)c1cc(N)c(OC)cc1Cl
Agent: [Ni]
Solvent: CO
Product: COc1cc(Cl)c(C(C)C)cc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.7 %

Procedure:
A mixture of 4-chloro-2-methoxy-5-(prop-1-en-2-yl)benzenamine (160 mg, 0.81 mmol), Raney-Ni (20 mg) in MeOH (5 mL) was stirred at RT under H2 (1 atm) atmosphere for 8 h. The mixture was filtered and the filtrate was concentrated in vacuo to afford the desired product (150 mg, 93% yield).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]2[N:8]=[C:9]([C:13]3[C:14]([NH2:18])=[N:15][O:16][N:17]=3)[N:10]([CH2:11][CH3:12])[C:4]=2[CH:3]=1.NC1C=CC=CC=1.[OH:26][C:27]1[CH:28]=[C:29]([C:33](=[O:45])[CH2:34][CH2:35][C:36]([N:38]2[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]2)=[O:37])[CH:30]=[CH:31][CH:32]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.COCCOC.CO.[Cu]I.CS(C)=O>[NH2:18][C:14]1[C:13]([C:9]2[N:10]([CH2:11][CH3:12])[C:4]3[CH:3]=[C:2]([O:26][C:27]4[CH:28]=[C:29]([C:33](=[O:45])[CH2:34][CH2:35][C:36]([N:38]5[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]5)=[O:37])[CH:30]=[CH:31][CH:32]=4)[N:7]=[CH:6][C:5]=3[N:8]=2)=[N:17][O:16][N:15]=1
Reactant: CCn1c(-c2nonc2N)nc2cnc(Br)cc21
Reactant: CN1CCN(C(=O)CCC(=O)c2cccc(O)c2)CC1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: COCCOC
Solvent: CS(C)=O
Product: CCn1c(-c2nonc2N)nc2cnc(Oc3cccc(C(=O)CCC(=O)N4CCN(C)CC4)c3)cc21
Temperature: 170 °C
Yield: 5 %

Procedure:
Under argon, to a suspension of 4-(6-bromo-1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-furazan-3-amine (prepared by the method of Example 8, Steps 3-7, substituting ethylamine for aniline in Step 3) (80 mg, 0.26 mmol) in toluene (4 mL) and DME (4 mL), was added the product of Step 2 (145 mg, 0.52 mmol), CuI (50 mg, 0.26 mmol), 1,10-phenanthroline (94 mg, 0.52 mmol), and Cs2CO3 (210 mg, 0.65 mmol). This mixture was then heated to 170° C. by microwave for 25 min. The reaction mixture was added DMSO (2.0 mL), diluted with EtOAC/MeOH, sonicated for 10 min, then filtered and concentrated. The residue was purified with reverse phase HPLC (10% MeCN/H2O→80% MeCN/H2O, containing 0.1% TFA), to afford the title compound as a pale yellow solid (7.3 mg, 5%). 1H NMR (400 MHz, MeOD) δ ppm 8.75 (s, 1H), 7.91 (d, 1H, 7.6 Hz), 7.73-7.75 (m, 1H), 7.59 (td, 1H, 8.0 Hz, 2.0 Hz), 7.45 (dt, 1H, 8 Hz, 0.8 Hz), 7.36 (s, 1H), 4.77 (q, 2H, 7.2 Hz), 3.40-3.58 (m, 8H), 2.86-3.14 (m, 4H), 2.98 (s, 3H), 1.50 (t, 3H, 7.2 Hz). MS (ES+) m/e 505 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:7][CH2:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([CH3:15])[CH:9]=2)[CH:3]1[C:16]([O:18][CH3:19])=[O:17].[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.C(Cl)(Cl)Cl.[BH3-]C#N.[Na+]>Cl.CO>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:4]2[CH:3]([C:16]([O:18][CH3:19])=[O:17])[C:2]([CH3:20])([CH3:1])[CH2:7][CH:6]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:5]=2)=[CH:9][C:10]=1[CH3:15]
Reactant: C1CCNC1
Reactant: COC(=O)C1C(c2ccc(F)c(C)c2)=CCCC1(C)C
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)C1C(c2ccc(F)c(C)c2)=CC(N2CCCC2)CC1(C)C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
A solution of 4a (11.05 g, 38.1 mmol) and pyrrolidine (8.13 g, 0.114 mol) in 11.5 mL of 5N HCl in methanol (57.1 mmol) and 100 mL chloroform was stirred at ambient temperature overnight and the volatiles were removed in vacuo. The residue was dissolved in 100 mL methanol and 5N HCl methanol was added until the mixture became acidic (bromocresol green). To the solution was added NaCNBH3 (2.40 g, 38.7 mmol) and the reaction was maintained at pH 3-5 by the dropwise addition of 5N HCl in methanol. After stirring overnight the volatiles were removed in vacuo. The residue was diluted with ether and 1N NaOH. The organic layer was washed with H2O and brine and dried (MgSO4). Removal of the volatiles in vacuo and purification of the residue by HPLC using 1% Et3N in 1:1 hexanes:EtOAc as the eluent provided 8.75 g of the oily product.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH:9]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)O)[CH:5]=[CH:4][N:3]=[CH:2]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C(COC)OC>[CH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:19]=[CH:20][C:11]=1/[CH:9]=[CH:8]/[CH2:7][CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: OC(CCCn1ccnc1)c1ccc2ccccc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: COCCOC
Product: C(=C/c1ccc2ccccc2c1)\CCn1ccnc1
Yield: 26.7 %

Procedure:
A mixture of 4-(1H-imidazol-1-yl)-1-(2-naphthyl)-1-butanol (0.450 g) and p-toluenesulfonic acid hydrate (0.589 g) in dimethoxyethane (20 ml) was refluxed for 16 hours. To the mixture was added water, then the whole was concentrated and extracted with ethyl acetate. The extract was washed with water and brine, dried and concentrated. The residue was chromatographed on silica gel (ethyl acetate-MeOH=20:1) followed by crystallization from ethyl acetate-hexane to give the titled compound (0.112 g) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12](Cl)=[O:13])=[CH:4][N:3]=1.[CH:15]1[CH:16]=[CH:17][N:18]2[CH2:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[NH:21][CH2:20][C:19]=12.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([N:21]2[C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[CH2:24][N:18]3[CH:17]=[CH:16][CH:15]=[C:19]3[CH2:20]2)=[O:13])=[CH:4][N:3]=1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: O=C(Cl)c1cnc(Cl)nc1C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cnc(Cl)nc1C(F)(F)F)N1Cc2cccn2Cc2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.1 %

Procedure:
2-Chloro-4-(trifluoromethyl)pyrimidine-5-carbonyl chloride (2.57 g) was added gradually to an ice-cooled solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]-benzodiazepine, (1.84 g) and diisopropylethylamine (1.37 g) in dichloromethane (50 ml). After stirring at room temperature for 18 hours, the reaction mixture was washed with water and saturated aqueous sodium bicarbonate. The dichloromethane solution was dried over anhydrous sodium sulfate and filtered through a short column of hydrous sodium magnesium silicate and further eluted with several volumes of dichloromethane. The combined organic phase was concentrated on a hot plate with the gradual addition of hexane until crystallization occurred. After cooling, the crystals were collected by filtration to yield the title compound (3.22 g), m.p. 221-223° C.
Reaction SMILES: [S:1]1[C:5]2[C:6]([C:10](Cl)=[O:11])=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[CH3:13][Si:14]([CH3:19])([CH3:18])[CH2:15][CH2:16][OH:17].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:13][Si:14]([CH3:19])([CH3:18])[CH2:15][CH2:16][O:17][C:10]([C:6]1[C:5]2[S:1][N:2]=[N:3][C:4]=2[CH:9]=[CH:8][CH:7]=1)=[O:11]
Reactant: C[Si](C)(C)CCO
Reactant: O=C(Cl)c1cccc2nnsc12
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)CCOC(=O)c1cccc2nnsc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.99 g (0.01 mol) of 7-benzothiadiazolecarboxylic acid chloride in 18 ml of toluene are added dropwise over a period of 25 minutes to a solution of 1.9 ml (0.013 mol) of 2-trimethylsilylethanol, 2.4 ml (0.017 mol) of triethylamine and 18 ml of toluene. The reaction mixture is then stirred for 16 hours at room temperature and afterwards poured onto ice/water and extracted twice with ethyl acetate. The extracts are combined, washed with water, dried over magnesium sulfate, filtered and concentrated and the same amount of hexane is added and the batch is filtered through silica gel. Concentration gives 2.0 g (71% of the theoretical yield) of product; m.p. 37°-39° C.
Reaction SMILES: [C:1]1([P:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([CH3:26])[CH:25]=1)[CH:21]=O>C(O)C>[CH3:17][C:18]1[CH:25]=[C:24]([CH:26]=[N:10][CH2:9][CH2:8][P:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:23]=[C:20]([CH3:21])[CH:19]=1
Reactant: Cc1cc(C)cc(C=O)c1
Reactant: NCCP(c1ccccc1)c1ccccc1
Solvent: CCO
Product: Cc1cc(C)cc(C=NCCP(c2ccccc2)c2ccccc2)c1
Yield: 98 %

Procedure:
Under Argon, a Solution of 2-Diphenylphosphino-Ethylamine (652.2 Mg, 2.84 Mmol) and 3,5-dimethyl-benzaldehyde (387.4 mg, 2.89 mmol) in ethanol (15 mL) was heated at 65° C. (oil bath) for 4 h. Then, the solvent was removed in-vacuo to give the desired product (>98% by 1H-NMR) as a colourless oil (993.2 mg, 2.8 mmol, quantitative).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Br:7][C:8]1[N:12]([CH3:13])[C:11]([CH:14]=O)=[N:10][CH:9]=1.Cl.[NH2:17][OH:18]>CCO>[Br:7][C:8]1[N:12]([CH3:13])[C:11](/[CH:14]=[N:17]/[OH:18])=[N:10][CH:9]=1
Reactant: Cn1c(Br)cnc1C=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cn1c(Br)cnc1/C=N/O
Temperature: 120 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
A mixture of K2CO3 (360 mg, 2.61 mmol), 5-bromo-1-methyl-1H-imidazole-2-carbaldehyde (98.5 mg, 0.521 mmol) and hydroxylamine hydrochloride (109 mg, 1.563 mmol) in EtOH (4 mL) was stirred at 120° C. under microwave irradiation for 60 minutes. The resulting suspension was filtered, washing through with EtOAc and MeOH. The filtrate was concentrated in vacuo to afford the title compound as a white solid (100 mg, 94%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][N:18]=2)[CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.CCN(C(C)C)C(C)C.[NH:36]1[CH:40]=[CH:39][N:38]=[C:37]1[NH:41][C:42](N1C=CN=C1)=[O:43]>CN(C=O)C.[Cl-].[Na+].O>[CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][N:18]=2)[CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:42]([NH:41][C:37]2[NH:36][CH:40]=[CH:39][N:38]=2)=[O:43])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(CN(CCCCN)Cc2nccc3ccccc23)c(C)c1
Reactant: O=C(Nc1ncc[nH]1)n1ccnc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnc(CN(CCCCNC(=O)Nc2ncc[nH]2)Cc2nccc3ccccc23)c(C)c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
To a warm (70° C.), stirred, solution of N-(3,5-Dimethyl-pyridin-2-ylmethyl)-N1-isoquinolin-1-ylmethyl-butane-1,4-diamine (0.130 g, 0.37 mmol) and DIPEA (0.39 mL, 2.24 mmol) in DMF (4 mL) was added freshly prepared imidazole-1-carboxylic acid (1H-imidazol-2-yl)-amide (2 equiv). After 1 hour, the mixture was cooled to room temperature, diluted with brine (5 mL) and extracted with CH2Cl2 (4×10 mL). The combined organic extracts were washed with water (5×10 mL), dried (Na2SO4) and concentrated. Purification of the crude material by column chromatography on silica gel (20:1:1 CH2Cl2-MeOH—NH4OH) provided 75 mg (42%) of COMPOUND 154 as a white solid. 1H NMR (CDCl3) δ 1.32-1.36 (m, 2H), 1.56-1.72 (m, 2H), 2.18 (s, 3H), 2.29 (s, 3H), 2.68-2.77 (m, 4H), 3.80 (s, 2H), 4.—(s, 2H), 6.72 (s, 2H), 7.24-7.26 (m, 1H), 7.39-7.44 (m, 1H), 7.57-7.63 (m, 2H), 7.74-7.78 (m, 2H), 7.86 (d, 1H, J=8.4 Hz), 8.46 (s, 1H), 8.50 (d, 1H, J=5.7 Hz); 13C NMR (CDCl3) δ 18.33, 18.72, 23.45, 27.95, 38.86, 55.10, 58.91, 59.22, 121.06, 126.47, 127.09, 127.31, 128.06, 130.36, 132.61, 133.16, 136.57, 139.42, 141.66, 144.62, 147.15, 153.65, 156.21, 158.75; ES-MS m/z 480 (M+23). Anal. Calcd. For C26H31N7O.0.8CH3OH: C, 66.62; H, 7.13; N, 20.29. Found: C, 66.84; H, 6.93; N, 20.23.