Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18](O)[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S([O:41][CH2:42][CH:43]2[CH2:47][O:46][C:45]([CH3:49])([CH3:48])[O:44]2)(=O)=O)=CC=1>CC#N>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:41][CH2:42][CH:43]3[CH2:47][O:46][C:45]([CH3:48])([CH3:49])[O:44]3)[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCC2COC(C)(C)O2)cc1
Reactant: COc1cc(O)cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(OCC2COC(C)(C)O2)cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 25 °C
Yield: 71.1 %

Procedure:
1.60 g (4.6 mmol) of 4-(3-hydroxy-5-methoxy-benzoylamino)-piperidine-1-carboxylic acid tert-butyl ester (example 168a) was dissolved in 50 ml of MeCN at rt; 1.29 g (9.4 mmol) of anhydrous potassium carbonate was added, followed by 1.495 g (4.8 mmol) of rac-2,2-dimethyl-1,3-dioxolan-4-yl-methyl p-toluenesulfonate. The reaction mixture was stirred at reflux for 22 hours. It was then cooled down to ambient temperature and poured into crashed ice and extracted twice with EtOAc. The organic phases were washed with water and brine, dried over MgSO4, filtered and evaporated i.V. and the residue (2.11 g) was purified by chromatography (SiO2, MeCl2/MeOH) to yield 1.52 g of the title compound as a colorless amorphous solid. MS: 465.2 (MH+).
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]#[N:8])[CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].CO.[Cl-].[NH4+]>O1CCCC1.O>[C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH2:8])[CH:2]=1
Reactant: N#Cc1cccc(-c2ccccc2)c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: NCc1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 62.8 %

Procedure:
Next, a solution of the resulting biphenyl-3-carbonitrile (821 mg, 4.58 mmol) in tetrahydrofuran (5 mL) was added to a solution of lithium aluminum hydride (0.435 g, 11.5 mmol) in tetrahydrofuran (5 mL) that had been cooled on an ice bath, and the solution was stirred for 6 hours at room temperature. The reaction solution was cooled on an ice bath, a mixture solution of methanol and water (9:1) was added thereto, an aqueous solution of saturated ammonium chloride was further added, filtration was carried out through Celite pad and insoluble matter was removed. The filtrate was partitioned, the organic layer was dried over anhydrous magnesium sulfate, and the title compound (527 mg, 63%) was obtained as a brown oil. This was used in the next reaction without further purification.
Reaction SMILES: [S:1](=[O:5])(=O)([OH:3])[OH:2].Cl.[C:7]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)(=[NH:9])[NH2:8]>>[C:7]([C:10]1[CH:11]=[CH:12][C:13]([OH:16])=[C:14]([S:1]([OH:3])(=[O:5])=[O:2])[CH:15]=1)(=[NH:8])[NH2:9]
Reactant: N=C(N)c1ccc(O)cc1
Reactant: O=S(=O)(O)O
Agent: Cl
Product: N=C(N)c1ccc(O)c(S(=O)(=O)O)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 15 ml of 60% fuming sulfuric acid, while being cooled in ice, was added slowly 10.0 g of 4-amidinophenol hydrochloride. After the addition, the mixture was stirred at room temperature for 4 hours, then poured slowly into 200 ml of ice water, and stirred for a while. The colorless solid which was precipitated was collected by filtration, washed with water, then with acetone, and dried to obtain 10.2 g of 5-amidino-2-hydroxybenzenesulfonic acid.
Reaction SMILES: [C:1]1(C)C=CC=C(C#N)C=1.NO.[OH:12][N:13]=[C:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CCO>[OH:12][N:13]=[C:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:1])[CH:16]=1
Reactant: NC(=NO)c1ccccc1
Reactant: Cc1cccc(C#N)c1
Agent: NO
Solvent: CCO
Product: Cc1cccc(C(N)=NO)c1
Yield: 97.7 %

Procedure:
The reaction of m-tolunitrile (1 g, 8.54 mmol) and hydroxylamine (0.78 cm3, 12.8 mmol, 1.5 eq) in EtOH (8.5 cm3) was performed in the same manner as in the preparation of N′-hydroxybenzimidamide, to give the product N′-hydroxy-3-methylbenzimidamide (1.25 g, 97.7%) as a white solid, mp 92° C. (lit 88-90° C.).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:12].[C:13]1([CH3:22])[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[OH:12][C:3]1[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:2]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH3:22]
Reactant: Cc1ccccc1B(O)O
Reactant: COC(=O)c1ccc(Br)c(O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2ccccc2C)c(O)c1
Temperature: 110 °C
Yield: 76.4 %

Procedure:
To a mixture of methyl 4-bromo-3-hydroxybenzoate (25 g, 0.108 mol) and o-tolylboronic acid (22 g, 0.162 mol) in a toluene (500 mL) water (100 mL) mixture, was added anhydrous potassium carbonate (44 g, 0.324 mol) followed by tetrakis (triphenylphosphine) palladium (0) (6.25 g, 0.054 mol). The reaction mixture was degassed with N2 and heated at 110° C. for 12 h. After cooling to RT, the reaction mixture was filtered through a celite pad that was washed further with ethyl acetate. Combined filtrates were washed with 10% solution of NaHCO3, water and brine solution. The solvents were dried over Na2SO4 and evaporated under vacuum. The residue was purified by chromatography (pet ether/EtOAc as an eluent) to afford the title compound as pale yellow solid (20 g, 77%). 1H NMR (DMSO-d6, 400 MHz) δ 9.85 (1H, s), 7.52 (1H, s), 7.44-7.46 (1H, m), 7.20-7.25 (3H, m), 7.14-7.16 (1H, m), 7.09-7.11 (1H, m), 3.84 (3H, s), 2.09 (3H, s).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:14][CH:13]2[CH:9]([CH2:10][C:11]3[S:17][C:16]([CH3:18])=[CH:15][C:12]=32)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(Cl)(Cl)Cl.C1(C=CC(O)=CC=1)O.C1C(=O)N([Br:38])C(=O)C1>CC(O)=O>[CH2:1]([O:3][C:4]([N:6]1[CH2:14][CH:13]2[CH:9]([CH2:10][C:11]3[S:17][C:16]([CH3:18])=[C:15]([Br:38])[C:12]=32)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)N1CCC2Cc3sc(C)cc3C2C1
Agent: Oc1ccc(O)cc1
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCC2Cc3sc(C)c(Br)c3C2C1

Procedure:
A solution of the product from step c) (411 mg, 1.55 mmol) in AcOH (3.8 ml) and CHCl3 (3.8 ml) was treated with hydroquinone (5 mg) and NBS (331 mg, 1.86 mmol) at 40° C. for 3 hours in the dark. Next, the reaction mixture was carefully quenched with sat. NaHCO3 (5 ml) and extracted with EtOAc (3×20 ml). The combined organic extracts were dried (MgSO4) and solvent evaporated in vacuo leaving the crude product that was purified by preparative TLC (hexanes:EtOAc-1:1) to give the subtitle compound. MS calculated for C14H18BrNO2S+H 344, observed 344, 346.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C1COCC1.O.C(OC)(C)(C)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:15]([CH3:14])(=[O:17])=[O:16])=[CH:4][N:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Brc1ccc(Br)nc1
Agent: CC(C)[Mg]Cl
Solvent: COC(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(Br)nc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2,5-dibromopyridine (5 g, 21.1 mmol) in THF (20 mL) at 0° C. was slowly added 2M isopropylmagnesium chloride in THF (14.4 ml). The mixture was stirred at 0° C. for 1 hour, cooled to −15° C. followed by the dropwise addition of methane sulfonyl chloride in 5 mL THF. The mixture was slowly warmed up to room temperature, diluted with water (5 mL) and t-butylmethyl ether (3×50 mL). The layers were separated and the aqueous layer extracted with t-butylmethyl ether (2×). The combined organic layers were washed with brine, dried MgSO4, filtered and concentrated under reduced pressure and purified by chromatography (silica gel, eluting with 30% hexane-70% ethyl acetate) to provide the titled compound. MS (CI) m/z 237 (M+1)+, 254 (M+NH4)+ 1H NMR (300 MHz, CDCl3) δ ppm: 8.92 (d, 1H), 8.06 (dd, 1H), 7.73 (d, 1H), 3.12 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:14]([NH2:15])=[CH:13][C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])=[CH:11][N:10]=1.Cl[C:25]1[C:34]2[C:29](=[CH:30][C:31]([F:36])=[CH:32][C:33]=2[F:35])[N:28]=[C:27]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)[C:26]=1[CH3:43].C1(P(C2CCCCC2)C2(C(C)C)CC(C(C)C)=CC(C(C)C)=C2C2C=CC=CC=2)CCCCC1.CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:14]([NH:15][C:25]2[C:34]3[C:29](=[CH:30][C:31]([F:36])=[CH:32][C:33]=3[F:35])[N:28]=[C:27]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=3)[C:26]=2[CH3:43])=[CH:13][C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])=[CH:11][N:10]=1
Reactant: COc1ccccc1-c1cnc(-c2ccccc2OC)c(N)c1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)C1=CC(C(C)C)=C(c2ccccc2)C(C(C)C)(P(C2CCCCC2)C2CCCCC2)C1
Solvent: Cc1ccccc1
Product: COc1ccccc1-c1cnc(-c2ccccc2OC)c(Nc2c(C)c(-c3ccccn3)nc3cc(F)cc(F)c23)c1
Temperature: 90 °C
Reaction time: 21.5 h

Procedure:
A mixture of 2,5-bis(2-methoxyphenyl)-3-pyridinamine (37.5 mg, 0.12 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(2-pyridinyl)quinoline (54.7 mg, 0.19 mmol), 2-dicyclohexylphosphino-2,4,6,-triisopropylbiphenyl (12.1 mg, 0.025 mmol), tris(dibenzylideneacetone)dipalladium (0) (11.9 mg, 0.013 mmol), and sodium tert-butoxide (36.7 mg, 0.38 mmol) in dry toluene (2.0 mL) was degassed by nitrogen. The mixture was heated to 90° C. After 21.5 h, the reaction was cooled to rt, then treated with water. After extracting twice with EtOAc, the organic layers were combined and dried over anhydrous magnesium sulfate. After filtration and concentration the residue was purified on basic alumina (0-30% EtOAc in hexanes) to afford an impure light yellow film. The film was further purified by HPLC (10-90% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution.) The desired fractions were concentrated then diluted with EtOAc. After washing twice with satd aq. sodium bicarbonate solution and once with brine, the solvent was removed under reduced pressure to yield a white solid as N-(2,5-bis(2-methoxyphenyl)-3-pyridinyl)-5,7-difluoro-3-methyl-2-(2-pyridinyl)-4-quinolinamine. 1H NMR (500 MHz, CDCl3) δ ppm 8.69 (1H, d, J=4.6 Hz), 8.52 (1H, d, J=1.7 Hz), 7.84 (1H, td, J=7.7, 1.7 Hz), 7.76 (1H, d, J=7.6 Hz), 7.62 (2H, m), 7.50 (1H, m), 7.41 (4H, m), 7.16 (1H, t, J=7.5 Hz), 7.08 (1H, d, J=8.1 Hz), 7.04 (3H, m), 3.98 (3H, s), 3.83 (3H, s), 2.06 (3H, br. s.). Mass Spectrum ESI (pos.) m/e: 561.3 (M+1).
Reaction SMILES: [H-].[Na+].[CH:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=1[O:25][CH3:26])=[O:4].[CH3:27]I.Cl>CN(C)C=O>[CH:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:27])[CH:9]=[C:8]2[CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=1[O:25][CH3:26])=[O:4]
Reactant: CI
Reactant: COC(=O)c1ccc(Cc2c[nH]c3ccc(C=O)cc23)c(OC)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cc2cn(C)c3ccc(C=O)cc23)c(OC)c1
Reaction time: 1 h
Yield: 80.9 %

Procedure:
Sodium hydride (1.23 g of a 60% dispersion in mineral oil) was added to dry N,N-dimethylformamide (100 ml), under an atmosphere of nitrogen. The mixture was cooled in an ice-bath, a solution of methyl 4-(5-formylindol-3-ylmethyl)-3-methoxybenzoate (9.0 g) in N,N-dimethylformamide (20 ml) added slowly, and the mixture stirred for 1 hr. Methyl iodide (4.34 g) was added slowly, stirring continued for 2.5 hr., then the mixture carefully acidified with hydrochloric acid (100 ml) to give an off-white precipitate which was purified by flash chromatography, eluting with 45:50:5 hexane:methylene chloride:ethyl acetate, to give a yellow oil which was crystallized from a mixture of ethyl acetate and hexane to give methyl 4-(5-formyl-1-methylindol-3-ylmethyl)-3-methoxybenzoate (7.6 g, 81%) as an off-white powder; mp 116°-118°; partial NMR(250 MHz, DMSO-d6): 3.80 (s, 3H, OCH3), 3.83(s, 3H, NCH3), 3.93(s, 3H, OCH 3), 4.11(s, 2H, ArCH2Ar'), 8.12(s, 1H, H4 -indole), 9.96(s, 1H, CHO).
Reaction SMILES: [Cl:1][C:2]1[C:22](F)=[CH:21][C:5]2[C:6]3[C:7](=[O:20])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][N:10]([CH3:14])[C:11]=3[CH:12]=[N:13][C:4]=2[C:3]=1[F:24].[F:25][C:26]1[CH:27]=[C:28]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:29]=[CH:30][C:31]=1[CH3:32]>CS(C)=O>[Cl:1][C:2]1[C:22]([N:36]2[CH2:35][CH2:34][N:33]([C:28]3[CH:29]=[CH:30][C:31]([CH3:32])=[C:26]([F:25])[CH:27]=3)[CH2:38][CH2:37]2)=[CH:21][C:5]2[C:6]3[C:7](=[O:20])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][N:10]([CH3:14])[C:11]=3[CH:12]=[N:13][C:4]=2[C:3]=1[F:24]
Reactant: CCOC(=O)c1cn(C)c2cnc3c(F)c(Cl)c(F)cc3c2c1=O
Reactant: Cc1ccc(N2CCNCC2)cc1F
Solvent: CS(C)=O
Product: CCOC(=O)c1cn(C)c2cnc3c(F)c(Cl)c(N4CCN(c5ccc(C)c(F)c5)CC4)cc3c2c1=O
Temperature: 80 °C
Reaction time: 20 h
Yield: 42.8 %

Procedure:
A stirred suspension of 1 g of ethyl 8-chloro-7,9-difluoro-4-methyl-1-oxo-1,4-dihydrobenzo[f][1,7]naphthyridine-2-carboxylate and 1.2 g of 1-(3-fluoro-4-methylphenyl)piperazine in 15 cm3 of dimethyl sulphoxide was heated to a temperature in the region of 80° C. After 20 hours, 0.6 g of 1-(3-fluoro-4-methylphenyl)piperazine was added and the heating was continued for an additional 8 hours. After 28 hours, the reaction mixture was cooled and then filtered. The precipitate was washed twice with 10 cm3 of water, twice with 5 cm3 of ethanol, and twice with 5 cm3 of diisopropyl ether. 0.64 g of ethyl 8-chloro-7-fluoro-9-[4-(3-fluoro-4-methylphenyl)piperazin-1-yl]-4-methyl-1-oxo-1,4-dihydrobenzo[f][1,7]naphthyridine-2-carboxylate was obtained in the form of a greenish-yellow solid, which melted at 350° C. with decomposition.
Reaction SMILES: C([Si](C)(C)[N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][Si](C(C)(C)C)(C)C)[CH:13]=2)[C:8]([CH3:23])=[CH:7]1)(C)(C)C.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[CH3:23][C:8]1[C:9]2[C:14](=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[NH:6][CH:7]=1
Reactant: Cc1cn([Si](C)(C)C(C)(C)C)c2cc(O[Si](C)(C)C(C)(C)C)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: Cc1c[nH]c2cc(O)ccc12

Procedure:
In analogy to the procedure described in example 27 d], 1-(tert-butyl-dimethyl-silanyl)-6-(tert-butyl-dimethyl-silanyloxy)-3-methyl-1H-indole was treated with tetrabutylammonium fluoride hydrate to obtain 3-methyl-1H-indol-6-ol as brown crystals.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[CH2:12]([O:14][CH2:15][C:16]1[N:17]([CH2:29][C:30]2([C:36]([NH2:38])=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[C:18]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]=[CH:20][C:19]=2[N:28]=1)[CH3:13].[OH-].[NH4+:40].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[NH2:40][C:20]1[C:19]2[N:28]=[C:16]([CH2:15][O:14][CH2:12][CH3:13])[N:17]([CH2:29][C:30]3([C:36]([NH2:38])=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[C:18]=2[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:21]=1
Reactant: [NH4+]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC1(C(N)=O)CCCCC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CC1(C(N)=O)CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
mCPBA (953 mg of 77% pure material, 4.25 mmol) was added to a solution of 1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexanecarboxamide (1.30 g, 3.54 mmol) in chloroform (15 mL); the reaction was stirred for one hour at ambient temperature. Ammonium hydroxide (15 mL) and p-toluenesulfonyl chloride (742 mg, 3.89 mmol) were added, and the mixture was stirred vigorously for two hours. The aqueous fraction was separated and extracted several times with chloroform. The combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with 2-7% methanol in dichloromethane) followed by recrystallization from acetonitrile to provide 1-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexanecarboxamide as a tan crystalline solid, mp 221-223° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C@:15](O)([CH2:16][C@@H:17]([O:36][C:37](=[O:39])[CH3:38])[CH2:18][C@@H:19]2[O:27][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:14]=[CH:13]3)[CH2:10][CH2:9]1)[CH3:7].ClCC(O)=O.[C:46](=[O:51])([O:49]C)[O:47][CH3:48]>>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([CH2:16][C@@H:17]([O:36][C:37](=[O:39])[CH3:38])[CH2:18][C@@H:19]2[O:27][C:28](=[O:35])[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:14][C@H:13]3[O:51][C:46]([O:47][CH3:48])=[O:49])[CH2:10][CH2:9]1)[CH3:7]
Reactant: COC(=O)OC
Reactant: CC(=O)O[C@H]1C[C@H](OC(=O)c2ccccc2)[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](C(C)C5OCCO5)CC[C@H]4[C@@H]3C=C[C@@]2(O)C1
Agent: O=C(O)CCl
Product: COC(=O)O[C@@H]1C=C2C[C@@H](OC(C)=O)C[C@H](OC(=O)c3ccccc3)[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(C)C4OCCO4)CC[C@H]3[C@H]12
Temperature: 100 °C

Procedure:
In 10 ml of dimethyl carbonate was dissolved 350 mg of 20-(1,3-dioxolan-2-yl)-3β-acetoxy-1α-benzoyloxypregn-6-en-5α-ol, followed by addition of 0.1 ml of monochloroacetic acid. The mixture was stirred in an atmosphere of argon gas under heating at a temperature of 100° C. for 10 hours. The reaction mixture was then worked up in the same manner as Example 132 to give 100 mg of 20-(1,3-dioxolan- 2-yl)-3β-acetoxy-1α-benzoyloxy-7α-(methoxycarbonyl)oxypregn-5-ene showing the following physical properties.
Reaction SMILES: C([Zn]CC)C.CCCCCC.[C:12]([OH:18])([C:14](F)(F)F)=[O:13].C(I)I.COC([CH:26]1[CH2:30][C:29](=[CH2:31])[CH2:28][N:27]1[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])=O.C[N+]1([O-])CCOCC1>C(Cl)Cl.[Os](=O)(=O)(=O)=O.O.CC(C)=O>[CH2:35]([O:34][C:32]([N:27]1[CH:14]([C:12]([OH:18])=[O:13])[CH2:31][C:29]2([CH2:30][CH2:26]2)[CH2:28]1)=[O:33])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: O=C(O)C(F)(F)F
Reactant: C=C1CC(C(=O)OC)N(C(=O)OCc2ccccc2)C1
Agent: O=[Os](=O)(=O)=O
Agent: CC[Zn]CC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Solvent: O
Solvent: ICI
Product: O=C(O)C1CC2(CC2)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 110 h
Yield: 68.4 %

Procedure:
Diethyl zinc (1.0 M in hexane (118 mL, 118 mmol) was added to a 3-neck round bottom flask containing a stir bar, DCM (120 mL) and equipped with an addition funnel and an Argon inlet adaptor. The solution was cooled to 0° C. before TFA (9.5 mL, 118 mmol) in DCM (40 mL) was added dropwise by addition funnel over 22 minutes. 20 minutes after completion of the addition, CH2I2 was added slowly over 4 minutes. 20 minutes after completion of addition, 4-Methylene-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester (8.10 g, 29.4 mmol) in DCM (30 mL) was added by cannula followed by a rinse with DCM (10 mL). 10 minutes later, the reaction mixture was warmed to room temperature and stirred for 110 hours. The reaction was quenched by addition of 100 mL saturated aqueous NH4Cl. The entire contents of the flask were poured into saturated aqueous NaHCO3 and the aqueous phase was extracted 3× with EtOAc. The combined organics were dried over MgSO4, filtered and concentrated. The residue was dissolved in THF (100 mL), acetone (33 mL) and H2O (33 mL) and N-methylmorpholine-N-oxide (3.45 g, 29.41 mmol) and osmium tetroxide (4 wt % in H2O, 5 mL, 0.818 mmol) were added sequentially. The reaction mixture was stirred 7 hours at room temperature then quenched with 100 mL saturated aqueous Na2SO3. The entire contents of the flask was poured into H2O and the aqueous layer was extracted 3× with DCM. The combined organics were dried over MgSO4, filtered and concentrated. The resulting residue was purified by silica column chromatography (10% to 25% EtOAc/hexane) to provide 5-Aza-spiro[2.4]heptane-5,6-dicarboxylic acid 5-benzyl ester (5.54 g, 65%).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.[CH3:13][O:14][N:15]=[C:16]1[C:24]2[C:19](=[CH:20][C:21](B(O)O)=[CH:22][CH:23]=2)[CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>COCCOC.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:13][O:14][N:15]=[C:16]1[C:24]2[C:19](=[CH:20][C:21]([C:2]3[CH:6]=[CH:5][O:4][C:3]=3[C:7]3[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=3)=[CH:22][CH:23]=2)[CH2:18][CH2:17]1
Reactant: Brc1ccoc1-c1ccncc1
Reactant: CON=C1CCc2cc(B(O)O)ccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: CON=C1CCc2cc(-c3ccoc3-c3ccncc3)ccc21
Temperature: 25 °C
Yield: 79.4 %

Procedure:
A degassed mixture of the product of Step 3 (2.7 g, 12 mmol), the product of Step 2 (2.5 g, 12 mmol) and potassium carbonate (13.2 g, 96 mmol) in ethylene glycol dimethyl ether (70 ml) and water (30 ml) was treated with triphenylphosphine (314 mg, 1.2 mmol) and palladium acetate (135 mg, 0.6 mmol), then heated under reflux for 1 hour. After cooling to room temperature, the mixture was filtered through filter aid and the filtrate diluted with water and ethyl acetate. The organic phase was separated, washed with water and brine, dried, concentrated in vacuo and the residue purified by silica gel chromatography to give the title compound (2.9 g, 74%); MS(ES+) m/e 305 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:35]=[C:36]([O:38][CH3:39])[CH:37]=1)[NH:6][C:7]1[N:34]=[C:10]2[C:11]([N:15]3[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][N:23]4C(=O)C5C(=CC=CC=5)C4=O)[CH2:17][CH2:16]3)=[N:12][CH:13]=[CH:14][N:9]2[N:8]=1.NN>C(O)C>[NH2:23][CH2:22][CH2:21][N:18]1[CH2:17][CH2:16][N:15]([C:11]2[C:10]3[N:9]([N:8]=[C:7]([NH:6][C:5]4[CH:35]=[C:36]([O:38][CH3:39])[CH:37]=[C:3]([O:2][CH3:1])[CH:4]=4)[N:34]=3)[CH:14]=[CH:13][N:12]=2)[CH2:20][CH2:19]1
Reactant: COc1cc(Nc2nc3c(N4CCN(CCN5C(=O)c6ccccc6C5=O)CC4)nccn3n2)cc(OC)c1
Agent: NN
Solvent: CCO
Product: COc1cc(Nc2nc3c(N4CCN(CCN)CC4)nccn3n2)cc(OC)c1

Procedure:
To a suspension of 2-[2-[4-[2-(3,5-dimethoxyanilino)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl]piperazin-1-yl]ethyl]isoindoline-1,3-dione in ethanol is added hydrazine (20 eq) and the clear colorless solution is refluxed for 2 h and monitored by HPLC. The solvent is removed under reduced pressure and the residue purified via preparative HPLC yielding the title compound “D20”;