Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])[CH:5]=[C:6]([F:10])[C:7]=1[CH:8]=O.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH2:26][C@H:27]([NH:29][CH2:30][C:31]([F:34])([CH3:33])[CH3:32])[CH3:28])=[CH:18]1.C(O)(=O)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4](/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])[CH:5]=[C:6]([F:10])[C:7]=1[C@@H:8]1[C:18]2[NH:17][C:25]3[C:20]([C:19]=2[CH2:26][C@@H:27]([CH3:28])[N:29]1[CH2:30][C:31]([F:34])([CH3:33])[CH3:32])=[CH:21][CH:22]=[CH:23][CH:24]=3
Reactant: COC(=O)/C=C/c1cc(F)c(C=O)c(F)c1
Reactant: C[C@H](Cc1c[nH]c2ccccc12)NCC(C)(C)F
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)/C=C/c1cc(F)c([C@@H]2c3[nH]c4ccccc4c3C[C@@H](C)N2CC(C)(C)F)c(F)c1
Temperature: 80 °C
Yield: 68 %

Procedure:
(E)-Methyl 3-(3,5-difluoro-4-formylphenyl)acrylate (6.58 g, 29.09 mmol) was added to a suspension of (R)—N-(1-(1H-indol-3-yl)propan-2-yl)-2-fluoro-2-methylpropan-1-amine (6.02 g. 24.24 mmol) in toluene (51.1 ml) and acetic acid (2.78 ml, 48.48 mmol). The reaction was heated to 80° C. for 5 hours. The reaction mixture was purified by ion exchange chromatography, using an SCX-2 column. The desired product was eluted from the column using 7M NH3/methanol and pure fractions were evaporated to dryness to afford a brown solid. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in heptane. Pure fractions were evaporated to dryness to afford the title product (7.52 g, 68.0%) as a yellow solid. 1H NMR (400 MHz, DMSO, 100° C.) δ 1.10 (3H, d), 1.12-1.31 (6H, m), 2.28-2.72 (2H, n), 2.84-3.09 (2H, m), 3.52-3.69 (1H, m), 3.76 (3H, s), 5.30 (1H, s), 6.64 (1H, d), 6.9-7.11 (2H, m), 7.21 (1H, d), 7.32 (2H, d), 7.42 (1H, d), 7.58 (1H, d), 10.14 (1H, s). m/z: ES+ [M+H]+ 457
Reaction SMILES: [C:1]([S:4][C@@H:5]([CH2:11][O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:6]CC(O)=O)(=[O:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.[S].[C:41](OC(=O)C)(=[O:43])[CH3:42]>C1(C)C=CC=CC=1.N1C=CC=CC=1>[C:41]([O:3][CH:1]1[S:4][C@@H:5]([CH2:11][O:12][Si:13]([C:26]([CH3:27])([CH3:29])[CH3:28])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:6][CH2:2]1)(=[O:43])[CH3:42]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)S[C@H](CCC(=O)O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [S]
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(=O)OC1CC[C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)S1

Procedure:
D-glutamic acid (1) was treated with sodium nitrite in hydrochloric acid to produce (R)-1,4-butyrolactone-4-carboxylic acid (2). Compound 2 was then reduced by borane-dimethyl sulfide complex in THF to give the corresponding (R)-4-(hydroxymethyl)-4-butyrolactone (4), which was subsequently treated with tert-butyldiphenylsilyl chloride in methylene chloride using imidazole as a catalyst to afford (R)-5-O-tert-butyldiphenylsilyl-4-hydroxymethyl-1,4-butyrolactone (53). The protected lactone 53 was opened with sodium hydroxide in ethanol and then converted to the methyl ester of 5-[(tert-butyldiphenylsilyl)oxy]-4-(R)-hydroxypentanoic acid (54) by reaction with dimethyl sulfate in dimethyl sulfoxide. Commpound 54 was transformed into the methyl ester of 5-[(tert-butyldiphenylsilyl)oxy]-4-(S)-iodopentanoic acid (55) by treatment with triphenylphosphine, imidazole and iodine. Displacement of the iodo group in compound 55 by thioacetate in toluene occurred readily to give the methyl ester of 4-(R)-(acetylthio)-5-[(tert-butyldiphenylsilyl)oxy]pentanoic acid (56). Compound 56 was then treated with 2 equivalents of diisobutylaluminum hydride (DIBAL) in toluene to reductively deprotect the sulfur and reduce the methyl ester to an aldehyde, thereby producing the thiolactol via spontaneous cyclization. The thiolactol was acetylated with acetic anhydride in pyridine to give 1-O-acetyl-5-O-(tert-butyldiphenylsilyl)-2,3-dideoxy-4-thio-L-ribofuranose (57): 1HNMR (CDCl3) delta 7.67 (m, 4H, ArH), 7.40 (m, 6H, ArH), 6.10 (m, 1H, 1-H), 3.70 (m, 1H, 4-H), 3.52 (m, 2H, 5-H), 2.20 (m, 2H, CH2), 2.00 (2 s, 3H, CH3CO--), 1.92 (m, 2H, CH2), 1.08 (s, 9H, tert-butyl).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C@@H:10]([OH:30])[CH:11]([N:14]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]O)=[CH:4][CH:3]=1.O.[C:32]1([CH3:42])[CH:37]=CC(S(O)(=O)=O)=C[CH:33]=1>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C@@H:10]2[CH:11]([N:14]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[NH:15][C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:12][CH2:33][C:32]([CH3:42])([CH3:37])[O:30]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)C(CO)[C@H](O)/C=C/c1ccc(Cl)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)C1CCC(C)(C)O[C@@H]1/C=C/c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 93 %

Procedure:
A mixture of 1,3-diol, 2-hydrazino (7C) (158 mg, 0.35 mmol) and p-toluene sulfonic acid monohydrate (6.8 mg, 0.035 mmol) in 10 mL anhydrous acetone was stirred at rt for 36 h, until the starting material was consumed as indicated by TLC (10:1/CH2Cl2/EtOAc). The reaction mixture was quenched with 5% NaHCO3 and extracted by CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4, and removed in vacuo. Purification by flash column chromatography on silica gel afforded the desired product as a white solid (93%).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:14]2[N:18]3[N:19]=[CH:20][C:21]([C:23]4[CH:24]=[N:25][N:26]([CH:28]([CH3:32])[C:29]([OH:31])=O)[CH:27]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=[O:6].Cl.[NH:36]1[CH2:41][CH2:40][CH:39]([C:42]#[N:43])[CH2:38][CH2:37]1>>[C:42]([CH:39]1[CH2:40][CH2:41][N:36]([C:29](=[O:31])[CH:28]([N:26]2[CH:27]=[C:23]([C:21]3[CH:20]=[N:19][N:18]4[C:14]([C:10]5[CH:9]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:33])([F:34])[F:1])=[O:6])[CH:13]=[CH:12][CH:11]=5)=[CH:15][N:16]=[C:17]4[CH:22]=3)[CH:24]=[N:25]2)[CH3:32])[CH2:37][CH2:38]1)#[N:43]
Reactant: CC(C(=O)O)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1
Reactant: N#CC1CCNCC1
Agent: Cl
Product: CC(C(=O)N1CCC(C#N)CC1)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 54, Step 3 starting from 2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}-1H-pyrazol-1-yl)propanoic acid and piperidine-4-carbonitrile hydrochloride (and Cat. No.). LCMS (M+H)+: m/z=566.2.
Reaction SMILES: [CH:1]([CH:3]([CH:13]([CH3:15])[CH3:14])[CH2:4][C:5]1[CH:9]([C:10]([CH3:12])=[CH2:11])[CH2:8][CH2:7][CH:6]=1)=[O:2].[Sn](Cl)(Cl)(Cl)Cl.[C:21](=O)([O-])[O-].[Na+].[Na+]>[N+](C)([O-])=O>[O:2]1[CH:1]2[CH2:11][CH:10]([CH3:12])[C:9]31[C:5]([CH2:4][CH:3]2[CH:13]([CH3:15])[CH3:14])=[C:6]([CH3:21])[CH2:7][CH2:8]3
Reactant: O=C([O-])[O-]
Reactant: C=C(C)C1CCC=C1CC(C=O)C(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Solvent: C[N+](=O)[O-]
Product: CC1=C2CC(C(C)C)C3CC(C)C2(CC1)O3

Procedure:
To a solution, cooled to -40°, of 3.3 g of 2-(2-formyl-3-methylbutyl)-3-isopropenyl-1-cyclopentene in 225 ml of nitromethane were added 45 ml of a 0.5-M solution of tin tetrachloride in nitromethane. The reaction mixture became intensely yellow in colour and an initially resulting precipitate dissolved again. The mixture was treated immediately with excess 2-N sodium carbonate solution and extracted with ether. After washing, the ethereal phase was dried in a conventional manner and the solvent was removed. Distillation under a high vacuum yielded 2.6 g of crude 3a,6-epoxy-7-isopropyl-1,4-dimethyl-2,3,3a,4,5,6,7,8-octahydroazulene in the form of a colourless oil which could be separated by chromatography on 40 times the amount of Florisil (magnesium silicate gel) with hexane/ether (19:1) into two pairs of epimers (A and B). Epimer A: b.p.0.01 ca 75°; IR(film):νmax = 1465/40, 1380, 1345, 1245, 1162, 1125, 1108, 1080, 1050, 995, 965, 945, 910, 880 cm-1. The odour is camphorous, woody. Epimer B: b.p.0.01 ca 80°IR(film):νmax = 1465/35, 1380, 1340, 1295, 1245, 1200/1195, 1170, 1145, 1110, 1060, 1030, 1000, 990, 950, 925, 910, 878 cm-1. The odour is camphorous, dull.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[CH:2]1.Br[C:15]1[S:16][CH:17]=[CH:18][N:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.CN(C=O)C>[S:16]1[CH:17]=[CH:18][N:19]=[C:15]1[N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[CH:2]1
Reactant: Brc1nccs1
Reactant: COC(=O)c1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CN(C)C=O
Product: COC(=O)c1cn(-c2nccs2)c2ccccc12
Temperature: 110 °C

Procedure:
To a solution of methyl 1H-indole-3-carboxylate (200 mg, 1.142 mmol) in NMP (Volume: 1142 μl) were added 2-bromothiazole (206 μl, 2.283 mmol) and cesium carbonate (1116 mg, 3.42 mmol) at RT. The mixture was heated at 110° C. for 2 h, then diluted with DMF, filtered and purified by HPLC to afford the title compound as a brown solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>N1C=CC=CC=1.C(Cl)Cl>[O:1]1[CH2:6][CH2:5][CH:4]([O:7][S:14]([C:11]2[CH:12]=[CH:13][C:8]([CH3:18])=[CH:9][CH:10]=2)(=[O:16])=[O:15])[CH2:3][CH2:2]1
Reactant: OC1CCOCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.3 %

Procedure:
To a solution of 133 g (1.31 mol) of tetrahydropyran-4-ol in pyridine (1.5 L) are added 373 g (1.95 mol) of p-toluenesulfonylchloride portionwise at 10° C. After complete addition the reaction is allowed to warm to room temperature and stirred for 18 h. The reaction is poured onto a stirred mixture of aqueous HCl/ice. The resulting precipitate is isolated by filtration and dissolved in DCM (1 L). The organic layer is washed with 1M aqueous HCl solution (1 L), followed by saturated aqueous NaHCO3 solution (1 L) and is then dried over Na2SO4. Filtration and concentration of the filtrate under reduced pressure gives 300 g of toluene-4-sulfonic acid tetrahydropyran-4-yl ester as an orange oil. Yield: 90%, ES-MS: m/z: 257 [M+H], 279 [M+Na]
Reaction SMILES: [C:1]1([PH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][C:15]([CH3:20])([CH3:19])[CH2:16][CH2:17]Cl>>[CH3:14][C:15]([CH3:20])([CH3:19])[CH2:16][CH2:17][P:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: c1ccc(Pc2ccccc2)cc1
Reactant: CC(C)(C)CCCl
Product: CC(C)(C)CCP(c1ccccc1)c1ccccc1

Procedure:
As a known compound, t-butylethyl, (i.e., 3,3-dimethylbutyl) diphenyl phosphine was also synthesized via the known displacement approach: the reaction of lithium diphenyl phosphide with 3,3-dimethylbutyl chloride provided the compound in good yield.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=2)[NH:6][N:5]=1.[CH3:16][Si:17]([CH3:24])([CH3:23])[CH2:18][CH2:19][O:20][CH2:21]Cl>CN(C=O)C>[Br:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=2)[N:6]([CH2:21][O:20][CH2:19][CH2:18][Si:17]([CH3:24])([CH3:23])[CH3:16])[N:5]=1
Reactant: O=[N+]([O-])c1cnc2[nH]nc(Br)c2c1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1nc(Br)c2cc([N+](=O)[O-])cnc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 82.7 %

Procedure:
NaH (0.165 g, 4.11 mmol, 60% suspension in mineral oil) was added portionwise to a cold (0° C.) solution of 3-bromo-5-nitro-1H-pyrazolo[3,4-b]pyridine (0.5 g, 2.06 mmol) in dry DMF (20 mL). The reaction mixture was stirred at 0° C. for 10 minutes, and 2-(trimethylsilyl)ethoxymethyl chloride (0.617 mL, 3.50 mmol) was added dropwise via a syringe. The cold bath was removed, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was placed in an ice bath, diluted with ethyl acetate (400 mL) and carefully quenched with water (50 mL). The aqueous layer was separated and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried, filtered and concentrated. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (20:1) to give 3-bromo-5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine (0.636 g, 83%) as a solid.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.C(=O)([O-])[O-].[K+].[K+].[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1.C(OCC)(=O)C>C1(C)C=CC=CC=1.C1OCCOCCOCCOCCOCCOC1>[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:2]2[N:1]=[C:8]([Cl:9])[N:7]=[C:5]([Cl:6])[N:4]=2)=[CH:19][CH:18]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Nc1ccc(Cl)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Clc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 52.8 %

Procedure:
To a mixture of cyanuric chloride (5.15 g, 27.9 mmol), potassium carbonate (3.98 g, 28.8 mmol) and 18-crown-6 (158 mg, 0.60 mmol) in toluene (40 ml), cooled in an ice bath, was added a solution of 4-chloroaniline (3.61 g, 28.3 mmol) in toluene (20 ml) over 15 minutes. After stirring at room temperature for 20 hours, the mixture was treated with ethyl acetate (60 ml) and filtered through a pad of celite under suction. The filtrate was concentrated under vacuum and recrystallized (chloroform) to give (4-chlorophenyl)-(4,6-dichloro-[1,3,5]triazin-2-yl)-amine (4.06 g, 53% yield) as a white solid. 1H NMR (d6-DMSO) δ 11.23 (1 H, s), 7.62 (2 H, d, J=9 Hz), 7.47 (2 H, d, J=9 Hz). 3C NMR (d6-DMSO) δ 169.5, 168.5, 163.6, 135.7, 128.6, 122.5, ESMS m/z 273 (M−H)−.
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:28]C(=O)C)([CH3:27])[CH3:26])[CH2:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=1)[OH:8])[CH3:2].C([O-])([O-])=O.[K+].[K+]>CO.O>[CH2:1]([N:3]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:28])([CH3:27])[CH3:26])[CH2:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])=[CH:11][CH:10]=1)[OH:8])[CH3:2]
Reactant: CCN(CCCCCC(C)(C)OC(C)=O)CCCC(O)c1ccc(NS(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCN(CCCCCC(C)(C)O)CCCC(O)c1ccc(NS(C)(=O)=O)cc1
Reaction time: 42.5 h
Yield: 89.6 %

Procedure:
A stirred solution of the product from Example 13 (1.35 g, 0.00296 mol) in methanol (80 ml) was treated with a solution of K2CO3 (2.04 g, 0.0148 mol) in water (5.9 ml) and the mixture was refluxed for 21.5 hours. It was kept at ambient temperature for 42.5 hours and concentrated to an aqueous residue which was mixed with water (10 ml) and CH2Cl2, acidified to pH 8.5-9 with 6 NHCl, saturated with NaCl and extracted with CH2Cl2. The extract was dried (MgSO4), concentrated and the residue chromatographed on silica gel with 0.5% NH4OH-9% MeOH--CH2Cl2 to give 1.1 g of the titled compound which is a compound of Formula I'. The high resolution mass spectrum had m/z 414(M+). Theory for C21H38N2O4S: 414.2552; measured: 414.2560.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][O:10][CH2:11][N:12]1[CH:20]=[N:19][C:18]2[C:17](=[O:21])[NH:16][C:15]([NH:22]C(=O)C)=[N:14][C:13]1=2.CN>>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][O:10][CH2:11][N:12]1[CH:20]=[N:19][C:18]2[C:17](=[O:21])[NH:16][C:15]([NH2:22])=[N:14][C:13]1=2
Reactant: CC(=O)Nc1nc2c(ncn2COCCOC2CCCCO2)c(=O)[nH]1
Agent: CN
Product: Nc1nc2c(ncn2COCCOC2CCCCO2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
A flask provided with a stirrer is loaded with 1.23 g (3.5 mmole) of 9-[2-(2-tetrahydropyranyloxy)ethoxymethyl]-N2 -acetylguanine obtained as described in Example 3 and 20 ml of a 25 percent aqueous solution of methylamine are added. The reaction mixture is stirred at room temperature for 2 hours and evaporated in vacuum at a temperature not above 30° C. The dray residue is recrystallized from an aqueous soluton of ethyl alcohol to give 0.86 g (80 percent) of 9-[2-(2-tetrahydropyranyloxy)ethoxymethyl]guanine.
Reaction SMILES: [NH2:1][NH2:2].Cl[C:4]1[N:5]=[N:6][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:8][CH:9]=1>>[NH:1]([C:4]1[N:5]=[N:6][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)[NH2:2]
Reactant: Clc1ccc(-c2ccncc2)nn1
Reactant: NN
Product: NNc1ccc(-c2ccncc2)nn1

Procedure:
The reaction of hydrazine with 3-chloro-6-(4-pyridinyl)pyridazine to produce 3-hydrazino-6-(4-pyridinyl)-pyridazine is carried out by heating the reactants at about 60° l C. to 100° C. in a suitable solvent, preferably but optionally under an inert atmosphere. The reaction is preferably run at about 75° C. to 85° C. and is conveniently and preferably run by heating the reactants in refluxing isopropyl alcohol, preferably under nitrogen. Other suitable solvents include dioxane, ethanol, 2-methoxyethanol, or the like. Optionally, the reaction can be run in the absence of a solvent.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([OH:17])=[C:12]([O:15][CH3:16])[CH:13]=2)[CH:8]=[C:7]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[N:6]=1)([CH3:3])[CH3:2].Cl[CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[C:12]([O:15][CH3:16])[CH:13]=2)[CH:8]=[C:7]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[N:6]=1)([CH3:3])[CH3:2]
Reactant: ClC1CCOCC1
Reactant: COc1cc2c(OC(C)C)nc(Nc3cc(C)[nH]n3)cc2cc1O
Product: COc1cc2c(OC(C)C)nc(Nc3cc(C)[nH]n3)cc2cc1OC1CCOCC1

Procedure:
Similar procedure as described in example 328 was used, starting from 1-Isopropoxy-7-methoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-ol and 4-chloro-tetrahydropyran to give [1-Isopropoxy-7-methoxy-6-(tetrahydro-pyran-4-yloxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 413(MH+).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][C:8]=1[O:16][CH3:17])(=O)=O.[Br-].[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Zn+]>C1COCC1.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>[CH3:17][O:16][C:8]1[CH:9]=[C:10]([C:13](=[O:15])[CH3:14])[CH:11]=[CH:12][C:7]=1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=1
Reactant: COc1cc(C(C)=O)ccc1OS(=O)(=O)C(F)(F)F
Reactant: [Zn+]c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cc(C(C)=O)ccc1-c1ccccn1
Temperature: 25 °C

Procedure:
A solution of 4-acetyl-2-methoxyphenyl trifluoromethanesulfonate (5.8 g, 19.5 mmol) in THF (100 mL) was degassed by bubbling argon through the solution for 15 min, then treated with 2-pyridylzinc bromide (39 mL of 0.5M in THF, 19.5 mmol) and Pd(PPh3)4 (1.1 g, 0.97 mmol). The resulting reaction mixture was degassed again and heated to reflux for 12 h under an atmosphere of argon. The reaction mixture was cooled to rt, concentrated and purified by flash column chromatography on silica gel eluting with EtOAc:hexanes (1:9 to 2:3) to afford 1-(3-methoxy-4-pyridin-2-ylphenyl)ethanone.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([NH2:12])[CH:10]=2)[NH:5][N:4]=1.[F:13][C:14]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[C:19]([F:26])[C:15]=1[C:16](O)=[O:17].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[F:13][C:14]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[C:19]([F:26])[C:15]=1[C:16]([NH:12][C:9]1[CH:10]=[C:11]2[C:3]([O:2][CH3:1])=[N:4][NH:5][C:6]2=[N:7][CH:8]=1)=[O:17]
Reactant: COc1n[nH]c2ncc(N)cc12
Reactant: O=C(O)c1c(F)ccc([N+](=O)[O-])c1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1n[nH]c2ncc(NC(=O)c3c(F)ccc([N+](=O)[O-])c3F)cc12
Reaction time: 24 h
Yield: 68.5 %

Procedure:
3-Methoxy-1H-pyrazolo[3,4-b]pyridin-5-amine (563 mg, 3.43 mmol) in N,N-dimethylformamide (17.1 mL) was sequentially treated with 2,6-difluoro-3-nitrobenzoic acid (766.2 mg, 3.772 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (723.2 mg, 3.772 mmol), and 1-hydroxybenzotriazole (509.7 mg, 3.772 mmol) at ambient temperature. After 24 hours, the reaction mixture was diluted with ethyl acetate, washed with water (4×), sodium bicarbonate (2×), and brine (1×), dried over sodium sulfate, and concentrated. The crude product was triturated with dichloromethane to provide 2,6-difluoro-N-(3-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-nitrobenzamide (820.6 mg, 2.350 mmol, 68.5% yield) as a solid. MS (APCI-neg) m/z=347.8 (M−H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].C[Si]([N-][Si](C)(C)C)(C)C.[K+].S(O[CH2:22][C:23]1[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=1)(=O)(=O)C.C(OCC)(=O)C>O1CCCC1>[CH3:34][O:33][C:25]1[CH:24]=[C:23]([CH:28]=[C:27]([O:29][CH3:30])[C:26]=1[O:31][CH3:32])[CH2:22][N:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6]
Reactant: COc1cc(COS(C)(=O)=O)cc(OC)c1OC
Reactant: O=C1CCCN1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(CN2CCCC2=O)cc(OC)c1OC
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
Combine 2-pyrrolidinone (2.85 g, 33.5 mmol) and tetrahydrofuran (70 mL). Cool to −78° C. using a dry-ice/acetone bath. Add a solution of potassium bis(trimethylsilyl)amide (67 mL, 0.5 M in toluene, 33.5 mol). After 45 minutes, add a solution of 3,4,5-trimethoxybenzyl mesylate (8.8 g, 32.02 mmol) in tetrahydrofuran (60 mL). After the addition of 3,4,5-trimethoxybenzyl mesylate is complete, heat to reflux. After 18 hours, cool the reaction mixture and partition between water and ethyl acetate. Separate the aqueous layer and extract 4 times with ethyl acetate. Dry the combined organic layers over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with ethyl acetate to give the title compound: Rf=0.35 (silica gel, ethyl acetate).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([N:14]=[C:15]=[O:16])(=[O:13])=[O:12])=[O:4].[NH2:17][C:18]1[N:22]=[C:21]([O:23][CH3:24])[N:20]([CH3:25])[N:19]=1.C1N2CCN(CC2)C1>C(Cl)Cl>[CH3:24][O:23][C:21]1[N:20]([CH3:25])[N:19]=[C:18]([NH:17][C:15]([NH:14][S:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:3]([O:2][CH3:1])=[O:4])(=[O:12])=[O:13])=[O:16])[N:22]=1
Reactant: COc1nc(N)nn1C
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(OC)n(C)n1
Reaction time: 72 h
Yield: 72.9 %

Procedure:
To a solution of 2-(methoxycarbonyl)benzenesulfonylisocyanate (80%, 1.41 g, 4.7 mmol) in methylene chloride (10 ml) at room temperature under nitrogen was added 3-amino-5-methoxy-1-methyl-1H-1,2,4-triazole (0.50 g, 3.9 mmol). DABCO (catalytic amount) was added, and the reaction mixture was stirred for 3 days. Isolation of the product by filtration and washing with methylene chloride gave 1.05 g of a white powder, m.p. 177°-180°.