Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][C:4]=1[NH:15][C:16]([C:18]1[NH:19][CH:20]=[CH:21][N:22]=1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1.O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][C:4]=1[NH:15][C:16]([C:18]1[NH:19][CH:20]=[CH:21][N:22]=1)=[S:32]
Reactant: COc1ccc(-c2ccccc2)cc1NC(=O)c1ncc[nH]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(-c2ccccc2)cc1NC(=S)c1ncc[nH]1
Temperature: 25 °C
Yield: 71.8 %

Procedure:
To a suspension of 0.31 g of imidazole-2-carboxylic acid (2.76 mmol) in 14 ml DMF was added 0.448 g of CDI (2.76 mmol), 0.38 ml triethylamine (2.76 mmol) and stirred at ambient temperature for 1 h. Then the mixture was refluxed for 30 min. After cooling to ambient temperature, 0.5 g of 5-phenyl-o-anisidine (2.5 mmol) was added and the reaction mixture was heated to reflux for 16 h. The mixture was evaporated and the residue taken up in water (40 ml) and extracted 3 times with methylene chloride. The combined organic phases were tried on sodium carbonate, evaporated and the residue was stirred in hot ethyl acetate. After filtration and drying, 0.11 g 1H-imidazole-2-carboxylic acid (4-methoxy-biphenyl-3-yl)-amide (14%) were obtained as a light yellow solid; M.p.: 276° C. 0.1 g of 1H-Imidazole-2-carboxylic acid (4-methoxy-biphenyl-3-yl)-amide (0.36 mmol) was taken up in toluene (5.0 ml) and treated with 0.435 g of Lawesson reagent (1.0 mmol). The reaction mixture was heated to reflux for 16 h. After cooling to ambient temperature, water (25 ml) was added and the mixture was extracted 3 times with dichloro methane. The combined organic phases were dried on sodium carbonate, evaporated and the residue triturated in methanol. 0.08 g of 1H-imidazole-2-carbothioic acid (4-methoxy-biphenyl-3-yl)-amide (73%) were obtained as a yellow solid; M.p.: 223–226° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][C:21]([C:25]3[CH:26]=[N:27][CH:28]=[N:29][CH:30]=3)=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[C:21]([C:25]5[CH:30]=[N:29][CH:28]=[N:27][CH:26]=5)[CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2cc(-c3cncnc3)ccc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2ccc(-c3cncnc3)cc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-6-pyrimidin-5-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:17]([C:18]3[N:26]=[C:25]([CH3:27])[N:24]=[C:23]4[C:19]=3[N:20]=[CH:21][N:22]4C3CCCCO3)=[CH:16][C:13]([CH:14]=O)=[CH:12][N:11]=2)=[CH:5][CH:4]=1.[NH2:34][CH2:35][C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1.[BH4-].[Na+].Cl.C(O)(C(F)(F)F)=O>ClCCl.C(O)C.CO.C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:17]([C:18]3[N:26]=[C:25]([CH3:27])[N:24]=[C:23]4[C:19]=3[N:20]=[CH:21][NH:22]4)=[CH:16][C:13]([CH2:14][NH:34][CH2:35][C:36]3[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=3)=[CH:12][N:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Nc2ncc(C=O)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Reactant: NCc1cccnc1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: Cl
Agent: [BH4-]
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Nc2ncc(CNCc3cccnc3)cc2-c2nc(C)nc3[nH]cnc23)cn1
Temperature: 25 °C
Reaction time: 1.42 h
Yield: 101.3 %

Procedure:
6-(6-Methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)nicotinaldehyde (113.7 mg, 0.255 mmol) was suspended in dichloromethane (1.3 mL) and ethanol (1.3 mL), and 3-(aminomethyl)pyridine (0.080 mL, 0.79 mmol) and tetraisopropoxytitanium (0.23 mL, 0.78 mmol) were added. The reaction was stirred under nitrogen at room temperature. After 85 min, sodium borohydride (33.8 mg, 0.893 mmol) and MeOH (1 mL) were added, and stirring was continued at room temperature. After another 70 min, 5N HCl (0.50 mL) was added, along with MeOH, and stirring was continued at room temperature for 3 days. More 5N HCl (0.20 mL) and MeOH were added, and stirring was continued at room temperature overnight. The suspension was diluted with DCM and MeOH and filtered through a Celite® (diatomaceous earth) pad, which was washed with DCM and MeOH. The filtrate was concentrated, treated with DCM, MeOH, TFA, and concentrated again. The material was dissolved with water and MeOH and purified by prep HPLC (10% to 100% MeCN/water with 0.1% TFA over 28 min with a total flow rate of 100 mL/min). The HPLC fractions with product were collected, concentrated, and dried under high vacuum, first in a water bath at 50° C., and then at room temperature overnight to give N-(6-methoxypyridin-3-yl)-3-(2-methyl-9H-purin-6-yl)-5-((pyridin-3-ylmethylamino)methyl)pyridin-2-amine (117.1 mg, 81% yield) as a TFA salt. 1H NMR (D2O, 400 MHz) δ 8.94 (s, 1H), 8.92-8.87 (m, 1H), 8.83 (d, J=5.87 Hz, 1H), 8.69 (d, J=8.22 Hz, 1H), 8.47 (s, 1H), 8.37 (s, 1H), 8.26 (d, J=2.15 Hz, 1H), 8.13-8.06 (m, 1H), 7.98 (dd, J=9.19 Hz, 2.54 Hz, 1H), 7.11 (d, J=9.19 Hz, 1H), 4.61 (s, 2H), 4.44 (s, 2H), 3.99 (s, 3H), 2.73 (s, 3H). m/z (ESI, +ve ion) 454 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[CH:11][NH:12][CH:13]=2)=[CH:5][CH:4]=1.[H-].[Na+].[CH3:16][Si:17]([CH2:20][CH2:21][O:22][CH2:23]Cl)([CH3:19])[CH3:18]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[CH:11][N:12]([CH2:23][O:22][CH2:21][CH2:20][Si:17]([CH3:19])([CH3:18])[CH3:16])[CH:13]=2)=[CH:5][CH:4]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: COc1ccc(-c2c[nH]cn2)cc1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(-c2cn(COCC[Si](C)(C)C)cn2)cc1
Yield: 61.2 %

Procedure:
Reaction of 4-(4-methoxyphenyl)-1H-imidazole (610 mg, 3.51 mmol), NaH (60%, 136 mg, 3.40 mmol), and SEMCl (656 uL, 3.71 mmol) followed by column chromatography on silica gel (hexane/EtOAC 1:1) gave the title compound (654 mg, 64%) as a yellow solid. 1H NMR (300 MHz, CDCl3) major isomer: δ 0.00 (s, 9H), 0.93 (t, 2H, J=7.5 Hz), 3.52 (t, 2H, J=7.5 Hz), 3.83 (s, 3H), 5.28 (s, 2H), 6.94 (d, 2H, J=9.0 Hz), 7.24 (s, 1H), 7.60 (s, 1H), 7.72 (d, 2H, J=9.0 Hz); minor isomer: δ 0.00 (s, 9H), 0.92 (t, 2H, J=7.5 Hz), 3.54 (t, 2H, J=7.5 Hz), 3.85 (s, 3H), 5.23 (s, 2H), 6.98 (d, 2H, J=9.0 Hz), 7.09 (s, 1H), 7.47 (d, 2H, J=9.0 Hz), 7.65 (s, 1H). ES-MS m/z 305 (M+H).
Reaction SMILES: CO[C:3]([C:5]1([NH:13][C:14](=[O:25])[CH2:15][C:16]2[CH:21]=[C:20]([Br:22])[C:19]([F:23])=[CH:18][C:17]=2[CH3:24])[CH2:10][CH2:9][N:8]([O:11][CH3:12])[CH2:7][CH2:6]1)=[O:4].CC(C)([O-])C.[K+]>CN(C)C=O>[Br:22][C:20]1[C:19]([F:23])=[CH:18][C:17]([CH3:24])=[C:16]([C:15]2[C:14](=[O:25])[NH:13][C:5]3([CH2:10][CH2:9][N:8]([O:11][CH3:12])[CH2:7][CH2:6]3)[C:3]=2[OH:4])[CH:21]=1
Reactant: COC(=O)C1(NC(=O)Cc2cc(Br)c(F)cc2C)CCN(OC)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CON1CCC2(CC1)NC(=O)C(c1cc(Br)c(F)cc1C)=C2O
Reaction time: 0.17 h

Procedure:
To a solution of 4-[2-(5-bromo-4-fluoro-2-methyl-phenyl)-acetylamino]-1-methoxy-piperidine-4-carboxylic acid methyl ester (6.0 g) in dimethylformamide (20 ml) at 100° C. was added potassium tert-butoxide (3.23 g) and stirring continued at 100° C. for 10 minutes. The reaction mixture was quenched at room temperature by addition of acetic acid (1.64 ml), diluted with water (20 ml) and extracted with tert-butyl methyl ether (3×). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The residue was triturated with acetonitrile, filtered and dried. Yield: 3.69 g of 3-(5-bromo-4-fluoro-2-methyl-phenyl)-4-hydroxy-8-methoxy-1,8-diaza-spiro[4.5]dec-3-en-2-one (title compound C19) as a solid, mp: 229-230° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:21][CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>CN(C=O)C>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:21][CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[N:3]=1
Reactant: ClCCN1CCCC1
Reactant: O=[N+]([O-])c1ccc2c(Cl)n[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2c(Cl)nn(CCN3CCCC3)c2c1
Temperature: 50 °C
Yield: 65 %

Procedure:
A mixture of 3-chloro-6-nitro-1H-indazole (2.4 g, 12 mmol) was treated with potassium carbonate (5.0 g, 36 mmol) in DMF (40 mL) for about 30 minutes, after which 1-(2-chloro-ethyl)-pyrrolidine (3.1 g, 18 mmol) was added. The mixture was heated to 50° C. for 6 hours, cooled to room temperature and filtered through a plug of silica gel which was rinsed with triethylamine/ethyl acetate (1/4). The combined filtrate was concentrated under reduced pressure and purified by flash chromatography (silica gel, triethylamine/ethyl acetate 1/30) to provide the title compound (2.3 g, 66%). 1H NMR (300 MHz, DMSO-d6) ppm 1.61 (m, 4H), 2.47 (m, 4H), 2.89 (t, J=6.44, 2H), 4.67 (t, J=6.44, 2H), 7.90 (m, 1H), 8.01 (m, 1H), 8.86 (m, 1H); MS (DCI/NH3) m/z 295 [M+H]+.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11](=[O:13])[CH3:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14](Cl)/[CH:15]=[CH:16]/[CH2:17]Cl.[Cl-].C(C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC)(=O)CCCCCCC.O>S1(CCCC1)(=O)=O>[C:1]1([S:7]([C:10]2([C:11](=[O:13])[CH3:12])[CH2:17][CH:16]2[CH:15]=[CH2:14])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: ClC/C=C/CCl
Reactant: CC(=O)CS(=O)(=O)c1ccccc1
Agent: CCCCCCCC(=O)C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC
Agent: [Cl-]
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: C=CC1CC1(C(C)=O)S(=O)(=O)c1ccccc1
Reaction time: 2 h

Procedure:
Utilizing a phase-transfer procedure similar to that described in Example I, phenylsulfonylacetone was reacted with 1,4-dichlorobutene-2 to obtain 1-phenylsulfonyl-1-acetyl-2-vinylcyclopropane. For the reaction, 9.91 grams phenylsulfonylacetone (Parish Chemical Co.) and 6.25 grams 1,4-dichlorobutene-2 were combined in 20 mls sulfolane containing 6.6 grams potassium hydroxide (85%) and 5 mole percent tricaprylylmethylammonium chloride. The reaction mixture was stirred at 35°-40° C. for 31/2 hours. One-hundred mls water was then added to dissolve the white granular precipitate which had formed and the mixture extracted several times with ether. A crude red oil (10.8 grams) was obtained after removal of the ether and further work-up utilizing a Waters Preparatory Liquid Chromatograph 500A equipped with a gel permeation column and operated at a flow rate of 0.1 l/min yielded the cis and trans isomers of 1-phenylsulfonyl-1-acetyl-2-vinylcyclopropane. ##STR18## trans 1-phenylsulfonyl-1-acetyl-2-vinylcyclopropane
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:5]=1[NH2:13]>CO>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[NH2:13]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1N
Solvent: CO
Product: COC(=O)c1cccc(N)c1N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3.0 g (15.3 mmol) Methyl-2-amino-3-nitro-benzoate were dissolved in 200 mL abs. MeOH. The solution was evacuated and rinsed with argon several times. 300 mg palladium on charcoal (10%) were added and again the mixture was evacuated and rinsed with argon a several times. Finally argon was exchanged by hydrogen (balloon filled with hydrogen) and the mixture was stirred for 4 h at room temperature. The reaction mixture was filtered over “Celite” and the filter residue was washed with 150 mL methanol. The filtrate was concentrated under reduced pressure to give pure methyl-2,3-diamino-benzoate as a brown oil. Yield: 2.53 g MS (ES+): m/e=167.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:22](=[O:23])[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:19])([F:20])[F:18])[CH:12]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(N)n(-c2cccc(C(F)(F)F)c2)n1
Reactant: O=C(Cl)Oc1ccccc1
Product: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2cccc(C(F)(F)F)c2)n1
Yield: 34.7 %

Procedure:
Following the procedure in Example 118A, 3-tert-butyl-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-5-amine (344 mg, 1.21 mmol) and phenyl chloroformate (0.25 mL, 1.82 mmol) were reacted to give phenyl 3-tert -butyl-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-5-ylcarbamate (119 mg, 0.42 mmol, 35%). 1H NMR (300 MHz, DMSO-d6) δ 10.05 (s, 1H), 7.62-7.50 (m, 3H), 7.58-7.43 (m, 3H), 7.23 (t, 1H), 7.12 (br s, 2H), 6.39 (s, 1H), 1.29 (s, 9H); LC-MS (ESI) m/z 404 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]([CH3:15])=[C:13]([C:16](O)=O)[CH:12]=[N:11]1.S(Cl)(Cl)=O.S(N)([NH2:26])(=O)=O>S1(CCCC1)(=O)=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]([CH3:15])=[C:13]([C:16]#[N:26])[CH:12]=[N:11]1
Reactant: Cc1c(C(=O)O)cnn1-c1c(Cl)cc(Cl)cc1Cl
Reactant: NS(N)(=O)=O
Solvent: O=S(Cl)Cl
Solvent: O=S1(=O)CCCC1
Product: Cc1c(C#N)cnn1-c1c(Cl)cc(Cl)cc1Cl
Yield: 76 %

Procedure:
By the method of Example 1, Step E, 25.6 g (0.0838 mole) of 1-(2,4,6-trichlorophenyl)-4-carboxy-5-methyl-1H-pyrazole, 114.3 g (0.961 mole) of thionyl chloride, and 12.7 g (0.132 mole) of sulfamide were reacted in 100 mL of sulfolane, yielding 18.25 g of 1-(2,4,6-trichlorophenyl)-4-cyano-5-methyl-1H-pyrazole as an oil which subsequently solidified. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[S:6][C:7]([C:15]#[N:16])=[C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:4]=2[CH:3]=1.B.[ClH:20].[OH-].[Na+]>O1CCCC1>[ClH:20].[NH2:16][CH2:15][C:7]1[S:6][C:5]2[CH:17]=[CH:18][C:2]([Br:1])=[CH:3][C:4]=2[C:8]=1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: N#Cc1sc2ccc(Br)cc2c1-c1ccccc1
Agent: B
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: NCc1sc2ccc(Br)cc2c1-c1ccccc1

Procedure:
Treat 1.4 g. 5-bromo-2-cyano-3-phenylbenzo [b ]thiophene (0.0045 mole) in 40 ml of tetrahydrofuran, with 10 ml of 1 molar borane in tetrahydrofuran. Reflux the solution for 11/2 hours. Slowly add 10 ml of 5% hydrochloric acid. Heat the mixture for 1/2 hour, cool and add sufficient sodium hydroxide solution to basicity. Extract the solution with ether and wash twice with water. Dry the ether layer (MgSO4), filter and mix with 50 ml of ether saturated with hydrogen chloride. Dry the precipitate to yield the title compound; m.p. over 225° (decomp).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][C:13]3[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=3[C:6]=2[CH:7]=1.[Cl:22][C:23]1[CH:24]=[C:25]([S:30]([O-:32])=[O:31])[CH:26]=[C:27]([Cl:29])[CH:28]=1.[Na+]>>[Cl:29][C:27]1[CH:26]=[C:25]([S:30]([C:2]2[CH:3]=[CH:4][C:5]3[O:14][C:13]4[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=4[C:6]=3[CH:7]=2)(=[O:31])=[O:32])[CH:24]=[C:23]([Cl:22])[CH:28]=1
Reactant: O=S([O-])c1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3ccc(Br)cc3c2C1
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCc2oc3ccc(S(=O)(=O)c4cc(Cl)cc(Cl)c4)cc3c2C1
Yield: 43 %

Procedure:
The product of Example 29, step B and sodium 3,5-dichlorobenzenesulfinate were coupled using the procedure of Example 29, step C. Purification by flash column chromatography (SiO2, 85:15 hexane/ethyl acetate) provided tert-butyl 8-(3,5-dichlorophenylsulfonyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (147 mg, 43%) as a yellow oil: 1H NMR (CDCl3, 300 MHz) δ 8.07 (s, 1H), 7.85-7.78 (m, 3H), 7.56 (d, J=8.7 Hz, 1H), 7.50 (t, J=1.8 Hz, 1H), 4.59 (s, 2H), 3.84 (t, J=5.4 Hz, 2H), 2.93-2.82 (m, 2H), 1.51 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[NH:10][C:11]1[O:15][C:14]([C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C@H:25]3[CH2:30][CH2:29][C@H:28]([CH2:31][C:32]([O:34]C)=[O:33])[CH2:27][CH2:26]3)=[N:23][CH:24]=2)=[O:17])=[N:13][N:12]=1.[OH-].[Na+]>C1COCC1.CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[NH:10][C:11]1[O:15][C:14]([C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C@H:25]3[CH2:26][CH2:27][C@H:28]([CH2:31][C:32]([OH:34])=[O:33])[CH2:29][CH2:30]3)=[N:23][CH:24]=2)=[O:17])=[N:13][N:12]=1
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)c3nnc(Nc4cc(F)c(F)cc4F)o3)cn2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C[C@H]1CC[C@H](c2ccc(NC(=O)c3nnc(Nc4cc(F)c(F)cc4F)o3)cn2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of methyl (trans-4-{5-[({5-[(2,4,5-trifluorophenyl)amino]-1,3,4-oxadiazol-2-yl}carbonyl)amino]pyridin-2-yl}cyclohexyl)acetate (Example 406, 355 mg, 0.725 mmol) in THF (5 mL) and MeOH (25 mL) was added a 2M solution of NaOH (1.8 mL). The resulting yellow solution was allowed to stir at ambient temperature for 16 hr then a further 1.8 mL of 2M NaOH was added and stirring was continued at ambient temperature for 16 hr. The volatile organics were removed by evaporation and residue adjusted to pH ˜1 with 2M HCl and the suspension was filtered and dried to leave 410 mg of a solid. This was suspended in acetic acid (4 mL) and heated to 120° C., giving an incomplete solution. This was allowed to cool, filtered and washed with water then dried overnight, to give the title compound (167 mg, 48%) as a solid; 1H NMR (CDCl3) δ 1.10-1.19 (m, 2H), 1.56-1.65 (m, 2H), 1.72-1.79 (m, 1H), 1.85-1.94 (m, 4H), 2.17 (d, 2H), 2.79-2.85 (m, 1H), 7.67-7.76 (m, 2H), 8:12-8.19 (m, 1H), 8.44 (d, 1H), 9.01 (s, 1H), 11.14 (s, 1H), 11.58 (s, 1H), CO2H not seen; MS m/e MH+ 476.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O.[CH:17]1([C:20](=[O:25])[CH2:21][C:22](=O)[CH3:23])[CH2:19][CH2:18]1.C(O)(C)C>CCCCCCC.C(OCC)(=O)C>[Br:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:22]([CH3:23])[C:21]([C:20]([CH:17]1[CH2:19][CH2:18]1)=[O:25])=[C:9]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccc(Br)cc1C(=O)c1ccccc1
Reactant: CC(=O)CC(=O)C1CC1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: Cc1nc2ccc(Br)cc2c(-c2ccccc2)c1C(=O)C1CC1
Reaction time: 16 h
Yield: 75 %

Procedure:
The title compound was prepared from (2-amino-5-bromo-phenyl)-phenyl-methanone [example A16] and 1-cyclopropyl-1,3-butanedione according to the procedure of example 1, except that the solvent was isopropanol, the reaction time was of 16 h and heptane/ethyl acetate (1:2) was used. Yield: 75%; MS: m/z=366 (M).
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[C:3](O)=[O:4].C(Cl)(=O)C(Cl)=O.[Br:13][C:14]1[N:15]=[C:16]2[C:22]([NH2:23])=[CH:21][NH:20][C:17]2=[N:18][CH:19]=1.C(O)C(N)(CO)CO.C(=O)([O-])[O-]>O1CCOCC1.CN(C=O)C>[Br:13][C:14]1[N:15]=[C:16]2[C:22]([NH:23][C:3](=[O:4])[CH:2]([CH3:6])[CH3:1])=[CH:21][NH:20][C:17]2=[N:18][CH:19]=1
Reactant: CC(C)C(=O)O
Reactant: Nc1c[nH]c2ncc(Br)nc12
Agent: NC(CO)(CO)CO
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CC(C)C(=O)Nc1c[nH]c2ncc(Br)nc12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-methyl propanoic acid (62.06 mg, 65.46 μL, 0.7044 mmol) in dioxane (1 mL) with DMF was added oxalyl chloride (87.9 mg, 60.43 μL, 0.6927 mmol) at ambient temperature. The resulting solution was stirred for 30 minutes at this temperature. To this solution was added 2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-amine (50 mg, 0.2347 mmol) and this was stirred for a further 4 hours at ambient temperature. The reaction mixture was then heated to 50° C. for 1 hour. After this time trisamine resin and carbonate resin were added and the sample filtered. This crude solution was taken onto the next step as is.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.[F:18][C@@H:19]1[C@@H:23]([CH2:24][OH:25])[O:22][C@@H:21](N2C=CC(=O)NC2=O)[CH2:20]1.[N-]=[N+]=[N-].[K+].[C@@H]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H](O)C1>P([O-])([O-])([O-])=O.[K+].[K+].[K+].CO>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:21]2[O:22][C@H:23]([CH2:24][OH:25])[C@@H:19]([F:18])[CH2:20]2)=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: O=c1ccn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Reactant: Nc1nc(Nc2ccccc2)c2nc[nH]c2n1
Agent: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Nc1nc(Nc2ccccc2)c2ncn([C@H]3C[C@H](F)[C@@H](CO)O3)c2n1
Temperature: 45 °C
Reaction time: 48 h
Yield: 48 %

Procedure:
2-Amino-6-phenylamino-9H-purine (0.63 g, 2.7 mmoles) and 2',3'-dideoxy-3'-fluorouridine (0.50 g, 2.2 mmoles) were suspended in 50 ml, 10 mM potassium phosphate buffer, pH 7.0, containing 0.04% potassium azide. Purine nucleoside phosphorylase (1120 I.U.) and thymidine phosphorylase (10,000 I.U.) (Krenitsky et al., Biochemistry, 20, 3615 (1981) and U.S. Pat. No. 4,381,344) immobilized on DEAE cellulose was added to the reaction and the suspension was stirred at 45° C. After 2 days, 100 ml MeOH was added to the reaction. The reaction was applied to a column containing AG1-X2 (OH-- form, 2.5×10 cm) and eluted with MeOH. Fractions containing product were pooled, concentrated, and flash chromatographed on silica gel (2.5×20 cm) with dichloromethane:acetone:methanol (97:2:1). Fractions containing product were combined and flash chromatographed on a second silica gel column (2.5×20 cm) with hexane:acetone (6:4). Solvent was removed and lyophilization yielded 0.364 g of 2-amino-9-(2,3-dideoxy-3-fluoro-β-D-erythro-pentofuranosyl)-6-phenylamino-9H-purine (49%): mp 193°-194° C.;
Reaction SMILES: C(OC(=O)[NH:7][C:8]([C:10]1[S:11][C:12]([S:26][CH3:27])=[C:13]([S:15]([C:18]2[CH:19]=[N:20][C:21](Cl)=[C:22]([Br:24])[CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])(C)(C)C.[NH2:29][C:30]1[C:35]([CH2:36][NH2:37])=[CH:34][N:33]=[C:32](C)[N:31]=1.C(Cl)Cl.[C:42]([OH:48])([C:44]([F:47])([F:46])[F:45])=[O:43]>C1COCC1>[F:45][C:44]([F:47])([F:46])[C:42]([OH:48])=[O:43].[NH2:29][C:30]1[C:35]([CH2:36][NH:37][C:21]2[N:20]=[CH:19][C:18]([S:15]([C:13]3[CH:14]=[C:10]([C:8]([NH2:9])=[NH:7])[S:11][C:12]=3[S:26][CH3:27])(=[O:16])=[O:17])=[CH:23][C:22]=2[Br:24])=[CH:34][N:33]=[CH:32][N:31]=1
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cnc(Cl)c(Br)c1
Reactant: Cc1ncc(CN)c(N)n1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cnc(NCc2cncnc2N)c(Br)c1

Procedure:
The reaction was conducted following the procedure for Example 164: step c, using {[4-(5-bromo-6-chloro-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.035 g, 0.067 mmol), 4-amino-5-aminomethyl-2-methylpyrimidine (0.018 g, 0.135 mmol), THF [2 mL], followed by DCM/TFA (1:1) and reverse-phase HPLC to yield the title compound. ESI-MS (m/z): Calcd. for C18H19BrN6O2S3: 528.48 (M+H); found 528.0, 529.9.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[NH:15]N.O.[NH:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1.Cl>C(O)C(F)(F)F>[N+:12]([C:9]1[C:8]2[C:20]3[CH2:19][NH:18][CH2:23][CH2:22][C:21]=3[NH:15][C:7]=2[C:6]([S:5][CH2:4][CH2:3][CH2:2][Cl:1])=[CH:11][CH:10]=1)([O-:14])=[O:13]
Reactant: NNc1cc([N+](=O)[O-])ccc1SCCCCl
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: OCC(F)(F)F
Solvent: O
Product: O=[N+]([O-])c1ccc(SCCCCl)c2[nH]c3c(c12)CNCC3
Temperature: 25 °C
Yield: 96.9 %

Procedure:
1-{2-[(3-Chloropropyl)sulfanyl]-5-nitrophenyl}hydrazine (100 mg, 0.38 mmol) and 4-piperidone mono hydrate (58 mg, 0.38 mmol) were dissolved in trifluoroethanol (1 mL) andheated at reflux for 1 hour. To this was added 12 N HCl (3 mL) and the reaction allowed to heat at reflux for 2 hours. The product percipatated out upon cooling to room temperature, it was filtered off and washed with cold 2-propanol to give 3-chloropropyl 9-nitro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-6-yl sulfide (120 mg, 75.4%). 1H NMR (CD3OD, 300 MHz): δ8.00 (d, 1H, J=8.4 Hz), 7.30 (d, 1H, J=8.4 Hz), 4.68 (s, 2H), 3.69 (t, 2H, J=6.2 Hz), 3.60 (t, 2H, J=6 Hz), 3.23 (t, 2H, J=6.2 Hz), 2.08 (q, 2H, J=6.2 Hz) ppm.