Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([N:13]3C(=O)C4=CC=CC=C4C3=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.O.NN.Cl>C(O)C>[NH2:13][CH:10]1[CH2:9][CH2:8][N:7]([CH2:6][C:5]2[CH:24]=[CH:25][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:12][CH2:11]1
Reactant: O=C1c2ccccc2C(=O)N1C1CCN(Cc2ccc(F)cc2)CC1
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: NC1CCN(Cc2ccc(F)cc2)CC1
Yield: 91.7 %

Procedure:
To a solution of 1-(p-fluorobenzyl)-4-phthalimidopiperidine (3.0 g, 8.9 mmol) in ethanol (30 ml) was added hydrazine monohydrate (0.7 ml) and the mixture was heated under reflux for 3 hours. After allowed to cool, to the reaction mixture was added 5N hydrochloric acid (50 ml) and insolubles were filtered off. Then, the filtrate was washed with chloroform (30 ml×3). The aqueous layer was neutralized with potassium carbonate and then extracted with chloroform (50 ml×4). After drying over anhydrous magnesium sulfate, the solvent was distilled off to give 1.7 g of the title compound. Yield=94%.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](O)=[O:13])=[O:7].[CH3:23][NH:24][CH3:25].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(CC1C=C(CN(C)C)C(O)=C(CN(C)C)C=1)C>[Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([N:24]([CH3:25])[CH3:23])=[O:13])=[O:7]
Reactant: CNC
Reactant: O=C(COc1ccc(Cl)cc1Cl)Nc1cccc(C(=O)O)c1
Agent: CN(C)Cc1cc(CN(C)C)c(O)c(CN(C)C)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1cccc(NC(=O)COc2ccc(Cl)cc2Cl)c1
Temperature: 25 °C
Yield: 55.7 %

Procedure:
To solution of 3-[2-(2,4-dichloro-phenoxy)-acetylamino]-benzoic acid (100 mg, 0.29 mmol), dimethylamine (0.031 ml, 0.59 mmol) in DMF 3.0 mL was added EDC (83.4 mg, 0.44 mmol), HOBt (58.9 mg, 0.44 mmol) and DIPEA (0.076 ml, 0.44 mmol). Reaction mixture was stirred at room temperature, and separated by EtoAC and brine. The organic phase was dried (MgSO4 anh) and concentrated. The residue was purified by silica gel column chromatography (CH2Cl2:MeOH=30:1) to give 3-[2-(2,4-dichloro-phenoxy)acetylamino]-N,N-dimethyl-benzamide as a white solid (59.3 mg, 56% yield).
Reaction SMILES: N1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)C=1.[Li+].C[CH:16]([N-:18]C(C)C)C.[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Br:37])[N:32]=2)Cl)[N:24]=1>C1COCC1>[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Br:37])[N:32]=2)[CH:7]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:16][N:18]=2)[C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:24]=1
Reactant: CC(C)[N-]C(C)C
Reactant: c1cncc(Cc2cccnc2)c1
Reactant: ClC(c1cccc(Br)n1)c1cccc(Br)n1
Agent: [Li+]
Solvent: C1CCOC1
Product: Brc1cccc(C(c2cccc(Br)n2)C(c2cccnc2)c2ccccn2)n1
Reaction time: 1 h

Procedure:
To the solution of 3-(pyridin-3-ylmethyl)pyridine (0.085 g, 0.5 mmol) in THF (5 mL) at −78° C. was added LDA (0.3 mL, 1.8 M) and stirred for 1 h. 2-Bromo-6-[(6-bromopyridin-2-yl)(chloro)methyl]pyridine (0.181 g, 0.5 mmol) in THF (2 mL) was added. The mixture was stirred at 0° C. for 1 h. The reaction was quenched with ice and extracted with CH2Cl2. The combined organic layer was dried, filtered, and concentrated to give a solid. The solid was purified by silica gel chromatography (50% EtOAc in hexane) to give 2-bromo-6-[1-(6-bromopyridin-2-yl)-2-pyridin-2-yl-2-pyridin-3-ylethyl]pyridine. 1H-NMR (500 MHz, CDCl3) δ 8.58 (d, 1H, J=1.9), 8.47 (d, 1H, J=4.9), 8.30 (dd, 1H, J=4.7, 1.5), 7.95 (d, 1H, J=8.1), 7.44 (td, 1H, J=7.6, 1.7), 7.39 (t, 2H, J=7.7), 7.28-7.33 (m, 2H), 7.20 (d, 1H, J=7.6), 7.15 (dd, 2H, J=7.7, 4.7), 7.10 (dd, 1H, J=7.9, 4.8), 6.97 (dd, 1H, J=7.4, 4.8), 5.45 (d, 1H, J=12.0), 5.29 (d, 1H, J=12.0). LRMS m/z (M+H) Calcd: 497.2, found: 496.9.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:12]1[C:16]2[CH:17]=[CH:18][C:19]([S:21]([N:24]([CH2:29][C@H:30]3[O:34][C:33]([CH3:36])([CH3:35])[N:32]([C:37]([O:39][C@@H:40]4[C@H:47]5[C@H:43]([O:44][CH2:45][CH2:46]5)[O:42][CH2:41]4)=[O:38])[C@H:31]3[CH2:48][C:49]3[CH:54]=[CH:53][C:52](O)=[CH:51][CH:50]=3)[CH2:25][CH:26]([CH3:28])[CH3:27])(=[O:23])=[O:22])=[CH:20][C:15]=2[O:14][CH2:13]1>>[O:12]1[C:16]2[CH:17]=[CH:18][C:19]([S:21]([N:24]([CH2:29][C@H:30]3[O:34][C:33]([CH3:36])([CH3:35])[N:32]([C:37]([O:39][C@@H:40]4[C@H:47]5[C@H:43]([O:44][CH2:45][CH2:46]5)[O:42][CH2:41]4)=[O:38])[C@H:31]3[CH2:48][C:49]3[CH:50]=[CH:51][C:52]([O:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:53][CH:54]=3)[CH2:25][CH:26]([CH3:27])[CH3:28])(=[O:23])=[O:22])=[CH:20][C:15]=2[O:14][CH2:13]1
Reactant: CC(C)CN(C[C@H]1OC(C)(C)N(C(=O)O[C@H]2CO[C@H]3OCC[C@H]32)[C@H]1Cc1ccc(O)cc1)S(=O)(=O)c1ccc2c(c1)OCO2
Reactant: CC(C)(C)OC(=O)NCCO
Product: CC(C)CN(C[C@H]1OC(C)(C)N(C(=O)O[C@H]2CO[C@H]3OCC[C@H]32)[C@H]1Cc1ccc(OCCNC(=O)OC(C)(C)C)cc1)S(=O)(=O)c1ccc2c(c1)OCO2

Procedure:
According to example 135 (with the exception that N-(tert-butoxycarbonyl)ethanolamine was used instead of phenethyl alcohol), (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (4S,5R)-5-{[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]methyl}-4-(4-hydroxybenzyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate was converted to the desired compound. MS(ESI): 798(M+Na).
Reaction SMILES: CN1C=C(C2C=CC=C(NC(C3SC4CCCCC=4C=3)=O)C=2C)N=C([O-])C1=O.[Na+].Br[C:31]1[N:36]=[C:35]([NH:37][C:38]2[CH:43]=[CH:42][C:41]([CH:44]([N:50]3[CH2:55][CH2:54][N:53]([CH2:56][CH3:57])[CH2:52][CH2:51]3)[C:45]([O:47][CH2:48][CH3:49])=[O:46])=[CH:40][CH:39]=2)[C:34](=[O:58])[N:33]([CH3:59])[CH:32]=1.[CH3:60][C:61]1[C:66](C2OC(C)(C)C(C)(C)O2)=[CH:65][CH:64]=[CH:63][C:62]=1[NH:76][C:77]([C:79]1[S:83][C:82]2[CH2:84][CH2:85][CH2:86][CH2:87][CH2:88][C:81]=2[CH:80]=1)=[O:78]>>[CH2:56]([N:53]1[CH2:54][CH2:55][N:50]([CH:44]([C:41]2[CH:42]=[CH:43][C:38]([NH:37][C:35]3[C:34](=[O:58])[N:33]([CH3:59])[CH:32]=[C:31]([C:66]4[CH:65]=[CH:64][CH:63]=[C:62]([NH:76][C:77]([C:79]5[S:83][C:82]6[CH2:84][CH2:85][CH2:86][CH2:87][CH2:88][C:81]=6[CH:80]=5)=[O:78])[C:61]=4[CH3:60])[N:36]=3)=[CH:39][CH:40]=2)[C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:51][CH2:52]1)[CH3:57]
Reactant: Cc1c(NC(=O)c2cc3c(s2)CCCCC3)cccc1C1OC(C)(C)C(C)(C)O1
Reactant: CCOC(=O)C(c1ccc(Nc2nc(Br)cn(C)c2=O)cc1)N1CCN(CC)CC1
Agent: Cc1c(NC(=O)c2cc3c(s2)CCCC3)cccc1-c1cn(C)c(=O)c([O-])n1
Agent: [Na+]
Product: CCOC(=O)C(c1ccc(Nc2nc(-c3cccc(NC(=O)c4cc5c(s4)CCCCC5)c3C)cn(C)c2=O)cc1)N1CCN(CC)CC1
Yield: 73.2 %

Procedure:
Using the same procedure as described for the preparation of 10, the reaction of ethyl 2-(4-(6-Bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-ylamino)phenyl)-2-(4-ethylpiperazin-1-yl)acetate (1.33 g) with N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl)-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-2-carboxamide (1.26 g) gave a 73% yield (1.39 g) of 45 as a tan foam: mp 168-170° C.; 1H NMR (300 MHz, CDCl3) δ 8.34 (s, 1H), 7.92 (d, 1H, J=7.8 Hz), 7.80 (d, 2H, J=8.7 Hz), 7.54 (s, 1H), 7.39 (d, 2H, J=8.7 Hz), 7.39 (s, 1H), 7.27 (t, 1H, J=8.1 Hz), 7.18 (dd, 1H, J=7.8, 1.2 Hz), 6.74 (s, 1H), 4.14 (m, 2H), 3.91 (s, 1H), 3.60 (s, 3H), 2.87 (t, 2H, J=5.7 Hz), 2.76 (t, 2H, J=5.7 Hz), 2.61 (br s, 8H), 2.32 (s, 3H), 1.88 (m, 2H), 1.77 (m, 4H), 1.17 (t, 3H, J=7.2 Hz), 1.05 (t, 3H, J=7.2 Hz); MS (ESI+) m/z 683 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([NH2:18])=[O:17])=[N:14][CH:15]=1.[H-].[Na+].[C:32](OC(=O)C)(=[O:34])[CH3:33].O>CN(C)C=O>[C:32]([NH:18][C:16]([C:13]1[CH:12]=[C:11]([CH3:19])[C:10]([CH:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])[S:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:15][N:14]=1)=[O:17])(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(C(N)=O)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)NC(=O)c1cc(C)c(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(F)cc2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
To a solution of 5-[(2,5-difluorophenyl)[(4-fluorophenyl)sulfonyl]methyl]-4-methylpyridine-2-carboxamide (150 mg, 0.36 mmol) obtained in Example 15 in N,N-dimethylformamide (7 ml), sodium hydride (60%, 34 mg, 0.79 mmol) was added at 0° C., and the mixture was stirred for 1 hour at room temperature. Subsequently, acetic anhydride (40 μl) was added to the reaction solution at 0° C., and the mixture was stirred for 1 hour at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, and was dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the resulting residue was subjected to silica gel chromatography. The fraction obtained from an elution with hexane:ethyl acetate=10:3 was concentrated under reduced pressure, and the resulting residue was washed with diethyl ether and n-hexane, and then was collected by filtration, to obtain the title compound (80 mg, 0.17 mmol, 48%) as a white solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:13][C:14](=[CH2:18])[C:15](=[O:17])[CH3:16].CCN(CC)CC>C(O)C.[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1>[CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([C:9](=[O:10])[CH2:13][CH:14]([CH3:18])[C:15](=[O:17])[CH3:16])=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(C=O)cc1
Reactant: C=C(C)C(C)=O
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)C(C)CC(=O)c1ccc(S(C)(=O)=O)cc1
Reaction time: 3 h
Yield: 4.3 %

Procedure:
To a stirred solution of 4-(methylsulfonyl)benzaldehyde (1.84 g, 10 mmol) in ethanol (8 mL) was added 3-methyl-3-buten-2-one (0.8 g, 9.5 mmol), 3-benzyl-5-(2-hydroxyethyl)4-methylthiazolium chloride (0.51 g, 1.9 mmol), and Et3N (2.65 mL, 19 mmol) at room temperature. After stirring for 3 hours, volatiles were removed by evaporation. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/hexane (1/2) to provide the subtitle compound (0.11 g).
Reaction SMILES: [CH:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH:13]=[CH2:14])=[CH2:2].C1(C)C=CC(S([O-])(=O)=[O:22])=CC=1.[NH+]1C=CC=CC=1.C(N(CC)CC)C.C(OC(Cl)C)C.[OH2:45]>O1CCCC1.C(OCC)(=O)C>[OH:45][CH:13]([O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH:1]([OH:22])[CH3:2])[CH3:14]
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: C=COCCOCCOCCOC=C
Reactant: O
Agent: CCOC(C)Cl
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(O)OCCOCCOCCOC(C)O
Reaction time: 6 h

Procedure:
The thus obtained partially hydroxypropylated polyhydroxystyrene, 90 g, was dissolved in 180 g of tetra-hydrofuran. With stirring under ice cooling, 2.3 g of triethylene glycol divinyl ether and then 1.8 g of pyridinium p-toluenesulfonate were added. Reaction was carried out for 6 hours at room temperature, 46.5 g of triethylamine and then 30.0 g of 1-chloroethyl ethyl ether were added, and reaction was carried out for a further 2 hours at room temperature. To the reaction mixture were added 500 g of ethyl acetate and 300 g of water, followed by separation. The ethyl acetate layer was washed twice with 300 g of water and then concentrated in vacuum. The residue was dissolved in 300 g of methanol and added dropwise to 20 liters of water whereupon a powdery solid precipitated. The solid was collected by filtration, washed with 20 liters of water, and dried in vacuum at 40° C. for 24 hours. On 1H-NMR analysis, it was identified to be a polymer (Polym. 5) in which 31.0 mol % of the hydrogen atoms of hydroxyl groups in polyhydroxystyrene were replaced by 1-ethoxyethyl groups, and the alcoholic hydroxyl group moieties which had been introduced in an amount of 2.0 mol % formed ether bonds with alcoholic hydroxyl groups of triethylene glycol di(1-hydroxyethyl) ether to provide crosslinking.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=O)=[CH:8][CH:7]=1)(=[O:4])=[O:3].CN1CCOCC1.ClC(OCC(C)C)=O.[CH3:31][NH:32][CH:33]([CH3:44])[CH2:34][O:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([CH3:42])[C:37]=1[CH3:43]>CN(C)C=O.C(N(CC)CC)C>[CH3:43][C:37]1[C:38]([CH3:42])=[CH:39][CH:40]=[CH:41][C:36]=1[O:35][CH2:34][CH:33]([N:32]([CH3:31])[C:13](=[O:15])[CH2:12][C:9]1[CH:8]=[CH:7][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:11][CH:10]=1)[CH3:44]
Reactant: CS(=O)(=O)Nc1ccc(CC(=O)O)cc1
Reactant: CNC(C)COc1cccc(C)c1C
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cccc(OCC(C)N(C)C(=O)Cc2ccc(NS(C)(=O)=O)cc2)c1C
Temperature: -10 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution containing 0.80 g (3.5 mmol) of 4-methanesulfonamido-phenylacetic acid (Example 32) in 20 ml of N,N-dimethylformamide (DMF) 0.46 ml (0.42 g, 4,2 mmol) of 4-methylmorpholine is added, the mixture is cooled to −10° C. and 0.65 ml (0.70 g, 5 mmol) of isobutyl chloroformate is added. After 10 minutes a solution containing 0.68 g (3.5 mmol) of N-methyl-2-(2,3-dimethylphenoxy)-1-methylethylamine (Example 44) in 3 ml of DMF pre-cooled to −10° C. is added, then the pH value of the mixture is adjusted to 8.5 by adding triethylamine. The reaction mixture is stirred at −10° C. for 1 hour, then at 0° C. for 1 hour. Then, the solvent is evaporated under reduced pressure and the solid residue is alkalinized by adding aqueous ammonia solution and distributed between water and ethyl acetate. The aqueous phase is washed twice with ethyl acetate, the combined organic phase is washed once with water, dried over sodium sulphate and evaporated. Thus, 1.13 g of the title substance are obtained as an amorphous substance, which is suitable to the next step without further purification. Yield: 80%.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)(N1C=CN=C1)=O.[F:13][C:14]1[CH:15]=[C:16]2[C:21](=[C:22]([OH:25])C=1F)[N:20]([NH:26][CH3:27])[CH:19]=[C:18]([C:28]([OH:30])=[O:29])[C:17]2=[O:31]>CN(C)C=O>[F:13][C:14]1[CH:15]=[C:16]2[C:21](=[C:22]([OH:25])[C:1]=1[N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)[N:20]([NH:26][CH3:27])[CH:19]=[C:18]([C:28]([OH:30])=[O:29])[C:17]2=[O:31]
Reactant: CNn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(O)c21
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CNn1cc(C(=O)O)c(=O)c2cc(F)c(-n3ccnc3)c(O)c21
Reaction time: 2 h
Yield: 59.4 %

Procedure:
Carbonyldiimidazole (32 mg) was added to a stirred solution of 6,7-difluoro-8-hydroxy-1-(methylamino)-4-oxo-1,4-dihydro -3-quinolinecarboxylic acid (50 mg) obtained in Reference example (i) in dry dimethylformamide (2 ml). Stirring was continued at room temperature for 2 hours and then at 80° C. for 5 hours. The solvent was removed under reduced pressure and the residue was suspended in water and the pH was adjusted to pH 5 with acetic acid. The precipitate which separated out was filtered and washed with methanol to give 35 mg of 6-fluoro-8-hydroxy-7-(1-imidazolyl)-1-(methylamino)-4-oxo -1,4-dihydro-3-quinolinecarboxylic acid as pale yellow powder, FAB-MS m/z 319 (MH+); 1H-NMR (d6 -DMSO) δ: 2.82 (3H,s), 7.10 (1H, d, J=10.7 Hz), 7.61 (1H, d). 7.75 (1H, d), 8.62 (1H,s), 8.92 (1H,s). 15.33 (1H, br.s).
Reaction SMILES: F[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:31][C@@H:32]([CH2:36][CH3:37])[C@H:33]([OH:35])[CH3:34]>CCCCO.CS(C)=O>[CH:11]([N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH:31][C@@H:32]([CH2:36][CH3:37])[C@H:33]([OH:35])[CH3:34])=[N:3][C:4]=2[NH:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)([CH3:13])[CH3:12]
Reactant: CC[C@H](N)[C@@H](C)O
Reactant: CC(C)n1cnc2c(NCc3cccnc3)nc(F)nc21
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC[C@H](Nc1nc(NCc2cccnc2)c2ncn(C(C)C)c2n1)[C@@H](C)O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of (2-fluoro-9-isopropyl-9H-purin-6-yl)-pyridin-3-ylmethyl-amine (30 mg, 1 eq, 0.10 mmol) in n-BuOH/DMSO (2.5 mL, 4:1) at room temperature under an argon atmosphere was added DIEA (0.2 mL, 10.96 eq, 1.14 mmol) followed by (2R,3S)-3-amino-pentan-2-ol (60 mg, 5.5 eq, 0.58 mmol). The reaction mixture was placed in a preheated oil bath at 160° C. and stirred at this temperature for 72 h. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo. The residue was partitioned between EtOAc (50 mL) and water (50 mL), the aqueous phase was extracted with more EtOAc (2×25 mL), and the combined organic phase was washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by gradient column chromatography on silica gel eluted with CHCl3:MeOH (100:0→98:2), to afford the title compound as a white solid. Yield: 25 mg (65%). (80% de 3S,2R: 20% de 3S,2S). 1H-NMR (d-CDCl3, 250 MHz): δ 0.90 & 1.05 (2×t, 3H, J=6.48 & 7.42 Hz, —NHCH(CH2CH3)CH(CH3)OH), 1.16 & 1.24 (2×d, 3H, J=6.31 & 6.16 Hz, —NHCH(CH2CH3)CH(CH3)OH) 1.57 (d, 6H, J=6.79 Hz, —CH(CH3)2), 1.77-2.09 (m, 2H, —NHCH(CH2CH3)CH(CH3)OH), 3.91-4.04 (m, 2H, —NHCH(CH2CH3)CH(CH3)OH), 4.58-4.69 (m, 1H, —CH(CH3)2), 4.83 (m, 3H, —HNCH2-Pyr & OH), 6.11-6.23 (m, 1H, —NHCH(CH2CH3)CH(CH3)OH), 7.24-7.32 (m, 3H, 2×Pyr-H+—N═CH—N—), 7.53-7.57 (m, 1H, Pyr-H), 7.74 (d, 1H, J=7.58 Hz, Pyr-H), 8.67 (m, 1H, HNCH2-Pyr). FABMS m/z (relative intensity): 370 ([M+H]+, 100), 324 (40), 289 (15), 243 (10), 233 (13), 199 (10). Accurate Mass (M+H): Actual: 370.2355, Measured: 370.2347.
Reaction SMILES: [NH2:1][CH:2]([CH:15]([CH3:17])[CH3:16])[C:3]([N:5]([CH3:14])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[N+:18]([C:21]1[C:22]([CH:34]=O)=[CH:23][C:24]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N:25][CH:26]=1)([O-:20])=[O:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C1COCC1.ClCCl>[CH3:16][CH:15]([CH3:17])[CH:2]([NH:1][CH2:34][C:22]1[C:21]([N+:18]([O-:20])=[O:19])=[CH:26][N:25]=[C:24]([O:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:23]=1)[C:3]([N:5]([CH3:14])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: O=Cc1cc(Oc2ccccc2)ncc1[N+](=O)[O-]
Reactant: CC(C)C(N)C(=O)N(C)CCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)C(NCc1cc(Oc2ccccc2)ncc1[N+](=O)[O-])C(=O)N(C)CCc1ccccc1
Reaction time: 5 h

Procedure:
A mixture of 2-amino-3,N-dimethyl-N-phenethyl-butyramide (1.5 g, 6.48 mmol), 5-nitro-2-phenoxy-pyridine-4-carbaldehyde (1.5 g, 6.1 mmol), dichloromethane (75 mL), and THF (75 mL) was stirred for 5 hrs. Sodium triacetoxyborohydride (3.0 g, 14.25 mmol) was then added and the resulting mixture was stirred 16 hrs. Sodium hydroxide solution ([0.1 N], 100 mL) was added, the organic layer was separated, treated with MgSO4, filtered and the solvent evaporated to yield an oil. The oil was purified by column chromatography (10%-40% ethyl acetate/heptane) to yield a residue.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])=[CH:12][CH:11]=1)([O-:9])=[O:8].C([N:26]([CH2:29][CH3:30])CC)C>O1CCCC1>[N+:7]([C:10]1[CH:15]=[CH:30][C:29]([N:26]([S:17]([C:20]([F:23])([F:21])[F:22])(=[O:18])=[O:19])[C:2]([C:1]([N:16]([C:13]2[CH:12]=[CH:11][C:10]([N+:7]([O-:9])=[O:8])=[CH:15][CH:14]=2)[S:17]([C:20]([F:23])([F:21])[F:22])(=[O:19])=[O:18])=[O:5])=[O:3])=[CH:12][CH:11]=1)([O-:9])=[O:8]
Reactant: CCN(CC)CC
Reactant: O=[N+]([O-])c1ccc(NS(=O)(=O)C(F)(F)F)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: O=C(C(=O)N(c1ccc([N+](=O)[O-])cc1)S(=O)(=O)C(F)(F)F)N(c1ccc([N+](=O)[O-])cc1)S(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Oxalyl chloride (0.825 gram; 0.0065 mole) is added dropwise to a stirred solution of N-4-nitrophenyl trifluoromethanesulfonamide (3.61 grams; 0.013 mole) and triethylamine (1.3 grams; 0.0128 mole) in dry tetrahydrofuran (40 mls) at 0° C. under a nitrogen atmosphere. After the addition is completed, the reaction mixture is warmed to room temperature and stirred thereat for 18 hours. The reaction mixture is then filtered, the solvent is evaporated from the filtrate, and water (20 mls) is added to the residue. The resulting precipitate is then filtered to obtain 3.29 grams (92% of theoretical) of crude yellow-colored product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18](=[O:33])[NH:19][C:20]3[NH:24][C:23]4[CH:25]=[CH:26][CH:27]=[C:28]([C:29]([O:31]C)=[O:30])[C:22]=4[N:21]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].C1COCC1>CO>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18](=[O:33])[NH:19][C:20]3[NH:24][C:23]4[CH:25]=[CH:26][CH:27]=[C:28]([C:29]([OH:31])=[O:30])[C:22]=4[N:21]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cccc2[nH]c(NC(=O)c3ccc4c(c3)CCN(C(=O)OC(C)(C)C)C4)nc12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2cc(C(=O)Nc3nc4c(C(=O)O)cccc4[nH]3)ccc2C1
Yield: 72.4 %

Procedure:
109 mg (0.242 mmol) of 6-(4-methoxycarbonyl-1H-benzoimidazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester was hydrolyzed using 1 mL of 2 N aq. LiOH, 4 mL of THF and 1 mL of methanol stirring at room temperature for one day as described in general procedure B. 76.5 mg (72%) of the 6-(4-Carboxy-1H-benzoimidazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester product was obtained. LCMS: 437 (M+1)+.
Reaction SMILES: [CH:1]1([C:4]2[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]#[N:29])=[CH:18][CH:17]=3)[C:7]3=[N:8][CH:9]=[C:10](Br)[C:11]([CH3:12])=[C:6]3[N:5]=2)[CH2:3][CH2:2]1.C(O)=O.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH:1]1([C:4]2[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]#[N:29])=[CH:18][CH:17]=3)[C:7]3=[N:8][CH:9]=[CH:10][C:11]([CH3:12])=[C:6]3[N:5]=2)[CH2:3][CH2:2]1
Reactant: Cc1c(Br)cnc2c1nc(C1CC1)n2Cc1ccc(-c2ccccc2C#N)cc1
Solvent: O=CO
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccnc2c1nc(C1CC1)n2Cc1ccc(-c2ccccc2C#N)cc1
Yield: 78 %

Procedure:
Toluene (30 ml) was added to 2.0 g (4.5 mmol) of 2-cyclopropyl-3-(2'-cyanobiphenyl-4-yl)methyl-6-bromo-7-methyl-3H-imidazo[4,5-b]pyridine, 1.24 g (27.0 mmol) of formic acid, 4.55 g (45.0 mmol) of triethylamine and 10% Pd--C (100 mg), followed by heating under reflux for 6 hours. After the reaction liquid was brought to room temperature and filtered to remove the catalyst, vacuum concentration was effected. Chloroform (50 ml) and water (50 ml) were added to the residue and the obtained mixture was caused liquid- liquid seperation. The aqueous phase was further extracted with chloroform (30 ml) twice. The organic phases were combined, dried over anhydrous magnesium sulfate and subjected to vacuum concentration. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to give 1.28 g of 2-cyclopropyl-3-(2'-cyanobiphenyl-4-yl)methyl-7-methyl-3H-imidazo[4,5-b]pyridine (yield 78%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[CH3:12][N:13]([CH3:22])[C:14]([C@@H:16]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1)=[O:15].C(N(CC)CC)C>CN(C)C=O>[NH2:8][C:6]1[N:7]=[C:2]([N:18]2[CH2:19][CH2:20][CH2:21][C@@H:16]([C:14]([N:13]([CH3:22])[CH3:12])=[O:15])[CH2:17]2)[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: CN(C)C(=O)[C@@H]1CCCNC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)[C@@H]1CCCN(c2ccc([N+](=O)[O-])c(N)n2)C1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of 6-chloro-3-nitropyridin-2-amine (4.15 g, 24.0 mmol) in N,N-dimethylformamide (41 mL) was added (R)—N,N-dimethylpiperidine-3-carboxamide (3.74 g, 2.40 mmol) followed by triethylamine (10.7 mL, 64.800 mmol). The reaction mixture was stirred at 80° C. for 16 h. The solvent was removed under reduced pressure and the residue was purified via column chromatography to afford (R)-1-(6-amino-5-nitropyridin-2-yl)-N,N-dimethylpiperidine-3-carboxamide.