Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][CH:5]([NH2:20])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([F:15])[F:14])=[C:8]([O:16][CH:17]([F:19])[F:18])[CH:7]=1.C(N(CC)CC)C.C[O:30][C:31](=O)[C:32]1[C:37]([NH:38][C:39]([CH:41]2[CH2:43][CH2:42]2)=[O:40])=[CH:36][CH:35]=[C:34]([Cl:44])[C:33]=1[CH2:45]Br>CN(C=O)C>[CH3:1][O:2][C:3](=[O:21])[CH2:4][CH:5]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([F:15])[F:14])=[C:8]([O:16][CH:17]([F:18])[F:19])[CH:7]=1)[N:20]1[CH2:45][C:33]2[C:32](=[C:37]([NH:38][C:39]([CH:41]3[CH2:43][CH2:42]3)=[O:40])[CH:36]=[CH:35][C:34]=2[Cl:44])[C:31]1=[O:30]
Reactant: COC(=O)c1c(NC(=O)C2CC2)ccc(Cl)c1CBr
Reactant: COC(=O)CC(N)c1ccc(OC(F)F)c(OC(F)F)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CC(c1ccc(OC(F)F)c(OC(F)F)c1)N1Cc2c(Cl)ccc(NC(=O)C3CC3)c2C1=O
Temperature: 90 °C
Yield: 17.2 %

Procedure:
To a solution of 3-amino-3-(3,4-bis-difluoromethoxy-phenyl)-propionic acid methyl ester (50 mg, 0.16 mmol) and triethyl amine (0.09 ml, 3.1 mmol) in DMF (2 ml) was added 2-bromomethyl-3-chloro-6-(cyclopropanecarbonyl-amino)-benzoic acid methyl ester (67 mg, 0.19 mmol). The mixture was heated at 90° C. under nitrogen atmosphere overnight. The solvent was removed in vacuo. The resulted oil was extracted with ethyl acetate (50 ml) and 1N HCl (50 ml). The organic layer was washed with water (30 ml), brine (30 ml) and dried over magnesium sulfate. The solvent was removed in vacuo and the resulted oil was purified by silica gel chromatography (hexane:ethyl acetate=2:1) to give 3-(3,4-bis-difluoromethoxy-phenyl)-3-[4-chloro-7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-propionic acid methyl ester as a off-white solid (15 mg, 17%). mp, 175–177° C.; 1HNMR (CDCl3): δ 0.88–0.94 (m, 2H, cyclopropyl ring CH2), 1.07–1.13 (m, 2H, cyclopropyl ring CH2), 1.65–1.68 (m, 1H, cyclopropyl ring CH), 3.14 (dd, J=6, 15 Hz, 1H, CHHCO), 3.28 (dd, J=10, 15 Hz, 1H, CHHCO), 3.70(s, 3H, OCH3), 4.13 (d, J=17 Hz, 1H, CHHN), 4.36 (d, J=17 Hz, 1H, CHHN), 5.79–5.85 (m, 1H, CHN), 6.23 (t, JH-F=75 Hz, 1H, OCF2H), 6.26 (t, JH-F=75 Hz, 1H, OCF2H), 7.28–7.41 (m, 4H, Ar), 8.45 (d, J=9 Hz, 1H, Ar), 10.38 (s, 1H, NHCO); 13C NMR (CDCl3): 8.45, 15.25, 16.16, 36.46, 46.34, 51.62, 52.31, 65.38, 111.38, 111.42, 115.57, 115.61, 118.64, 119.76, 119.80, 121.76, 121.81, 122.77, 125.45, 133.14, 136.89, 137.03, 138.86, 142.29, 142.21, 168.79, 170.20, 172.73; Anal. Calcd. for C24H21ClF4N2O6: C, 52.90; H, 3.88; N, 5.14. Found: C, 52.78; H, 3.80; N, 5.01.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:10][C:11]1[CH:15]=[CH:14][NH:13][N:12]=1.O=[C:17]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[CH2:24]([C:17]1[NH:10][C:11]2=[N:12][NH:13][CH:14]=[C:15]2[CH:4]([C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[Cl:1])[C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:25][CH2:26][CH3:27]
Reactant: Nc1cc[nH]n1
Reactant: O=Cc1ccccc1Cl
Reactant: CCCCC(=O)CC(=O)OCC
Product: CCCCC1=C(C(=O)OCC)C(c2ccccc2Cl)c2c[nH]nc2N1

Procedure:
The title compound was prepared from 2-chlorobenzaldehyde, 3-aminopyrazole and ethyl 3-ketoheptanoate in the same manner as in Example 1.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[C:11]1[CH2:12][CH2:13][CH2:14][N:15]=1>CO.O>[F:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[CH:11]1[CH2:12][CH2:13][CH2:14][NH:15]1
Reactant: Fc1ccc(F)c(C2=NCCC2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Fc1ccc(F)c(C2CCCN2)c1
Reaction time: 2 h
Yield: 79.8 %

Procedure:
NaBH4 (12 g, 314.9 mmol) was added to a solution of 5-(2,5-difluorophenyl)-3,4-dihydro-2H-pyrrole (28.5 g, 157.4 mmol) in a mixture of MeOH:H2O (4:1, 250 mL) and stirring was continued at 25-35° C. for 2 h. The reaction mixture was quenched with 1N aqueous HCl solution and basified with 2N aqueous NaOH solution, extracted with DCM, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 23 g of the title compound.
Reaction SMILES: [CH2:1]([N:9]1[C:17](=[O:18])[C:16]2[C:11](=[C:12]3[CH:21]=[N:20][NH:19][C:13]3=[N:14][CH:15]=2)[C:10]1=[O:22])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1C(=O)N([Br:30])C(=O)C1.O>C(Cl)Cl>[Br:30][C:21]1[C:12]2[C:13](=[N:14][CH:15]=[C:16]3[C:17](=[O:18])[N:9]([CH2:1][CH2:2][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:10](=[O:22])[C:11]3=2)[NH:19][N:20]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1c2cnc3[nH]ncc3c2C(=O)N1CCc1ccccc1
Solvent: O
Solvent: ClCCl
Product: O=C1c2cnc3[nH]nc(Br)c3c2C(=O)N1CCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.2 %

Procedure:
To a solution of 7-phenethylpyrazolo[3,4-b]pyrrolo[3,4-d]pyridine-6,8(3H,7H)-dione (1 g, 3.4 mmol) in CH2Cl2 (15 mL), freshly recrystallised NBS (0.66 g, 3.76 mmol) was added and the reaction was stirred at room temperature for 3 h. The reaction was monitored by TLC, and on completion of the reaction; water (50 mL) was added and the reaction mixture was extracted with EtOAc (3×100 mL). The combined EtOAc layer was dried over sodium sulphate and evaporated under vacuo to give a residue which was purified by column chromatography (silica gel, gradient 0-10% EtOAc in a solution of 60:40 hexane and chloroform) to afford 1-bromo-7-phenethylpyrazolo[3,4-b]pyrrolo[3,4-d]pyridine-6,8(3H,7H)-dione (1 g, 79%) as a solid. 1HNMR (400 MHz, DMSO-d6) δ: 14.80 (s, 1H), 8.01 (s, 1H), 7.15-7.35 (m, 5H), 3.85 (t, 2H), 2.95 (t, 2H); LCMS: [M+H] 371.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@H:11]3[CH2:12][CH:13]=[C:14]2[C:15](=[O:17])[CH3:16])[CH2:6]1)(=[O:3])[CH3:2].C[Al](C)C.O.O1CCO[CH2:34][CH2:33]1>CCCCCC.[Cu]Br>[C:1]([O:4][CH:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@H:11]3[CH2:12][C@@H:13]([CH2:33][CH3:34])[C@@H:14]2[C:15](=[O:17])[CH3:16])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: C1COCCO1
Reactant: CC(=O)OC1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(C(C)=O)=CC[C@@H]32)C1
Agent: [Cu]Br
Agent: C[Al](C)C
Solvent: CCCCCC
Solvent: O
Product: CC[C@@H]1C[C@H]2[C@@H]3CC=C4CC(OC(C)=O)CC[C@]4(C)[C@H]3CC[C@]2(C)[C@H]1C(C)=O
Temperature: 22 °C
Reaction time: 3 h

Procedure:
3.56 g (10 mmol) of 3-acetoxy-pregna-5,16-dien-20-one is dissolved in 20 ml of dioxane at 20° C. and mixed with 143.3 g (1 mmol) of copper(I) bromide. 11 ml (11 mmol) of a 1 molar solution of trimethyl aluminum in hexane is added to the reaction at room temperature under nitrogen atmosphere and, after completion of the addition, stirred for 3 hours more at 22° C. For hydrolysis of the reaction solution, 1 ml of water dissolved in 5 ml of dioxane is carefully added to the reaction. It is stirred for 10 minutes more and the inorganic precipitate is filtered off with dioxane and washed again. The dioxane solution is concentrated by evaporation on a rotary evaporator and the residue is chromatographed on silica gel with ethyl acetate/hexane as eluent. After concentration by evaporation of the fractions, 1.72 g of 3-acetoxy-16α-ethyl-pregn-5-en-20-one (45% of theory) of a melting point of 114.9° C. is obtained.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7](OC)([O:9]C)[CH3:8])=[N:4][CH:3]=1.FC(F)(F)C(O)=O.O>ClCCl>[Cl:1][C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:8])=[N:4][CH:3]=1
Reactant: COC(C)(OC)c1ncc(Cl)s1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)c1ncc(Cl)s1
Reaction time: 8 h

Procedure:
To a solution of 5-Chloro-2-(1,1-dimethoxy-ethyl)-thiazole (3.5 g) in dichloromethane (20 ml) was added trifluoroacetic acid (30 ml) and water (1 ml). The resulting mixture was stirred overnight at ambient, concentrated to an oil, diluted with diethyl ether, washed with 10% sodium bicarbonate, water and brine, dried (magnesium sulfate), filtered and concentrated to afford the sub-titled compound as a yellow solid in quantitative yield (2.6 g); 1H NMR (400 Mhz, CDCl3) δ 2.7 (3H, s), 7.8 (1H, s).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[C:15]([C:18]1[CH:52]=[CH:51][C:21]([C:22]([N:24]2[CH2:28][C@@H:27]([N:29]3[CH2:34][CH2:33][N:32]([S:35]([CH3:38])(=[O:37])=[O:36])[CH2:31][CH2:30]3)[CH2:26][C@H:25]2[C:39]([NH:41][C:42]2[CH:50]=[CH:49][C:45]([C:46]([OH:48])=[O:47])=[CH:44][CH:43]=2)=[O:40])=[O:23])=[CH:20][CH:19]=1)(=[NH:17])[NH2:16]>C(O)C.S(=O)(=O)(O)O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[C:15]([C:18]1[CH:19]=[CH:20][C:21]([C:22]([N:24]2[CH2:28][C@@H:27]([N:29]3[CH2:34][CH2:33][N:32]([S:35]([CH3:38])(=[O:37])=[O:36])[CH2:31][CH2:30]3)[CH2:26][C@H:25]2[C:39]([NH:41][C:42]2[CH:43]=[CH:44][C:45]([C:46]([O:48][CH2:2][CH3:3])=[O:47])=[CH:49][CH:50]=2)=[O:40])=[O:23])=[CH:51][CH:52]=1)(=[NH:16])[NH2:17]
Reactant: CS(=O)(=O)N1CCN([C@H]2C[C@@H](C(=O)Nc3ccc(C(=O)O)cc3)N(C(=O)c3ccc(C(=N)N)cc3)C2)CC1
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc(NC(=O)[C@@H]2C[C@H](N3CCN(S(C)(=O)=O)CC3)CN2C(=O)c2ccc(C(=N)N)cc2)cc1
Temperature: 60 °C
Reaction time: 44 h
Yield: 118.5 %

Procedure:
To a stirred solution of compound prepared in Example 20 (500 mg) in ethanol (25 mL) was added concentrated sulfuric acid (20 drops) at 0° C. The resulting mixture was stirred at 60° C. for 44 h whereupon the mixture was concentrated in vacuo. The resulting residue was purified by Prep-HPLC (0.1% TFA containing CH3CN—H2O gradient) to provide the title compound (307 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N+:5]([O-])=[CH:4][CH:3]=1.[CH3:9][N:10](C)C(Cl)=O.C(#N)C.C[Si](C#N)(C)C>O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:9]#[N:10])[CH:3]=1
Reactant: CN(C)C(=O)Cl
Reactant: [O-][n+]1ccc(Cl)cc1
Agent: C[Si](C)(C)C#N
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: N#Cc1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
4-Chloropyridine N-oxide (7.53 g, 58.1 mmol) and N,N-dimethylcarbamoyl chloride (9.36 g, 87.0 mmol) were added to acetonitrile (200 ml), and trimethylsilyl cyanide (11.5 g, 116 mmol) was added dropwise thereto. The mixture was stirred at room temperature for 18 hrs. The reaction mixture was combined with ethyl acetate and water. The organic layer was successively washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel (200 g) column chromatography. The fractions eluted with n-hexane-ethyl acetate (3:1, v/v) were collected, concentrated to give the titled compound (8.05 g, 99%) as a pale yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:18]([F:19])=[C:17]([F:20])[CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=O)=[C:5]([F:21])[CH:4]=1)[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[N-]1C=CN=C1.[NH2:39][O:40][CH2:41][CH2:42][OH:43]>C1COCC1>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:18]([F:19])=[C:17]([F:20])[CH:16]=[CH:15][C:11]=2[C:12]([NH:39][O:40][CH2:41][CH2:42][OH:43])=[O:14])=[C:5]([F:21])[CH:4]=1)[CH3:2]
Reactant: NOCCO
Reactant: CCc1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: c1c[n-]cn1
Solvent: C1CCOC1
Product: CCc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65 %

Procedure:
The title compound was prepared from the reaction of the product of Step D, 2-[(4-ethyl-2-fluorophenyl)amino]-3,4-difluorobenzoic acid (93 mg, 0.32 mmol) dissolved in dry THF (5 mL), and carbonyldiimidazole (CDI) (102 mg, 0.63 mmol). Within 10 minutes, a bright yellow solution was obtained and conversion to the imidazolide was confirmed by TLC (50% EtOAc/hexanes). A solution of 2-(aminooxy)ethanol (97 mg, 1.26 mmol) in THF (5 mL) was then added and the mixture stirred for 15 hours at room temperature. The reaction solvent was removed under reduced pressure and the residue partitioned between 1 M HCl (50 mL) and EtOAc (50 mL). The EtOAc layer was then washed with water (50 mL) and saturated NaCl solution (50 mL), dried (Na2SO4), and the solvent removed under reduced pressure to afford an oil which was purified by flash column chromatography on silica gel (50% EtOAc/hexanes) to give 2-[(4-ethyl-2-fluorophenyl)amino]-3,4-difluoro-N-(2-hydroxyethoxy)benzamide as a cream solid (65%); m.p. (EtOAc/hexanes) 134-138° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.84 (br s, 1 H), 8.76 (br s, 1 H), 7.43-7.37 (m, 1 H), 7.14-7.02 (m, 2 H), 6.90 (dd, J=8.3, 1.5 Hz, 1 H), 6.83 (td, J=8.6, 4.4 Hz, 1 H), 4.70 (br s, 1 H), 3.86 (t, J=4.9 Hz, 2 H), 3.57 (t, J=4.9 Hz, 2 H), 2.54 (q, J=7.6 Hz, 2 H), 1.15 (t, J=7.6 Hz, 3 H).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:15][CH:14]2[CH2:16][CH:7]([C:8]3[CH:9]=[CH:10][C:11]([NH2:17])=[CH:12][C:13]=32)[CH2:6]1)(=[O:4])=[O:3].Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([NH:35][CH3:36])(=[O:34])=[O:33])[C:22]([Cl:37])=[CH:21][N:20]=1.C(O)(C)C.C(=O)(O)[O-].[Na+]>>[Cl:37][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([NH:35][CH3:36])(=[O:34])=[O:33])=[N:24][C:19]([NH:17][C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[CH:7]2[CH2:16][CH:14]3[CH2:15][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6]2)=[N:20][CH:21]=1
Reactant: CS(=O)(=O)N1CC2CC(C1)c1cc(N)ccc12
Reactant: CNS(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CNS(=O)(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CC3CN(S(C)(=O)=O)C2)ncc1Cl
Temperature: 130 °C

Procedure:
Into a microwave tube was dissolved 10-methanesulfonyl-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2(7),3,5-trien-4-ylamine (50 mg, 0.2 mmol) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzenesulfonamide (64.5 mg, 0.194 mmol) in isopropyl alcohol (1 mL, 10 mmol). The tube was heated in the microwave at 130° C. for 20 minutes. The reaction solution was poured into saturated sodium bicarbonate solution and was extracted with methylene chloride (6×20 ml). The reaction was dried over magnesium sulfate filtered and was rotovaped to a clear oil. Upon addition of ethyl acetate and hexanes 2-[5-Chloro-2-(10-methanesulfonyl-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-trien-4-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzenesulfonamide crashed out as a white solid 63.03 mg, 60%). MP: 207° C. dec.; 1H-NMR (CDCl3) δ 9.09 (s, 1H), 8.43 (d, J=8.3 Hz, 1H), 8.14 (s, 1H); 7.96 (d, J=7.8 Hz, 1H), 7.64-7.58 (m, 2H) 7.17 (d, J=7.8 Hz, 1H), 6.98 (m, 1H), 4.62 (br s, 1H), 3.67-3.53 (m, 2H), 3.38-3.39 (m, 2H), 3.20 (br s, 1H), 3.14 (br s, 1H), 2.66 (d, J=5.3 Hz, 3H), 2.42-2.35 (m, 1H), 2.03 (s, 3H), 1.84 (d, J=11.1 Hz, 1H), 1.57 (s, 3H), LC/MS (ESI+): 549 (M+H).
Reaction SMILES: [CH:1]([C:4]1[S:5][CH:6]=[C:7]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16](OC(C)(C)C)=O)[CH2:12][CH2:11]2)[N:8]=1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O.[Br:30][C:31]1C(Cl)=[C:33]([N+:38]([O-:40])=[O:39])[C:34]([NH2:37])=[N:35][CH:36]=1>C(Cl)Cl>[Br:30][C:31]1[C:16]([N:13]2[CH2:12][CH2:11][N:10]([CH2:9][C:7]3[N:8]=[C:4]([CH:1]([CH3:2])[CH3:3])[S:5][CH:6]=3)[CH2:15][CH2:14]2)=[C:33]([N+:38]([O-:40])=[O:39])[C:34]([NH2:37])=[N:35][CH:36]=1
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Reactant: CC(C)c1nc(CN2CCN(C(=O)OC(C)(C)C)CC2)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1nc(CN2CCN(c3c(Br)cnc(N)c3[N+](=O)[O-])CC2)cs1
Reaction time: 1 h
Yield: 64.7 %

Procedure:
tert-Butyl 4-((2-isopropylthiazol-4-yl)methyl)piperazine-1-carboxylate (0.380 g, 1.15 mmol, 1.0 eq) was dissolved in DCM (3.6 mL) and the mixture cooled in an ice-water bath before the dropwise addition of TFA (3.6 mL). Stirring was continued at this temperature for 1 h and the solvents were removed in vacuo. The resulting crude material was azeotroped with toluene and dried. The resulting 2-isopropyl-4-(piperazin-1-ylmethyl)thiazole (supposedly 0.260 g, 1.15 mmol, 1.1 eq) was suspended in iPrOH (3.5 mL) and DIPEA (0.9 mL). To this solution, 5-bromo-4-chloro-3-nitropyridin-2-amine (0.270 g, 1.05 mmol, 1 eq) was added and the reaction mixture was heated and stirred for 17 h at 65° C. The mixture was filtered, washed with iPrOH (3×3 mL), Et2O (2×3 mL) and dried to give the title compound as a bright yellow powder (0.300 g, 59%); 1H-NMR (500 MHz, DMSO-d6): δ 1.31 (d, J=7.0 Hz, 6H, iPr—CH3), 2.53-2.65 (br s, 4H, piperazine N(CH2)2), 3.06 (m, 4H, piperazine N(CH2)2), 3.20-3.33 (m, 1H, iPr—CH), 3.61 (s, 2H, NCH2), 6.96 (s, 2H, NH2), 7.31 (s, 1H, thiazole 5-H), 8.15 (s, 1H, pyridine 6-H); LC (Method B)-MS (ESI, m/z): Rt=2.81 min—4411443 [(M+H+), Br isotopic pattern, 100%].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.CN(C)C=O.[CH2:15]([NH:17][CH2:18][CH3:19])[CH3:16]>S(Cl)(Cl)=O>[CH2:15]([N:17]([CH2:18][CH3:19])[C:7](=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[CH3:16]
Reactant: CCNCC
Reactant: O=C(O)c1ccccn1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CCN(CC)C(=O)c1ccccn1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A slurry of picolinic acid (10.2 g, 83.3 mmol) in 100 mL of thionyl chloride was stirred at ambient temperature for 10 min. Dimethylformamide (0.5 mL) was carefully added dropwise via a syringe. After 3 hours the mixture became a clear, homogeneous solution. Excess thionyl chloride and dimethylformamide were removed under reduced pressure. The residue was azeotroped 3× with dry toluene, dissolved in 100 mL of dichloromethane, cooled to 0° C. and treated dropwise with diethylamine (34.5 mL, 330 mmol) over a 12 minute period. The reaction mixture was stirred for 72 hours at ambient temperature and then filtered through a pad of Celite® filter aid. The filtrate was poured into 200 mL of water. The organic phase was collected and the aqueous phase was extracted with 3×100 mL of dichloromethane. The combined organic extracts were washed successively with 1N NaOH, water, and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by normal phase flash chromatography eluting with 100% ethyl acetate. Like fractions containing product were combined and concentrated under reduced pressure to give N,N diethylpicolinamide 14. (12.6 g, 70.8 mmol). 1H NMR (400 MHz, Chloroform-d) δ 8.47 (ddd, J=4.8, 1.7, 1.0 Hz, 1H), 7.71-7.62 (m, 1H), 7.45 (ddd, J=7.8, 1.9, 0.8 Hz, 1H), 7.27-7.17 (m, 1H), 3.46 (q, J=7.1 Hz, 2H), 3.26 (q, J=7.1 Hz, 2H), 1.16 (t, J=7.1 Hz, 3H), 1.04 (t, J=7.1 Hz, 3H). LCMS: (M+H)+, 179.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[O:8][C@@H:7]1[C:9]([OH:11])=O)=[O:5])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.[CH2:27]([CH:34]([NH2:42])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:35]([CH:34]([NH:42][C:9]([C@H:7]1[O:8][C@@H:6]1[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:11])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CCOC(=O)[C@H]1O[C@@H]1C(=O)O
Reactant: NC(Cc1ccccc1)Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CCOC(=O)[C@H]1O[C@@H]1C(=O)NC(Cc1ccccc1)Cc1ccccc1

Procedure:
The reactions and treatments of Example 1 were repeated using (2S,3S)-3-ethoxycarbonyloxirane-2-carboxylic acid (1.01 g, 6.31 mmol.), N-hydroxysuccimide (726 mg, 6.31 mmol.), N,N'-dicyclohexylcarbodiimide (1.30 g, 6.31 mmol.), and α-benzylphenethylamine (1.43 g, 6.31 mmol.). Thus prepared product was purified by silica gel column chromatography (chloroform/methanol=50/1) to give the desired compound as a pale yellow oil (2.22 g, yield: quantitatively).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:25]([OH:27])[CH3:26]>O1CCOCC1>[OH:27][CH2:25][CH2:26][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:17])[CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][CH:7]=1
Reactant: O=C(CCc1ccccc1)c1ccc(O)cc1
Reactant: CC(O)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: O=C(CCc1ccccc1)c1ccc(OCCO)cc1

Procedure:
A mixture of 1-(4-hydroxy-phenyl)-3-phenyl-propan-1-one from Example K (6.9 g, 30.5 mmol), and cesium carbonate (19.9 g, 61 mmol) was dissolved in dioxane (300 mL). This mixture was heated to reflux for 1 hour then treated with iodoethanol (2.85 mL, 36.5 mmol) and refluxed overnight; the reaction mixture was cooled and concentrated. The product was partitioned between EtOAc and 1N HCl. The organic layer was dried (MgSO4) and concentrated to dryness. Purification by silica gel chromatography, eluting with EtOAc:hexane (30:70 to 50:50) gave the title compound, m.p. 41-43° C. 1H NMR (CDCl3) δ 1.96 (t, 1 H), 3.02 (t, 2 H), 3.22 (t, 2 H), 3.95 (m, 2 H), 4.10 (m, 2 H), 6.92 (d, 2 H), 7.15-7.28 (m, 5 H), 7.90 (d, 2 H).
Reaction SMILES: [CH3:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:16]3[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=3)[C:10]([CH:18]([CH3:24])[C:19]([O:21]CC)=[O:20])=[CH:9][C:8]2=[O:25])=[CH:4][CH:3]=1.[OH-].[K+].O.Cl>C(O)C>[CH3:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:16]3[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=3)[C:10]([CH:18]([CH3:24])[C:19]([OH:21])=[O:20])=[CH:9][C:8]2=[O:25])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)c1cc(=O)n(Cc2ccc(C)cc2)c2ccc(C)cc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(Cn2c(=O)cc(C(C)C(=O)O)c3cc(C)ccc32)cc1

Procedure:
A solution of ethyl α-[1-(4-methylbenzyl)-6-methyl-1,2-dihydro-2-oxoquinol-4-yl]propionate (0.1 g.) in ethanol (2.0 ml.), containing potassium hydroxide (0.07 g.) and water (0.2 ml.), was heated under reflux for 2 hours. The ethanol was then removed in vacuo and the residue was dissolved in water (10 ml.). The solution obtained was acidified, by addition of 5 N-hydrochloric acid, to give a creamy solid, which was separated by filtration, washed with water and air dried to give α-[1-(4-methylbenzyl)-6-methyl-1,2-dihydro-2-oxoquinol-4-yl]propionic acid, 0.08 g., m.p. 188°-190° C., (m.p. 193°-194° C., after recrystallisation from ethanol).
Reaction SMILES: [CH:1]([N:4]=[C:5]=[S:6])([CH3:3])[CH3:2].[NH2:7][C:8]1[C:17]2[N:18]=[C:19]([CH2:29][O:30][CH2:31][CH3:32])[N:20]([CH2:21][C:22]([NH:25][C:26](=[O:28])[CH3:27])([CH3:24])[CH3:23])[C:16]=2[C:15]2[CH:14]=[CH:13][C:12]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][NH2:40])=[CH:11][C:10]=2[N:9]=1>ClCCl>[NH2:7][C:8]1[C:17]2[N:18]=[C:19]([CH2:29][O:30][CH2:31][CH3:32])[N:20]([CH2:21][C:22]([NH:25][C:26](=[O:28])[CH3:27])([CH3:24])[CH3:23])[C:16]=2[C:15]2[CH:14]=[CH:13][C:12]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][NH:40][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[S:6])=[CH:11][C:10]=2[N:9]=1
Reactant: CC(C)N=C=S
Reactant: CCOCc1nc2c(N)nc3cc(OCCCCCCN)ccc3c2n1CC(C)(C)NC(C)=O
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3cc(OCCCCCCNC(=S)NC(C)C)ccc3c2n1CC(C)(C)NC(C)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 34.7 %

Procedure:
Isopropyl isothiocyanate (255 μL, 2.38 mmol) was added to a stirred suspension of N-{2-[4-amino-7-(6-aminohexyloxy)-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}acetamide (prepared as described in Part I of Example 49, 1.02 g, 2.17 mmol) in dichloromethane (100 mL) at 0° C. The mixture was stirred for 30 minutes at 0° C., then was allowed to warm to room temperature and was stirred over the weekend. The solution was concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, gradient elution with 7.5-10% methanol in dichloromethane) followed by recrystallization from acetonitrile. The crystals were dissolved in 1:1 dichloromethane/methanol and the resulting solution was concentrated under reduced pressure to afford a white powder that was dried under vacuum at 60° C. to yield 0.43 g of N-(2-{4-amino-2-(ethoxymethyl)-7-[(6{[(isopropylamino)carbonothioyl]amino}hexyl)oxy]-1H-imidazo[4,5-c]quinolin-1-yl}-1,1-dimethylethyl)acetamide as a white powder, mp 110-120° C.