Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:14])[C:4](=O)[C:3]=1[C:16]#[N:17].[OH2:18].[NH2:19][NH2:20]>C(O)C>[NH2:17][C:16]1[C:3]2[C:4](=[O:18])[N:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[CH3:14])[CH:6]=[CH:7][C:2]=2[NH:20][N:19]=1
Reactant: O
Reactant: Cc1ccccc1-n1ccc(Cl)c(C#N)c1=O
Reactant: NN
Solvent: CCO
Product: Cc1ccccc1-n1ccc2[nH]nc(N)c2c1=O
Temperature: 90 °C

Procedure:
To a solution of 4-chloro-1-(2-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile obtained in Step D (3.15 g) in ethanol (10 mL) was added hydrazine monohydrate (1.58 mL) at room temperature. The reaction mixture was heated overnight at 90° C., and cooled to room temperature. The reaction mixture was concentrated under reduced pressure, to the residue was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (3.14 g).
Reaction SMILES: [CH3:1][O:2][CH2:3]/[CH:4]=[CH:5]/[C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[C:13]1[CH:16]=[CH:17][CH:18]=[CH:19][C:12]1=[N:11][C:10]=2[NH2:20].[H][H]>C(OCC)(=O)C.CO.[Pd]>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[C:13]1[CH:16]=[CH:17][CH:18]=[CH:19][C:12]1=[N:11][C:10]=2[NH2:20]
Reactant: COC/C=C/c1cnc2c(N)nc3ccccc3c2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COCCCc1cnc2c(N)nc3ccccc3c2c1
Reaction time: 3 h

Procedure:
To a solution of (E)-2-(3-methoxyprop-1-enyl)benzo[f][1,7]naphthyridin-5-amine (Example 34) in ethyl acetate/methanol (1:4, 0.05 M) was added 10% wt palladium on carbon (0.2 eq.). Hydrogen gas was introduced via a balloon, and the reaction was stirred for 3 hours. The mixture was filtered through a pad of celite, washing with dichloromethane. The filtrate was concentrated en vacuo and the crude product was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give 2-(3-methoxypropyl)benzo[f][1,7]naphthyridin-5-amine as a white solid. 1H NMR (CDCl3): δ 8.64 (d, 1H), 8.46 (d, 1H), 8.19 (d, 1H), 7.66 (d, 1H), 7.53 (m, 1H), 7.31 (m, 1H), 6.56 (bs, 2H), 3.37 (t, 2H), 3.31 (s, 3H), 2.91 (t, 2H), 1.93-2.00 (m, 2H). LRMS [M+H]=268.1.
Reaction SMILES: CN(C)C1[C:12]2[C:7](=[CH:8]C=C[C:11]=2[N:13]([CH3:15])C)[CH:6]=CC=1.[Cl:17][C:18]([O:20][CH:21](Cl)[CH3:22])=[O:19].C(O)C>C1(C)C=CC=CC=1>[ClH:17].[CH2:21]([O:20][C:18]([C@H:15]1[CH2:8][C:7]([CH3:6])=[CH:12][CH2:11][NH:13]1)=[O:19])[CH3:22]
Reactant: CC(Cl)OC(=O)Cl
Reactant: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@H]1CC(C)=CCN1
Product: Cl
Reaction time: 1 h

Procedure:
A stirred solution of the above intermediate (13.56 g, 49.7 mmol) in toluene (150 ml), under nitrogen, was heated under reflux for 2 hours, using a Dean-Stark trap. 1,8-Bis(dimethylamino)naphthalene (1.08 g, 5.0 mmol) was then added, heating continued for a further 1 hour, the reaction mixture allowed to cool and the Dean-Stark trap removed. After the addition of 1-chloroethyl chloroformate (10.7 ml, 14.2 g, 99.5 mmol), the reaction mixture was stirred under reflux for 16 hours, allowed to cool, treated with absolute ethanol (80 ml), stirred under reflux for 2 hours more and evaporated under reduced pressure. The residue was partitioned between ethyl acetate (100 ml) and 1M hydrochloric acid (50 ml), then the aqueous phase separated, neutralised with solid sodium bicarbonate and extracted with dichloromethane (3×200 ml). Evaporation under reduced pressure of the dried (MgSO4), combined extracts provided a brown residue which was purified by chromatography on silica gel, using a 0-5% methanol in dichloromethane elution gradient, and then converted to the required hydrochloride salt using excess ethereal hydrogen chloride. The product was further purified by dissolution in dichloromethane (20 ml), filtration (to remove residual silica gel), dilution of the filtrate with ether (200 ml), filtration, washing of the precipitate with ether and drying in vacuo. A sample of this purified product (5.77 g) was crystallised from a mixture of ether and ethanol to afford the title compound as white crystals, m.p. 110°-111° C. Rf 0.35 (SS 3).
Reaction SMILES: [O:1]1CCCO[CH:2]1[C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:17])=[O:16].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>CC(C)=O.O>[CH:2]([C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:16])=[O:17])=[O:1]
Reactant: N#Cc1ccc(C2OCCCO2)c(S(=O)(=O)c2ccccc2)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC(C)=O
Solvent: O
Product: N#Cc1ccc(C=O)c(S(=O)(=O)c2ccccc2)c1
Temperature: 160 °C
Reaction time: 0.1 h

Procedure:
In an Emrys microwave, 4-(1,3-dioxan-2-yl)-3-(phenylsulfonyl)benzonitrile (260 mg, 0.789 mmol) and pyridinium 4-toluenesulfonate (149 mg, 0.592 mmol; 0.75 eq.) in acetone/water (1:1, 3 ml) were heated with stirring at 160° C. for 6 min. The reaction mixture was then added to water (50 ml) and extracted with ethyl acetate (8×20 ml). The combined organic phases were subsequently washed with saturated sodium chloride solution (2×30 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. The title compound was obtained as a solid (0.21 g, quant.).
Reaction SMILES: [Mg].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Br:13][C:14]1[C:15]([F:25])=[C:16]([CH:20]=[C:21]([F:24])[C:22]=1[F:23])[C:17](Cl)=[O:18].S(=O)(=O)(O)O>C1(C)C=CC=CC=1.C(O)C.C(Cl)(Cl)(Cl)Cl>[Br:13][C:14]1[C:15]([F:25])=[C:16]([CH:20]=[C:21]([F:24])[C:22]=1[F:23])[C:17]([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])=[O:18]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(Cl)c1cc(F)c(F)c(Br)c1F
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C(=O)OCC)C(=O)c1cc(F)c(F)c(Br)c1F
Reaction time: 0.67 h
Yield: 98.6 %

Procedure:
Magnesium turnings (0.22 g) and carbon tetrachloride (0.1 ml) was added to absolute ethanol (1.5 ml). To the stirring suspension was added dropwise a solution of diethyl malonate (1.4 g) and absolute ethanol (2 ml) in toluene (6 ml) during 25 minutes at 50°-60° C. The mixture was stirred for 40 minutes, and then cooled. A solution of 3-bromo-2,4,5-trifluorobenzoyl chloride (2.27 g) in anhydrous toluene (3 ml) was added dropwise to the solution at -8°~-4.5° C. during 28 minutes. The mixture was stirred for 2 hours and then mixed with ice-chilled diluted sulfuric acid. The resulting organic layer was collected and the water layer was extracted with toluene (6 ml×4). The combined organic layer was washed with water, dried over anhydrous sodium sulfate and then concentrated to give the title compound (3.25 g) as pale yellow oil.
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.Br[CH2:13][CH2:14][CH2:15][C:16]([O:18]CC)=[O:17].Cl.C(=O)(O)[O-].[Na+].[CH2:27]([O:29]CC)[CH3:28]>O>[CH:2]1([N:1]([CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:27](=[O:29])[CH3:28])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: NC1CCCc2ccccc21
Reactant: CCOC(=O)CCCBr
Reactant: CCOCC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(=O)N(CCCC(=O)O)C1CCCc2ccccc21
Yield: 57.7 %

Procedure:
R1 =--CH3, R=1,2,3,4-tetrahydro-1-naphthyl, n=3 14.7 g of 1-amino-1,2,3,4-tetrahydronaphthalene and 9.7 g of ethyl 4-bromobutyrate are stirred together for 48 hours at room temperature. After addition of 200 ml of diethyl ether thereto the resulting precipitate is filtered off, and the filtrate is shaken with dilute hydrochloric acid. The hydrochloric acid extract is neutralized (pH approx. 7) with dilute ammonia solution. The separated oil is taken up in diethyl ether, and the residue (10.9 g), which remains after drying and distilling off the solvent, is taken up in 100 ml of benzene. After the addition of 5.9 g of ethyldiisopropylamine thereto, 3.6 g of acetyl chloride are added slowly and dropwise while stirring. After 3 hours the resulting reaction mixture is mixed with 200 ml of diethyl ether and shaken successively with water, dilute hydrochloric acid and sodium bicarbonate solution. The residue (12.4 g), remaining after drying and distilling off the solvent, is taken up in 100 ml of benzene and mixed with a solution of 3.0 g of potassium hydroxide in 20 ml of ethanol. After 24 hours the mixture is shaken out with water, and the aqueous phase is acidified. The initial oily precipitate is taken up in dichloromethane. After distilling off the solvent, the product crystallizes out after several days. It is recrystallized from a mixture (2:1) of isopropyl alcohol and petrol ether to obtain 7.9 g (57.7% of theory) of 4-[N-(1,2,3,4-tetrahydro-1-naphthyl)acetamido]butyric acid, MP 141° to 142°.
Reaction SMILES: [C:1]1([CH2:7][C:8]2[N:13]=[C:12]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]=[C:10]([Cl:21])[N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)C.O.[Pd]>[ClH:21].[C:1]1([CH2:7][C:8]2[NH:13][CH:12]([CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:11][CH2:10][N:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: Clc1cc(Cc2ccccc2)nc(Cc2ccccc2)n1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: Cl
Product: c1ccc(CC2=NCCC(Cc3ccccc3)N2)cc1
Yield: 97.9 %

Procedure:
A solution of the 2,4-di(phenylmethyl)-6-chloropyrimidine (2.3 g, 7.81 mmol) obtained in (ii) in ethanol (50 ml) and water (5 ml) was hydrogenated at about 3 atmospheres in the presence of 10% palladium on charcoal catalyst (380 mg) until hydrogen uptake had ceased. After filtration through Hyflo (Trade mark; diatomaceous earth) to remove the catalyst, the solution was evaporated in vacuo. Addition of ethanol (50 ml) and evaporation followed by addition of toluene (50 ml) and evaporation afforded a white foam which was dried at 45° C., at a pressure of 20mmHg for 48 hours, to give 2.3 g 2,4-di(phenylmethyl)-3,4,5,6-tetrahydropyrimidine hydrochloride, m.pt., 50°-57° C. (deliquesces). M+ (-HCl) found: 264.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[C:7]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([CH:18]=O)[CH:16]=[CH:17][C:11]=3[CH:10]=2)[CH:6]=[CH:5][C:4]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[NH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32].CCN(CC)CC.[BH4-].[Na+]>CO>[F:27][C:2]([F:1])([F:26])[C:3]1[CH:8]=[C:7]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([CH2:18][NH:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])[CH:16]=[CH:17][C:11]=3[CH:10]=2)[CH:6]=[CH:5][C:4]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=Cc1ccc2cc(-c3ccc(-c4ccccc4)c(C(F)(F)F)c3)sc2c1
Reactant: NCCC(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(O)CCNCc1ccc2cc(-c3ccc(-c4ccccc4)c(C(F)(F)F)c3)sc2c1
Temperature: 50 °C
Yield: 43.9 %

Procedure:
To a solution of 2-(2-trifluoromethyl-biphenyl-4-yl)-benzo[b]thiophene-6-carbaldehyde (23 mg, 0.05 mmol) in 3 mL MeOH, β-alanine (8.7 mg, 0.1 mmol) and catalytic amount Et3N are added. The suspension is heated to 50° C. for 0.5 hours, followed by the addition of 2 mg of NaBH4. After Pre-LC-MS, 10 mg of 3-{[2-(2-trifluoromethyl-biphenyl-4-yl)-benzo[b]thiophen-6-ylmethyl]-amino}-propionic acid is obtained as a white solid. MS m/z 456[M+1]+. 1H NMR (MeOD-d4): δ 8.22 (d, 1H), 7.93 (m, 2H), 7.86 (d, 1H), 7.81 (s, 1H), 7.40 (m, 1H), 7.34 (d, 1H), 7.28 (m, 3H), 7.24 (m, 2H), 4.26 (s, 2H), 3.15 (t, 2H), 2.52 (t, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.C(N(CC)C(C)C)(C)C>COCCOC.O.[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>[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Reactant: OB(O)c1ccccc1F
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Solvent: O
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2F)nc1-c1ccc(C)cc1
Yield: 58.6 %

Procedure:
Methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (100 mg; 0.300 mmol), 2-fluorophenylboronic acid (126 mg; 0.901 mmol), tetrakis(triphenylphosphine) palladium(0) (34.7 mg; 0.030 mmol) were placed in a 5 mL reaction tube and dissolved in a mixture of degassed DME (1.50 mL) and water (0.5 mL). N,N-Diisopropylethylamine (0.185 mL; 1.202 mmol) was added, the tube was sealed and irradiated in a microwave oven at 130° C. for 1 h. The reaction mixture was partitioned between brine and dichloromethane, filtered over a phase separator filter (1PS) and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a linear gradient of ethylacetate (5-40%) in heptane to give 69 mg (41%) of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[C:7]([N+:24]([O-])=O)[CH:6]=1)=[O:4].C(O)(=O)C.O>O1CCOCC1.O.[Fe]>[NH2:24][C:7]1[CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:10]=[CH:9][C:8]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]1
Reactant: COC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.2 %

Procedure:
To a solution of tert-butyl 4-[4-(methoxycarbonyl)-2-nitrophenyl]piperazine-1-carboxylate (200 mg, 0.547 mmol) in 1,4-dioxane-water (2:1) (6.0 mL), iron powder (76 mg, 1.37 mmol) and acetic acid (1 mL) were added under ice-cold conditions, and the mixture was stirred at room temperature overnight. The reaction solution was added water and a saturated aqueous solution of sodium hydrogen carbonate under ice-cold conditions, filtered through a pad of celite, and extracted with ethyl acetate. Then, the organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/acetone). The title compound (83 mg (yield 45%)) was obtained as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[C:9](Br)[CH:10]=2)[S:5][CH2:4][CH2:3]1.C([Li])CCC.CN([CH:22]=[O:23])C.[Cl-].[NH4+]>C1COCC1>[CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:22]=[O:23])[CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: CC1(C)CCSc2ccc(Br)cc21
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(C)CCSc2ccc(C=O)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
9.4 g (36.6 mmol) of 4,4-dimethyl-6-bromothiochroman and 100 ml of THF were introduced into a three-necked flask under a stream of nitrogen. 16.1 ml of an n-butyllithium solution (2.5M in hexane) were added dropwise at −78° C. and stirring was carried out for 30 min. 2.7 ml (38.4 mmol) of DMF were then added dropwise and the mixture was permitted to heat to room temperature. The reaction mixture was poured into an aqueous ammonium chloride solution and extracted with ethyl ether. The organic phase was separated by settling, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a silica column eluted with a mixture of dichloromethane and hexane (50/50). After evaporating the solvents, 6.1 g (81%) of the expected aldehyde were recovered in the form of a yellow oil.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1)=[O:3].CO[C:16](OC)([N:18]([CH3:20])[CH3:19])[CH3:17]>>[CH3:19][N:18]([CH3:20])[C:16]([CH3:17])=[CH:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:5]=1)=[O:3]
Reactant: CC(=O)c1cccc(C(F)(F)F)c1
Reactant: COC(C)(OC)N(C)C
Product: CC(=CC(=O)c1cccc(C(F)(F)F)c1)N(C)C

Procedure:
A mixture of 20.0 g of 3-trifluoromethylacetophenone and 20 ml of N,N-dimethylacetamide dimethyl acetal was stirred and heated at reflux for 3 hours. The mixture was evaporated in vacuo to give a red solid. The solid was triturated with n-hexane and filtered. The solid was washed with n-hexane and dried to give 18.0 g of 3-(dimethylamino)-1-[3-(trifluoromethyl)phenyl]-2-buten-1-one as red crystals, mp 71°-73° C.
Reaction SMILES: C([O:5][C:6](=[O:44])[CH2:7][N:8]1[CH:12]=[C:11]([NH:13][C:14]([C:16]2[C:17]([NH:25]C(OC(C)(C)C)=O)=[N:18][N:19]3[CH:24]=[CH:23][CH:22]=[N:21][C:20]=23)=[O:15])[C:10]([C:33]2[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=2[O:40][CH:41]([F:43])[F:42])=[N:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:25][C:17]1[C:16]([C:14]([NH:13][C:11]2[C:10]([C:33]3[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=3[O:40][CH:41]([F:42])[F:43])=[N:9][N:8]([CH2:7][C:6]([OH:44])=[O:5])[CH:12]=2)=[O:15])=[C:20]2[N:21]=[CH:22][CH:23]=[CH:24][N:19]2[N:18]=1
Reactant: CC(C)(C)OC(=O)Cn1cc(NC(=O)c2c(NC(=O)OC(C)(C)C)nn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nn2cccnc2c1C(=O)Nc1cn(CC(=O)O)nc1-c1cc(Cl)ccc1OC(F)F
Temperature: 25 °C
Reaction time: 6 h
Yield: 96.6 %

Procedure:
To a solution of [4-[(2-tert-butoxycarbonylamino-pyrazolo[1,5-a]pyrimidine-3-carbonyl)-amino]-3-(5-chloro-2-difluoromethoxy-phenyl)-pyrazol-1-yl]-acetic acid tert-butyl ester (0.91 g, 1.43 mmol) in dichloromethane (7 mL) was added TFA (15 mL) and the mixture left to stir at room temperature for 6 hours. The solvent was evaporated and the resultant residue azeotroped with dichlormethane/methanol to afford the title compound as a pale yellow solid (0.66 g, 97%). LCMS (Method 3) [M+H]+=477.8, RT=2.95 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 13.15 (br s, 1H), 9.56 (s, 1H), 8.93 (dd, 1H, J=1.5, 6.8 Hz), 8.37-8.34 (m, 1H), 8.35 (s, 1H), 7.63 (dd, 1H, J=2.8, 8.8 Hz), 7.56 (d, 1H, J=2.8 Hz), 7.46 (d, 1H, J=8.9 Hz), 7.26 (t, 1H, J=73.4 Hz), 7.00 (dd, 1H, J=4.5, 6.8 Hz), 6.58 (br s, 2H), 5.05 (s, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[C:14]([NH2:23])[C:13]=2[N:12]=[C:11]1[CH2:24][CH2:25][O:26][CH3:27].C(N(CC)CC)C.[C:35]1([S:41](Cl)(=[O:43])=[O:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>ClCCl>[NH2:23][C:14]1[C:13]2[N:12]=[C:11]([CH2:24][CH2:25][O:26][CH3:27])[N:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][S:41]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)(=[O:43])=[O:42])[C:22]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCCCCCCN
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCCCCCCNS(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 42.9 %

Procedure:
Under a nitrogen atmosphere a solution of 1-(8-aminooctyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.0 g, 2.7 mmol) in dichloromethane (50 mL) was cooled to 0° C. Triethylamine (415 μL, 2.98 mmol) was added followed by benzenesulfonyl chloride (345 μL, 2.71 mmol). The reaction mixture was allowed to warm slowly to ambient temperature and then it was maintained overnight. The reaction mixture was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography (50 g of silica gel eluting with 7.5% methanol in dichloromethane). The purified material was recrystallized from propyl acetate, triturated with hexanes, and then dried in a vacuum oven to provide 590 mg of N-{8-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]octyl}benzenesulfonamide as a yellow powder, m.p. 146–149° C. Analysis: Calculated for C27H35N5O3S: % C, 63.63; % H, 6.92; % N, 13.74. Found: % C, 62.96; % H, 7.03; % N, 13.09. Karl Fisher showed 0.16% or 0.045 mole water.
Reaction SMILES: CC([O:4][C:5](/N=N/C(OC(C)C)=O)=[O:6])C.[C:15]([C:19]1[CH:20]=[C:21]([NH:31][C:32]([NH:34][C@@H:35]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[C@H:38]([O:45][C:46]3[CH:47]=[CH:48][C:49]4[N:50]([C:52]([CH:55]([CH3:57])[CH3:56])=[N:53][N:54]=4)[CH:51]=3)[CH2:37][CH2:36]2)=[O:33])[N:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)[N:23]=1)([CH3:18])([CH3:17])[CH3:16].[OH:58][CH:59]1[CH2:64][CH2:63][N:62]([CH2:65][CH2:66]O)[CH2:61][CH2:60]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[CH:5]([OH:6])=[O:4].[C:15]([C:19]1[CH:20]=[C:21]([NH:31][C:32]([NH:34][C@@H:35]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[C@H:38]([O:45][C:46]3[CH:47]=[CH:48][C:49]4[N:50]([C:52]([CH:55]([CH3:57])[CH3:56])=[N:53][N:54]=4)[CH:51]=3)[CH2:37][CH2:36]2)=[O:33])[N:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:66][CH2:65][N:62]3[CH2:63][CH2:64][CH:59]([OH:58])[CH2:60][CH2:61]3)[CH:25]=2)[N:23]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Reactant: CC(C)c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(O)c4)c4ccccc43)cn12
Reactant: OCCN1CCC(O)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCN5CCC(O)CC5)c4)c4ccccc43)cn12
Product: O=CO
Temperature: 25 °C

Procedure:
DIAD (51.0 μL, 0.260 mmol) was added to a solution of Intermediate 22d (75.0 mg, 0.13 mmol), 4-hydroxy-1-piperidine-ethanol (28.0 mg, 0.19 mmol), and Ph3P (68.0 mg, 0.26 mmol) in THF (1.5 mL) at 0° C. The reaction was stirred at RT over the weekend then partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM. Further purification by HPLC (C18 X-select column, 25-98% MeCN in H2O, 0.1% HCO2H) gave the title compound as a white powder after freeze-drying (57 mg, 62%). LCMS (Method 5): Rt 3.32 min, m/z 707.4 [MH+]. 1H NMR (400 MHz, d4-MeOD): 1.31 (9H, s), 1.42 (3H, d, J 6.8), 1.45 (3H, d, J 6.8), 1.62-1.72 (2H, m), 1.86-2.04 (4H, m), 2.04-2.14 (1H, m), 2.21-2.30 (1H, m), 2.69-2.79 (2H, m), 3.11-3.19 (4H, m), 3.51 (1H, sept, J 6.9), 3.70-3.78 (1H, m), 4.26 (2H, t, J 5.3), 4.89 (1H, dd, J 8.9, 5.8), 5.45 (1H, t, J 4.1), 6.33 (1H, s), 7.05 (1H, ddd, J 8.4, 2.7, 0.8), 7.09-7.13 (2H, m), 7.19-7.25 (3H, m), 7.26-7.33 (2H, m), 7.42 (1H, t, J 8.1), 7.61 (1H, dd, J 9.7, 0.6), 8.01 (1H, d, J 1.7), 8.42 (1H, br s).
Reaction SMILES: [Na+].[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([O-:10])=[O:9])[CH:3]=1.N1C=CC=CC=1.Br[C:18]([CH3:25])([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C=O)C.C(Cl)Cl>[CH2:22]([O:21][C:19](=[O:20])[C:18]([CH3:25])([S:8]([C:4]1[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=1)(=[O:10])=[O:9])[CH3:24])[CH3:23]
Reactant: O=S([O-])c1cccnc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)S(=O)(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The crude 3-pyridylsulfinic acid sodium salt (4.4 mmol, synthesised by variation A) was suspended in DMF (20 mL). Pyridine (0.8 mL) and ethyl α-bromoisobutyrate (1 mL) were added. The reaction was stirred at room temperature under nitrogen for 18 h. The reaction mixture was diluted with DCM (200 mL), washed with water (2×100 mL), brine (1×50 mL) and dried over Na2SO4. Filtration, concentration under reduced pressure, followed by column chromatography (silica, eluent DCM, 0-10% ethyl acetate) afforded 0.24 g of 2-methyl-2-(pyridine-3-sulfonyl)-propionic acid ethyl ester.