Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH:12]1[CH:17]([CH3:18])[CH2:16][CH2:15][NH:14][CH2:13]1)[C:3]1[C:4]2[CH:11]=[CH:10][NH:9][C:5]=2[N:6]=[CH:7][N:8]=1.[C:19]([CH2:21][C:22](O)=[O:23])#[N:20].C(N(CC)CC)C.CC(C)(C)C(Cl)=O.[OH-].[Na+].[C:41]([OH:53])(=[O:52])[CH2:42][C:43]([CH2:48][C:49]([OH:51])=[O:50])([C:45]([OH:47])=[O:46])[OH:44]>O.C(Cl)Cl>[C:41]([OH:53])(=[O:52])[CH2:42][C:43]([CH2:48][C:49]([OH:51])=[O:50])([C:45]([OH:47])=[O:46])[OH:44].[CH3:18][C@@H:17]1[CH2:16][CH2:15][N:14]([C:22](=[O:23])[CH2:21][C:19]#[N:20])[CH2:13][C@@H:12]1[N:2]([CH3:1])[C:3]1[C:4]2[CH:11]=[CH:10][NH:9][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: CC1CCNCC1N(C)c1ncnc2[nH]ccc12
Reactant: N#CCC(=O)O
Agent: CC(C)(C)C(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: C[C@@H]1CCN(C(=O)CC#N)C[C@@H]1N(C)c1ncnc2[nH]ccc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 67.2 %

Procedure:
To a clean, dry, nitrogen-purged 500 ml reactor were charged methyl-(4-methyl-piperidin-3-yl)-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine (25.0 g, 0.102 mol) and methylene chloride (250 ml). The mixture was stirred at room temperature for a minimum of 2.5 hours. To a clean, dry, nitrogen-purged 1 L reactor were charged cyanoacetic acid (18.2 g, 0.214 mol), methylene chloride (375 ml), and triethyl amine (30.1 ml, 0.214 mol). The mixture was cooled to −15.0-5.0° C. over one hour and trimethylacetyl chloride (25.6 ml, 0.204 mol) was added at a rate to maintain the temperature below 0° C. The reaction was held for a minimum of 2.5 hours, then the solution of the amine was added at a rate that maintained the temperature below 0° C. After stirring for 1 hour, the mixture was warmed to room temperature and 1M sodium hydroxide (125 ml) was added. The organic layer was washed with water (125 ml) The methylene chloride solution was displaced with acetone until a volume of 500 ml and a temperature of 55-65° C. had been achieved. Water (75 ml) was charged to the mixture while maintaining the temperature at 55-65° C. A solution of citric acid (20.76 g, 0.107 mol) in water (25.0) was charged and the mixture was cooled to room temperature. The reactor was stirred for a minimum of 5 hours and then the resulting solids were isolated by filtration and washed with acetone (2×75 ml), which was sent to the filter. The salt was charged into a clean, dry, nitrogen-purged 1 L reactor with 2B ethanol (190 ml) and water (190 ml). The slurry was heated to 75-85° C. for a minimum of 4 hours. The mixture was cooled to 20-30° C. and stirred for an additional 4 hours. The solids were isolated by filtration and washed with 2B ethanol (190 ml). After drying in a vacuum oven at 50° C. with a slight nitrogen bleed, 34.6 g (67.3%) of the title compound were isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:16](=S)[CH2:17][C:18](=O)[CH3:19])[C@H:13]([C:22]([O:24][CH3:25])=[O:23])[CH2:12]1)(=[O:10])=[O:9].Cl.[O:27]1[CH2:32][CH2:31][CH:30]([NH:33][NH2:34])[CH2:29][CH2:28]1>>[CH3:25][O:24][C:22]([C@@H:13]1[CH2:12][C@@H:11]([S:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])(=[O:9])=[O:10])[CH2:15][N:14]1[C:16]1[N:33]([CH:30]2[CH2:31][CH2:32][O:27][CH2:28][CH2:29]2)[N:34]=[C:18]([CH3:19])[CH:17]=1)=[O:23]
Reactant: NNC1CCOCC1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=S)CC(C)=O
Agent: Cl
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1c1cc(C)nn1C1CCOCC1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-methyl 4-(2-chlorophenylsulfonyl)-1-(3-oxobutanethioyl)pyrrolidine-2-carboxylate (example 253c) was reacted with (tetrahydropyran-4-yl)hydrazine hydrochloride (CAS Reg. No. 194543-22-1) to give the title compound as orange oil. MS (ESI): m/z=468.1 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH3:3].[C:17](N1C=CN=C1)(N1C=CN=C1)=[S:18]>CN(C)C=O>[N:16]([C:13]1[CH:14]=[CH:15][C:10]([N:7]2[CH2:8][CH2:9][N:4]([CH:2]([CH3:1])[CH3:3])[CH2:5][CH2:6]2)=[CH:11][CH:12]=1)=[C:17]=[S:18]
Reactant: CC(C)N1CCN(c2ccc(N)cc2)CC1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC(C)N1CCN(c2ccc(N=C=S)cc2)CC1
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 101.3 %

Procedure:
A solution of 4-[4-(1-methylethyl)-1-piperazinyl]benzenamine (1.6 g, ˜6.8 mmol) (from Step B above) in N,N-dimethylformamide (25 mL) was added dropwise over 20 min to a cooled (−15° C.) solution of thiocarbonyldiimidazole (1.4 g, 7.7 mmol) (Aldrich) in N,N-dimethylformamide (30 mL). After the addition was complete, the mixture was stirred at −15° C. for 20 min, then the cooling bath was removed and the solution was stirred for 1 h. Ice-water was added and the mixture was extracted with ether. The ether layer was dried (MgSO4), filtered, and evaporated to give 1-(4-isothiocyanatophenyl)-4-(1-methylethyl)piperazine (1.8 g, quantitative yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]2.[CH3:20][O:21][C:22]1[CH:32]=[CH:31][CH:30]=[CH:29][C:23]=1[O:24][CH2:25][CH:26]1[CH2:28][O:27]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:28][CH:26]([OH:27])[CH2:25][O:24][C:23]1[CH:29]=[CH:30][CH:31]=[CH:32][C:22]=1[O:21][CH3:20])[C:14](=[O:19])[CH2:13][CH2:12]2
Reactant: O=C1CCc2cc(-c3ccc(F)cc3F)ccc2N1
Reactant: COc1ccccc1OCC1CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1OCC(O)CN1C(=O)CCc2cc(-c3ccc(F)cc3F)ccc21
Yield: 49.3 %

Procedure:
To a solution of 6-(2,4-difluorophenyl)-3,4-dihydroquinolin-2(1H)-one (180 mg, 0.69 mmol) (PT-012, made as in Example 1B, above) and 2-((2-methoxyphenoxy)methyl)oxirane (162 mg, 0.90 mmol) in anhydrous N,N-dimethylformamide (2 ml) was added caesium carbonate (326 mg, 1.00 mmol) in a 5 ml Personal Chemistry microwave reaction vial. The reaction vial was sealed, and subjected to microwave irradiation at 180° C. for 40 minutes. The reaction was cooled, poured into water (10 mL), extracted with ethyl acetate (2×30 mL), and the combined organic phases washed with water (30 mL), 2N sodium carbonate (30 mL), brine (40 mL), dried over sodium sulfate, and the solvent removed under reduced pressure. The residue was subjected to reverse phase HPLC with a gradient of acetonitrile/water (2% to 98%) to afford 6-(2,4-difluorophenyl)-1-(2-hydroxy-3-(2-methoxyphenoxy)propyl)-3,4-dihydroquinolin-2(1H)-one (148 mg, 0.34 mmol, 49%) (compound No. 88)). LCMS mz 440.0 (M+H), 462.0 (M+Na), anal HPLC>95% in purity. 1H NMR (400 MHz; CDCl3) δ 7.46 (d, J=8.6 Hz, 1H); 7.36 (m, 2H); 7.31 (bs, 1H); 6.88-7.03 (m, 6H); 4.36 (m, H); 4.27 (s, 1H), 4.26 (d, J=2.3 Hz, 1H); 4.15 (dd, J=9.8 and 5.5 Hz, 1H); 4.00-4.10 (m, 2H); 3.88 (s, 3H), 2.99 (m, 2H); 2.76 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[CH3:14][O:15][C:16]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH2:19].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:19][CH2:18][C:17]3[CH:20]=[CH:21][CH:22]=[C:23]([O:24][CH3:25])[C:16]=3[O:15][CH3:14])[CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Reactant: COc1cccc(CN)c1OC
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COc1cccc(CNc2ccc3c(=O)[nH]nc(Cl)c3c2)c1OC
Yield: 18.5 %

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (150 mg, 0.578 mmol), 2,3-dimethoxybenzylamine (0.094 mL, 0.636 mmol), Pd2(dba)3 (53 mg, 0.058 mmol), rac-BINAP (112 mg, 0.180 mmol) and NaOtBu (139 mg, 1.445 mmol) in DMA (5 mL) was heated at 85° C. for 2 h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO3, brine and dried (Na2SO4). Chromatography on silica (EtOAc/hexanes) afforded 4-chloro-6-(2,3-dimethoxy-benzylamino)-2H-phthalazin-1-one (37 mg) as an off white solid, 1H (400 MHz, d6-DMSO) δ: 3.79 (s, 3H), 3.80 (s, 3H), 4.40 (d, 2H), 6.83 (s, 1H), 6.88 (dd, 1H), 7.00 (m, 2H), 7.14 (dd, 1H), 7.53 (t, 1H), 7.91 (d, 1H), 12.33 (bs, 1H) ppm; m/z (M+1) 345.92.
Reaction SMILES: [CH2:1]([N:3]([CH2:29][CH3:30])[C:4]([NH:6][CH:7]1[CH2:21][C@H:20]2[C@@H:10]([CH2:11][C:12]3[C:22]4[C:15](=[CH:16][CH:17]=[CH:18][C:19]2=4)[NH:14][C:13]=3[CH:23]2SCCS2)[N:9]([CH3:28])[CH2:8]1)=[O:5])[CH3:2].O.S(Cl)(Cl)(=O)=[O:33].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[CH2:1]([N:3]([CH2:29][CH3:30])[C:4]([NH:6][C@H:7]1[CH2:21][C@H:20]2[C@@H:10]([CH2:11][C:12]3[C:22]4[C:15](=[CH:16][CH:17]=[CH:18][C:19]2=4)[NH:14][C:13]=3[CH:23]=[O:33])[N:9]([CH3:28])[CH2:8]1)=[O:5])[CH3:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCN(CC)C(=O)NC1C[C@@H]2c3cccc4[nH]c(C5SCCS5)c(c34)C[C@H]2N(C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4[nH]c(C=O)c(c34)C[C@H]2N(C)C1
Reaction time: 3 h
Yield: 61 %

Procedure:
Under argon, 2.12 g (5 mmol) of 1,1-diethyl-3-[2-(1,3-dithiolan-2-yl)-6-methyl-8ergolinyl]urea is dissolved in 40 ml of chloroform. Then 3.5 g of silica gel is added and, under vigorous agitation, 3.5 ml of water is introduced dropwise. During a time period of 30 minutes, a solution of 1.18 ml of sulfuryl chloride in 30 ml of chloroform is added dropwise. After 3 hours of agitation at room temperature, 7.5 g of potassium carbonate is added and the mixture vigorously stirred for 20 minutes. The precipitate is filtered off and rinsed with chloroform. The precipitate is moistened with ethanol and introduced into 300 ml of saturated sodium chloride solution which is then repeatedly extracted with chloroform. The chloroform extracts and the chloroform filtrate are dried together over magnesium sulfate and evaporated. Subsequent crystallization takes place from ethyl acetate, thus isolating 1.16 g of 1,1-diethyl-3-(6-methyl-2-formyl-8α-ergolinyl)urea (61% yield).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([F:10])[C:5]([Br:11])=[CH:4][CH:3]=1.F[B-](F)(F)F.[O:17]=[N+:18]=[O:19]>C(#N)C.[Cl-].[Na+].O>[NH2:1][C:2]1[C:3]([N+:18]([O-:19])=[O:17])=[CH:4][C:5]([Br:11])=[C:6]([F:10])[C:7]=1[C:8]#[N:9]
Reactant: O=[N+]=O
Reactant: N#Cc1c(N)ccc(Br)c1F
Agent: F[B-](F)(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: N#Cc1c(N)c([N+](=O)[O-])cc(Br)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 52 %

Procedure:
To a cooled (0° C.) solution of 6-amino-3-bromo-2-fluoro-benzonitrile (8.0 g, 37 mmol) in acetonitrile (40 mL) under nitrogen was added dropwise a solution of nitronium tetrafluoroborate in acetonitrile. The reaction mixture and stirred for 16 h at RT. The reaction mixture was treated with brine and extracted with ethyl acetate. The organic fraction was washed with water followed by brine and dried over anhydrous sodium sulfate, filtered and concentrated. Purification by column chromatography (10 to 20% ethyl acetate:hexanes) afforded 5.0 g (52%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 8.6 (d, J=6.9 Hz, 1H), 6.8-7.1 (br. s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)[CH:6]=[C:5]2[C:17]([OH:19])=O.CCN=C=NCCCN(C)C.Cl.[CH:32]1[CH:33]=C[C:35]2[N:40](O)N=[N:38][C:36]=2[CH:37]=1.NC1C=NC=CC=1>CN(C=O)C.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)[CH:6]=[C:5]2[C:17]([NH:38][C:36]1[CH:35]=[N:40][CH:33]=[CH:32][CH:37]=1)=[O:19]
Reactant: O=C(O)c1cc(-c2ccco2)nc2ccc(Br)cc12
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Nc1cccnc1)c1cc(-c2ccco2)nc2ccc(Br)cc12
Reaction time: 0.08 h
Yield: 32.3 %

Procedure:
To a 250 ml three necked round bottom flask equipped with thermo pocket under argon atmosphere was added 6-bromo-2-(furan-2-yl)quinoline-4-carboxylic acid (5 g) in DMF (15 ml). The solution was stirred for 5 minutes. After 5 minutes, EDAC.HCl (N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride) (3.6 g), HOBT (2.54 g) and DMAP (3.83 g) were added at RT and the reaction mixture was stirred at room temperature for 0.5 h. 3-amino pyridine (1.6 g) was then added in one lot and the reaction was allowed to stir at RT for 12 hours. The completion of the reaction was monitored by TLC using ethyl acetate:hexanes (5:5) as a mobile phase. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (100 ml) and then washed with water (5×100 ml). The ethyl acetate layer was dried over anhydrous sodium sulphate and then solvent was distilled out and the crude was subjected to purification by silica gel column chromatography, eluting with 1.5% methanol in methylene chloride to provide 6-bromo-2-(furan-2-yl)-N-(pyridin-3-yl)quinoline-4-carboxamide (2.0 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21].N1C2[C:25](=[CH:26]C=CC=2)[C:24]2(COC3C=C4C(=C[C:31]2=3)CCO4)[C:23]1=O.BrCCCCC.ClCC1C=NC(OC)=NC=1>>[C:24]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21])([CH2:25][CH3:26])([CH3:31])[CH3:23]
Reactant: O=C1Nc2ccccc2[C@@]12COc1cc3c(cc12)CCO3
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Agent: COc1ncc(CCl)cn1
Solvent: CCCCCBr
Product: CCC(C)(C)N1C(=O)[C@]2(COc3cc4c(cc32)CCO4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 5 and making non-critical variations using (3R)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and 1-bromopentane to replace 5-(chloromethyl)-2-methoxypyrimidine, (3R)-t-pentyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (78%) as a colorless solid: mp 128-129° C. (diethyl ether); 1H NMR (300 MHz, CDCl3) δ7.33-7.26 (m, 1H), 7.17 (d, J=7.1 Hz, 1H), 7.07-7.02 (m, 1H), 6.91 (d, J=7.8 Hz, 1H), 6.49 (s, 1H), 6.41 (s, 1H), 4.92 (d, J=8.9 Hz, 1H), 4.67 (d, J=8.9 Hz, 1H), 8.64 (t, J=4.5 Hz, 2H), 3.87-3.63 (m, 2H), 2.99 (t, J=4.5 Hz, 2H), 1.79-1.69 (m, 2H), 1.40-1.35 (m, 4H), 0.94-0.89 (m, 3H); 13C NMR (75 MHz, CDCl3) δ177.5, 161.6, 161.2, 142.4, 133.0, 128.6, 123.8, 123.0, 120.3, 119.7, 118.7, 108.4, 93.1, 80.5, 72.3, 57.6, 40.3, 29.0, 27.1, 22.3, 13.9; MS (ES+) m/z 349.9 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16]([NH2:18])=[S:17])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:20](I)[CH2:21][CH2:22][CH3:23]>>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16](=[NH:18])[S:17][CH2:20][CH2:21][CH2:22][CH3:23])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1cccc(NC(N)=S)c1
Reactant: CCCCI
Product: CCCCSC(=N)Nc1cccc(CNC(=O)OC(C)(C)C)c1
Yield: 92 %

Procedure:
Using the compound obtained in Example 24 as a starting material and also using n-butyl iodide as a reagent, reaction was performed as in Example 29 to give 220 mg of the titled compound (yield, 92%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:13][C:12]2[CH2:11][CH2:10][N:9]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8][C:7]=2[C:6]=1[OH:21])=[O:4].[CH2:22]1[CH2:32]CN2C(=NCCC2)C[CH2:23]1.BrC(C)C.C(O)(=O)C>O1CCCC1.CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:13][C:12]2[CH2:11][CH2:10][N:9]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:8][C:7]=2[C:6]=1[O:21][CH:22]([CH3:32])[CH3:23])=[O:4]
Reactant: C1CCC2=NCCCN2CC1
Reactant: COC(=O)c1sc2c(c1O)CN(C(=O)OC(C)(C)C)CC2
Solvent: CC(C)Br
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)c1sc2c(c1OC(C)C)CN(C(=O)OC(C)(C)C)CC2
Temperature: 82 °C
Reaction time: 2.5 h
Yield: 68.4 %

Procedure:
To a solution of 10.96 g (0,035 mol) of 2-methoxycarbonyl-3-hydroxy-5-tert-butoxycarbonyl-6,7-dihydro-4H-thieno[3,2-c]pyridine (prepared as described in Preparation 6) in 125 mL of tetrahydrofuran were added 8.14 g (0.0535 mol) of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene and 6.55 g (0.053 mol) of 2-bromopropane. The solution was heated at reflux for 4 hours. An additional 3.28 g (0.0266 mol) of 2-bromopropane and 4.07 g (0.0268 mol) of DBU dissolved in 75 mL of DMF were added, and the reaction mixture was stirred at 82° C. for 2.5 hours, cooled to 24° C., and stirred for 3 days. The reaction mixture was added to 550 g of ice water containing 10 mL of glacial acetic acid. The aqueous mixture was extracted four times with 100 mL portions of diethyl ether. The ethereal extracts were combined, washed with saturated aqueous sodium bicarbonate, with water and brine, dried over sodium sulfate, and the solvent was removed by evaporation under reduced pressure to afford 13 g of crystalline 2-methoxycarbonyl-3-isopropoxy-5-tert-butoxycarbonyl-6,7-dihydro-4H-thieno[3,2-c]pyridine, mp 76°-81° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[CH:2]1.[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(Cl)Cl.O>CCOCC>[C:10]([C:5]1[NH:1][CH:2]=[C:3]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)c1cc[nH]c1
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)c1c[nH]c(C(=O)c2ccccc2)c1
Reaction time: 0.25 h
Yield: 69.8 %

Procedure:
Under nitrogen, methyl pyrrole-3-carboxylate (5 g., 40 mmoles) was combined with benzoyl chloride (4.8 ml., 40 mmoles) and stannic chloride (9.2 ml. 80 mmoles) in 75 ml. of methylene chloride and stirred for 3 hours at room temperature. Ice and water (50 ml.) was added slowly and stirring continued for an additional 15 minutes. Ether (150 ml.) was then added and, after equilibration, the phases separated. The upper, organic phase was washed sequentially with 50 ml. of water, 50 ml. of 1 N sodium hydroxide and 50 ml. of water, and evaporated to dryness to yield crude product (6.4 g. of solid). Recrystallization from acetonehexane gave purified methyl 5-benzoylpyrrole-3-carboxylate (4.1 g., Rf 0.4 on silica gel thin layer chromatography eluted with ethyl acetate-1/hexane-5/5% acetic acid).
Reaction SMILES: ClCl.BrBr.N([O-])=O.[Na+].ClC1SC2C=C(Cl)C=CC=2N=1.Cl[C:21]1[CH:30]=[CH:29][C:24]2[N:25]=[C:26]([NH2:28])[S:27][C:23]=2[CH:22]=1.ClC1SC2C=C([F:41])C=CC=2N=1>>[F:41][C:21]1[CH:30]=[CH:29][C:24]2[N:25]=[C:26]([NH2:28])[S:27][C:23]=2[CH:22]=1
Reactant: Nc1nc2ccc(Cl)cc2s1
Reactant: Fc1ccc2nc(Cl)sc2c1
Agent: BrBr
Agent: ClCl
Agent: Clc1ccc2nc(Cl)sc2c1
Product: Nc1nc2ccc(F)cc2s1

Procedure:
The starting compounds of the formula III wherein X is chlorine or bromine can be prepared from corresponding 2-benzothiazole-amines by reaction with a warm concentrated hydrohalic acid and sodium nitrite [See H. Mazzone and G. Pappalardo, Il Farmaco, Ed. Sc. 32, 348-354 (1977)]. Thus, for example, 2,6-dichlorobenzothiazole (m.p. 99°-101° C.) can be obtained from 6-chloro-2-benzothiazole-amine, and 2-chloro-6-fluorobenzothiazole (m.p. 92°-93° C.) can be obtained from 6-fluoro-2-benzothiazole-amine.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[NH2:10][CH2:11][C:12]1[N:20]=[C:19]2[C:15]([N:16]=[CH:17][N:18]2[C@H:21]2[C@H:25]([OH:26])[C@H:24]([OH:27])[C@@H:23]([CH2:28][O:29][CH3:30])[O:22]2)=[C:14]([NH:31][CH2:32][CH:33]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:13]=1.C(N(CC)CC)C.CCCCC>CN1CCCC1=O>[OH:26][C@@H:25]1[C@H:24]([OH:27])[C@@H:23]([CH2:28][O:29][CH3:30])[O:22][C@H:21]1[N:18]1[CH:17]=[N:16][C:15]2[C:19]1=[N:20][C:12]([CH2:11][NH:10][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1)=[N:13][C:14]=2[NH:31][CH2:32][CH:33]([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Solvent: CCCCC
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNc4ccc(C#N)cn4)nc32)[C@H](O)[C@@H]1O
Temperature: 120 °C
Yield: 15.6 %

Procedure:
6-Chloronicotinonitrile (78 mg, 0.56 mmol) was added to a stirred solution of (2R,3R,4S,5R)-2-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino}-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (250 mg, 0.51 mmol) (example 1) and triethylamine (57 mg, 0.56 mmol) in N-methyl-2-pyrrolidinone (10 ml). The reaction mixture was heated at 120° C. for 24 hr. The reaction mixture was then partitioned between water and ethyl acetate. The ethyl acetate layer was separated, washed with brine and dried with anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give a residue that was purified by column chromatography on silica gel eluting with a solvent system of dichloromethane:methanol (95:5) to give material that was still impure and hence re-purified by column chromatography on silica gel eluting with a solvent system of ethyl acetate:methanol (90:10) to give a yellow oil which was treated with pentane to give the title compound (47 mg) as a solid. MS: 594 (MH+).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([F:10])[C:7]([F:11])=[C:6]([F:12])[CH:5]=1)=O.[CH2:13]([CH2:15][NH2:16])[OH:14]>C1(C)C=CC=CC=1>[F:12][C:6]1[CH:5]=[C:4]([CH:2]([NH:16][CH2:15][CH2:13][OH:14])[CH3:1])[CH:9]=[C:8]([F:10])[C:7]=1[F:11]
Reactant: CC(=O)c1cc(F)c(F)c(F)c1
Reactant: NCCO
Solvent: Cc1ccccc1
Product: CC(NCCO)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.2 %

Procedure:
A mixture of 3,4,5-trifluoroacetophenone (2.0 g), ethanolamine (2.0 g), and toluene (20 mL) was heated under reflux in a Dean-Stark apparatus for 2.5 hours. The reaction solution was concentrated under reduced pressure, and then the residue was diluted with ethanol (30 mL) and sodium borohydride (1.0 g) was added under ice-cooling. The mixture was stirred at room temperature for three hours and then diluted with a 2 N sodium hydroxide solution and chloroform. Thereafter, the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography using a silica gel (chloroform:methanol=50:1 to 5:1) to obtain 860 mg of the title compound.
Reaction SMILES: Br[C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]2[C:5]([NH:6][C:7]([CH3:18])([CH3:17])[C:8](=[O:16])[NH:9]2)=[CH:4][CH:3]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O.C(=O)([O-])[O-].CN(C)C=O>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.O.C(OCC)(=O)C>[CH3:15][O:14][C:12]([C:11]1[C:2]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[O:20][CH3:19])=[CH:3][CH:4]=[C:5]2[C:10]=1[NH:9][C:8](=[O:16])[C:7]([CH3:18])([CH3:17])[NH:6]2)=[O:13]
Reactant: COc1ccccc1B(O)O
Reactant: COC(=O)c1c(Br)ccc2c1NC(=O)C(C)(C)N2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1c(-c2ccccc2OC)ccc2c1NC(=O)C(C)(C)N2
Temperature: 80 °C
Reaction time: 48 h
Yield: 53.3 %

Procedure:
A mixture of 7-bromo-8-methoxycarbonyl-3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 1, 203 mg, 0.64 mmol), 2-methoxyphenylboronic acid (196 mg, 1.28 mmol), cessium carbonate (629 mg, 1.92 mmol) and bis(triphenylphosphine)palladium dichloride (II) (45.8 mg, 0.06 mmol) was suspended with anhydrous N,N-dimethylformamide (3 ml) and stirred at 80° C. for 2 days. After the mixture was cooled down, ethyl acetate (30 mL) and water (30 mL) were added thereto and the mixture was partitioned. The organic layer was washed with water (30 mL) and saturated brine (30 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (116 mg) as a pale yellow amorphous product. (Yield 31%)