Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([NH:8][C:9]([NH:11][CH2:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=2)=[O:10])[S:6][CH:7]=1.ClC1C=C(C=CC=1Cl)[CH2:25][NH:26]C(NC1SC=C(CNC)N=1)=O>>[F:20][C:15]1[CH:14]=[C:13]([CH:18]=[C:17]([F:19])[CH:16]=1)[CH2:12][NH:11][C:9]([NH:8][C:5]1[S:6][CH:7]=[C:3]([CH2:2][NH:26][CH3:25])[N:4]=1)=[O:10]
Reactant: CNCc1csc(NC(=O)NCc2ccc(Cl)c(Cl)c2)n1
Reactant: O=C(NCc1cc(F)cc(F)c1)Nc1nc(CCl)cs1
Product: CNCc1csc(NC(=O)NCc2cc(F)cc(F)c2)n1

Procedure:
The title compound was prepared from the above 1-(4-Chloromethyl-thiazol-2-yl)-3-(3,5-difluoro-benzyl)-urea following the procedure described for Intermediate 3.
Reaction SMILES: OC1NC2C(C=1)=CC=CC=2.COC1NC2C(C=1)=CC=CC=2.C[O:23][C:24]1[CH:25]=[C:26]2[C:30](=[N:31][CH:32]=1)[NH:29][C:28]([CH3:33])=[CH:27]2>>[OH:23][C:24]1[CH:25]=[C:26]2[C:30](=[N:31][CH:32]=1)[NH:29][C:28]([CH3:33])=[CH:27]2
Reactant: COc1cnc2[nH]c(C)cc2c1
Agent: COc1cc2ccccc2[nH]1
Agent: Oc1cc2ccccc2[nH]1
Product: Cc1cc2cc(O)cnc2[nH]1
Yield: 108 %

Procedure:
The intermediate, 5-hydroxy-2-methyl-7-azaindole, was prepared as follows. A. To a solution of 5-methoxy-7-azaindole (240 mg, 1.62 mmol) in THF (10 mL) was added a 60% suspension of sodium hydride in oil (71 mg, 1.78 mmol) at RT under argon. The mixture was stirred at RT for 5 minutes and phenylsulphonyl chloride (250 μL, 1.95 mmol) was added and the mixture was stirred for 16 h, quenched with saturated ammonium chloride (20 mL) and extracted with ethyl acetate (3×25 μL). The combined organic layers were washed with brine (50 mL), dried, filtered and concentrated. The residue was purified by flash chromatography (1% MeOH in dichloromethane+0.5% triethylamine) to afford N-phenylsulphonyl-5-methoxy-7-azaindole (325 mg, 70%) as a solid. 1H NMR (400 MHz, CDCl3) δ 8.12 (3H, m), 7.65 (1H, dd, J=3.8), 7.54 (1H, m), 7.45 (2H, m), 7.28 (1H, d, J=2.8 Hz), 6.51 (1H, d, J=3.8 Hz), 3.82 (3H, s). (M+H)+=289. B. A solution (2.7M) of n-butyllithium in hexanes (0.48 mL, 1.30 mmol) was added to a solution of N-phenylsulphonyl-5-methoxy-7-azaindole (220 mg, 0.76 mmol) in THF (7.0 mL) at −78° C. under argon. The resulting solution was stirred at −78° C. for 1 h and methyl iodide (120 μL, 1.91 mmol) was added. The resulting mixture was stirred at −78° C. for 2 h, quenched with saturated ammonium chloride (20 mL) and extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with brine (50 mL), dried, filtered and concentrated. The residue was purified by flash chromatography (1% MeOH in dichloromethane+0.1% triethylamine) to afford (170 mg, 73%) of a (5:1) mixture of N-phenylsulphonyl-5-methoxy-2-methyl-7-azaindole, m/z 303 (M+H+), analytical HPLC retention time=1.83 min and N-tolylsulphonyl-5-methoxy-2-methyl-7-azaindole, m/z 317, retention time=1.97 min. C. To a solution of above mixture of compounds in (3:1) THF-methanol (4 mL) was added a 10% solution of sodium hydroxide in water (3 mL) at room temperature. The mixture was heated to 65° C. for 1 h, cooled to room temperature, neutralized to pH 7 with a saturated ammonium chloride solution and extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with brine (50 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by flash column chromatography on silica gel (1% MeOH in dichloromethane+0.1% triethylamine) to afford 5-methoxy-2-methyl-7-azaindole (35 mg, 66%). (M+H)+=163. D. The procedure described above for the preparation of hydroxyindole from methoxyindole in Example 1 was applied to 5-methoxy-2-methyl-7-azaindole (35 mg, 0.2 mmol) to afford 5-hydroxy-2-methyl-7-azaindole (32 mg, 100%) which was used directly without any further purification. LC/MS; (M+H)+=135.
Reaction SMILES: C([O:8][C:9](=[O:31])[CH:10]([CH2:27][CH:28]([CH3:30])[CH3:29])[N:11]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])C1C=CC=CC=1.[H][H]>CO.[C].[Pd]>[C:23]([O:22][C:20]([CH2:19][N:11]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH:10]([C:9]([OH:31])=[O:8])[CH2:27][CH:28]([CH3:30])[CH3:29])=[O:21])([CH3:24])([CH3:25])[CH3:26]
Reactant: CC(C)CC(C(=O)OCc1ccccc1)N(CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)CC(C(=O)O)N(CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 100.9 %

Procedure:
N-(t-butyloxycarbonyl)methyl-N-t-butyloxycarbonyl-D,L-leucine benzyl ester (3.5 g) was dissolved in methanol (25 ml), and 10% palladium-carbon (200 mg) was added. The resulting mixture aerated with hydrogen was allowed to react at room temperature for 3 h, filtered and concentrated under reduced pressure to remove the solvent to give a white foam-like solid (2.8 g, 100%), which was directly used for the next reaction.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[C:15]([CH2:17][C:18]1[O:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:21][N:22]=1)#[N:16].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[C:15]([C:17](=[C:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[C:18]1[O:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:21][N:22]=1)#[N:16]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: N#CCc1nnc(-c2ccccc2)o1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC(=C1CCNCC1)c1nnc(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
To a mixture of N-Boc-4-piperidone (0.200 g, 1.00 mmol) and 2-(cyanomethyl)-5-phenyl-1,3,4-oxadiazole in dry THF (5 mL), at 5° C. under Ar, was added NaHMDS solution (1M in THF, 1.1 mL, 1.1 mmol) and the mixture was then stirred at room temperature for 16 h. The reaction was quenched with MeOH (1 mL) and then the mixture was evaporated to dryness. The residue was taken up in HCl-dioxane (4 M, 2 mL) and the reaction mixture was kept at room temperature for 20 h before again being evaporated to dryness. The residue was taken up in EtOAc, washed (sat. NaHCO3×2, brine), dried (MgSO4) and evaporated to give the title compound (0.212 g, 80%) as a dark red semi-solid, which was used as such in the next step:
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[O:8][C:7]([CH:9]3[CH2:11][CH2:10]3)=[N:6][C:5]2=[C:12]([C:15]#[N:16])[C:13]=1[CH3:14].[C:18](=O)([O-])[O-:19].[K+].[K+]>O.CN(C)C=O.CO>[Br:1][C:2]1[C:3]([O:19][CH3:18])=[C:4]2[O:8][C:7]([CH:9]3[CH2:11][CH2:10]3)=[N:6][C:5]2=[C:12]([C:15]#[N:16])[C:13]=1[CH3:14]
Reactant: Cc1c(Br)c(F)c2oc(C3CC3)nc2c1C#N
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(Br)c(C)c(C#N)c2nc(C3CC3)oc12
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 51.3 %

Procedure:
6-Bromo-2-cyclopropyl-7-fluoro-5-methyl-1,3-benzoxazole-4-carbonitrile (I-77) (4.88 g, 16.5 mmol) was suspended in a mixed solvent of methanol (30 ml) and N,N-dimethylformamide (50 ml), potassium carbonate (4.57 g, 33.0 mmol) was added, followed by stirring at 60° C. for 30 minutes. With cooling with ice, water was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated away. The residue was suspended in a mixed solvent of methanol (30 ml) and N,N-dimethylformamide (50 ml), potassium carbonate (4.57 g, 33.0 mmol) was added, followed by again stirring at 60° C. for 14 hours. With cooling with ice, water was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated away. The precipitated solid was washed with a mixed solvent of ethyl acetate/isopropyl ether and collected by filtration to obtain the entitled compound (2.599 g, 64%) as a colorless solid.
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([C:23](=[O:26])[NH:24][CH3:25])=[CH:19][C:18]=4[O:27][CH3:28])[N:12]=[CH:11][C:10]=3[N:9]3[CH:29]=[N:30][C:31](C(OCC=C)=O)=[C:8]3[C@H:7]2[CH2:38][CH3:39])[CH2:5][CH2:4][CH2:3][CH2:2]1.O>C(#N)C1C=CC=CC=1.C1(C)C=CC=CC=1.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>[CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([C:23]([NH:24][CH3:25])=[O:26])=[CH:19][C:18]=4[O:27][CH3:28])[N:12]=[CH:11][C:10]=3[N:9]3[CH:29]=[N:30][CH:31]=[C:8]3[C@H:7]2[CH2:38][CH3:39])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=CCOC(=O)c1ncn2c1[C@@H](CC)N(C1CCCC1)c1nc(Nc3ccc(C(=O)NC)cc3OC)ncc1-2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: N#Cc1ccccc1
Solvent: O
Product: CC[C@@H]1c2cncn2-c2cnc(Nc3ccc(C(=O)NC)cc3OC)nc2N1C1CCCC1
Temperature: 155 °C
Yield: 11.8 %

Procedure:
A mixture of (R)-allyl 5-cyclopentyl-6-ethyl-3-(2-methoxy-4-(methylcarbamoyl)phenylamino)-5,6-dihydroimidazo[1,5-f]pteridine-7-carboxylate 1-3 (37 mg, 0.07 mmol) and tetrakis(triphenylphosphine)palladium(0) (7 mg) in benzonitrile (0.5 ml) and toluene saturated with water (0.5 ml) was heated under microwave irradiation at 155° C. for 1 hour. The mixture was cooled down to room temperature and evaporated to dryness. The residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, concentrated in vacuo and partitioned between ethyl acetate and a saturated aqueous solution of sodium bicarbonate. The organic phase was dried over magnesium sulphate and concentrated in vacuo to afford the title compound as a white solid (3.7 mg, 12% yield); 1H NMR (CDCl3) 0.73-0.85 (3H, m), 1.50-2.20 (10H, m), 3.00, 3.02 (3H, 2×s), 3.95, 3.96 (3H, 2×s), 4.50-4.65 (1H, m), 4.66-4.75 (1H, m), 6.10-6.24 (1H, m), 6.85-6.94 (1H, m), 7.21-7.30 (1H, m), 7.40-7.49 (1H, m), 7.68-7.75 (1H, m), 7.89-7.97 (1H, m), 8.20-8.28 (1H, m), 8.48-8.55 (1H, m); LC/MS M+1 (obs.) 448.61, LC/MS M-1 (obs.) 446.72.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[O:8].C1(C)C(S([CH2:18][N+:19]#[C-:20])(=O)=O)=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO>[O:8]1[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:20][N:19]=[CH:18]1
Reactant: O=Cc1ccccn1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: c1ccc(-c2cnco2)nc1

Procedure:
Picolinaldehyde (2.5 g, 23 mmol) and toluenesulfonylmethyl isocyanide (5.3 g, 27 mmol) were dissolved in methanol (30 ml), and potassium carbonate (3.5 g, 25 mmol) was added thereto. The mixture was refluxed for 30 minutes. The solvent was evaporated, and ethyl acetate and water were added to the residue. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated. The residue was subjected to a silica gel column chromatography. The fractions eluted with hexane-ethyl acetate (2:3, v/v) were collected and concentrated to give the titled compound.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:9][C:10]1([CH3:29])[O:14][C:13](=[O:15])[N:12]([CH:16]2[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]2)[C@H:11]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O.ClCCCl>[I:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][CH:19]1[CH2:18][CH2:17][CH:16]([N:12]2[C@@H:11]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:10]([CH3:9])([CH3:29])[O:14][C:13]2=[O:15])[CH2:21][CH2:20]1
Reactant: Nc1ccccc1I
Reactant: CC1(C)OC(=O)N(C2CCC(=O)CC2)[C@H]1c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC1(C)OC(=O)N(C2CCC(Nc3ccccc3I)CC2)[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The starting material (see Intermediate M synthesis) was a mixture of S:R stereoisomers (˜3:1). To a vial charged with 2-iodoaniline (commercially available from Sigma-Aldrich, Milwaukee, Wis.) (0.100 g, 0.457 mmol) were added (S)-5,5-dimethyl-3-(4-oxocyclohexyl)-4-phenyloxazolidin-2-one (0.131 g, 0.457 mmol), DCE (1.826 mL) and AcOH (0.039 mL, 0.685 mmol). The mixture was stirred at room temperature for 15 minutes prior to the addition of sodium triacetoxyborohydride (0.213 g, 1.004 mmol). The pale yellow suspension was then stirred overnight at room temperature. Water was added to the mixture and the resulting mixture was transferred to a separatory funnel and extracted with DCM (2×). The combined organic layers were dried with Na2SO4, filtered, and dried under reduced pressure. The material thus obtained was purified with a 25 g SNAP column (Biotage) ramping EtOAc in heptane (10% DCM throughout, 0-50%) providing the desired product as a mixture of isomers according to LC-MS (2:1 cis:trans). m/z (ESI) 491.1 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH:15]=[C:14]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: C1CCNC1
Reactant: CS(=O)(=O)c1ccc(N2CCC(=O)CC2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CS(=O)(=O)c1ccc(N2CC=C(N3CCCC3)CC2)cc1
Yield: 78 %

Procedure:
A solution of 24 g (0.0947 mol) of the compound of (b), 12 ml (10.2 g/0.143 mol) of pyrrolidine, 240 mg of p-toluenesulfonic acid and 150 ml of benzene is heated at reflux with the azeotropic removel of water for 6 hours. After cooling the resulting precipitate is collected and triturated with ethyl ether to afford 22.5 g (78%) of title compound: m.p. 141°-143° C.; IR (KBr) 1650, 1580, 1300, and 1130 cm-1 ; NMR (CDCl3)δ 7.75 (d, 2H), 6.85 (d, 2H), 4.30-4.10 (m, 1H), 3.95-3.45 (m, 4H), 3.25-2.85 (m, 4H) 3.05 (s, 3H), 2.65-2.30 (m, 2H), and 1.95-1.70 (m, 4H).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([CH2:50][CH3:51])=[N:5][C:6]([CH2:48][CH3:49])=[CH:7][C:8]=1[N:9]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]2[N:25]=[N:26][N:27](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:28]=2)=[CH:14][CH:13]=1)[CH3:10]>CO>[Cl:2][C:3]1[C:4]([CH2:50][CH3:51])=[N:5][C:6]([CH2:48][CH3:49])=[CH:7][C:8]=1[N:9]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]2[NH:28][N:27]=[N:26][N:25]=2)=[CH:16][CH:17]=1)[CH3:10]
Reactant: CCc1cc(N(C)Cc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(Cl)c(CC)n1
Agent: Cl
Solvent: CO
Product: CCc1cc(N(C)Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(Cl)c(CC)n1
Reaction time: 6 h

Procedure:
Concentrated hydrochloric acid (0.4 ml) was added to a suspension of 3-chloro-2,6-diethyl-4-[N-(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methyl-N-methylamino]pyridine (A) (220 mg) in methanol (5 ml) and the mixture was stirred for 6 hours. Volatile material was removed by evaporation and the residue partitioned between ether and sodium carbonate solution. The aqueous layer was separated, acidified to pH 6 with 4M hydrochloric acid and extracted with dichloromethane (3×25 ml). The combined organic extracts were dried and solvent removed by evaporation. The residue was purified by flash chromatography eluting with dichloromethane/methanol (9:1 v/v) to give 3-chloro-2,6-diethyl-4-[N-(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl-N-methylamino]pyridine as a solid, m.p. 110° C. (decomposition); NMR (d6 -DMSO): 1.1(d, of t, 6H), 2.64(q, 2H), 2.74(s, 3H), 2.84(q, 2H), 4.37(s, 2H), 6.81(s, 1H), 7.07(d, 2H), 7.27(d, 2H), 7.6(m, 4H); mass spectrum (+ve FAB, DMSO): 432,434(M+H)+ ; microanalysis, found: C, 64.6; H, 6.0; N, 17.9%; C24H25N6Cl.0.75H2O.0.125C4H10O requires: C, 64.4; H, 5.9; N, 18.4%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].Br[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[CH:27][CH:26]=1>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])[C:25]1[CH:26]=[CH:27][C:28]([O:31][CH2:32][C:33]([F:34])([F:35])[F:36])=[CH:29][CH:30]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Reactant: FC(F)(F)COc1ccc(Br)cc1
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(OCC(F)(F)F)cc1)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[(3,4-dichloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 9) and 1-bromo-4-(2,2,2-trifluoro-ethoxy)-benzene in analogy to Example 1a): MS (ISP): 478.1 and 480.1 (M+H)+, 378.2 and 380.0 ((M-Boc)+H)+ (100%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([O:16][CH3:17])=[C:12]([CH:15]=2)[CH:13]=O)[CH:5]=[CH:4][N:3]=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([NH:31][CH2:13][C:12]2[CH:15]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:9]=[CH:10][C:11]=2[O:16][CH3:17])[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: COc1ccc(-c2ccnc(Cl)n2)cc1C=O
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: COc1ccc(-c2ccnc(Cl)n2)cc1CNC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Intermediate 86 was coupled with 4-Amino-piperidine-1-carboxylic acid tert-butyl ester following procedure B. LC-MS showed the product was >95% pure and had the expected M+H+ of 433.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:14](C(OC)=O)=[C:8]2[C:9]([NH2:13])=[CH:10][CH:11]=[CH:12][N:7]2[N:6]=1)=[O:4].[OH-].[Na+].Cl>OS(O)(=O)=O>[NH2:13][C:9]1[C:8]2[N:7]([N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:14]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)c1nn2cccc(N)c2c1C(=O)OC
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Nc1cccn2nc(C(=O)O)cc12
Temperature: 80 °C
Reaction time: 6.5 h

Procedure:
50% Aqueous H2SO4 (60 mL) is added to 4-Aminopyrazolo[1,5-a]pyridine-2,3-dicarboxylic acid dimethyl ester (1.47 g, 5.90 mmol) under air. The mixture is warmed to 80° C. After 6.5 h, the solution is cooled to 0° C. and then neutralized with 10 N aq. NaOH. The resulting slurry is acidified to pH 3 with 1 M aq. HCl. The volatiles are removed under reduced pressure. The residue is washed with 30% EtOH in CH2Cl2. The volatiles are removed under reduced pressure to afford 4-aminopyrazolo[1,5-a]pyridine-2-carboxylic acid in Na2SO4. LC-MS m/z (M+H+): 178.01. A solution of conc. H2SO4 (6.0 mL) and ethanol (120 mL) is added to the crude 4-aminopyrazolo[1,5-a]pyridine-2-carboxylic acid. The mixture is warmed to 75° C. for 3.5 h. After cooling to rt, the mixture is made basic with dropwise addition of sat. aq. NaHCO3. The volatiles are removed under reduced pressure. The aqueous mixture is filtered (EtOAc rinse). The aqueous solution is extracted with EtOAc (3×250 mL). The combined organics are dried over Na2SO4, filtered, and concentrated to afford the title compound as dark brown solid. LC-MS m/z (M+Na+): 228.03.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([CH2:8][C:9]2[CH:10]=[N:11][C:12]([NH:16][CH3:17])=[CH:13][C:14]=2[CH3:15])[CH2:5][CH2:4][N:3]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(N(CC)CC)C.[F:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][C:40]2[N:45]=[CH:44][C:43]([C:46](Cl)=[O:47])=[CH:42][CH:41]=2)=[CH:35][CH:34]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][C:40]2[N:45]=[CH:44][C:43]([C:46]([N:16]([CH3:17])[C:12]3[N:11]=[CH:10][C:9]([CH2:8][N:6]4[CH2:5][CH2:4][N:3]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[C@@H:2]([CH3:1])[CH2:7]4)=[C:14]([CH3:15])[CH:13]=3)=[O:47])=[CH:42][CH:41]=2)=[CH:35][CH:34]=1
Reactant: O=C(Cl)c1ccc(Oc2ccc(F)cc2)nc1
Reactant: CNc1cc(C)c(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(N(C)C(=O)c2ccc(Oc3ccc(F)cc3)nc2)ncc1CN1CCN(C(=O)OC(C)(C)C)[C@@H](C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,1-Dimethylethyl (2S)-2-methyl-4-{[4-methyl-6-(methylamino)-3-pyridinyl]methyl}-1-piperazinecarboxylate (D101) (0.038 g, 0.11 mmol) was dissolved in dry DCM (2 mL). Triethylamine (0.016 g, 0.16 mmol) was added dropwise and after 5 minutes a solution of the acid chloride from step 1 in dry DCM (2 mL) was added dropwise. The reaction mixture was then left stirring under argon at room temperature overnight. Saturated aqueous NaHCO3 (15 mL) was added and the aqueous layer extracted with DCM (3×5 mL). The organic extracts were dried (Na2SO4) and the crude product was purified by column chromatography. Elution with a 0-100% EtOAc/petroleum ether gradient gave the title compound as a colourless oil (0.026 g). MS (ES): MH+ 550.4
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:26][C:27]1[C:36]2[C:31](=[CH:32][C:33]([S:39](Cl)(=[O:41])=[O:40])=[C:34]([O:37][CH3:38])[CH:35]=2)[N:30]=[CH:29][CH:28]=1.[NH4+].[Cl-]>C1COCC1>[Cl:26][C:27]1[C:36]2[C:31](=[CH:32][C:33]([S:39]([N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:15][CH:14]=3)[C:9]3[S:10][CH:11]=[CH:12][N:13]=3)(=[O:40])=[O:41])=[C:34]([O:37][CH3:38])[CH:35]=2)[N:30]=[CH:29][CH:28]=1
Reactant: COc1ccc(CNc2nccs2)cc1
Reactant: COc1cc2c(Cl)ccnc2cc1S(=O)(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2cc3nccc(Cl)c3cc2OC)cc1
Reaction time: 0.25 h
Yield: 36.4 %

Procedure:
To a flask containing ice cold suspension of N-(4-methoxybenzyl)thiazol-2-amine (171 mg, 0.776 mmol) in THF (2844 μl) was added lithium bis(trimethylsilyl)amide (1M in THF) (1479 μl, 1.479 mmol) faster than drop wise. The mixture was stirred for 15 mins prior to the drop wise addition of a solution of 4-chloro-6-methoxyquinoline-7-sulfonyl chloride (216 mg, 0.739 mmol) in THF (2.0 ml, 0.4 ml wash). The solution was allowed to stir for 4 hr (ice melt) providing a brown solution containing primarily product according to LC-MS. The mixture was added to a flask containing sat. aq. NH4Cl. The aqueous mixture was extracted 2× with EtOAc and the combined organics were dried with Na2SO4, filtered, and dried under reduced pressure. The crude material was purified with a 40 g HP silicycle column ramping EtOAc in heptane (0-50%, 10% DCM throughout) affording product, 4-chloro-6-methoxy-N-(4-methoxybenzyl)-N-(thiazol-2-yl)quinoline-7-sulfonamide (128 mg, 0.269 mmol, 36.4% yield) as a yellow solid. m/z (ESI) 476.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[C:4]([CH3:13])[CH:3]=1.Cl[CH2:15][CH2:16][CH2:17][S:18](Cl)(=[O:20])=[O:19]>>[O:19]=[S:18]1(=[O:20])[CH2:17][CH2:16][CH2:15][N:1]1[C:2]1[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:13])[CH:3]=1
Reactant: CCOC(=O)c1ccc(N)cc1C
Reactant: O=S(=O)(Cl)CCCCl
Product: Cc1cc(N2CCCS2(=O)=O)ccc1C(=O)O

Procedure:
Using ethyl 4-amino-2-methylbenzoate (5.3 g) and 3-chloropropane-1-sulfonyl chloride (4.8 mL) and by the reaction and treatment in the same manner as in Preparation Example 16, the title compound (6.49 g) was obtained.
Reaction SMILES: [H-].[Na+].[CH2:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:4]=[CH2:5].Br[CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19]>CN(C=O)C>[C:9]([O:8][C:7](=[O:13])[N:6]([CH2:3][CH:4]=[CH2:5])[CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19])([CH3:12])([CH3:11])[CH3:10]
Reactant: C=CCCCBr
Reactant: C=CCNC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCCCN(CC=C)C(=O)OC(C)(C)C
Temperature: 40 °C
Yield: 116.2 %

Procedure:
To a suspension of NaH (3.05 g, 76.33 mmol of 60% NaH in oil; washed with hexanes) in DMF (30 mL) was added tert-butyl N-allylcarbamate (6.0 g, 38.2 mmol) in a dropwise fashion. The mixture was stirred at room temperature for approximately 10 minutes whereupon 5-bromo-1-pentene (6.78 mL, 57.24 mmol) was added in a dropwise fashion. The reaction was heated to 40° C. for approximately 2 hours whereupon the reaction was partitioned between ethyl acetate and water. The organic layer was washed with water (2×'s), brine, dried (MgSO4), filtered and concentrated to give 10 grams of the title compound as an oil: MS(EI) 226 (M+H+).