Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([CH2:15][C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)[C:12]([NH2:14])=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].Cl.[NH2:22][C:23]1[S:27][N:26]=[C:25]([CH3:28])[CH:24]=1.O.O.O.[O-]C1C=CC=CC=1.[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:8]([C:7]1[CH:6]=[CH:5][C:4]([NH:10][C@H:11]([CH2:15][C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)[C:12]([NH2:14])=[O:13])=[CH:3][C:2]=1[NH:22][C:23]1[S:27][N:26]=[C:25]([CH3:28])[CH:24]=1)#[N:9]
Reactant: N#Cc1ccc(N[C@H](Cc2cccs2)C(N)=O)cc1Br
Reactant: Cc1cc(N)sn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(Nc2cc(N[C@H](Cc3cccs3)C(N)=O)ccc2C#N)sn1
Yield: 33.9 %

Procedure:
A mixture of (R)-2-(3-bromo-4-cyanophenylamino)-3-(thiophen-2-yl)propanamide (35 mg, 0.100 mmol), 5-amino-3-methylisothiazole hydrochloride (25 mg, 0.166 mmol), sodium phenoxide trihydrate (52 mg, 0.305 mmol), xantphos (14 mg, 0.024 mmol) and Pd2 dba3 (10 mg, 0.010 mmol) in dioxane (2 mL) was degassed with argon, then was heated by microwave at 170 C for 30 min. The mixture was concentrated in vacuo. The residue was purified by HPLC to give (R)-2-(4-cyano-3-(3-methylisothiazol-5-ylamino)phenylamino)-3-(thiophen-2-yl)propanamide (13 mg).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH:14]=[C:13]([C:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[N:17]([CH2:24][CH3:25])[N:16]=2)[CH:12]=[N:11]1.CI.[C:28]([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH2:24]([N:17]1[C:18]2[C:19](=[N:20][CH:21]=[CH:22][CH:23]=2)[C:15]([C:13]2[CH:12]=[N:11][N:10]([C:2]3[N:1]([CH3:28])[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=3)[CH:14]=2)=[N:16]1)[CH3:25]
Reactant: O=C([O-])[O-]
Reactant: CCn1nc(-c2cnn(-c3nc4ccccc4[nH]3)c2)c2ncccc21
Agent: [Cs+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CCn1nc(-c2cnn(-c3nc4ccccc4n3C)c2)c2ncccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.5 %

Procedure:
A mixture of 3-[(1-(1H-benzo[d]imidazol-2-yl)-1H-pyrazol-4-yl]-1-ethyl-1H-pyrazolo[4,3-b]pyridine (8 mg), MeI (2.278 μL) and Cs2CO3 (15.83 mg) in DMF (2 mL) was stirred at room temperature for 3 h, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane). Crystallization from AcOEt/hexane gave the title compound (4.80 mg).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([O:9]C)[CH:6]=[CH:5][C:4]=1[C:11]1[C:12](=[O:27])[O:13][C:14]2[C:19]([C:20]=1[CH2:21][CH2:22]OC)=[CH:18][CH:17]=[C:16]([C:25]#[N:26])[CH:15]=2.B(Br)(Br)Br.O.C(OCC)(=O)C>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:4]=1[C:11]1[C:12](=[O:27])[O:13][C:14]2[C:19]([C:20]=1[CH:21]=[CH2:22])=[CH:18][CH:17]=[C:16]([C:25]#[N:26])[CH:15]=2
Reactant: COCCc1c(-c2ccc(OC)cc2OC)c(=O)oc2cc(C#N)ccc12
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=Cc1c(-c2ccc(O)cc2O)c(=O)oc2cc(C#N)ccc12
Temperature: -30 °C
Reaction time: 4 h

Procedure:
3-(2,4-Dimethoxy-phenyl)-4-(2-methoxy-ethyl)-2-oxo-2H-chromene-7-carbonitrile (380 mg, 1.04 mmol) was dissolved in CH2Cl2 (12 mL) at room temperature in a 200 ml round bottom flask. The reaction mixture was then cooled to −30° C., and BBr3 (1.8 ml) was added, then the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was cooled to 0° C. and water (40 mL) was added, followed by ethyl acetate (50 mL). The reaction mixture was then poured into a separation funnel. The organic layer separated and washed with water (1×40 ml) and brine (1×30 ml). The organic layer was dried over sodium sulfate and concentrated. The product was purified on silica gel eluted with 50%-100% ethyl acetate in hexanes to yield the title compounds as a foam and a yellow solid, respectively.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)(O)[O-].[K+].O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCC(=O)OCc1ccccc1
Temperature: -5 °C
Reaction time: 38 h

Procedure:
N-(t-Butoxycarbonyl)glycine (8.75 g, 0.05 mole) and benzyl bromide (9.4 g, 0.055 mole) were slurried in 20 ml of dimethylformamide and treated with 6.0 g (0.06 mole) of potassium bicarbonate under argon. After stirring for 38 hours, water was added to give a mass of chunky white solid which was filtered and washed with water. The solid was taken up in ethyl acetate, dried (sodium sulfate), evaporated to a solid, and recrystallized from 600 ml of hot hexane. Cooling to -5° C. for two hours and filtering gave 11.6 g of crystalline flakes, melting point 72°-73° C., in two crops.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([Cl:17])[CH:16]=1)[O:5][C:6]1[C:7]([OH:13])=[N:8][CH:9]=[CH:10][C:11]=1[CH3:12].Br[CH2:19][C:20]1[C:28]2[C:23](=[N:24][CH:25]=[CH:26][CH:27]=2)[N:22](C(OC(C)(C)C)=O)[N:21]=1.C(=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([Cl:17])[CH:16]=1)[O:5][C:6]1[C:7](=[O:13])[N:8]([CH2:19][C:20]2[C:28]3[C:23](=[N:24][CH:25]=[CH:26][CH:27]=3)[NH:22][N:21]=2)[CH:9]=[CH:10][C:11]=1[CH3:12]
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2cccnc21
Reactant: Cc1ccnc(O)c1Oc1cc(Cl)cc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccn(Cc2n[nH]c3ncccc23)c(=O)c1Oc1cc(Cl)cc(Br)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-(3-bromo-5-chlorophenoxy)-4-methylpyridin-2-ol (11-5; 75 mg, 0.238 mmol) and tert-butyl 3-(bromomethyl)-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (74.4 mg, 0.238 mmol) was added potassium carbonate (33 mg, 0.238 mmol) and the resulting mixture was stirred at 25° C. for 18 hours. After this time, the mixture was filtered and then purified on Gilson LC using a Luna column (10μ, C18, 250×21.2 cm) eluting with 5-95% ACN/water with 0.1% TFA). The desired fractions were concentrated to dryness and the resulting solid was dissolved in trifluoroacetic acid (2 mL) This solution was concentrated on the rotary evaporator to give the title compound. LRMS (M+1)=446.7
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]([C:19]#[C:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].CC1(C)S[C@@H]2[C@H](NC(CC3C=CC=CC=3)=O)C(=O)N2[C@H]1C(O)=O>P([O-])([O-])([O-])=O>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][C@H:12]([NH:11][C:9](=[O:10])[CH2:8][O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:19]#[C:20][Si:21]([CH3:22])([CH3:23])[CH3:24])[CH3:18]
Reactant: CCOC(=O)CC(C#C[Si](C)(C)C)NC(=O)COc1ccccc1
Agent: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: CCOC(=O)C[C@@H](C#C[Si](C)(C)C)NC(=O)COc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Racemic ethyl 3-(phenoxyacetamido)-5-(trimethylsilyl)-4-pentynoate (1g) was suspended in phosphate buffer (250 mL, 0.01 molar, prepared from 0.1 molar pH 7.24 solution obtained from sigma). The pH of the solution was adjusted 7.8 using dilute sodium hydroxide. Under slow stirring, 100 units of immobilized penicillin G acylase (Boehringer-Mannheim) was added. The reaction mixture was stirred at room temperature for 48 hours. The reaction mixture was extracted with ethyl acetate (75 mL×3). The organic extracts were combined, dried over sodium sulfate, filtered and evaporated to dryness to give the desired amide, (S)-ethyl-3-(phenoxyacetamido)-5-(trimethylsilyl)-4-pentynoate. The immobilized enzyme was filtered off from the aqueous phase using Whatman No.1 filter paper. The pH of the aqueous phase was adjusted to 8.0 using dilute sodium hydroxide, and extracted with ethyl acetate (75 mL×3). The extracts were combined, dried over sodium sulfate, filtered and evaporated to dryness to give the desired amine, (R)-ethyl-3-amino-5-(trimethylsilyl)-4-pentynoate.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6]1[C:10](=[O:11])[CH2:9][CH2:8][CH2:7]1)=[O:5].[C:12]1([C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)O)[OH:13].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[C:10]12([O:13][C:12]3[CH:14]=[CH:16][CH:17]=[CH:18][C:19]=3[O:11]1)[CH2:9][CH2:8][CH2:7][CH:6]2[C:4]([O:3][CH2:2][CH3:1])=[O:5]
Reactant: CCOC(=O)C1CCCC1=O
Reactant: Oc1ccccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)C1CCCC12Oc1ccccc1O2

Procedure:
A mixture of 15.7 g. of ethyl cyclopentanone-2-carboxylate, 11 g. of pyrocatechol, 0.5 g. of p-toluenesulphochloride and 0.5g. of p-toluenesulphonic acid in 100 cc. of anhydrous benzene is refluxed until the theoretical amount of water no longer distils azeotropically. The mixture is washed first with dilute NaOH and then with H2O until neutral. After drying with Na2SO4 the solvent is removed under vacuum. The residual oil is fractionated, and the desired product boils at 136°-139°C./0.3 mm.
Reaction SMILES: [CH2:1]([NH:8][NH2:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][C:11]([CH3:18])([CH3:17])[C:12](=O)[CH2:13][C:14]#[N:15]>>[CH2:1]([N:8]1[C:14]([NH2:15])=[CH:13][C:12]([C:11]([CH3:18])([CH3:17])[CH3:10])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNCc1ccccc1
Reactant: CC(C)(C)C(=O)CC#N
Product: CC(C)(C)c1cc(N)n(Cc2ccccc2)n1
Yield: 36.3 %

Procedure:
Following the procedure in Example 161A Step 3, benzylhydrazine (977 mg, 8.0 mmol) and 4,4-dimethyl-3-oxopentanenitrile (1.0 g, 8.0 mmol) to give 1-benzyl-3-tert-butyl-1H-pyrazol-5-amine (666 mg, 2.90 mmol, 36%). 1H NMR (300 MHz, DMSO-d6) δ 7.32-7.21 (m, 3H), 7.09 (d, 2H), 5.17 (s, 1H), 5.05 (d, 4H), 1.15 (s, 9H); LC-MS (ESI) m/z 230 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:25])[CH2:3][N:4]([S:14]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[I:24])(=[O:16])=[O:15])[C:5]1[N:6]=[CH:7][S:8][C:9]=1[C:10]([O:12]C)=O.[H-].[Na+].O.Cl>CN(C)C=O>[F:1][CH:2]([F:25])[CH2:3][N:4]1[C:5]2[N:6]=[CH:7][S:8][C:9]=2[C:10]([OH:12])=[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[I:24])[S:14]1(=[O:15])=[O:16]
Reactant: COC(=O)c1scnc1N(CC(F)F)S(=O)(=O)Cc1ccccc1I
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S1(=O)C(c2ccccc2I)=C(O)c2scnc2N1CC(F)F
Temperature: 0 °C
Reaction time: 12 h

Procedure:
2.0 g (4 mmol) of methyl 4-{(2,2-difluoroethyl)[(2-iodobenzyl)sulfonyl]amino}-1,3-thiazole-5-carboxylate were dissolved in 25 ml of dimethylformamide and cooled to 0° C., and 143.3 mg (6 mmol) of sodium hydride were added. After addition, the mixture was warmed to RT and stirred for 12 h. Thereafter, the reaction mixture was poured onto 100 ml of water and brought to pH 4-5 with 2N HCl. The precipitate formed was filtered off and washed with water. This gave 1.7 g of compound I-a-14.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8](Cl)=[O:9])=[CH:4][CH:3]=1.Cl.[CH3:14][NH:15][O:16][CH3:17]>C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>[CH3:17][O:16][N:15]([CH3:14])[C:8](=[O:9])[CH2:7][O:6][C:5]1[CH:11]=[CH:12][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: O=C(Cl)COc1ccc(F)cc1
Reactant: CNOC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CON(C)C(=O)COc1ccc(F)cc1
Reaction time: 0.33 h
Yield: 73 %

Procedure:
2-(4-Fluorophenoxy)ethanoic acid chloride was added slowly to a stirred suspension of N,O-dimethylhydroxylamine hydrochloride (55.80 g, 572 mmol) in saturated K2CO3 and ethyl acetate (375 mL). A moderately exothermic reaction occurred (larger scale reactions are cooled with an ice bath), and after 20 minutes, the reaction mixture was partitioned between water and ether. The ether layer was washed with 1 M HCl and saturated NaCl, and dried over MgSO4. The dried solution was filtered and concentrated under vacuum to give N-methoxy-N-methyl-2-(4-fluorophenoxy)ethanamide, a compound of formula (Z), as a yellow oil which solidified to an off-white crystalline solid, 113.05 g (73% yield from starting acid); 1H NMR (CDCl3, 400 mHz) δ 3.21 (s, 3H), 3.73 (s, 3H), 4.75 (s, 2H), 6.87 (m, 2H), 6.95 (m, 2H) ppm.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:10]([CH:11]=O)=[CH:9][N:8]=[C:7]3[N:13]([CH2:16][CH3:17])[N:14]=[CH:15][C:6]=23)[CH2:3][CH2:2]1.Cl.[NH2:19][OH:20].C([O-])(=O)C.[Na+]>C(O)C>[CH:1]1([NH:4][C:5]2[C:10]([CH:11]=[N:19][OH:20])=[CH:9][N:8]=[C:7]3[N:13]([CH2:16][CH3:17])[N:14]=[CH:15][C:6]=23)[CH2:3][CH2:2]1
Reactant: NO
Reactant: CCn1ncc2c(NC3CC3)c(C=O)cnc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCn1ncc2c(NC3CC3)c(C=NO)cnc21
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a stirred solution of 4-cyclopropylamino-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (300 mg, 0.00129 mole) in ethanol, hydroxylamine hydrochloride (359 mg, 0.0051 mole) and sodium acetate (424 mg, 0.0051 mole) were added. The reaction mixture was allowed to stir at room temperature for about 50 minutes. Ethanol was removed under reduced pressure and residue was poured in water. The organic compound was extracted with ethyl acetate. Ethyl acetate layer was dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure to afford white solid compound. Yield: 270 mg. m/z: (M++1) 246.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:22]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[NH:15][C:14]=3[N:13]=[C:12]([NH:23]C(=O)C(C)(C)C)[N:11]=2)=[CH:5][CH:4]=1.[OH-].[Na+].C(Cl)(Cl)Cl.CO>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[C:22]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[NH:15][C:14]=3[N:13]=[C:12]([NH2:23])[N:11]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(Nc2nc(NC(=O)C(C)(C)C)nc3[nH]c4ccccc4c23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc(Nc2nc(N)nc3[nH]c4ccccc4c23)cc1
Yield: 64 %

Procedure:
Using the general procedure described above, the reaction of 10 (80 mg, 0.20 mmol) and 1 N NaOH provided 40 mg of AAG106 as an off-white solid in 64% yield. TLC Rf 0.30 (chloroform-methanol 15:1); mp 208.9-209.1° C.; 1H NMR (DMSO-d6) δ 3.76 (s, 3H, OCH3), 6.19 (s, 2H, NH2, exch), 7.09-8.05 (m, 8H, Ar—H), 8.26 (s, 1H, 4-NH, exch), 11.27 (s, 1H, 9-NH, exch). Anal. Calculated (C17H15N5O. 0.35 CH3OH): C, 65.83; H, 5.22; N, 22.12. Found: C, 66.08; H, 5.22; N, 21.81.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[NH:10][C:9]2=[O:17])=[CH:4][CH:3]=1.Cl[C:19]1[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]2[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=2[N:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:29][Si:28]([CH3:31])([CH3:30])[CH2:27][CH2:26][O:25][CH2:24][N:23]1[C:22]2[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=2[N:20]=[C:19]1[O:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[NH:10][C:9]2=[O:17])=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCn1c(Cl)nc2ccccc21
Reactant: O=c1[nH]c2cccnc2n1-c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1c(Oc2ccc(-n3c(=O)[nH]c4cccnc43)cc2)nc2ccccc21
Temperature: 25 °C
Yield: 72.6 %

Procedure:
3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (370 mg), 2-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole (507 mg) and cesium carbonate (1.17 g) in DMF (10 mL) was heated at 100° C. for 4 h. After cooling to rt, the mixture was partitioned between AcOEt and H2O. The organic layer was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography (SiO2, hexane/AcOEt=1/1 to 0/1) to give 3-{4-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (560 mg) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([NH:13][CH2:14][CH2:15][OH:16])=[N:10]2)=[CH:5][C:4]=1[N+:17]([O-])=O.[Cl-].[NH4+]>C(O)C.CN(C)C=O.[Fe]>[NH2:17][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:3]=1[O:2][CH3:1])[N:10]=[C:9]([NH:13][CH2:14][CH2:15][OH:16])[CH:8]=[CH:7]2
Reactant: COc1cc2nc(NCCO)ccc2cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1cc2nc(NCCO)ccc2cc1N
Yield: 95.9 %

Procedure:
A mixture of 2-(7-methoxy-6-nitro-quinolin-2-ylamino)-ethanol (0.5 g, 1.90 mmol), iron powder (0.32 g, 5.70 mmol) and ammonium chloride (0.32 g, 5.70 mmol) in a mixture of ethanol and water (3/1, 16 mL) was heated at reflux for 2 hours. The reaction mixture was then filtered through a CELITE™ pad, the filtrate was evaporated under reduced pressure and the residue was triturated ten times with a mixture of dichloromethane and methanol (9/1, 50 mL). The residue was concentrated under reduced pressure to afford 0.425 g of 2-(6-amino-7-methoxy-quinolin-2-ylamino)-ethanol as a brown solid.
Reaction SMILES: [CH3:1][NH:2][C:3]([C@@:5]1([N:15]2[CH:23]=[N:22][C:21]3[C:16]2=[N:17][C:18]([Cl:33])=[N:19][C:20]=3[NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([I:32])[CH:27]=2)[C@@H:12]2[C@@H:8]([O:9]C(C)(C)[O:11]2)[CH2:7][S:6]1)=[O:4]>C(O)(=O)C>[CH3:1][NH:2][C:3]([C@@:5]1([N:15]2[CH:23]=[N:22][C:21]3[C:16]2=[N:17][C:18]([Cl:33])=[N:19][C:20]=3[NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([I:32])[CH:27]=2)[C@@H:12]([OH:11])[C@@H:8]([OH:9])[CH2:7][S:6]1)=[O:4]
Reactant: CNC(=O)[C@]1(n2cnc3c(NCc4cccc(I)c4)nc(Cl)nc32)SC[C@@H]2OC(C)(C)O[C@@H]21
Solvent: CC(=O)O
Product: CNC(=O)[C@]1(n2cnc3c(NCc4cccc(I)c4)nc(Cl)nc32)SC[C@H](O)[C@@H]1O
Temperature: 55 °C
Reaction time: 12 h
Yield: 50.9 %

Procedure:
4 mL of 80% aqueous acetic acid solution were added to 42 mg (0.07 mmol) of (3aS,4R, 6aR)-4-[2-chloro-6-(3-iodobenzylamino)purin-9-yl]-2,2-dimethyltetrahydrothieno[3,4-d][1,3]dioxole-4-carboxylic acid methyl amide from the aforementioned Experimental Example 11, which was then stirred at 55° C. for 12 h. The reaction mixture was distilled under reduced pressure, and then the pH of the concentrate was adjusted to neutral by adding a saturated ammonia methanol solution. The concentrate was purified by silica gel column chromatography using the eluant (dichloromethane and methanol=7:1) to obtain 20 mg (yield: 52%) of (2R,3S,4R)-2-[2-chloro-6-(3-iodobenzylamino)purin-9-yl)-3,4-dihydroxytetrahydrothiophene-2-carboxylic acid methyl amide as white solids (see Table 1).
Reaction SMILES: [C:1]([C:4]1([CH2:17][CH2:18][CH2:19][NH2:20])[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)(=[O:3])[NH2:2].[C:21](OC(=O)C)(=[O:23])C.C(OCC)(=O)C>C(O)=O>[C:1]([C:4]1([CH2:17][CH2:18][CH2:19][NH:20][CH:21]=[O:23])[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)(=[O:3])[NH2:2]
Reactant: NCCCC1(C(N)=O)c2ccccc2-c2ccccc21
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Solvent: CCOC(C)=O
Product: NC(=O)C1(CCCNC=O)c2ccccc2-c2ccccc21
Temperature: 30 °C
Reaction time: 1 h

Procedure:
To a stirred hot (50° C.) solution of 6.2 g (23 mM) of 9-carbamoyl-9-(3-aminopropyl)fluorene in 50 ml of 98% formic acid were added dropwise over ten minutes 17 ml of acetic anhydride. The reaction mixture was cooled to about 30° C. and stirred for one hour, and then added to 100 ml of ice water. The aqueous mixture was diluted by addition of 100 ml of ethyl acetate, and the organic layer was separated, washed with two 50 ml portions of 5% w/v aqueous sodium bicarbonate, twice with 5 ml portions of 1N hydrochloric acid, again with sodium bicarbonate, and finally with water. The solution was dried and the solvent was removed by evaporation under reduced pressure to provide 2.0 g of 9-carbamoyl-9-(3-formamidopropyl)fluorene. mp 160°-161° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]1[CH2:16][CH2:15][NH:14][CH2:13]1)[CH2:7][CH2:6][CH2:5]2.C=O.[C:19](O)(=O)C.C([BH3-])#N.[Na+]>CO.CO.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]1[CH2:16][CH2:15][N:14]([CH3:19])[CH2:13]1)[CH2:7][CH2:6][CH2:5]2
Reactant: Brc1ccc2c(c1)CCCN2C1CCNC1
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CN1CCC(N2CCCc3cc(Br)ccc32)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 6-bromo-1-(pyrrolidin-3-yl)-1,2,3,4-tetrahydroquinoline (200 mg, 0.71 mmol) in 7 mL anhydrous methanol was treated with formaldehyde (37% aqueous solution, 79 μL, 1.07 mmol) followed by acetic acid (100 μL, 1.78 mmol). The solution was treated with sodium cyanoborohydride (67 mg, 1.07 mmol). The suspension was stirred at room temperature for 3 hours. The mixture was concentrated to dryness and partitioned between 20 mL 1N NaOH and 100 mL of CH2Cl2. After extraction, the organic layer was dried over Na2SO4, filtered and concentrated to give an oily residue which was subjected to flash chromatography on silica gel using 5% 2M NH3 in MeOH/CH2Cl2. A yellow oil was obtained (153 mg, 72.9%). 1H-NMR (CDCl3) δ 7.10 (dd, J=2.4, 8.7 Hz, 1H), 7.04 (d, J=2.4 Hz, 1H), 6.57 (d, J=9.0 Hz, 1H), 4.47-4.38 (m, 1H), 3.26 (t, J=5.7 Hz, 2H), 2.81-2.68 (m, 4H), 2.60-2.55 (m, 1H), 2.40-2.24 (m, 1H), 2.35 (s, 3H), 2.24-2.13 (m, 1H), 1.92-1.79 (m, 3H). MS(ESI): 295.1 and 297.1 (M+1).
Reaction SMILES: CS[C:3]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[CH:4][N+:5]([O-:7])=[O:6].[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH2:21])[CH:15]=1>CCO>[N:8]1([C:3]([NH:21][CH2:20][C:16]2[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=2)=[CH:4][N+:5]([O-:7])=[O:6])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CSC(=C[N+](=O)[O-])N1CCCCC1
Reactant: NCc1cccnc1
Solvent: CCO
Product: O=[N+]([O-])C=C(NCc1cccnc1)N1CCCCC1
Yield: 28.6 %

Procedure:
In 20 ml of EtOH was dissolved 0.8 g (0.004 mole) of 1-methylthio-1-piperidino-2-nitroethylene followed by addition of 0.4 g (0.004 mole) of 3-pyridylmethylamine. The mixture was refluxed for 2 hours. The ethanol was distilled off and the residue was purified by silica gel column chromatography to give 0.3 g of the title compound as a pale yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:9][C@@H:8]([CH3:10])[CH2:7][C:6]=1OS(C(F)(F)F)(=O)=O)=[O:4].[CH3:19][O:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][O:31][CH3:32])=[CH:25][C:24]=1B(O)O.[Li+].[Cl-]>COCCOC.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>[CH3:1][O:2][C:3]([C:5]1[CH2:9][C@@H:8]([CH3:10])[CH2:7][C:6]=1[C:25]1[CH:24]=[C:23]([O:22][CH2:21][O:20][CH3:19])[CH:28]=[CH:27][C:26]=1[O:29][CH2:30][O:31][CH3:32])=[O:4]
Reactant: COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)C[C@H](C)C1
Reactant: COCOc1ccc(OCOC)c(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: COCCOC
Product: COCOc1ccc(OCOC)c(C2=C(C(=O)OC)C[C@@H](C)C2)c1
Reaction time: 2 h
Yield: 81.6 %

Procedure:
Prepare a mixture of 4-Methyl-2-trifluoromethanesulfonyloxy-cyclopent-1-enecarboxylic acid methyl ester 3a (2.5 g, 8.7 mmol), 2,5-Bis-methoxymethoxy phenylboronic acid 7 (2.31 g. 9.5 mmol), tetrakis(triphenylphosphine)palladium (485 mg, 0.435 mmol), and LiCl (1.1 g, 26.1 mmol) in DME (80 mL). Add 2.0 M solution of Na2 CO3 (10 mL, 21.7 mmol) and heat the reaction to reflux and stir for 2 hours. Cool the reaction to room temperature and partitioned between CH2Cl2 and saturated aqueous NaHCO3. Separate and extract the aqueous solution with CH2Cl2 (2×). Combine the organic extracts, dry (Na2SO4), filter and concentrate in vacuo. Purify by flash chromatography (125 g SiO2, 0-30% EtOAc/hexane and 30% EtOAc/hexane) to afford 2-(2,5-Bis-methoxymethoxy-phenyl)-4-methyl-cyclopent-1-enecarboxylic acid methyl ester 8a (2.4 g, 7.1 mmol, 83%) as a yellow oil. 1H NMR (δ, 400 MHz, CDCl3): 7.02 (d, 1H, J=9.2 Hz), 6.90 (dd, 1H, J=9.2, 3.1 Hz), 6.80 (d, 1H, J=3.1 Hz), 5.10 (s, 2H), 5.03 (s, 2H), 3.56 (s, 3H), 3.48 (s, 3H), 3.44 (s, 3H), 3.01-2.91 (m, 2H), 2.53-2.37 (m, 3H), 1.14 (d, 3H, J=6.6 Hz). HRMS calcd. 337.1651; found (electrospray, M+1) 337.1647.