Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([C:20](=[O:29])[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[C:7]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:8]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:10]=1.II.FC(F)(F)C(O[I:37](C1C=CC=CC=1)OC(=O)C(F)(F)F)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl.O>[CH3:14][O:13][CH2:12][O:11][C:9]1[C:8]([I:37])=[C:7]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:6]([C:20](=[O:29])[C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)=[C:5]([O:4][CH2:3][O:2][CH3:1])[CH:10]=1
Reactant: COCOc1cc(CC(=O)OC)c(C(=O)c2ccc(OC)cc2)c(OCOC)c1
Reactant: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Agent: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COCOc1cc(OCOC)c(C(=O)c2ccc(OC)cc2)c(CC(=O)OC)c1I
Temperature: -30 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
Methyl 3,5-bis(methoxymethoxy)-2-(4-methoxybenzoyl)-phenylacetate (0.75 g, 1.9 mmol) obtained in Example 134, Step 2 was dissolved in dichloromethane (20 mL). The resulting solution was cooled to −30° C., and iodine (0.47 g, 1.9 mmol) and [bis(trifluoroacetoxy)iodo]benzene (0.8 g, 1.9 mmol) were successively added thereto in an atmosphere of argon, followed by stirring for 2 hours. To the reaction mixture was added a saturated aqueous solution of sodium thiosulfate, and the mixture was further stirred for one hour, while the temperature was raised to room temperature. To the reaction mixture was added water for liquid separation, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/4-1/2) to obtain methyl 3,5-bis(methoxymethoxy)-2-iodo-6-(4-methoxybenzoyl)phenylacetate (0.95 g, 96%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:20][CH2:19][C:13]3([NH:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C=O.Cl[CH2:24]CCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[CH3:24][N:18]1[C:13]2([CH2:19][CH2:20][N:10]([C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH2:11][CH2:12]2)[CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: ClCCCl
Reactant: O=[N+]([O-])c1ccc(N2CCC3(CCCCN3)CC2)cc1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Product: CN1CCCCC12CCN(c1ccc([N+](=O)[O-])cc1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 9-(4-nitrophenyl)-1,9-diazaspiro[5.5]undecane (680 mg), 37% aqueous formaldehyde solution (1 mL), and 1,2-dichloroethane (10 mL) was added sodium triacetoxyborohydride (1.57 g), followed by stirring at room temperature overnight. To the reaction mixture were added water and a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform twice. The extract was dried over anhydrous sodium sulfate and then the solvent was evaporated under reduced pressure to obtain 1-methyl-9-(4-nitrophenyl)-1,9-diazaspiro[5.5]undecane (0.68 g) as a yellow solid.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:24])[CH2:15][NH:16]CC1C=CC=CC=1)[CH3:3]>CO.[Pd]>[CH3:3][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:11])[CH3:12])[C:5]=1[NH:13][C:14](=[O:24])[CH2:15][NH2:16])[CH3:1]
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CNCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CN
Reaction time: 20 h
Yield: 80.2 %

Procedure:
To a solution of N-[2,6-bis(1-methylethyl)phenyl]-2-[(phenylmethyl)amino]acetamide (Example V) (0.80 g, 2.5 mmol) in methanol (10 mL) is added 20% Pd/C (0.1 g). The mixture is stirred under an atmosphere of hydrogen for 20 hours. After filtration and concentration, flash chromatography (ethyl acetate) affords 0.47 g of the title compound as a white solid; mp 88°-95° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[S:12][C:13]([Br:16])=[CH:14][CH:15]=2)=[O:10])=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].C([O-])([O-])=O.[K+].[K+].[SH:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1>CN(C=O)C.O>[OH:33][C:30]1[CH:31]=[CH:32][C:27]([S:26][C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]3[S:12][C:13]([Br:16])=[CH:14][CH:15]=3)=[O:10])=[CH:4][C:3]=2[N+:17]([O-:19])=[O:18])=[CH:28][CH:29]=1
Reactant: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1ccc(Br)s1
Reactant: Oc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Sc2ccc(O)cc2)c([N+](=O)[O-])c1)c1ccc(Br)s1
Temperature: 80 °C
Yield: 78.6 %

Procedure:
The product of Example 241b (1.50 g, 4.34 mmol) was dissolved in DMF to which K2CO3 (1.20 g, 8.69 mmol), and 4-mercapto-phenol (548 mg, 4.34 mmol) were added. The reaction mixture was then heated to 80° C. for 2 hrs. At this point the reaction mixture was cooled to room temperature and diluted with water which was then extracted with ethyl acetate to isolate the desired compound (1.54 g, 78%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=1[N+:16]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[Sn]Cl>CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=1[NH2:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(OCc2ccccc2)c1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Product: Cc1cccc(OCc2ccccc2)c1N
Temperature: 80 °C

Procedure:
To a stirred solution of 1-benzyloxy-3-methyl-2-nitrobenzene (5.0 g, 20.6 mmol) in EtOAc (150 mL) is added SnCl2 (23.2 g, 103 mmol) and the suspension is heated at 80° C. overnight. The suspension is filtered and the filtrate washed with sat. NaHCO3 and extracted with EtOAc. The combined organic layers are washed with water, brine, then dried over MgSO4 and filtered. The solvent is removed under reduced pressure and the residue is purified by flash chromatography (hexanes/EtOAc=10:1 to 5:1) to give the title compound as a yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:5])[CH:3]=O.S(Cl)(Cl)=O.ClCCCl.[NH:14]1[C:23](=[O:24])[C:22]2[NH:21][CH:20]=[N:19][C:18]=2[N:17]=[C:15]1[NH2:16]>O>[CH3:1][N:2]([CH:5]=[N:16][C:15]1[NH:14][C:23](=[O:24])[C:22]2[NH:21][CH:20]=[N:19][C:18]=2[N:17]=1)[CH3:3]
Reactant: CN(C)C=O
Reactant: Nc1nc2nc[nH]c2c(=O)[nH]1
Solvent: ClCCCl
Solvent: O
Solvent: O=S(Cl)Cl
Product: CN(C)C=Nc1nc2nc[nH]c2c(=O)[nH]1
Temperature: 80 °C
Reaction time: 6 h
Yield: 85 %

Procedure:
131.6 g (1.8 mol) of N,N-dimethylformamide and 42.8 g (0.36 mol) of thionyl chloride were added to 500 ml of 1,2-dichloroethane, and then 45.3 g (0.3 mol) of guanine (manufactured by Sumika Fine Chemicals Co., Ltd.) was added, followed by stirring at 80° C. for 6 hours. After cooling, the reaction mixture was added to 1000 ml of water to separate out the water layer, and then the water layer was neutralized with sodium hydrogen carbonate. The precipitating crystal was collected by filtration and washed with 100 ml of water to yield 52.6 g (0.255 mol) of a white crystal of N-dimethylaminomethyleneguanine (yield 85%).
Reaction SMILES: [CH:1]1[C:10]2[CH:11]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13][CH:12]3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1[C:10]2[CH:11]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13][CH:12]3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC2c3cccc4c3N(CCC4)C2CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cc2c3c(c1)C1CCNCCC1N3CCC2
Temperature: 20 °C
Reaction time: 3 h
Yield: 59 %

Procedure:
To a solution of tert-butyl (±)-5,6,8,9,10,11,12,12a-octahydro-4H,7aH-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline-10-carboxylate in CH2Cl2 (2.4 mL) was added TFA (0.6 mL). This was stirred at 20° C. for 3 h. The reaction mixture was diluted with CH2Cl2 (50 mL) and washed with saturated NaHCO3 (50 mL) and brine (50 mL), dried over MgSO4 and concentrated in vacuo to afford the title compound as a yellow oil (87 mg, 59%). 1H NMR (CDCl3, 300 MHz) δ 1.77-2.13 (m, 7H), 2.56-2.79 (m, 5H), 2.83-2.93 (m, 1H), 3.00-3.16 (m, 2H), 3.33-3.41 (td, 1H, J=3.7, 9.2 Hz), 3.60 (td, 1H, J=4.4, 9.1 Hz), 6.50 (t, 1H, J=7.3 Hz), 6.76 (t, 2H, 8.0 Hz) ppm.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:28](O)=[O:29])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:31]([O:38][CH2:39][CH2:40][NH:41][CH:42]1[CH2:45][O:44][CH2:43]1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.O>[Si:31]([O:38][CH2:39][CH2:40][N:41]([CH:42]1[CH2:45][O:44][CH2:43]1)[C:28]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:14]([OH:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:18][CH2:19][CH2:20][CH2:21]2)[N:11]=1)=[O:29])([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]
Reactant: O=C(O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OCCNC1COC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)OCCN(C(=O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1)C1COC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
To a stirred solution mixture of 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (283) (158 mg, 0.39 mmol) and [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-oxetan-3-yl-amine (8 g) (104 mg, 0.47 mmol) in dimethylformamide (3 mL) were added N,N-diisopropylethylamine (0.2 mL, 1.17 mmol) and HATU (222 mg, 0.59 mmol). The reaction mixture was stirred at room temperature for 1 h, followed by the addition of water (50 mL). the mixture was extracted with ethyl acetate (3×20 mL) and the combined organic part was washed with water (3×50 mL) and brine (2×30 mL) and dried and concentrated. The crude product was purified by Combi-Flash column (eluted at 20-30% ethyl acetate in hexane) to get 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-oxetan-3-yl-amide (296) (240 mg, 99.43%) as a yellow gummy mass.
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH3:10])[CH2:3][O:4]/[CH:5]=[CH:6]/[C:7](=[O:9])[CH3:8].C(N(CC)CC)C.FC(F)(F)S(O[Si:25]([CH3:28])([CH3:27])[CH3:26])(=O)=O.C(=O)(O)[O-].[Na+]>C(OCC)C.C(Cl)(Cl)(Cl)Cl>[CH3:1][C:2]([CH3:11])([CH3:10])[CH2:3][O:4]/[CH:5]=[CH:6]/[C:7](=[CH2:8])[O:9][Si:25]([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(=O)/C=C/OCC(C)(C)C
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: C=C(/C=C/OCC(C)(C)C)O[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 102.2 %

Procedure:
(E)-4-(2,2-dimethylpropoxy)but-3-en-2-one (14 g, 90 mmol) and triethylamine (10 g, 101 mmol) were combined in ethyl ether (200 mL). Trimethylsilyl trifluoromethanesulfonate (20 g, 90 mmol) (Aldrich) in carbon tetrachloride (30 mL) was added at −5° C. over 0.5 hr. This was stirred for 0.5 hr at 0° C. This was poured into cold 5% sodium bicarbonate (50 mL) and the organics were extracted into hexane. This was washed with saturated aqueous sodium chloride, dried (MgSO4), and evaporated to give 21 g of [(E)-3-(2,2-dimethylpropoxy)-1-methylene-allyloxy]trimethylsilane.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([S:9](Cl)(=[O:11])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.Cl.[CH3:23][CH:24]1[CH:29]=[C:28]([CH3:30])[CH:27]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[O:26][NH:25]1>ClCCl>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([S:9]([N:25]2[CH:24]([CH3:23])[CH:29]=[C:28]([CH3:30])[CH:27]([C:31]3[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=3)[O:26]2)(=[O:11])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(C2ONC(C)C=C2C)cc1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C2ON(S(=O)(=O)c3ccc(NC(C)=O)cc3)C(C)C=C2C)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred suspension of 4-N-acetylsulphanilyl chloride (2.7 g, 11.55 mmol) and triethylamine (1.95 g, 19.25 mmol) in dichloromethane (50 ml) was added portionwise solid 3,6-dihydro-3,5-dimethyl-6-(4-methoxyphenyl)-2H-1,2-oxazine hydrochloride (1.97 g, 7.70 mmol). The resulting solution was stirred at room temperature for 5 h then washed with water three times, aqueous sodium hydroxide (2M), water and brine. The organic phase was dried over magnesium sulphate, filtered and evaporated, the resulting foam was purified on flash silica eluting with ethylacetate-hexane (3:2) to give 2-(4-acetamidobenzenesulphonyl)-3,6-dihydro-3,5-dimethyl-6-(4-methoxyphenyl)-2H-1,2-oxazine as a white foam. 1H NMR (CDCl3) δ 1.39(3H,s), 1.41(3H, d), 2.20(3H, s), 3.79(3H, s), 4.45(1H, m), 5.19(1H, s), 5.68(1H, d), 6.80(2H, d), 7.13(2H, d), 7.57(1H, bs), 7.59(2H, d), 7.80(2H, d).
Reaction SMILES: [CH:1]1[CH:10]=[C:9]2[C:11]([O:13][C:14](=O)[C:7]3=[C:8]2[C:3](=[C:4]([N+:16]([O-:18])=[O:17])[CH:5]=[CH:6]3)[CH:2]=1)=[O:12].Cl.[NH2:20][OH:21]>N1C=CC=CC=1>[OH:21][N:20]1[C:14](=[O:13])[C:7]2[CH:6]=[CH:5][C:4]([N+:16]([O-:18])=[O:17])=[C:3]3[C:8]=2[C:9](=[CH:10][CH:1]=[CH:2]3)[C:11]1=[O:12]
Reactant: NO
Reactant: O=C1OC(=O)c2ccc([N+](=O)[O-])c3cccc1c23
Agent: Cl
Solvent: c1ccncc1
Product: O=C1c2cccc3c([N+](=O)[O-])ccc(c23)C(=O)N1O
Yield: 72.4 %

Procedure:
4-Nitro-1,8-naphthalic anhydride (2.61 g, 10.7 mmol) and hydroxylamine hydrochloride (1.5 g, 21.4 mmol) were reacted in pyridine (50 mL) following the procedure of Example 1. The crude product was recrystallized from ethanol to give 2.0 g of the title compound, mp 255-260° C.;
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([F:15])[C:9]=1[CH:16]([C:22](OCC)=[O:23])[C:17](OCC)=[O:18].C(N(CCCC)CCCC)CCC>[OH-].[Na+]>[OH:18][C:17]1[C:16]([C:9]2[C:10]([F:15])=[CH:11][C:12]([F:14])=[CH:13][C:8]=2[F:7])=[C:22]([OH:23])[N:3]2[N:4]=[CH:5][CH:6]=[C:2]2[N:1]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1c(F)cc(F)cc1F
Reactant: Nc1cc[nH]n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCN(CCCC)CCCC
Product: Oc1nc2ccnn2c(O)c1-c1c(F)cc(F)cc1F
Temperature: 175 °C
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
A mixture of 3-amino-pyrazole (0.06 mol), diethyl (2,4,6-trifluorophenyl)-malonate (0.06 mol, obtained from Example 1) and tributylamine (30 ml) was heated with reflux at 175° C. for four hours. The reaction mixture was cooled to 100° C. Aqueous sodium hydroxide (10.3 g/120 ml H2O) was added and the reaction mixture was stirred for 30 min. and cooled to ambient temperature. The organic Phase was separated off and the aqueous Phase was extracted with diethylether. The aqueous Phase was acidified with concentrated hydrochloric acid. The precipitate was collected by filtration and dried to yield 15.7 g (93 %) of the pale yellow product having a melting point of 280° C.
Reaction SMILES: [F:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH3:8])[O:4][C@H:3]1N1C=CC(=O)NC1=O.[Cl:17][C:18]1[C:26]([Cl:27])=[CH:25][C:21]2[N:22]=[CH:23][NH:24][C:20]=2[CH:19]=1>C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O>[Cl:27][C:26]1[C:18]([Cl:17])=[CH:19][C:20]2[N:24]([C@@H:3]3[O:4][C@H:5]([CH3:8])[C@@H:6]([OH:7])[C@H:2]3[F:1])[CH:23]=[N:22][C:21]=2[CH:25]=1
Reactant: C[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](F)[C@@H]1O
Reactant: Clc1cc2nc[nH]c2cc1Cl
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Product: C[C@H]1O[C@@H](n2cnc3cc(Cl)c(Cl)cc32)[C@H](F)[C@@H]1O
Temperature: 80 °C
Reaction time: 648 h

Procedure:
2′,5′-Dideoxy-2′-fluorouridine (1.1 g, 4.8 mmoles) was dissolved in 950 mL of 50 mmoler pH 6.0 citrate buffer. 5,6-Dichlorobenzimidazole (Townsend and Revankar, Chem. Rev. 1970, 70:389) (0.53 g, 2.9 mmoles) was added followed by 71,250 units of N-deoxyribofuranosyl transferase (Freeman, et.al, Bioorg. & Med. Chem. 1995, 3(4):447-58). The reaction was placed in a 50° C. water bath and gently shaken for 27 days. The enzyme was precipitated by heating to 80° C. then cooling to room temperature. Celite (50-60 g) was added and the reaction filtered. The product was extracted with ethyl acetate (3×). The ethyl acetate was removed in vacuo and the residue purified by chromatography on 75 g of silica gel eluted with ethyl acetate. The product containing fractions were combined and the solvents removed in vacuo. The yield was 0.5 g, 56%. MS (APCl(+)): m/z, 305; 1H NMR (DMSO-d6) δ8.51 (s, 1H, H-2), 8.03 (s,1H, Ar—H), 7.98 (s,1H, Ar—H), 6.32 (d,1H, H-1′, J=18 Hz), 5.72 (d, 1H, OH-3′, J=6 Hz), 5.34 (d, 1H, H-2′, J=53 Hz), 4.0 (m, 2H,), 1.32 (d, 3H, H-5′, J=4 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][C:7]2[C:8](=[O:27])[NH:9][C:10]3[C:15]([C:16]=2[CH3:17])=[C:14](OS(C(F)(F)F)(=O)=O)[CH:13]=[C:12]([CH3:26])[CH:11]=3)=[CH:4][CH:3]=1.[Si]([O:37][C:38]([O:40][CH3:41])=[CH2:39])(C(C)(C)C)(C)C.C([O-])(=O)C.[Na+]>CN(C)C=O.C(OCC)(=O)C.[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:41][O:40][C:38](=[O:37])[CH2:39][C:14]1[CH:13]=[C:12]([CH3:26])[CH:11]=[C:10]2[C:15]=1[C:16]([CH3:17])=[C:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:29][CH:28]=1)[C:8](=[O:27])[NH:9]2
Reactant: Cc1cc(OS(=O)(=O)C(F)(F)F)c2c(C)c(Cc3ccc(Cl)cc3)c(=O)[nH]c2c1
Reactant: C=C(OC)O[Si](C)(C)C(C)(C)C
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1cc(C)cc2[nH]c(=O)c(Cc3ccc(Cl)cc3)c(C)c12
Temperature: 120 °C

Procedure:
A mixture of trifluoromethanesulfonic acid 3-(4-chlorobenzyl)-4,7-dimethyl-2-oxo-1,2-dihydroquinolin-5-yl ester (1.1 g), 1-(tert-butyldimethylsilyloxy)-1-methoxyethene (2.7 mL), sodium acetate (0.25 g), bis(dibenzylideneacetone) palladium (0.07 g) and 1,1′-bis(diphenylphospino) ferrocene (0) (0.07 g) in N,N-dimethylformamide (15.0 mL) was heated by microwave irradiation at 120° C. for 15 minutes. The mixture was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride solution, water and saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel, eluting with a mixture of ethyl acetate and dichloromethane (0:1 to 1:3 by volume) gave title compound as a pale orange oil, 1.75 g.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]([OH:15])=O)[N:3]=1.Cl.C([O:21][C:22](=[O:31])[C@@H:23]([NH2:30])[CH2:24][O:25]C(C)(C)C)(C)(C)C>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]([NH:30][C@@H:23]([CH2:24][OH:25])[C:22]([OH:31])=[O:21])=[O:15])[N:3]=1
Reactant: CC(C)(C)OC[C@H](N)C(=O)OC(C)(C)C
Reactant: O=C(O)c1nc(Cl)c2ccccc2c1O
Agent: Cl
Product: O=C(N[C@@H](CO)C(=O)O)c1nc(Cl)c2ccccc2c1O

Procedure:
Prepared in analogy to Example A-2 e) and f) from 1-chloro-4-hydroxy-isoquinoline-3-carboxylic acid from Example A-2 d) and (S)-2-amino-3-tert-butoxy-propionic acid tert-butyl ester hydrochloride; MS-(+)-ion: M+1=310.9 amu.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[Li]CCCC.CCCCCC.[O:20]=[C:21]1[CH2:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23][CH2:22]1>CCOCC.O>[Br:8][C:4]1[N:3]=[C:2]([C:21]2([OH:20])[CH2:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[CH2:23][CH2:22]2)[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)n1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)CC1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCCC(O)(c2cccc(Br)n2)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 64.1 %

Procedure:
To a solution of 2,6-dibromopyridine (0.2 g, 0.84 mmol) in Et2O (20 mL) at −78° C. was added 2.5 M solution of n-BuLi in hexane (3.7 mL, 0.928 mmol) over 30 min. The mixture was stirred at −78° C. for 30 minutes. To it was dropped tert-butyl 4-oxoazepane-1-carboxylate (180 mg, 084 mmol) in Et2O (20 mL) over 15 minutes. After the mixture was stirred for one hour, to it was added H2O (100 mL). The aqueous layer was extracted with EtOAc (100 mL×2). The combined organic layers were washed with 10% solution of NaOH and brine, dried over MgSO4, concentrated under reduced pressure. The crude product was purified by silica gel chromatography using petroleum ether/EtOAc (9:1) as eluting solvents to afford tert-butyl 4-(6-bromopyridin-2-yl)-4-hydroxyazepane-1-carboxylate as an oil (200 mg, 62.5%). MS (ESI) m/z: 371 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:3]([Cl:16])=[N:4][C:5]2[CH:6]=[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]3=[CH:9][C:10]=2[N:11]=1.[CH2:17]([NH2:20])[C:18]#[CH:19]>O1CCOCC1>[Cl:16][C:3]1[C:2]([NH:20][CH2:17][C:18]#[CH:19])=[N:11][C:10]2[CH:9]=[C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]3=[CH:6][C:5]=2[N:4]=1
Reactant: C#CCN
Reactant: Clc1nc2cc3ccccc3cc2nc1Cl
Solvent: C1COCCO1
Product: C#CCNc1nc2cc3ccccc3cc2nc1Cl
Yield: 72.7 %

Procedure:
A mixture of 2,3-dichlorobenzo[g]quinoxaline (0.634 g, 2.55 mmol), propargylamine (0.21 ml, 3.05 mmol) and TEA (0.53 mL, 3.83 mmol) in 15 mL of dioxane was heated to reflux for 4.5 hours. After evaporating the resulting mixture under vacuum, the crude product was chromatographed (CH2Cl2) to afford the title compound as a yellow solid (0.496 g, 73%); mp 169-172° C.; IR (KBr, cm−1) 3412, 3283, 3235, 1570, 1508, 1335; 1H NMR (DMSO) δ 8.44 (s, 1H), 8.26 (s, 1H), 8.16-8.06 (m, 3H), 7.58-7.54 (m, 1H), 7.51-7.48 (m, 1H), 4.28 (dd, J=6.1, 2.5, 2H), 3.12 (t, J=2.5, 1H); LC/MS 97.8% (220 nm), m/z (M+H+) 268.
Reaction SMILES: [Cl:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N:11]=[C:12]=[S:13])[NH:4][C:3]1=O.C1C=C(OC(OC2N=CC=CC=2)=S)N=CC=1.NC1C=CC=C2C=1C(Cl)=CN2>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N:11]=[C:12]=[S:13])[NH:4][CH:3]=1
Reactant: O=C1Nc2cccc(N=C=S)c2C1Cl
Agent: CN(C)c1ccncc1
Agent: Nc1cccc2[nH]cc(Cl)c12
Agent: S=C(Oc1ccccn1)Oc1ccccn1
Solvent: ClCCl
Product: S=C=Nc1cccc2[nH]cc(Cl)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
3-Chloro-4-isothiocyanatooxindole. 4-Dimethylaminopyridine (0.031 g, 0.256 mmol) and di-2-pyridyl thionocarbonate (0.983 g, 4.23 mmol) are added to a solution of 4-amino-3-chloroindole (0.655 g, 2.82 mmol) in methylene chloride. The resulting mixture is stirred at room temperature for 1 hour. The volatile organics are removed by rotary evaporation and the crude residue is purified via silica gel column chromatography using 20% ethyl acetate/hexanes as the eluent. The appropriate fractions are combined and the solvents removed by rotary evaporation to yield 0.511 g of 3-chloro-4-isothiocyanatoindole as a yellow solid (96%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:10][N:11]([C:13]3[CH2:18][CH2:17][C:16](=[O:19])[NH:15][N:14]=3)[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[CH:26]1([C:29](Cl)=[O:30])[CH2:28][CH2:27]1>>[CH:26]1([C:29]([NH:1][C:2]2[CH:7]=[C:6]([C:8]3[C:9]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[N:10][N:11]([C:13]4[CH2:18][CH2:17][C:16](=[O:19])[NH:15][N:14]=4)[CH:12]=3)[CH:5]=[CH:4][N:3]=2)=[O:30])[CH2:28][CH2:27]1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1cc(-c2cn(C3=NNC(=O)CC3)nc2-c2ccccc2)ccn1
Product: O=C1CCC(n2cc(-c3ccnc(NC(=O)C4CC4)c3)c(-c3ccccc3)n2)=NN1
Yield: 80.8 %

Procedure:
The reaction was carried out in the same manner as in Example 9 except for using 56.0 mg (0.17 mmol) of 4-(2-aminopyridin-4-yl)-1-(1,4,5,6-tetrahydro-6-oxopyridazin-3-yl)-3-phenyl-1H-pyrazole obtained in Example 49 in place of 4-(2-aminopyridin-4-yl)-3-(4-fluorophenyl)-1-([1,2,4]triazolo[4,3-b]pyridazin-6-yl)-1H-pyrazole, and using 19.3 mg (0.19 mmol) of cyclopropylcarbonyl chloride in place of acetic anhydride to obtain 55.0 mg of the title compound as a white powder. (Yield: 82%)