Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]3[C@@H:16]([CH3:17])[CH2:15][N:14]([CH2:18][CH3:19])[C:13](=[O:20])[C:9]3=[C:10]([O:11]C)[C:6]=2[C:5](=[O:21])[N:4]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([Cl:30])[CH:24]=2)[N:3]=1.B(Br)(Br)Br.CO>ClCCl>[NH2:1][C:2]1[C:7]2[N:8]3[C@@H:16]([CH3:17])[CH2:15][N:14]([CH2:18][CH3:19])[C:13](=[O:20])[C:9]3=[C:10]([OH:11])[C:6]=2[C:5](=[O:21])[N:4]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([Cl:30])[CH:24]=2)[N:3]=1
Reactant: CCN1C[C@H](C)n2c(c(OC)c3c(=O)n(Cc4ccc(F)c(Cl)c4)nc(N)c32)C1=O
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: CCN1C[C@H](C)n2c(c(O)c3c(=O)n(Cc4ccc(F)c(Cl)c4)nc(N)c32)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (6S)-4-amino-2-(3-chloro-4-fluorobenzyl)-10-methoxy-8-ethyl-6-methyl-7,8-dihydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-dione (62 mg, 0.14 mmol) in anhydrous dichloromethane (2 mL), a solution of boron tribromide in dichloromethane (0.43 mL, 0.43 mmol; 1 M) was added. After stirring at room temperature for 30 minutes, the reaction mixture was treated with anhydrous methanol, stirred for 30 minutes, and concentrated under vacuum. The procedure was repeated twice. The residue was subjected to purification on preparative reverse phase high pressure column chromatography. Collection and lyophilization of appropriate fractions provided the title compound.
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[C:10](Cl)[C:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([O:22][CH3:23])=[O:21])=[CH:17][CH:18]=3)[NH:13][C:12]=2[N:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][CH2:27][CH2:28][CH2:29][N:30]([CH3:35])[CH2:31][CH2:32][CH2:33][NH2:34].CO>>[NH2:26][CH2:27][CH2:28][CH2:29][N:30]([CH3:35])[CH2:31][CH2:32][CH2:33][NH:34][C:10]1[C:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([O:22][CH3:23])=[O:21])=[CH:17][CH:18]=3)[NH:13][C:12]=2[N:24]=[C:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:9]=1
Reactant: CN(CCCN)CCCN
Reactant: COC(=O)c1ccc2c(c1)[nH]c1nc(Cc3ccccc3)nc(Cl)c12
Solvent: CO
Product: COC(=O)c1ccc2c(c1)[nH]c1nc(Cc3ccccc3)nc(NCCCN(C)CCCN)c12
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
In a 2-5 mL microwave vial was added methyl 2-benzyl-4-chloro-9H-pyrimido[4,5-b]indole-7-carboxylate (0.050 g, 0.142 mmol) and N1-(3-aminopropyl)-N1-methylpropane-1,3-diamine (0.115 mL, 0.711 mmol) in MeOH (2.000 mL, 49.4 mmol) to give a tan suspension. The vial was placed in the microwave and heated to 140° C. for 30 min. After 30 minutes, the mixture was concentrated to dryness on a rotavap. and the residue was purified by flash chromatography and lyophilized from CH3CN to afford two distinct products: Example 45 as the mono-N-alkylated product: methyl 4-((3-((3-aminopropyl)(methyl)amino)propyl)amino)-2-benzyl-9H-pyrimido[4,5-b]indole-7-carboxylate (44 mg, 67.2% yield) as a white solid; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.44 (dt, J=13.8, 6.6 Hz, 2H) 1.72 (dt, J=13.7, 6.8 Hz, 2H) 2.11 (s, 3H) 2.24-2.30 (m, 2H) 2.33 (t, J=6.7 Hz, 2H) 2.47 (br. s., 2H) 3.51-3.61 (m, 2H) 3.76-3.85 (m, 3H) 3.97 (s, 2H) 7.08-7.15 (m, 1H) 7.17-7.24 (m, 2H) 7.27-7.34 (m, 2H) 7.50 (t, J=5.3 Hz, 1H) 7.76 (dd, J=8.2, 1.6 Hz, 1H) 7.92 (d, J=1.6 Hz, 1H) 8.20 (d, J=8.2 Hz, 1H); MS m/z 461.2 (M+H)+; HPLC >99%, RT=1.63 minutes.
Reaction SMILES: [OH:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:5]2[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10][C:4]=2[CH:3]=1.C1C(=O)N([Br:30])C(=O)C1>C(Cl)Cl>[Br:30][C:3]1[C:4]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[CH2:7][CH2:6][C:5]=2[CH:18]=[C:19]([N+:20]([O-:22])=[O:21])[C:2]=1[OH:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCc2cc(O)c([N+](=O)[O-])cc2CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2cc([N+](=O)[O-])c(O)c(Br)c2CC1
Yield: 80.7 %

Procedure:
Bromination of 1,1-dimethylethyl 7-hydroxy-8-nitro-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (71 mg) was performed with NBS (41 mg) in DCM (2.2 ml) and SiO2 (426 mg) at −15° C. under nitrogen. After 15 minutes SiO2 was filtered off and the solvent was evaporated under reduced pressure. The crude was purified on silica gel (ethyl acetate/petroleum ether, 1/9) obtaining the title compound as a yellow solid (72 mg).
Reaction SMILES: [H-].[Na+].[C:3]12([C:13]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=3[OH:20])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.[CH2:21]1COCC1>>[C:3]12([C:13]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=3[O:20][CH3:21])[CH2:4][CH:5]3[CH2:11][CH:9]([CH2:8][CH:7]([CH2:6]3)[CH2:12]1)[CH2:10]2
Reactant: Oc1cc(Br)ccc1C12CC3CC(CC(C3)C1)C2
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: COc1cc(Br)ccc1C12CC3CC(CC(C3)C1)C2

Procedure:
1.6 g (53 mmol) of sodium hydride (80% in oil) and 50 mi of THF are introduced into a round-bottomed flask and a solution of 15 g (49 mmol) of the phenol obtained above in (a), dissolved in 100 mi of DMF, is added dropwise. The mixture is stirred until gaseous evolution has ceased and 3.1 ml (49 mmol) of methyl iodide are then introduced. The mixture is stirred at room temperature for four hours, the reaction medium is poured into water and the organic phase is separated after settling has taken place, then dried over magnesium sulphate and evaporated. The residue obtained is ground in the minimum amount of hexane and filtered off. 12.6 g (80%) of 2-(1-adamantyl)-5-bromoanisole, melting point 159°-160° C., are collected.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:17][C:18]#[N:19].O>CN(C=O)C>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=[CH:9][C:10]([O:13][CH2:17][C:18]#[N:19])=[CH:11][CH:12]=1
Reactant: N#CCCl
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCOc1ccc(-c2ccccc2)cc1
Temperature: 70 °C

Procedure:
To a solution of 4-phenylphenol (3.4 g, 20 mmol) in DMF (75 ml) was added sodium hydride (0.88 g of a 60% dispersion in oil, 22 mmol). The mixture was stirred at 70° C. under nitrogen until a clear solution was obtained, then cooled to 50° C. To the mixture was added chloroacetonitrile (1.5 ml, 24 mmol). A precipitate formed immediately. The mixture was cooled to room temperature, poured into water (300 ml), and extracted with ether. The ether extracts were dried (MgsO4), filtered and evaporated. Recrystallization of the residue from methanol provided [1,1'-biphenyl]-4yloxyacetonitrile, mp 81°-83° C.
Reaction SMILES: [Br:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:18]1([Li])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1>[Br:1][C:2]1[C:15]2[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([OH:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([C:2]3[CH:15]=[CH:6][CH:5]=[CH:4][CH:3]=3)([OH:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: [Li]c1ccccc1
Reactant: O=C1c2ccccc2C(=O)c2c(Br)cccc21
Solvent: C1CCOC1
Product: OC1(c2ccccc2)c2ccccc2C(O)(c2ccccc2)c2c(Br)cccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
9.37 g (32.4 mmol) of 1-bromoanthraquinone was put into a 500 mL three neck-flask, and the atmosphere of the flask was substituted with nitrogen. 150 mL of tetrahydrofuran (abbreviation: THF) was added to the flask, and then 34.0 mL (71.3 mmol) of phenyllithium (2.1 mol/L dibutyl ether solution) was added in one portion. The solution was stirred for 24 hours at room temperature. After the reaction was completed, the reaction solution was washed with water, and the aqueous layer was extracted with ethyl acetate. The extracted part was combined with the organic layer, and then dried with magnesium sulfate. After drying, the mixture was subjected to suction filtration, and the filtrate was concentrated, resulting in 14.4 g of 1-bromo-9,10-diphenyl-9,10-dihydroanthracene-9,10-diol as a brown, oily compound in 100% yield.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[H][H]>C(O)C>[Cl:1][CH2:2][C@@H:3]([OH:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: [H][H]
Reactant: CCOC(=O)CC(=O)CCl
Solvent: CCO
Product: CCOC(=O)C[C@H](O)CCl

Procedure:
In a stainless steel autoclave, 12.4 mg (0.008 mmol) of Ru2Cl4 ((R)-BIPHEMP)2NEt3 was charged, and the air in the autoclave was replaced with nitrogen. Further, 6.6 ml of ethanol and 2.7 ml (20 mmol) of ethyl 4-chloroacetoacetate were added, and the nitrogen in the autoclave was replaced with hydrogen. At a hydrogen pressure of 10 kgf/cm2, it was stirred for 2 hours at 100° C. After termination of the reaction, the conversion ratio, selectivity and optical purity were measured under the same chromatography conditions as in Example 5. At a conversion ratio of 95.5%, selectivity of 93.9% and optical purity of 95.7%ee, ethyl 4-chloro-(S)-3-hydroxybutyrate was obtained.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10](F)=[C:11](F)[C:12]=3F)[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:21]([NH:23][CH2:24][CH2:25][CH:26]1[O:31][CH2:30][CH2:29][NH:28][CH2:27]1)[CH3:22]>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([N:28]4[CH2:29][CH2:30][O:31][CH:26]([CH2:25][CH2:24][NH:23][CH2:21][CH3:22])[CH2:27]4)[CH:12]=3)[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CCNCCC1CNCCO1
Product: CCNCCC1CN(c2ccc3c(=O)c(C(=O)O)cn(C4CC4)c3c2)CCO1

Procedure:
By the use of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 2-(2-ethylaminoethyl)morpholine, the reaction is similarly carried out as Example 11 to give 1-cyclopropyl-7-[2-(2-ethylaminoethyl)morpholino] -1,4-dihydro-4-oxoquinoline-3-carboxylic acid.
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([C:9]1[CH:10]=[C:11]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]#[N:32])=[CH:25][C:24]=3[CH2:33][CH:34]([CH3:36])[CH3:35])=[CH:19][C:18]=2[CH2:37][C:38]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH:41]=[CH:40][CH:39]=2)[CH:12]=[CH:13][C:14]=1[O:15]C)[CH:6]([CH3:8])[CH3:7].O>C(Cl)Cl>[OH:15][C:14]1[CH:13]=[CH:12][C:11]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]#[N:32])=[CH:25][C:24]=3[CH2:33][CH:34]([CH3:36])[CH3:35])=[CH:19][C:18]=2[CH2:37][C:38]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH:41]=[CH:40][CH:39]=2)=[CH:10][C:9]=1[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: COc1ccc(-c2ccc(-c3ccc(CCC#N)cc3CC(C)C)cc2Cc2cccc3ccccc23)cc1CC(C)C
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CC(C)Cc1cc(-c2ccc(-c3ccc(CCC#N)cc3CC(C)C)cc2Cc2cccc3ccccc23)ccc1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
1.44 ml (1.44 mmol, 3.00 eq.) of a 1 M solution of BBr3 in CH2Cl2 was added to a solution of 270.8 mg (0.48 mmol) 3-(3,2″-Diisobutyl-4-methoxy-2′-naphthalen-1-ylmethyl-[1,1′:4′,1″]-terphenyl-4″-yl)propionitrile (68) in 25 ml dry CH2Cl2 at 0° C. via syringe. After that the solution was stirred for 60 min at 0° C. and then for 12 h at r.t. The reaction mixture was then added to water and extracted with CH2Cl2. The comb. org. fractions were dried over MgSO4 and evaporated. Column chromatography (hexanes/EtOAc (2+1)) yielded 261.9 mg (0.48 mmol, 98.89%) 3-(4-Hydroxy-3,2″-diisobutyl-2′-naphthalen-1-ylmethyl-[1,1′:4′,1″]-terphenyl-4″-yl)propionitrile (69) as a colorless oil. Rf (hexanes/EtOAc (2+1))=0.40. 1H-NMR (500 MHz, CDCl3): δ=0.53 (d, 6H, J=6.62 Hz, 2*CH3), 0.79 (d, 6H, J=6.62 Hz, 2*CH3), 1.47 (m, 1H, CH), 1.73 (m, 1H, CH), 2.24 (d, 2H, J=7.41 Hz, CH2), 2.39 (d, 2H, J=7.09 Hz, CH2), 2.58 (t, 2H, J=7.41 Hz, CH2CH2CN), 2.90 (t, 2H, J=7.41 Hz, CH2CH2CN), 4.38 (s, 2H, CH2Naphthyl), 4.58 (s, 1H, OH), 6.76 (d, 1H, J=8.04 Hz), 6.97 (m, 2H), 7.00 (m, 1H), 7.08-7.16 (m, 5H), 7.30-7.41 (m, 4H), 7.67 (dm, 1H, J=8.04 Hz), 7.72 (dm, 1H, J=8.51 Hz), 7.78 (dm, 1H, J=8.04 Hz). MS (EI): m/z=553 (11), 552 (43), 551 (100), 141 (49). HR-MS (EI): Calcd. for C40H41NO: 551.318814. Found: 551.318350.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Cl:8][C:9]1[CH:35]=[CH:34][C:12]([CH2:13][O:14][C:15]2[CH:16]=[C:17]([CH:31]=[CH:32][CH:33]=2)[C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[S:27](=[O:30])(=[O:29])[NH2:28])=[O:19])=[CH:11][CH:10]=1>CN(C)C1C=CN=CC=1.O1CCCC1>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][O:14][C:15]2[CH:16]=[C:17]([CH:31]=[CH:32][CH:33]=2)[C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[S:27]([NH:28][C:1](=[O:3])[CH3:2])(=[O:30])=[O:29])=[O:19])=[CH:34][CH:35]=1
Reactant: CC(=O)OC(C)=O
Reactant: NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccc(Cl)cc2)c1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.7 %

Procedure:
In a stream of nitrogen and at 0° C., 0.12 ml (1.30 mmol) of acetic anhydride was added to an anhydrous tetrahydrofuran (10 ml) solution containing 500 mg (1.20 mmol) of 3-(4-chlorobenzyloxy)-N-(2-sulfamoylphenyl)benzamide produced in Reference Example 4 and 293 mg (2.40 mmol) of 4-dimethylaminopyridine, the mixture was stirred at room temperature for 1 hour and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water, a potassium hydrgensulfate aqueous solution and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was recrystallized from an ethyl acetate-diethyl ether mixed solvent to obtain 290 mg (yield: 52.7%) of the title compound.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[CH2:27]([C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=1)[CH:28]([CH3:30])[CH3:29]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:35](=[O:36])[C:34]3[CH:38]=[CH:39][C:31]([CH2:27][CH:28]([CH3:29])[CH3:30])=[CH:32][CH:33]=3)[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: CC(C)Cc1ccc(C(=O)O)cc1
Agent: Cl
Product: CC(C)Cc1ccc(C(=O)N[C@H]2CC[C@H](CCN3CCCCC3c3coc4cccc-4c3)CC2)cc1

Procedure:
The title compound, off-white solid (89 mg, 73%), MS (ISP) m/z=487.4 [(M+H)+], mp 190° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 4-isobutyl-benzoic acid.
Reaction SMILES: [F:1][C:2]1[C:3]([N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2.N1C=CC=CC=1>CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>[F:1][C:2]1[C:3]([N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([CH3:12])[CH2:6][CH2:5]2
Reactant: Cc1ccc2c(-n3ccnc3)c(F)ccc2n1
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Solvent: c1ccncc1
Product: CC1CCc2c(ccc(F)c2-n2ccnc2)N1

Procedure:
A solution of 10.2 g (44.9 mmole) of 6-fluoro-5-(imidazol-1-yl)-2-methylquinoline, 16.7 g (180 mmole) of pyridine:diborane complex (that commercially available from Aldrich) and 200 ml of glacial acetic was stirred for about 22 hours at about 20° C. The solution was evaporated to reduce its volume, then 100 ml of 10% hydrochloric acid was added in small portions. The solution was heated on a steam bath for about one hour, then cooled with an ice bath and basified (pH 9 to 10) with 10% aqueous sodium hydroxide. The solid was separated by filtration, washed with water, and dissolved in ethyl acetate and dried. Recrystallization from aqueous ethanol provided 6-fluoro-5-(imidazol-1-yl)-1,2,3,4-tetrahydro-2-methylquinoline, m.p. 162°-164° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C@@H:4]([CH2:13][OH:14])[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].Cl.C(N(CC)CC)C.[S:24](Cl)([C:27]1[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=1)(=[O:26])=[O:25].C(N(CC)CC)C.Cl>ClCCl.CN(C)C1C=CN=CC=1.O>[CH3:1][O:2][C:3](=[O:15])[CH:4]([NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7])[CH2:13][O:14][S:24]([C:27]1[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=1)(=[O:26])=[O:25]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)C(COS(=O)(=O)c1ccc(C)cc1)NC(=O)OC(C)(C)C
Temperature: 6 °C
Reaction time: 8 h
Yield: 67.1 %

Procedure:
A solution of Boc-D-serine methyl ester (9.59 g, 43.8 mmol) in dichloromethane (100 ml) was stirred at −10° C. during the addition of 4-(dimethylamino)pyridine (270 mg, 2.19 mmol), triethylamine hydrochloride (4.19 g, 43.8 mmol) and tosyl chloride (8.35 g, 43.8 mmol). Triethylamine (6.10 ml, 43.8 mmol) was added dropwise at −10° C. over 35 minutes and the resultant slurry was allowed to stand at 6° C. overnight. The reaction mixture was poured into a mixture of ice (35 g), water (35 ml) and 2N hydrochloric acid (20 ml). The aqueous phase was extracted with dichloromethane (35 ml) and the combined organic solutions washed with brine (2*25 ml), dried (anhydrous magnesium sulfate) and concentrated in vacuo to a pale yellow oil. The oil was dissolved in diethyl ether (100 ml) and cooled to 6° C. Once crystallisation started, petrol ether (75 ml) was added in five portions over two hours, and crystallisation was allowed to proceed at 6° C. overnight to give 2-tert-butoxycarbonylamino-3-(toluene-4-sulfonyloxy)-propionic acid methyl ester (10.98 g, 67%).
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.S(Cl)([Cl:23])=O>ClC(Cl)Cl>[Cl:23][CH2:2][CH2:3][N:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=c1c2ccccc2nc(-c2ccccc2)n1CCO
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=c1c2ccccc2nc(-c2ccccc2)n1CCCl
Reaction time: 2 h

Procedure:
To a stirred mixture of 15 parts of 3-(2-hydroxyethyl)-2-phenyl-4-(3H)-quinazolinone and 375 parts of trichloromethane are added dropwise 24 parts of thionyl chloride at room temperature. Upon completion, stirring is continued for 2 hours at reflux. The reaction mixture is evaporated. Water is added to the residue and the whole is neutralized with a sodium hydrogen carbonate solution. The product is extracted with trichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is crystallized from a mixture of 2,2'-oxybispropane and petroleumether. The product is filtered off and dried, yielding 11.6 parts of 3-(2-chloroethyl)-2-phenyl-4(3H)-quinazolinone.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.Br[CH:13]([CH2:16]Br)[CH2:14][OH:15]>>[OH:15][CH2:14][CH:13]([O:9][C:8]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH3:7])[CH2:16][O:9][C:8]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH3:7]
Reactant: COc1cc(C=O)ccc1O
Reactant: OCC(Br)CBr
Product: COc1cc(C=O)ccc1OCC(CO)Oc1ccc(C=O)cc1OC
Yield: 71.8 %

Procedure:
Vanillin (30.4 g, 0.2 m) is reacted with 2,3-dibromopropanol (21.8 g, 0.1 mol) according to the procedure employed in Example 41 to obtain 25.86 g of 4,4'-[[1-(hydroxymethyl)-1,2-ethanediyl]bis(oxy)]bis[3-methoxybenzaldehyde]. This intermediate (3.60 g, 0.01 m) is reacted with ethyl cyanoacetate as described in Example 41 to yield 4.3 g of product which mas spectroscopy indicated had the structure: ##STR32## When dissolved in methylene chloride, the product has an absorption maximum (λmax) at 361 nm.
Reaction SMILES: CC1(C)[C@H]2CC[C@]1(CS(O)(=O)=O)C(=O)C2.[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[CH2:22][C@H:21]([NH2:26])[CH2:20]2.O.[C:28](Cl)(=[O:37])[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CCOC(C)=O>[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[CH2:22][C@H:21]([NH:26][C:28](=[O:37])[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:20]2
Reactant: N[C@H]1Cc2ccc(Br)cc2C1
Reactant: O=C(Cl)OCc1ccccc1
Agent: CC1(C)[C@H]2CC[C@]1(CS(=O)(=O)O)C(=O)C2
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(N[C@H]1Cc2ccc(Br)cc2C1)OCc1ccccc1
Reaction time: 18 h
Yield: 99.4 %

Procedure:
To (S)-5-bromo-2,3-dihydro-1H-inden-2-amine((1R,4S)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate (13.95 mmol, 6.2 g) in EtOAc (93 mL)/Water (93 mL) was added benzyl carbonochloridate (15.35 mmol, 2.62 g) dropwise at 0° C. under an argon atmosphere. The reaction was left to stir for 18 hrs. The aqueous layer was removed before washing the organic with brine. The organics were dried over MgSO4 before filtering and removing the solvent in vacuo to give the title compound as a white solid (4.8 g, 99%). 1H NMR (400 MHz, CDCl3) δ 2.79 (m, 2H), 3.25 (m, 2H), 4.53 (d, 1H), 4.93 (brs, 1H), 5.10 (s, 2H), 7.08 (d, 1H) 7.31 (m, 7H).
Reaction SMILES: [CH2:1]([C:5]1[C:6](=[O:13])[NH:7][C:8](=S)[NH:9][C:10]=1[CH3:11])[CH2:2][CH2:3][CH3:4].ClCC(O)=[O:17]>>[CH2:1]([C:5]1[C:6](=[O:13])[NH:7][C:8](=[O:17])[NH:9][C:10]=1[CH3:11])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(C)[nH]c(=S)[nH]c1=O
Reactant: O=C(O)CCl
Product: CCCCc1c(C)[nH]c(=O)[nH]c1=O
Temperature: 25 °C

Procedure:
A suspension of 5-butyl-6-methyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one in 10% aqueous chloroacetic acid (100 mL) is stirred at reflux for 3 hours and then allowed to cool to room temperature. The suspension is cooled in an ice bath for a few minutes and then filtered. The solid is thoroughly washed with H2O and dried, yielding pure 5-butyl-6-methyl-1H-pyrimidine-2,4-dione as a white solid. 1H NMR (DMSO-d6, 300 MHz) δ 10.86 (br s, 1H), 10.57 (br s, 1H), 2.17 (m, 2H), 2.01 (s, 3H), 1.25 (m, 4H), 0.85 (t, J=6.9 Hz, 3H) ppm. MS: m/z 183 [M+1].
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][C:13]=2[F:19])[N:4]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:3]=1.[F:28][C:29]1[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[C:30]=1[C:31](O)=[O:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CN(C1C=CN=CC=1)C.CCOC(C)=O>[Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[O:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:31](=[O:32])[C:30]3[C:34]([O:38][CH3:39])=[CH:35][CH:36]=[CH:37][C:29]=3[F:28])=[CH:14][C:13]=2[F:19])[N:4]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:3]=1
Reactant: COc1cccc(F)c1C(=O)O
Reactant: C[Si](C)(C)CCOCn1cc(Br)c2c(Oc3ccc(N)cc3F)ccnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(F)c1C(=O)Nc1ccc(Oc2ccnc3c2c(Br)cn3COCC[Si](C)(C)C)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To a stirred solution of 4-(3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorobenzenamine (400 mg, 0.85 mmol), 2-fluoro-6-methoxybenzoic acid (226 mg, 1.33 mmol), and HATU (641 mg, 1.33 mmol) in DMF (6 mL) was added DIPEA (387 mg, 3 mmol), followed by DMAP (50 mg). The resulting mixture was stirred at rt overnight, diluted with EtOAc, and washed with saturated aq. K2HPO4 solution and brine. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, eluting with 30% EtOAc/CH2Cl2) to give the desired product (370 mg, 72%) as a white solid. LC/MS(ESI+) m/z 605 (M+H)+.