Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][C:4](Br)=[CH:5][C:6]=1[C:7]1[S:11][C:10]([NH:12][C:13](=[O:22])[C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:9][C:8]=1[CH3:23].O1C2C=CC(C3SC(NC(=O)C4C(F)=CC=CC=4F)=NC=3C)=CC=2OC1>>[F:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([F:20])[C:14]=1[C:13]([NH:12][C:10]1[S:11][C:7]([C:6]2[CH:5]=[CH:4][S:3][CH:2]=2)=[C:8]([CH3:23])[N:9]=1)=[O:22]
Reactant: Cc1nc(NC(=O)c2c(F)cccc2F)sc1-c1cc(Br)sc1Br
Agent: Cc1nc(NC(=O)c2c(F)cccc2F)sc1-c1ccc2c(c1)OCO2
Product: Cc1nc(NC(=O)c2c(F)cccc2F)sc1-c1ccsc1

Procedure:
Compound 62 was prepared from was prepared from Compound 61 as described for the preparation of Compound 57.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[CH3:10][O:11][CH2:12][CH2:13]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:10][O:11][CH2:12][CH2:13][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: COCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCn1cnc2ccccc21
Temperature: 100 °C
Reaction time: 20 h
Yield: 87.5 %

Procedure:
In a nitrogen atmosphere, a mixture of 118 g of benzimidazole, 94.5 g of 2-chloroethyl methyl ether, 138 g of potassium carbonate, and 400 g of N,N-dimethylformamide was heated and stirred at 100° C. for 20 hours. The reaction mixture was subjected to conventional aqueous work-up and distillation under reduced pressure for purification, to give 154 g of 1-(2-methoxyethyl)-1H-benzimidazole (boiling point 125° C./33 Pa, yield 87%).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[S:9][C:10]([Br:14])=[CH:11][C:12]=1[Br:13].O>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:13][C:12]1[CH:11]=[C:10]([Br:14])[S:9][C:8]=1[C:8]1[S:9][CH:10]=[CH:11][CH:12]=1
Reactant: Brc1cc(Br)c(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1cc(Br)c(-c2cccs2)s1
Yield: 44.2 %

Procedure:
Tetrakis(triphenylphosphine)palladium (3 mmol) and 100 mL of an aqueous 2N sodium carbonate solution were added to a solution of 2-thiophene-boric acid (5.0 mmol) and 2,3,5-tribromothiophene (100 mmol) in a mixture of 200 mL of toluene and 100 mL of ethanol in a nitrogen atmosphere. The resulting mixture was refluxed for 24 hours. The reaction mixture was combined with water, and extracted with toluene. The extract solution was washed with water, and dried over magnesium sulfate. The solvent was evaporated to obtain a crude product. The crude product was purified by column chromatography and by recrystallization from hexane to obtain the intended product (22.1 mmol) in a 22% yield.
Reaction SMILES: C[Si]([N:5]=[C:6]=[O:7])(C)C.[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]3[O:23][CH2:22][C:21]([CH2:24][NH:25][OH:26])=[CH:20][C:19]=3[CH:27]=2)[CH:9]=1>O1CCCC1>[OH:26][N:25]([CH2:24][C:21]1[CH2:22][O:23][C:18]2[CH:17]=[CH:16][C:15]([CH2:14][C:10]3[CH:9]=[N:8][CH:13]=[CH:12][CH:11]=3)=[CH:27][C:19]=2[CH:20]=1)[C:6]([NH2:5])=[O:7]
Reactant: C[Si](C)(C)N=C=O
Reactant: ONCC1=Cc2cc(Cc3cccnc3)ccc2OC1
Solvent: C1CCOC1
Product: NC(=O)N(O)CC1=Cc2cc(Cc3cccnc3)ccc2OC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.5 %

Procedure:
1.84 ml of trimethylsilyl isocyanate was added dropwise to a solution of 3.03 g (11.3 mmol) of N-[6-(3-pyridylmethyl)-2H-1-benzopyran-3-ylmethyl]hydroxylamine in tetrahydrofuran (30 ml) at 0° C. over 5 minutes, followed by stirring overnight at room temperature. Then, the solvent was evaporated in vacuo, the residue was purified by silica gel chromatography (chloroform:methanol:concentrated ammonia water=300:9:1−100:9:1), followed by recrystallization in a mixed solvent of chloroform-methanol-ethyl acetate to obtain 2.41 g (yield=68.5%) of the desired compound as white columnar crystal.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[CH:9][O:8][C:7]=1[C:11]([F:14])([F:13])[F:12])=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:14][C:11]([F:12])([F:13])[C:7]1[O:8][CH:9]=[CH:10][C:6]=1[CH2:4][OH:3]
Reactant: CCOC(=O)c1ccoc1C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccoc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2-trifluoromethyl-furan-3-carboxylic acid ethyl ester (2.2 g, 10.5 mmoles) in tetrahydrofuran (150 ml) was treated portionwise during 0.5 h with lithium aluminium hydride (0.55 g, 14.5 mmoles) under a nitrogen atmosphere. When the addition was complete the mixture was stirred at room temperature for 18 h, then quenched by the addition of excess acetone (1 ml) and then water (1 ml). After diluting with ethyl acetate (200 ml) the grey precipitate was removed by filtration. The filtrate was dried and evaporation of the solvent afforded (2-trifluoromethyl-furan-3-yl)-methanol as a colourless oil. This material was used immediately in the next step.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:4]=1)#[N:2].[C:16](OC)(=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[SH:19].C(N(CC)CC)C>C1(C)C=CC=CC=1>[N:11]1[CH:12]=[CH:13][CH:14]=[N:15][C:10]=1[S:9][C:5]1[N:4]=[C:3]([C:1]2[S:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[C:16](=[O:24])[N:2]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccccc1S
Reactant: N#Cc1cccc(Sc2ncccn2)n1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=c1nc(-c2cccc(Sc3ncccn3)n2)sc2ccccc12
Yield: 5.2 %

Procedure:
2-Cyano-6-(2-pyrimidinyl)thiopyridine (1.30 g, 6.07 mmol) and methyl thiosalicylate (1.53 g, 9.10 mmol) were dissolved in toluene (100 ml), and triethylamine (1.70 ml, 12.1 mmol) was added thereto. The mixture was refluxed for 18 hrs. The solvent was evaporated, and the residue was recrystallized from ethanol to give the titled compound (0.11 g, 5%) as pale yellow crystals.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([NH2:11])=[C:4]([CH3:12])[CH:3]=1.Cl.[CH2:14]([O:21][C:22]([C:24](=[CH2:29])[C:25]([O:27][CH3:28])=[O:26])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:28][O:27][C:25](=[O:26])/[C:24](/[C:22]([O:21][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:23])=[CH:29]/[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([NH2:11])=[C:4]([CH3:12])[CH:3]=1
Reactant: Cc1cc(I)cc([N+](=O)[O-])c1N
Reactant: C=C(C(=O)OC)C(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCN(CC)CC
Product: COC(=O)/C(=C/c1cc(C)c(N)c([N+](=O)[O-])c1)C(=O)OCc1ccccc1
Temperature: 70 °C
Yield: 71 %

Procedure:
4-iodo-2-methyl-6-nitrobenzenamine.HCl (6.28 g, 20 mmol) and tetrabutylammonium chloride (6.67g, 24 mmol)was dissolved in DMF(30-40 mL) which was degassed for 10 min, followed by the addition of methyl 2-(benzyloxycarbonyl)acrylate (5.65 g, 24 mmol ) and Pd(OAc)2 (0.674 g, 3 mmol), and triethylamine (8.0 mL, 57 mmol) under N2. The mixture was heated at 70° C. for 2.5 hours (the reaction was monitored by LC-MS and TLC, ethyl acetate/hexanes=1:1, Rf=0.24). All volatiles were removed, and the residue was dissolved in CHCl3, which was washed with brine twice, and the organic layer was dried over MgSO4. After filtration, solvents were removed in vacuo and the residue was subjected to flash chromatography using EtOAc/hexanes (1:4, 1:2, 1:1) as eluent to give the title compound as an orange solid 6.87g (71%, yield). All of these solids were refluxed in ethyl acetate (125 mL) and the resulting dark brown solution was filtered. The filtrate was cooled down to r.t. and stored in refrigerator (4° C.) for 2 hrs, then filtered to afford the title compound in a very pure form as an orange solid (5.26 g, recovery yield 62%). 1HNMR (CDCl3, 500 MHz) δ 8.23 (s, 1H), 7.47 (s, 1H), 7.33 (br s, 5H), 7.28 (s, 1H), 6.36 (v br s, 3H), 5.12 (s, 2H), 3.82 (s, 3H), 2.14 (s, 3H); Mass Spec. 386.14 (MH+), Calc. for C19H19N3O6 385.13.
Reaction SMILES: C=O.[CH3:3][C:4]1[S:13][C:12]2[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[N:8]=[C:7]([N:18]3[CH2:23][CH2:22][NH:21][C@@H:20]([CH2:24][CH2:25][C:26]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[CH:29]=[CH:28][CH:27]=4)[CH2:19]3)[C:6]=2[CH:5]=1.[C:36](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH3:3][C:4]1[S:13][C:12]2[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[N:8]=[C:7]([N:18]3[CH2:23][CH2:22][N:21]([CH3:36])[C@@H:20]([CH2:24][CH2:25][C:26]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[CH:29]=[CH:28][CH:27]=4)[CH2:19]3)[C:6]=2[CH:5]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCc2cccc3ccccc23)C1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)[C@@H](CCc2cccc3ccccc23)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97.1 %

Procedure:
Add formaldehyde (56 μL, 0.70 mmol, 37% in water) to a solution of (S)-2-methyl-10-[3-(2-naphthalen-1-yl-ethyl)-piperazin-1-yl]-4H-3-thia-4,9-diaza-benzo[f]azulene (290 mg, 0.64 mmol) in methylene chloride (20 mL). Stir 15 min at ambient temperature. Add sodium triacetoxyborohydride (204 mg, 0.96 mmol) and stir 30 min at ambient temperature. Dilute with saturated sodium bicarbonate solution and extract with methylene chloride. Dry the extracts with sodium sulfate, filter and concentrate the filtrate. Purify by radial silica gel chromatography using a 2 mm plate and 2N ammonia in methanol-methylene chloride (1%–2%) as the eluent to give 290 mg (97%) of the title compound: mass spectrum (ion spray): m/z=467 (M+1), 465 (M−1). HR-MS calculated for C29H31N4S: 467.2269. Found 467.2278. HPLC: Symmetry C18 column (3.5 μm, 4.6×50 mm). Gradient 5% to 90% solvent B in 7 min. Solvent A was 0.1% (v/v) TFA in water and solvent B was acetonitrile. Retention time 5.7 min; 100% pure.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]>C1(C)C=CC=CC=1>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCNCC1
Reactant: CCOC(=O)CBr
Solvent: Cc1ccccc1
Product: CCOC(=O)CN1CCN(CC)CC1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
8.9 ml of ethylpiperazine are placed in 91.5 ml of toluene in a round-bottomed flask. A solution of 4.1 ml of ethyl bromoacetate in 11.6 ml of toluene is added dropwise. The mixture is refluxed at 110° C. for one hour, concentrated to a small volume and left in a refrigerator for 3 hours. A white precipitate forms, which is filtered off and washed with dichloromethane. The filtration liquors are evaporated; 7 g of expected product are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[N:5]=1)[CH3:2].Cl[CH2:25][C:26]1[N:30]([CH3:31])[C:29]2[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=2[N:27]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:25][C:26]3[N:30]([CH3:31])[C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[N:27]=3)=[CH:21][CH:22]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)nc1OCC
Reactant: Cn1c(CCl)nc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc4ccccc4n3C)cc2)nc1OCC
Temperature: 80 °C
Reaction time: 5 h
Yield: 83.7 %

Procedure:
A mixture of ethyl 3-[3-ethoxy-1-(4-hydroxybenzyl)-1H-pyrazol-4-yl]propionate (600 mg), 2-chloromethyl-1-methyl-1H-benzimidazole (360 mg), potassium carbonate (550 mg) and N,N-dimethylformamide (10 ml) was stirred at 80° C. for 5 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[3-ethoxy-1-[4-(1-methyl-1H-benzimidazol-2-ylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (730 mg, yield: 84%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]([CH2:15][N:16](CC2C=CC=CC=2)CC2C=CC=CC=2)([CH2:13][F:14])[CH2:9]1)C1C=CC=CC=1.O.NN>C(O)C.[C].[Pd]>[NH2:16][CH2:15][C:10]1([CH2:13][F:14])[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: FCC1(CN(Cc2ccccc2)Cc2ccccc2)CCN(Cc2ccccc2)C1
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: NCC1(CF)CCNC1

Procedure:
1-Benzyl-3-(dibenzylaminomethyl)-3-fluoromethylpyrrolidine (4.55 g) was dissolved in ethanol (40 ml), and 10% palladium-carbon (1 g) and hydrazine monohydrate (2.15 g) were added. The mixture was refluxed for 1 hour. After the completion of the reaction, the catalyst was removed, and the mixture was concentrated to give the object compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6](=[O:11])OC(=O)[NH:9][C:4]=2[CH:3]=1.[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[C:17]([F:23])[CH:16]=1>O1CCCC1>[NH2:9][C:4]1[CH:3]=[C:2]([Cl:1])[CH:13]=[CH:12][C:5]=1[C:6]([NH:20][CH2:19][C:18]1[CH:21]=[CH:22][C:15]([Br:14])=[CH:16][C:17]=1[F:23])=[O:11]
Reactant: NCc1ccc(Br)cc1F
Reactant: O=c1[nH]c2cc(Cl)ccc2c(=O)o1
Solvent: C1CCOC1
Product: Nc1cc(Cl)ccc1C(=O)NCc1ccc(Br)cc1F
Yield: 79.9 %

Procedure:
A mixture of 7-chloro-2H-3,1-benzoxazine-2,4(1H)-dione (18.4 g) and 4-bromo-2-fluorobenzylamine (26 g) in tetrahydrofuran (200 ml) was refluxed for 15 minutes. After cooling, tetrahydrofuran was evaporated to give a residue. Recrystallization from isopropyl ether gave 2-amino-N-(4-bromo-2-fluorobenzyl)-4-chlorobenzamide (26.6 g).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][OH:20])=[CH:14][CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:23][N:24]1[C:28]([CH3:29])=[C:27]([C:30](O)=[O:31])[C:26](=[O:33])[N:25]1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl.O>[OH:20][CH2:19][CH2:18][O:17][C:13]1[CH:12]=[C:11]2[C:16]([C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:30]([C:27]4[C:26](=[O:33])[N:25]([C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)[N:24]([CH3:23])[C:28]=4[CH3:29])=[O:31])=[CH:22][CH:21]=3)=[CH:8][CH:9]=[N:10]2)=[CH:15][CH:14]=1
Reactant: Nc1ccc(Oc2ccnc3cc(OCCO)ccc23)cc1
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(OCCO)ccc34)cc2)c(=O)n(-c2ccccc2)n1C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
To a solution of 2-((4-(4-aminophenoxy)quinolin-7-yl)oxy)ethanol (0.14 g, 0.5 mmol), 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carb oxylic acid (0.11 g, 0.51 mmol) in DCM (1.5 mL) was added HOAT (0.014 g, 0.1 mmol), and EDCI (0.11 g, 0.6 mmol). The reaction was refluxed for 3 hours. The cooled mixture was diluted with water (30 mL) and filtered. The solid was collected and stirred in a mixture of EtOAc (3 mL) and water (3 mL) overnight. The solid was collected by filtration and dried in vacuo at 50° C. for 9 hours to afford the title compound as a gray-white solid (180 mg, 74.7%).
Reaction SMILES: [C:1]1(=[O:8])[O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:9]([OH:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[OH:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: OCc1ccccc1
Reactant: O=C1CCCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: O=C(CCCCCO)OCc1ccccc1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of ε-caprolactone (a) (40 g), benzyl alcohol and p-toluenesulfonic acid monohydrate (0.7 g) was stirred at 100° C. for 16 hours. The reaction mixture was treated in the conventional manner and was distilled under reduced pressure (1 mmHg, 140°-154° C.) to give the title compound (b).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([N:18]=[N+:19]=[N-:20])[CH2:12]2)=[C:4]([NH:21][CH2:22][CH:23]2[CH2:25]C2)[N:3]=1>C(OCC)(=O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([N:18]=[N+:19]=[N-:20])[CH2:12]2)=[C:4]([N:21]2[CH2:22][CH2:23][CH2:25]2)[N:3]=1
Reactant: [N-]=[N+]=N[C@H]1C[C@H](n2cnc3c(NCC4CC4)nc(N)nc32)O[C@@H]1CO
Solvent: CCOC(C)=O
Product: [N-]=[N+]=N[C@H]1C[C@H](n2cnc3c(N4CCC4)nc(N)nc32)O[C@@H]1CO
Yield: 56 %

Procedure:
The title compound was prepared in a manner analogous to the preparation of 2-amino-9-(3-azido-2,3-dideoxy-β-D-erythropentofuranosyl)-6-cyclopropylmethylamino-9H-purine (Example 15b). The reaction was worked up in an analogous manner except the combined ethyl acetate fractions were back washed with 150 mL of 1M potassium carbonate two times prior to chromatography. The product was isolated in 56% yield, 0.373 g, mp.=141°-143°C.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]5[C:28](=[O:40])[N:29]([C:33]6[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=6)[N:30]=[CH:31][CH:32]=5)=[O:26])=[CH:20][C:19]=4[F:41])=[C:11]3[C:10]([CH:42]3[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]3)=[N:9]2)=CC=1.C(O)(C(F)(F)F)=O>>[F:41][C:19]1[CH:20]=[C:21]([NH:24][C:25]([C:27]2[C:28](=[O:40])[N:29]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[N:30]=[CH:31][CH:32]=2)=[O:26])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:8][N:9]=[C:10]([CH:42]3[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]3)[C:11]=12
Reactant: COc1ccc(Cn2nc(C3CCN(C)CC3)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC(c2n[nH]c3nccc(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)c23)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 23.8 %

Procedure:
A 50 mL round-bottomed flask was charged with N-(4-(1-(4-methoxybenzyl)-3-(1-methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (16.3 mg, 0.0241 mmol) and CF3COOH (5 mL). The reaction mixture was stirred at 80° C. overnight. The solvent was removed and the residue was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 50/1 to 10/1, v/v) to afford product, which was further purified by preparative HPLC to afford the desired product (3.2 mg, 16.9%). LRMS (APCI pos): >99% purity, 254 nm, m/e 558 (M+1). 1H NMR (400 MHz, CD3OD) δ 11.94 (s, 1H), 8.24-8.36 (m, 3H), 8.03 (dd, 1H), 7.65 (m, 2H), 7.49 (m, 1H), 7.41 (m, 1H), 7.22-7.30 (m, 2H), 6.31 (d, 1H), 3.62 (m, 2H), 3.45 (m, 1H), 3.14-3.26 (m, 2H), 2.87 (s, 3H), 2.39-2.58 (m, 2H), 2.14-2.32 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:40])[C:3](=[O:39])[CH2:4][O:5][C:6]([C:8]1[CH:9]=[C:10]([CH:36]=[CH:37][CH:38]=1)[CH2:11][N:12]1[C:16](=[O:17])[C:15]2([CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)[N:14]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:13]1)=[O:7].Cl>O1CCOCC1>[O:17]=[C:16]1[C:15]2([CH2:18][CH2:19][NH:20][CH2:21][CH2:22]2)[N:14]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:13][N:12]1[CH2:11][C:10]1[CH:9]=[C:8]([CH:38]=[CH:37][CH:36]=1)[C:6]([O:5][CH2:4][C:3]([N:2]([CH3:1])[CH3:40])=[O:39])=[O:7]
Reactant: CN(C)C(=O)COC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)c1
Agent: Cl
Solvent: C1COCCO1
Product: CN(C)C(=O)COC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To tert-butyl 3-(3-((2-(dimethylamino)-2-oxoethoxy)carbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.26 g, 0.47 mmol) was added 4M solution of HCl in dioxane (5 mL). After stirring at room temperature for 2 hours, the reaction mixture was concentrated in vacuo to obtain 2-(dimethylamino)-2-oxoethyl 3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate as a hydrochloride salt.
Reaction SMILES: C(=O)(OC)[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([F:12])=[CH:5][C:4]=1[Br:13]>[OH-].[Na+]>[Br:13][C:4]1[CH:5]=[C:6]([F:12])[C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]=1[OH:2]
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(F)cc1Br
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1cc(O)c(Br)cc1F
Reaction time: 3 h
Yield: 65.7 %

Procedure:
A stirred solution of 1031 g (3.5 moles) of 2-bromo-4-fluoro-5-nitrophenyl methyl carbonate in 300 mL of 2.3N aqueous sodium hydroxide was heated to reflux and stirred for three hours. The hot reaction mixture was filtered through diatomaceous earth. Any material remaining in the reaction vessel was washed onto the filter cake with 1000 mL of water. The filtrate was cooled to 8°-10° C., and 560 mL of concentrated hydrochloric acid was added, with stirring, over one hour. The resultant solid was collected by filtration. Any material remaining in the reaction vessel was washed onto the filter cake with 1000 mL of water. The dried filter cake was recrystallized from toluene to give, in two crops, 543 g of 2-bromo-4-fluoro-5-nitrophenol, m.p. 124°-126° C.
Reaction SMILES: [CH2:1]([NH:4][S:5]([C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]([N+:15]([O-:17])=[O:16])[C:9]=1Cl)(=[O:7])=[O:6])[CH2:2][CH3:3].[H-].[Na+].[OH2:21]>>[CH2:1]([NH:4][S:5]([C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]([N+:15]([O-:17])=[O:16])[C:9]=1[OH:21])(=[O:7])=[O:6])[CH2:2][CH3:3]
Reactant: O
Reactant: CCCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Agent: [H-]
Agent: [Na+]
Product: CCCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1O
Yield: 69.1 %

Procedure:
Following the general hydrolysis procedure outlined in example 15, N-propyl-2,6-dichloro-3-nitrobenzenesulfonamide (1.0 , 3.19mmol), 60% NaH (393 mg, 3.19 mmol) and water (58 μL, 3.19 mmol) were reacted to form the desired product (650 mg, 69%). LC-MS (m/z) 295.0 (M+).
Reaction SMILES: [OH:1][C:2]1([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[OH-].[Na+].[O:17](C(OC(C)(C)C)=O)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1>[CH2:8]([C:2]1([OH:1])[CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:17])[CH2:4][CH2:3]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: OC1(Cc2ccccc2)CCNCC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(O)(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4-hydroxy-4-benzyl piperidine (0.66 g, 3.5 mmol) in 1M NaOH (7 mL, 7 mmol) and dioxane (5 mL) at 0° C. was treated with BOC2O (0.76 g, 3.5 mmol), warmed to room temperature, stirred for 16 hours, adjusted to pH<7 with 10% citric acid, and extracted twice with ethyl acetate. The combined extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated to provide the desired product.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]([C:10]2[N:11]([CH3:18])[CH:12]=[C:13]([N+:15]([O-])=O)[CH:14]=2)=[O:9])[CH:4]=[C:3]1[C:19]([NH:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[O:20]>CO.[Pd]>[NH2:15][C:13]1[CH:14]=[C:10]([C:8]([NH:7][C:5]2[CH:4]=[C:3]([C:19]([NH:21][CH2:22][CH2:23][N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)=[O:20])[N:2]([CH3:1])[CH:6]=2)=[O:9])[N:11]([CH3:18])[CH:12]=1
Reactant: Cn1cc(NC(=O)c2cc([N+](=O)[O-])cn2C)cc1C(=O)NCCN1CCOCC1
Agent: [Pd]
Solvent: CO
Product: Cn1cc(NC(=O)c2cc(N)cn2C)cc1C(=O)NCCN1CCOCC1
Reaction time: 5 h

Procedure:
1-Methyl-4-{[(1-methyl-4-nitro-1H-pyrrol-2-yl)carbonyl]amino}-N-[2-(4-morpholinyl)ethyl]-1H-pyrrole-2-carboxamide (150 mg, 0.371 mmol; see step (iv) above) was suspended in methanol (25 mL) to which Pd/C-10% (108 mg) was added at 0° C. under a nitrogen with stirring. The reaction mixture was hydrogenated for 5 h at room temperature and atmospheric pressure. The catalyst was removed over Kieselguhr and methanol was removed under reduced pressure to give the title compound, which was used without further purification.