Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].[C:24]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)#[N:25]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10]([C:29]2[CH:30]=[CH:31][C:26]([C:24]#[N:25])=[CH:27][CH:28]=2)[N:11]=1)=[O:5])[CH3:2]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1nc(Br)c2snc(-c3ccc(F)cc3)c2c1O
Product: CCOC(=O)c1nc(-c2ccc(C#N)cc2)c2snc(-c3ccc(F)cc3)c2c1O

Procedure:
The title compound was synthesized in analogy to Example 1 from 7-bromo-3-(4-fluoro-phenyl)-4-hydroxy-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester and 4-cyanophenylboronic acid: MS (m/z) 420.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=1.[Br:12]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:1][C:2]1[N:3]=[N:4][C:5]([C:8]([F:9])([F:11])[F:10])=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(F)(F)F)nn1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)c1ccc(CBr)nn1
Yield: 13.5 %

Procedure:
A mixture of 3-methyl-6-(trifluoromethyl)pyridazine (70 mg), N-bromosuccinimide (84 mg), azobisisobutyronitrile (14.1 mg), and CCl4 (3 ml) was heated under reflux for 2 days. The solvent was evaporated to dryness under vacuum. The residue obtained was purified by chromatography column on silica gel (AIT, Flashsmart BP-SUP, 20-40 μm) using a mixture of EtOAc/hexane as eluent to give 14 mg (14%) of the title compound along with 15.3 mg (11%) of the dibrominated derivative.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[F:26][C:27]1[CH:28]=[C:29]([NH:34]N)[CH:30]=[CH:31][C:32]=1[CH3:33]>>[F:26][C:27]1[CH:28]=[C:29]([N:34]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:30]=[CH:31][C:32]=1[CH3:33]
Reactant: Cc1ccc(NN)cc1F
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Product: Cc1ccc(-n2nccc2-c2nn(-c3cccc(OC(F)(F)F)c3)ccc2=O)cc1F

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and (3-fluoro-4-methyl-phenyl)-hydrazine according to example 43 gave the desired product. MS: M=431.0 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])=[CH:4][CH:3]=1.C(OO)(=[O:15])C.C([O-])(=O)C.[Na+].O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH:11]2[O:15][CH2:12]2)=[CH:4][CH:3]=1
Reactant: C=CCCCc1ccc(Cl)cc1
Reactant: CC(=O)OO
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Clc1ccc(CCCC2CO2)cc1

Procedure:
To a solution of 5-(4-chlorophenyl)pent-1-ene (43.2 g) in dichloromethane (400 mL) was added dropwise with stirring a mixture of 40% peracetic acid (200 mL) and sodium acetate (6.5 g). The resulting mixture was heated under reflux for 2 hours, cooled, and stirred with water (400 mL). The dichloromethane layer was separated, washed with dilute aqueous potassium carbonate until neutral, water, and dried (MgSO4) and evaporated to give 46.7 g of 5-(4-chlorophenyl)-1,2-epoxypentane as a colorless oil.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([CH3:8])=[CH:6][CH:7]=1.[F:10][C:11]([F:19])([F:18])[C:12]([F:17])([F:16])C(O)=O.[Na].CN1CCCC1=O>[Cu]I.CCCCCC>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([C:12]([F:17])([F:16])[C:11]([F:19])([F:18])[F:10])=[CH:3][C:4]=1[CH3:9]
Reactant: Cc1ccc(I)cc1C
Reactant: O=C(O)C(F)(F)C(F)(F)F
Agent: [Cu]I
Agent: [Na]
Solvent: CN1CCCC1=O
Solvent: CCCCCC
Product: Cc1ccc(C(F)(F)C(F)(F)F)cc1C
Temperature: 170 °C

Procedure:
Into a nitrogen purged, flame dried round bottom flask was added 4-iodo-o-xylene (15.0 g, 64.7 mmol), sodium pentafluoropropionic acid (16.8 g, 90.5 mmol), copper (I) iodide (12.3 g, 64.6 mmol) and 100 mL of anhydrous N-methylpyrrolidinone. The reaction mixture was heated at 170° C. for 16 hours, then cooled to room temperature, and run through a thick silica gel plug with hexane. The collected yellow liquids were then evaporated to dryness on a rotary evaporator, and the oil distilled at 60° C. (10−1 Torr) to collect the desired product (9.14 g, 63%) as a colorless liquid. Analysis of the product provided the following data: 1H NMR (200 MHz, CDCl3) δ=2.347 (s, 6H), 7.247 (d, J=7.8 Hz, 1H), 7.357 (s, 1H), 7.401 (s, 1H). 13C NMR (50 MHz, CDCl3) δ=19.810, 19.840, 124.013 (t, J=6.1 Hz), 127.472 (t, J=6.1 Hz), 130.158, 137.563, 141.205. GC-MS: m/z: 224 (C10H9F5).
Reaction SMILES: C1(O[C:8](=[O:16])[NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)C=CC=CC=1.[N:17]1([CH2:23][C:24]2[CH:25]=[N:26][C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>CS(C)=O>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([NH:9][C:8]([N:20]2[CH2:21][CH2:22][N:17]([CH2:23][C:24]3[CH:25]=[N:26][C:27]4[C:32]([CH:33]=3)=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:18][CH2:19]2)=[O:16])[CH:11]=1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Reactant: c1ccc2ncc(CN3CCNCC3)cc2c1
Solvent: CS(C)=O
Product: O=C(Nc1cccnc1)N1CCN(Cc2cnc3ccccc3c2)CC1
Yield: 80 %

Procedure:
A solution of pyridin-3-yl-carbamic acid phenyl ester (0.3 g) and 3-piperazin-1-ylmethyl-quinoline (0.32 g) in DMSO (0.5 mL) was heated in a microwave reactor at 100° C. for 0.5 h. The reaction mixture was partitioned between DCM and water. The combined organic layers were washed with brine (3×), dried (Na2SO4), and concentrated. The residue was purified by column chromatography to yield the title compound as a beige solid (80%). 1H NMR (400 MHz, CDCl3): 8.92 (d, J=2.3 Hz, 1H), 8.72 (d, J=2.3 Hz, 1H), 8.28 (d, J=8.1 Hz, 1H), 8.23-8.21 (m, 1H), 8.13-8.10 (m, 2H), 7.84-7.82 (m, 1H), 7.74-7.70 (m, 1H), 7.59-7.55 (m, 1H), 7.37-7.34 (m, 2H), 3.77 (s, 2H), 3.64-3.62 (m, 4H), 2.62-2.59 (m, 4H).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[CH2:6][C:7]([C@@H:25]1[CH2:29][S:28][CH2:27][N:26]1C(OCC1C=CC([N+]([O-])=O)=CC=1)=O)=[C:8]2[C:12]([O:14]CC1C=CC([N+]([O-])=O)=CC=1)=[O:13])[CH3:3].[H][H]>O1CCCC1.P([O-])([O-])([O-])=O.[OH-].[OH-].[Pd+2]>[OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[CH2:6][C:7]([C@@H:25]1[CH2:29][S:28][CH2:27][NH:26]1)=[C:8]2[C:12]([OH:14])=[O:13])[CH3:3]
Reactant: [H][H]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C([C@@H]3CSCN3C(=O)OCc3ccc([N+](=O)[O-])cc3)C[C@H]12
Agent: [Pd+2]
Agent: O=P([O-])([O-])[O-]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C([C@@H]3CSCN3)C[C@H]12
Yield: 6.3 %

Procedure:
A solution of 4-nitrobenzyl (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-[(4R)-3-(4-nitrobenzyloxycarbonyl)thiazolidin-4-yl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (2.00 g) in a mixture of tetrahydrofuran (30 ml) and phosphate buffer (pH 6.5) (30 ml) was hydrogenated under atmospheric pressure of hydrogen over palladium hydroxide on carbon (20%, 0.6 g) for 3 hours at ambient temperature. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give an aqueous solution. The solution was washed with ethyl acetate, subjected to a column chromatography on silica gel (75 g), and eluted with a mixture of acetonitrile and 75:25, V/V). The fractions containing the object compound were collected and lyophilized to give (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-[(4R)-thiazolidin-4-yl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (0.06 g) as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:10][C@@H:11]1[O:15][C:14]([CH3:17])([CH3:16])[N:13]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C@H:12]1[CH2:28][C:29]1[CH:34]=[CH:33][C:32](OC(=O)C(F)(F)F)=[CH:31][CH:30]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[Cl-].[CH3:51][C:52]1[CH:53]=[CH:54][C:55]([Sn](CCCC)(CCCC)CCCC)=[N:56][CH:57]=1>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:10][C@@H:11]1[O:15][C:14]([CH3:16])([CH3:17])[N:13]([C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[C@H:12]1[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([C:55]2[CH:54]=[CH:53][C:52]([CH3:51])=[CH:57][N:56]=2)=[CH:33][CH:34]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C)cn1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@@H]1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1Cc1ccc(OC(=O)C(F)(F)F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc(C[C@H]3[C@H](C[C@H](Cc4ccccc4)NC(=O)OC(C)(C)C)OC(C)(C)N3C(=O)OCc3ccccc3)cc2)nc1
Yield: 41.8 %

Procedure:
A solution containing the product from Example 23I (0.114 g, 0.162 mmol) in DMF (1.6 mL) was treated with LiCl (0.068 g, 1.60 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.034 g, 0.048 mmol), and the product from Example 74A (0.367 g, 0.961 mmol), heated at 100° C. for 16 hours, cooled and partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-15% ethyl acetate in dichloromethane. The product was purified by reversed phase chromatography on a C18 column eluting with 5-100% acetonitrile in water (0.1% TFA) to give the title compound (0.044 g, 42% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=O)[C:4]([CH3:9])([CH3:8])[CH2:5][O:6]C.[C:11](#[N:13])[CH3:12].[H-].[Na+].Cl>C1(C)C=CC=CC=1>[CH3:1][O:2][CH2:3][C:4]([CH3:9])([CH3:8])[C:5](=[O:6])[CH2:12][C:11]#[N:13]
Reactant: CC#N
Reactant: COCC(C)(C)C(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COCC(C)(C)C(=O)CC#N
Temperature: 25 °C
Yield: 90.7 %

Procedure:
A solution of 1.74 g (12 mmol) of 3-methoxy-2,2-dimethyl-propionic acid methyl ester and 0.9 mL (17 mmol) of acetonitrile in toluene (5 mL) is added dropwise to the refluxing suspension of 0.67 g (17 mmol) of sodium hydride (60% in mineral oil) in toluene (5 mL). After the addition, the reaction mixture is stirred at reflux for 3 h. After this time, the reaction mixture is cooled to room temperature and neutralized to pH˜6-7 by adding 1M aqueous HCl solution. The aqueous layer is extracted with ethyl acetate (3×20 mL). The organic layers are combined, washed with brine (1.5 L), dried over Na2SO4 and filtered. The filtrate is concentrated under reduced pressure to yield 1.69 g of 5-methoxy-4,4-dimethyl-3-oxo-pentanenitrile as a brown oil, which is used in the next step without further purification. Yield: 91%; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.1 (6H, s), 3.2 (3H, s), 3.3 (sH, s), 4.2 (2H, s).
Reaction SMILES: [CH3:1][CH:2]1[N:7]([CH2:8][CH2:9][CH2:10][NH2:11])[CH2:6][CH2:5][CH2:4][CH2:3]1.[O:12]=[C:13]1[NH:21][CH:20]=[N:19][C:18]2[N:17]([CH2:22][CH2:23][C:24](OCC)=[O:25])[CH:16]=[N:15][C:14]1=2>C(#N)C>[O:12]=[C:13]1[NH:21][CH:20]=[N:19][C:18]2[N:17]([CH2:22][CH2:23][C:24]([NH:11][CH2:10][CH2:9][CH2:8][N:7]3[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]3[CH3:1])=[O:25])[CH:16]=[N:15][C:14]1=2
Reactant: CCOC(=O)CCn1cnc2c(=O)[nH]cnc21
Reactant: CC1CCCCN1CCCN
Solvent: CC#N
Product: CC1CCCCN1CCCNC(=O)CCn1cnc2c(=O)[nH]cnc21
Temperature: 120 °C
Reaction time: 0.42 h

Procedure:
0.565 g (3.62 mmol) of 1-(3-aminopropyl)-2-pipecoline was placed into a 10 ml round bottom flask with a magnetic stirring bar. The flask was heated to 120° C. and 250 mg (1.06 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propionic acid, ethyl ester (AIT-0027) was added. The mixture was heated for two hours at 120° C. and was allowed to cool. The resultant light orange viscous oil was treated with 8 ml acetonitrile and was stirred for about 25 min. The solution was filtered and the solid was washed with acetonitrile and then with ether. This yielded 254 mg of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-N-[3-(2-methylpipiridin-1-yl)propyl]propanamide (AIT-0044) as an off-white solid.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]([C:19]1[CH:24]=[C:23]([Cl:25])[C:22]([Cl:26])=[C:21]([Cl:27])[CH:20]=1)=[CH:4][C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12]1([CH2:18][NH:17][CH2:16]1)[O:11][CH2:10]2)=[O:6].CCN(CC)CC.[C:37](O)(=[O:41])[CH:38]([CH3:40])[CH3:39].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[F:29][C:2]([F:1])([F:28])[C:3]([C:19]1[CH:20]=[C:21]([Cl:27])[C:22]([Cl:26])=[C:23]([Cl:25])[CH:24]=1)=[CH:4][C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12]1([CH2:18][N:17]([C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[CH2:16]1)[O:11][CH2:10]2)=[O:6]
Reactant: O=C(C=C(c1cc(Cl)c(Cl)c(Cl)c1)C(F)(F)F)c1ccc2c(c1)COC21CNC1
Reactant: CC(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)C(=O)N1CC2(C1)OCc1cc(C(=O)C=C(c3cc(Cl)c(Cl)c(Cl)c3)C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To the stirred solution of hydrochloride salt of 5′-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-2-enoyl)-3′H-spiro[azetidine-3,1′-isobenzofuran](Preparation 26, 1.0 g, 2.2 mmol, 1 eq) in DMF (10 mL) was added Et3N (2.4 mL, 17.3mmol, 8 eq) followed by addition of iso-butyric acid (0.38 g, 4.32mmol, 2 eq), HOBt (0.29 g, 2.16 mmol, 1 eq) and EDC.HCl (0.62 g, 3.24 mmol, 1.5 eq) at room temperature. Resulting reaction mixture was stirred at room temperature for 18 hours under nitrogen atmosphere. After consumption of starting material, reaction mixture was quenched by water (30 mL) and extracted with ethyl acetate (3×25 mL). Combined organic layer was washed with aqueous sodium bicarbonate (50 mL), aqueous LiCl solution (2×50 mL), brine (50 mL) and dried over sodium sulfate. Organic layer was concentrated in vacuo to get brown sticky oil (1.0 g, Crude). Purification was done by Combiflash chromatography using 40 g Redisep column. Compound was eluted in 40% ethyl acetate in n-hexane to get title compound as off white solid (0.5 g, 43%). 1H NMR (400 MHz, CDCl3) δ: 1.13-1.17 (m, 6H), 2.46-2.53 (m, 1H), 4.25 (d, J=10.64 Hz, 1H), 4.30-4.34 (m, 2H), 4.52 (d, J=9.32 Hz, 1H), 5.15 (s, 2H), 7.27 (s, 2H), 7.40 (d, J=1.36 Hz, 1H), 7.49 (d, J=8.04 Hz, 1H), 7.68 (s, 1H), 7.84 (d, J=7.92 Hz, 1H). LC-MS (m/z): 531.9 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:18])[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH2:11].[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1.CN(C)C(=N)N(C)C>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:18])[CH:10]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:11][N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1
Reactant: C=C(C(=O)c1ccc(Cl)cc1Cl)c1ccccc1
Reactant: c1c[nH]cn1
Agent: CN(C)C(=N)N(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(c1ccc(Cl)cc1Cl)C(Cn1ccnc1)c1ccccc1
Yield: 12 %

Procedure:
A solution of 1-(2,4-dichlorophenyl)-2-phenylpropen-1-one (4 g), imidazole (1.36 g) and tetramethylguanidine (0.5 ml) in tetrahydrofuran (100 ml) was heated at reflux for 12 hours. The reaction mixture was cooled and concentrated under reduced pressure to yield a gum. The gum was dissolved in ethyl acetate, washed with distilled water, and acidified with 4N hydrochloric acid. The resulting aqueous phase was basified with sodium hydrogen carbonate and extracted with ethyl acetate. The organic phase was separated, washed with distilled water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to yield an oil which was chromatographed on silica gel in methanol/dichloromethane (1:9) to yield 1-(2,4-dichlorophenyl)-3-(imidazol-1-yl)-2-phenylpropan-1-one (600 mg), which was treated with ethereal hydrogen chloride to yield the hydrochloride salt of 1-(2,4-dichlorophenyl)-3-(imidazol-1-yl)-2-phenylpropan-1-one, m.p. 110° C., (Found: C, 55.38; H, 4.37; N, 7.40; C18H15Cl3N2O.1/2H2O requires C, 55.34; H, 4.13; N, 7.17) having the formula: ##STR12##
Reaction SMILES: C(N(CC)CC)C.F[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([CH2:18][C:19]1[C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]([O:29][CH3:30])[C:22]([C:31]2[CH:35]=[CH:34][O:33][CH:32]=2)=[CH:21][CH:20]=1)(=[O:17])=[O:16].Cl.Cl.[CH2:38]([N:40]([CH2:43][CH:44]1[CH2:47][CH2:46][NH:45]1)[CH2:41][CH3:42])[CH3:39]>C(#N)C>[CH2:38]([N:40]([CH2:43][CH:44]1[CH2:47][CH2:46][N:45]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([CH2:18][C:19]1[C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]([O:29][CH3:30])[C:22]([C:31]2[CH:35]=[CH:34][O:33][CH:32]=2)=[CH:21][CH:20]=1)(=[O:17])=[O:16])[CH2:41][CH3:42])[CH3:39]
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2F)ccc(-c2ccoc2)c1OC
Reactant: CCN(CC)CC1CCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCN(CC)CC1CCN1c1ccccc1S(=O)(=O)Cc1ccc(-c2ccoc2)c(OC)c1C(=O)OC
Temperature: 140 °C
Yield: 59.6 %

Procedure:
Triethylamine (0.762 ml) was added to a solution of methyl 6-(2-fluorobenzenesulphonylmethyl)-3-(furan-3-yl)-2-methoxybenzoate (Intermediate 96, 0.0657 g) and 2-Diethylaminomethylazetidine dihydrochloride (Intermediate 206, 0.314 g) in acetonitrile (10 ml) and the mixture was sealed in a microwave vial and heated in the microwave for 3 hours at 140° C. The mixture was cooled to room temperature and evaporated to dryness. DCM and water were added to the residue and the pH was adjusted to 6 by addition of 1M HCl. The organic layer was separated, washed with water, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of DCM: methanol: acetic acid:water (350:20:3:2) to give methyl 6-[2-(2-diethylaminomethylazetidin-1-yl)benzenesulphonylmethyl]-3-(furan-3-yl)-2-methoxybenzoate (0.051 g) as a brown gum.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:11]=2[CH:29]=1.[C:30]([NH:33][C:34]1[CH:39]=[CH:38][C:37]([SH:40])=[CH:36][CH:35]=1)(=[O:32])[CH3:31]>>[C:30]([NH:33][C:34]1[CH:39]=[CH:38][C:37]([S:40][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:15][C:14](=[O:16])[O:13][C:12]([CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)[C:11]=3[CH:29]=2)=[CH:36][CH:35]=1)(=[O:32])[CH3:31]
Reactant: O=C1Nc2ccc(OCCCCCl)cc2C(C2CCCCC2)(C2CCCCC2)O1
Reactant: CC(=O)Nc1ccc(S)cc1
Product: CC(=O)Nc1ccc(SCCCCOc2ccc3c(c2)C(C2CCCCC2)(C2CCCCC2)OC(=O)N3)cc1

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-dicyclohexyl-4H-3,1-benzoxazin-2-one and 4-acetamido-thiophenol.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[C:7]([C:9]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][N:14]3[C:22]([C:25]([N:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:26])=[CH:23][CH:24]=[C:13]3[CH2:12]2)=[O:10])[CH:6]=[CH:5][C:4]=1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]([F:42])([F:41])[F:40].C(N(CC)C(C)C)(C)C.[CH2:52]1[O:54][C@H:53]1[CH2:55][OH:56]>CO>[CH3:2][C:3]1[CH:8]=[C:7]([C:9]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][N:14]3[C:22]([C:25]([N:27]4[CH2:28][CH2:29][N:30]([CH2:52][C@@H:53]([OH:54])[CH2:55][OH:56])[CH2:31][CH2:32]4)=[O:26])=[CH:23][CH:24]=[C:13]3[CH2:12]2)=[O:10])[CH:6]=[CH:5][C:4]=1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]([F:40])([F:42])[F:41]
Reactant: Cc1cc(C(=O)N2Cc3ccc(C(=O)N4CCNCC4)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Reactant: OC[C@H]1CO1
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N2Cc3ccc(C(=O)N4CCN(C[C@@H](O)CO)CC4)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Temperature: 60 °C

Procedure:
To a solution of 10,11-dihydro-10-[[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl]-3-(1-piperazinylcarbonyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine hydrochloride salt of Example 5, Step B (0.50 g, 0.84 mmol) and N,N-diisopropylethyl amine (0.16 mL, 0.92 mmol) in methanol (5 mL) was added (S)-(−)-glycidol (0.10 mL, 1.51 mmol). The reaction mixture was heated to 60° C. for 4 hours then cooled and concentrated in vacuo. The residue was partitioned between dichloromethane and water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a white foam. Purification by flash chromatography on silica gel using a solvent system of 5% methanol in chloroform provided the title product, which was redissolved in dichloromethane and evaporated to dryness in vacuo to a white foam (0.36 g).
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[H][H]>CCOC(C)=O.[Pd]>[NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1N
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(N)c1N

Procedure:
Methyl 2-amino-3-nitrobenzoate (117; 3.2 g) was dissolved in EtOAc (100 mL) and 10% Pd on C (200 mg) was added. The resulting reaction mixture was hydrogenated under 1 atm of hydrogen at room temperature for 2 days and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to afford essentially quantitative yield of methyl 2,3-diaminobenzoate 118.
Reaction SMILES: C[O:2][C:3]1[N:8]=[C:7]([O:9]C)[C:6]([C:11]2[CH:26]=[CH:25][C:14]([CH2:15][CH2:16][NH:17]C(=O)OC(C)(C)C)=[CH:13][CH:12]=2)=[CH:5][N:4]=1.[ClH:27]>>[ClH:27].[NH2:17][CH2:16][CH2:15][C:14]1[CH:13]=[CH:12][C:11]([C:6]2[C:7](=[O:9])[NH:8][C:3](=[O:2])[NH:4][CH:5]=2)=[CH:26][CH:25]=1
Reactant: COc1ncc(-c2ccc(CCNC(=O)OC(C)(C)C)cc2)c(OC)n1
Agent: Cl
Product: NCCc1ccc(-c2c[nH]c(=O)[nH]c2=O)cc1
Yield: 86 %

Procedure:
To tert-butyl 4-(2,4-dimethoxypyrimidin-5-yl)phenethylcarbamate (0.5 g, 1.39 mmol) was added aqueous hydrochloric acid (6 M, 15 mL) and the reaction mixture stirred at reflux for 4 hours. No starting material was observed by LCMS. The precipitate was filtered, washed with water (5 mL) and dried under reduced pressure (50° C.) to give a pale yellow solid, 5-(4-(2-aminoethyl)phenyl)pyrimidine-2,4(1H,3H)-dione hydrochloride (0.32 g, 1.35 mmol, 86%).
Reaction SMILES: [CH:1]1[NH:2][C:3]2[N:9]=[C:8]([NH2:10])[N:7]=[C:6](Cl)[C:4]=2[N:5]=1.[H-].[Na+].CN(C)C=[O:17]>>[NH:7]1[C:6](=[O:17])[C:4]2[NH:5][CH:1]=[N:2][C:3]=2[N:9]=[C:8]1[NH2:10]
Reactant: CN(C)C=O
Reactant: Nc1nc(Cl)c2nc[nH]c2n1
Agent: [H-]
Agent: [Na+]
Product: Nc1nc2nc[nH]c2c(=O)[nH]1
Temperature: 100 °C

Procedure:
6-Chloroguanine (0.75 g) and sodium hydride (60% in oil, 0.18 g) in dry dimethylformamide were stirred at room temperature for one hour. DL-erythro-2,2-Dimethyl-4-p-toluenesulfonyloxymethyl-5-hydroxymethyl-1,3-dioxolane [0.70 g, prepared according to A. Holy, Coll. Czech. Chem. Commun Vol 44, pages 593-612 (1979)] was added and the reaction mixture was heated at 100° C. for 17 hours, after which it was filtered through a Celite pad, and the solution was evaporated in vacuo. The residue was refluxed with acetic acid (25 ml) for 2 hours. The solvent was evaporated and the residue was coevaporated with water (3×5 ml). The residue was dissolved in a small volume of 1N hydrochloric acid, and added to a column of Dowex 50×8 (H+, 70 ml)which was eluted with water (1 liter) followed by aqueous ammonia (diluted 1/10). The elution was monitored by a UV detector. The appropriate fractions were evaporated in vacuo, and the residue was coevaporated with water several times, finally dissolved in boiling water (230 ml) and filtered to give 9-(DL-erythro-2,3,4-trihydroxybutyl) guanine (0.20 g). NMR (DMSO-d6)δ: 7,8 (s,8C-H); 6.4 (NH2); 4.22 (N-CH2).