Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:18]([O-])([OH:20])=[O:19]>>[N+:18]([C:10]1[CH:9]=[C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:13]=[CH:12][C:11]=1[NH:14][C:15](=[O:17])[CH3:16])([O-:20])=[O:19]
Reactant: CC(=O)Nc1ccc(Oc2ccccc2)cc1
Reactant: O=[N+]([O-])O
Product: CC(=O)Nc1ccc(Oc2ccccc2)cc1[N+](=O)[O-]
Temperature: -15 °C
Reaction time: 2 h

Procedure:
N-(4-phenoxy-phenyl)-acetamide (1.00 g, 4.03 mmol) prepared in Step A was dissolved in fuming nitric acid (2 mL), and the mixture was stirred for 2 h at −15° C. After completion of the reaction, the reaction mixture was poured into 100 mL of ice water, which was then extracted with ethyl acetate. The extracted organic solution was dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure, and the residue was purified by column chromatography to give the title compound (0.67 g, 2.33 mmol).
Reaction SMILES: [OH:1][C:2]([C:5]1[O:6][CH:7]=[C:8]([C:10]([O:12]CC)=O)[N:9]=1)([CH3:4])[CH3:3].[NH2:15][CH2:16][C@@H:17]([N:19]1[CH:23]=[CH:22][C:21]([C:24]2[CH:31]=[C:30]([F:32])[C:27]([C:28]#[N:29])=[C:26]([Cl:33])[CH:25]=2)=[N:20]1)[CH3:18]>>[Cl:33][C:26]1[CH:25]=[C:24]([C:21]2[CH:22]=[CH:23][N:19]([C@@H:17]([CH3:18])[CH2:16][NH:15][C:10]([C:8]3[N:9]=[C:5]([C:2]([OH:1])([CH3:3])[CH3:4])[O:6][CH:7]=3)=[O:12])[N:20]=2)[CH:31]=[C:30]([F:32])[C:27]=1[C:28]#[N:29]
Reactant: CCOC(=O)c1coc(C(C)(C)O)n1
Reactant: C[C@@H](CN)n1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Product: C[C@@H](CNC(=O)c1coc(C(C)(C)O)n1)n1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1

Procedure:
The title compound was prepared using the procedure described in Example 52(g) starting from ethyl 2-(2-hydroxypropan-2-yl)oxazole-4-carboxylate (0.75 mmol, 150 mg) and (S)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (0.75 mmol, 209 mg). Yield 87 mg. 1H-NMR (400 MHz; DMSO-d6): δ 1.45 (d, 3H), 1.49 (s, 6H), 3.55-3.61 (m, 1H), 3.66-3.73 (m, 1H), 4.69-4.74 (m, 1H), 5.66 (s, 1H), 7.03 (d, 1H), 7.88-7.93 (m, 2H), 8.0 (s, 1H), 8.19 (t, 1H), 8.51 (s, 1H). LC-MS: [M+1]=432.31.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10](O)=[O:11])[N:7]([CH2:13][C:14]2[CH:18]=[C:17]([C:19]3[S:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[O:16][N:15]=2)[N:6]=1)=[O:4].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.Cl.[CH:41]([N:44]1[CH2:49][CH2:48][CH:47]([NH2:50])[CH2:46][CH2:45]1)([CH3:43])[CH3:42]>C(Cl)Cl.CCN(CC)CC>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10](=[O:11])[NH:50][CH:47]2[CH2:48][CH2:49][N:44]([CH:41]([CH3:43])[CH3:42])[CH2:45][CH2:46]2)[N:7]([CH2:13][C:14]2[CH:18]=[C:17]([C:19]3[S:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[O:16][N:15]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1cc(C(=O)O)n(Cc2cc(-c3ccc(Cl)s3)on2)n1
Reactant: CC(C)N1CCC(N)CC1
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C(=O)NC2CCN(C(C)C)CC2)n(Cc2cc(-c3ccc(Cl)s3)on2)n1
Reaction time: 0.5 h

Procedure:
To 1 g 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1H-pyrazole-3,5-dicarboxylic acid 3-methyl ester in 10 ml DCM and 1.4 ml NEt3, 667 mg BOP-Cl were added at RT and the mixture was stirred for 30 min. After addition of 563 mg 1-Isopropyl-piperidin-4-ylamine hydrochloride the mixture was stirred for 16 h. After removal of the solvent under reduced pressure the residue was purified by silica gel chromatography eluting with DCM/MeOH/AcOH/H2O 20:10:1:1 to yield a white solid. Yield: 800 mg MS (ES+): m/e=492, chloro pattern.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]([CH2:21][CH3:22])[C:19]([C:23](=[O:26])[CH2:24][CH3:25])=[CH:18][C:17]=2[CH3:27])=[CH:12][CH:11]=1.C(OCC)(=O)C>C1COCC1>[Br:1][C:18]1[C:17]([CH3:27])=[C:16]([C:13]2[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=2)[N:20]([CH2:21][CH3:22])[C:19]=1[C:23](=[O:26])[CH2:24][CH3:25]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCC(=O)c1cc(C)c(-c2ccc(Cl)cc2)n1CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(=O)c1c(Br)c(C)c(-c2ccc(Cl)cc2)n1CC
Temperature: -78 °C
Reaction time: 5 h
Yield: 77.9 %

Procedure:
A solution of N-bromosuccinimide (0.35 g, 1.99 mmol) in THF (10 ml) was added dropwise to a stirred solution of 1-(5-(4-chlorophenyl)-1-ethyl-4-methyl-1H-pyrrol-2-yl)propan-1-one (compound 51b, 0.5 g, 1.81 mmol) in THF (25 ml) at about −78° C. The resulting reaction mixture was stirred at about −78° C. for 5 hr. The reaction mixture was then allowed to warm to 25° C. slowly during further 3 to 4 hr. The progress of the reaction was monitored by TLC. The solvent was evaporated from the reaction mixture under reduced pressure and to the residue so obtained was added ethyl acetate (50 ml). The mixture so obtained was washed with saturated sodium bicarbonate solution (1×30 ml) followed by washing with water (1×30 ml). The combined organic layer was then dried over anhydrous Na2SO4. The solvent was evaporated from the dried organic layer under reduced pressure to obtain a crude product, which was then purified by flash column chromatography 10% ethyl acetate in hexanes as an eluent to obtain the title compound (0.5 g, 78.0%).
Reaction SMILES: [OH:1][C@@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[C:19]([Si:23]([CH3:26])([CH3:25])Cl)([CH3:22])([CH3:21])[CH3:20].N1C=CN=C1.O>CN(C=O)C>[O:1]([C@@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][C:4]([O:6][CH3:7])=[O:5])[Si:23]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:26])[CH3:25]
Reactant: CCCCCCCCCCC[C@H](O)CC(=O)OC
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCC[C@@H](CC(=O)OC)O[Si](C)(C)C(C)(C)C
Reaction time: 17 h

Procedure:
12.9 g of methyl (S)-3-hydroxytetradecanoate are dissolved in 50 ml of DMF under argon 9.0 g of t-butyldimethylchlorosilane are added thereto, 8.5 g of imidazole are then added portionwise and the mixture is left to stir for 17 hours. The reaction mixture is poured into 300 ml of water and extracted three times with 50 ml of diethyl ether. The combined organic phases are dried, filtered and evaporated. By distillation at 140°-145° C./0.07 mm there is obtained methyl (S)-3-(t-butyldimethylsiloxy)tetradecanoate as a colourless oil.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[N:8]([CH:9]2[CH2:15][CH:14]3[N:16]([CH2:17][CH2:18][C:19]4([C:25]5[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=5)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[C:7]2[CH:35]=[CH:36][CH:37]=[CH:38][C:6]=2[N:5]=1.C(N(CC)CC)C.[NH2:46][S:47]([C:50]1[CH:51]=[C:52]([CH:56]=[CH:57][C:58]=1[Cl:59])[C:53](Cl)=[O:54])(=[O:49])=[O:48]>ClCCl>[Cl:59][C:58]1[CH:57]=[CH:56][C:52]([C:53]([N:22]2[CH2:23][CH2:24][C:19]([CH2:18][CH2:17][N:16]3[C@H:11]4[CH2:12][CH2:13][C@@H:14]3[CH2:15][CH:9]([N:8]3[C:7]5[CH:35]=[CH:36][CH:37]=[CH:38][C:6]=5[N:5]=[C:4]3[CH3:3])[CH2:10]4)([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:32])[F:34])[CH:26]=3)[CH2:20][CH2:21]2)=[O:54])=[CH:51][C:50]=1[S:47]([NH2:46])(=[O:49])=[O:48]
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2cccc(C(F)(F)F)c2)CCNCC1
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(C(F)(F)F)c2)CCN(C(=O)c2ccc(Cl)c(S(N)(=O)=O)c2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 2-methyl-1-[8-(2-{4-[3-(trifluoromethyl)phenyl]piperidin-4-yl}ethyl)-8-azabicyclo[3.2.1]oct-3-yl]-1H-benzimidazole dihydrochloride (0.1 g, 0.2 mmol), triethylamine (0.056 mL, 0.4 mmol) and 3-(aminosulfonyl)-4-chlorobenzoyl chloride (0.056 g, 0.22 mmol) in dichloromethane (2 mL) was stirred at rt for 1.5 h. The reaction mixture was diluted with dichloromethane, washed with saturated sodium bicarbonate solution, dried, concentrated and purified by three successive chromatographies on silica gel eluting with mixtures of methanol in dichloromethane to give 2-chloro-5-({4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-[3-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)benzenesulfonamide as a wax (0.002 g, 2%). 1H NMR (400 MHz, CD3OD3) δ 7.79-7.94 (m, 2H), 7.57-7.71 (m, 5H), 7.40-7.54 (m, 2H), 7.15-7.21 (m, 2H), 4.73 (m, 1H), 4.15 (m, 1H), 3.39-3.55 (m, 4H), 3.16-3.22 (m, 1H), 2.52 (s, 3H), 2.34-2.50 (m, 3H), 2.22-2.32 (m, 1H), 1.94-2.12 (m, 10H), 1.68-1.74 (m, 2H). HRMS C36H39ClF3N5O3S m/z 714.2492 (M+H)Cal., 714.2496 (M+H)Obs..
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[NH:15][C:14]4[CH:16]=[CH:17][CH:18]=[C:19]([CH2:20][O:21][CH3:22])[C:13]=4[N:12]=3)=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH3:25][Si:26]([CH2:29][CH2:30][O:31][CH2:32]Cl)([CH3:28])[CH3:27]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:15]([CH2:32][O:31][CH2:30][CH2:29][Si:26]([CH3:28])([CH3:27])[CH3:25])[C:14]4[CH:16]=[CH:17][CH:18]=[C:19]([CH2:20][O:21][CH3:22])[C:13]=4[N:12]=3)=[N:9][N:8]([CH2:32][O:31][CH2:30][CH2:29][Si:26]([CH3:28])([CH3:27])[CH3:25])[C:5]2=[N:6][CH:7]=1
Reactant: COCc1cccc2[nH]c(-c3n[nH]c4ncc(Br)cc34)nc12
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1cccc2c1nc(-c1nn(COCC[Si](C)(C)C)c3ncc(Br)cc13)n2COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-bromo-3-(4-methoxymethyl-1H-benzoimidazol-2-yl)-1H-pyrazolo[3,4-b]pyridine Compound 11 (1.2 g, 4.19 mmol) was dissolved in dry THF (20 mL). The solution was cooled to 0° C. before sodium hydride (0.37 g, 60% in mineral oil, 9.25 mmol) was added in portions. The suspension was stirred at 0° C. for additional 15 minutes before (trimethylsilyl)ethoxymethyl chloride (1.78 mL, 10.06 mmol) was added. The reaction was warmed to room temperature and stirred overnight. Solvent was removed and the residue was purified by silica gel chromatography (10% to 50% ethyl acetate in hexanes) to yield 5-bromo-3-[4-methoxymethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine Compound 12a (1.59 g, 77%) as amber oil. 1H NMR (300 MHz, CDCl3) δ 9.35 (d, 1H, J=2.4 Hz), 8.84 (d, 1H, J=2.4 Hz), 7.74 (d, 1H, J=5.4 Hz), 7.57 (m, 2H), 6.45 (s, 2H), 6.09 (s, 2H), 5.26 (s, 2H), 3.86 (m, 4H), 3.77 (s, 3H), 1.13 (t, 2H, J=7.2 Hz), 1.05 (t, 2H, J=7.8 Hz), 0.14 (s, 9H), 0.03 (s, 9H); MS (ESI) m/z: 619 (M+H+).
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:14]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:13][CH:12]=[CH:11][CH2:10][N:9]1[S:25]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)(=[O:27])=[O:26])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:18]([O:17][C:15]([CH:14]1[CH2:13][CH:12]=[CH:11][CH2:10][N:9]([S:25]([C:28]2[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=2)(=[O:26])=[O:27])[CH:8]1[C:6]([OH:7])=[O:5])=[O:16])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COc1ccc(S(=O)(=O)N2CC=CCC(C(=O)OCc3ccccc3)C2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(S(=O)(=O)N2CC=CCC(C(=O)OCc3ccccc3)C2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-(4-Methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2,3-dicarboxylic acid 3-benzyl ester 2-tert-butyl ester (1.6 g, 3.2 mmol) was dissolved in anhydrous methylene chloride (16 mL) and treated with trifluoroacetic acid (4 mL). The solution was stirred at ambient temperature for 3 hrs and then the solvents were removed in vacuo. The residue was coevaporated with toluene two times and then purified by column chromatography (silica) to yield 1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2,3-dicarboxylic acid 3-benzyl ester; MS: (M+H)+ 446.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.[CH3:10][Mg]Br>C1COCC1>[OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][C:6]([CH3:10])([OH:9])[CH2:5][CH2:4]1
Reactant: O=C1CCC(CO)CC1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC1(O)CCC(CO)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 4-(hydroxymethyl)cyclohexanone (1.0 g, 7.8 mmol) in THF (20 mL) was added methyl magnesium bromide (3.0 M in Et2O, 7.8 mL, 23.4 mmol) dropwise at 0° C. for 5 min. The mixture was allowed to warm to room temperature and stirred at the same temperature for 2 h. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc (2×20 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 80% EtOAc/hexane as eluent) to provide compound A112-1 (300 mg, 27%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[N:8]=[C:9]([NH2:12])[S:10][CH:11]=1.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[S:21](Cl)(=[O:23])=[O:22]>>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[S:21]([NH:12][C:9]1[S:10][CH:11]=[C:7]([C:3]2[S:4][CH:5]=[CH:6][C:2]=2[Cl:1])[N:8]=1)(=[O:23])=[O:22]
Reactant: Nc1nc(-c2sccc2Cl)cs1
Reactant: O=S(=O)(Cl)c1c(Cl)cccc1Cl
Product: O=S(=O)(Nc1nc(-c2sccc2Cl)cs1)c1c(Cl)cccc1Cl

Procedure:
The title compound was prepared from 4-(3-chloro-2-thienyl)-1,3-thiazol-2-amine (59 mg) and 2,6-dichlorobenzenesulfonyl chloride (66 mg) as descrbed in the synthetic METHOD B to give a yellow solid (34.5 mg) with purity >90%: MS (pos) m/z 425.3, 427.3; HRMS m/z 423.8730 (calc. of monoisotopic mass for C13 H7 Cl3 N2 O2 S3 gives 423.8735).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:12]=[C:13]2[CH:19]=[CH:18][N:17]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:14]2=[N:15][CH:16]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[C:1]1([C:11]2[CH:12]=[C:13]3[CH:19]=[CH:18][N:17]([S:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)(=[O:21])=[O:22])[C:14]3=[N:15][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3cc(Br)cnc32)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3cc(-c4ccccc4)cnc32)cc1

Procedure:
A mixture of phenyl boronic acid (1.74 g), 5-bromo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine [5 g, Reference Example 9(d)], (tetrakis)tripyhenylphosphine palladium[0] (0.49 g) and saturated aqueous sodium bicarbonate solution (133 mL) and dimethylformamide (266 mL), under nitrogen, was heated at reflux temperature overnight. The reaction mixture was filtered through Hyflo and then evaporated. The residue was partitioned between ethyl acetate (50 mL) and water (25 mL) and the aqueous layer was extracted with ethyl acetate (25 mL). The combined organic phases were washed with water (25 mL), then with brine (20 mL), then dried over magnesium sulfate and then evaporated. The residue subjected to chromatography on silica eluting with a mixture of pentane and ether (1;1, v/v) to give the title compound as a white solid, mp. 151–152° C. MS: 335 (MH+).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH:21]1[C:30]2[N:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:24][CH2:23][CH2:22]1)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][NH2:20])=[CH:15][CH:14]=1.C(OC(=O)[NH:37][CH2:38][CH:39]=O)(C)(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][NH:20][CH2:39][CH2:38][NH2:37])=[CH:17][CH:18]=1)[CH:21]1[C:30]2[N:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:24][CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)NCC=O
Reactant: NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: NCCNCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 17 %

Procedure:
Using General Procedure B: To a stirred solution of N′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (250 mg, 0.629 mmol) and (2-oxo-ethyl)-carbamic acid tert-butyl ester (100 mg, 0.628 mmol) in THF (6.3 mL) was added NaBH(OAc)3 (173 mg, 0.816 mmol) and the mixture was stirred at room temperature for 22 h. Purification of the crude material by column chromatography on silica gel (200:5:1 CH2Cl2/MeOH/NH4OH) afforded a colourless oil (47 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][N:3]=1.S(Cl)([Cl:13])=O>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([Cl:13])=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccnc(Cl)c1
Product: O=C(Cl)c1ccnc(Cl)c1

Procedure:
A solution of 2-chloropyridine-4-carboxylic acid (10 g) in thionyl chloride (90 mL) was heated under reflux for 20 hours. The excess thionyl chloride was removed by distillation at atmospheric pressure and the oily residue was distilled to give 9.26 grams of 2-chloropyridine-4-carbonyl chloride having a boiling point of 144°-148° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](Br)=[CH:8][C:9]=1[O:10][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[CH3:12])=[O:4].CC1(C)C(C)(C)OB([C:29]2[CH:30]=[C:31]3[CH:37]=[CH:36][NH:35][C:32]3=[N:33][CH:34]=2)O1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.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>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:29]2[CH:30]=[C:31]3[CH:37]=[CH:36][NH:35][C:32]3=[N:33][CH:34]=2)=[CH:8][C:9]=1[O:10][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[CH3:12])=[O:4]
Reactant: COC(=O)c1sc(Br)cc1OC(C)c1ccccc1Cl
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)c1sc(-c2cnc3[nH]ccc3c2)cc1OC(C)c1ccccc1Cl
Temperature: 140 °C
Yield: 45.3 %

Procedure:
5-Bromo-3-[1-(2-chloro-phenyl)-ethoxy]-thiophene-2-carboxylic acid methyl ester (200 mg, 0.53 mmol, 1.0 Eq.), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (195 mg, 0.80 mmol, 1.5 Eq.) and Pd(PPh3)4 (61 mg, 0.05 mmol, 0.1 Eq.) were dissolved in toluene (1.6 mL) and ethanol (0.4 mL). 2M K2CO3 (0.8 mL, 1.60 mmol, 3.0 Eq.) was added and the reaction heated under microwave conditions at 140° C. for 10 minutes. The reaction was partitioned between EtOAc (10 mL) and water (10 mL) and the aqueous phase extracted with EtOAc (3×10 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (ISCO Companion™, 12 g column, 0-100% EtOAc/petroleum Ether) to give the sub-title compound as a yellow solid (100 mg, 0.24 mmol, 45%); 1H NMR (400 MHz, CDCl3) δ1.75(3H, d), 3.94 (3H, s), 5.88 (1H, q), 6.64 (1H, d), 6.94 (1H, s), 7.26-7.34 (2H, m), 7.38-7.44 (2H, m), 7.71 (1H, dd), 8.17 (1H, d), 8.44 (1H, d).
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][N:5]=1)[CH3:2]>CO.[Pd]>[NH2:10][C:7]1[CH:8]=[CH:9][C:4]([N:3]([CH2:13][CH3:14])[CH2:1][CH3:2])=[N:5][CH:6]=1
Reactant: CCN(CC)c1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CO
Product: CCN(CC)c1ccc(N)cn1
Yield: 94.5 %

Procedure:
40 g of the 2-diethylamino-5-nitropyridine was subjected to catalytic reduction in one liter of methanol through the use of 2 g of 10% Pd-C. The catalyst was removed by filtration, and the filtrate was concentrated to give 32 g of 5-amino-2-diethylaminopyridine (yield: 95%, oleaginous form).
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:25]1[CH:29]=[CH:28][CH:27]=[N:26]1>CN(C1C=CN=CC=1)C.CC#N>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21]([N:25]3[CH:29]=[CH:28][CH:27]=[N:26]3)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: c1cn[nH]c1
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CC(C)(C)c1nc2cc(S(=O)(=O)n3cccn3)ccc2n1CC1CCOCC1

Procedure:
Following the same procedure in Example 1, Step A, using 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (76 mg, 0.20 mmol), pyrazole (34 mg, 0.50 mmol) and DMAP (82 mg, 0.67 mmol) in MeCN (5 mL). The crude product was purified by MPLC using Hex/EtOAc (1:1) on silica gel to give 46 mg (56% yield) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.36-1.54 (m, 4 H), 1.56 (s, 9 H), 2.15-2.41 (m, 1 H), 3.23-3.38 (m, 2 H), 3.88 (m, 2 H), 4.37 (d, J=7.62 Hz, 2H), 6.47 (dd, J=2.73, 1.56 Hz, 1 H), 7.73 (d, J=1.37 Hz, 1 H), 7.77-7.85 (m, 1 H), 7.86-7.94 (m, 1 H), 8.26 (d, J=1.56 Hz, 1 H), 8.30 (d, J=2.73 Hz, 1 H); MS (ESI) (M+H)+=403.0; Anal. Calcd for C20H26N4O3S+0.50 TFA+0.20 EtOAc (477.15): C, 54.88; H, 5.94; N, 11.74. Found: C, 54.78; H, 5.83; N, 11.69.
Reaction SMILES: [OH2:1].[NH2:2][CH:3]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5].[Cl:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=[CH:18][CH:17]=1.[ClH:26]>O1CCOCC1>[OH2:5].[OH2:1].[ClH:15].[ClH:26].[NH2:2][CH:3]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[CH:18][CH:17]=2)=[CH:12][CH:13]=1)[C:4]([OH:6])=[O:5]
Reactant: Clc1ccnc2ccccc12
Reactant: Nc1ccc(CC(N)C(=O)O)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: NC(Cc1ccc(Nc2ccnc3ccccc23)cc1)C(=O)O
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 129.7 %

Procedure:
A mixture of 2-amino-3-(4-aminophenyl)-propionic acid hydrate (0.27 g, 1.5 mmol), 4-chloro-quinoline (0.245 g, 1.5 mmol) and conc. HCl (0.43 g) in dioxane (3 mL) is stirred at 120° C. temperature for 30 min in a tightly closed Pierce glass reaction vial. After cooling the liquid phase is separated and the solid residue is washed with acetonitrile (3×3 mL) and diethyl ether (5 mL) to give the title compound (0.405 g, 65%) as yellow solid.
Reaction SMILES: Cl.[OH:2][CH:3]1[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[C@H:4]1[NH2:5].[CH3:14][C:15]([CH:17]1[C:23](=[O:24])[CH2:22][C:21]([CH3:26])([CH3:25])[CH2:20][C:18]1=[O:19])=O>CO>[CH3:26][C:21]1([CH3:25])[CH2:22][C:23](=[O:24])[C:17](=[C:15]([NH:5][C@@H:4]2[C@@H:6]([OH:7])[C@H:8]([OH:9])[C@@H:10]([CH2:12][OH:13])[O:11][C@@H:3]2[OH:2])[CH3:14])[C:18](=[O:19])[CH2:20]1
Reactant: CC(=O)C1C(=O)CC(C)(C)CC1=O
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: Cl
Solvent: CO
Product: CC(N[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O)=C1C(=O)CC(C)(C)CC1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 188.5 %

Procedure:
Glucosamine hydrochloride (50 g, 231 mmol) was suspended in anhydrous methanol (500 mL), then 2-acetyl-dimedone sodium salt (47.3 g, 231 mmol) was added. The reaction mixture was stirred at room temperature for 10 minutes, then 2-acetyl-dimedone (21.1 g, 115.9 mmol) was added. The reaction mixture was stirred under reflux for 2.5 hours and monitored by tlc. At the completion of the reaction (TLC: MeCN—H20, 10:2), the reaction mixture was cooled to room temperature and filtered. The filtrate was evaporated and the resulting solid residue was washed on a funnel with ether (3×500 mL) and dried to give crude product (75 g, 94%). No further purification was required for the next reaction.