Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[C:18]2[N:17]=[C:16]([CH3:19])[NH:15][C:14]=2[CH:13]=[CH:12][CH:11]=1.[H-].[Na+]>CN(C=O)C.CO>[CH2:1]([N:15]1[C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([Br:9])[C:18]=2[N:17]=[C:16]1[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Reactant: Cc1nc2c(Br)cccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1nc2c(Br)cccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzyl chloride (1.527 mL) was added to a solution of 4-bromo-2-methyl-1H-benzimidazole (1.40 g) and sodium hydride (0.531 g) in DMF (10 mL) at 0° C. The mixture was stirred at room temperature under a dry atmosphere for 1 h. The reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 5%-50% EtOAc in hexane) to give 1-benzyl-4-bromo-2-methyl-1H-benzo[d]imidazole (1.88 g) as tan oil. The mixture of 1-benzyl-4-bromo-2-methyl-1H-benzo[d]imidazole (496 mg), 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (700 mg), Pd(Ph3P)4 (87 mg), sodium carbonate (476 mg) and THF (18 mL)-water (0.90 mL) was heated at 100° C. for 1 h under microwave irradiation. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10%-50% EtOAc in hexane) to give 3-[4-(1-benzyl-2-methyl-1H-benzimidazol-4-yl)phenyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (450 mg) as white crystals.
Reaction SMILES: N(OC(C)(C)C)=O.[CH2:8]([O:10][C:11]([C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:23]=[CH:22][C:21](N)=[CH:20][CH:19]=2)[CH:17]=1)=[O:12])[CH3:9]>CN(C)C=O.[Cl-].[Na+].O>[CH2:8]([O:10][C:11]([C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:17]=1)=[O:12])[CH3:9]
Reactant: CCOC(=O)c1cn(-c2ccc(N)cc2)cn1
Agent: CC(C)(C)ON=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(-c2ccccc2)cn1
Temperature: 65 °C
Yield: 69.4 %

Procedure:
Tert-butyl nitrite (535 mg, 5.19 mmol) in dry dimethylformamide (15 ml) was heated to 65° C. under nitrogen and then 1-(4-aminophenyl)imidazole-4-carboxylic acid ethyl ester (see part (ii)) (800 mg, 3.463 mmol) in dry dimethylformamide (5 ml) was added over 10 minutes. The mixture was heated at 65° C. for a further 20 minutes and then cooled to room temperature. The mixture was poured into saturated brine (50 ml) and extracted with dichloromethane (3×20 ml). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. Purification by flash chromatography on silica gel eluting with dichloromethane gave the title compound (520 mg, 70%) as an off-white solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[O:32]([CH2:43][CH2:44][NH:45][CH2:46][CH2:47][O:48][C@@H:49]1[O:57][C@@H:56]([CH3:58])[C@@H:54]([OH:55])[C@@H:52]([OH:53])[C@@H:50]1[OH:51])[C@@H:33]1[O:41][C@@H:40]([CH3:42])[C@@H:38]([OH:39])[C@@H:36]([OH:37])[C@@H:34]1[OH:35]>CN(C=O)C>[C@@H:49]1([O:48][CH2:47][CH2:46][N:45]([CH2:44][CH2:43][O:32][C@@H:33]2[O:41][C@@H:40]([CH3:42])[C@@H:38]([OH:39])[C@@H:36]([OH:37])[C@@H:34]2[OH:35])[C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:17])[O:57][C@@H:56]([CH3:58])[C@@H:54]([OH:55])[C@@H:52]([OH:53])[C@@H:50]1[OH:51]
Reactant: O=C(O)CCCCC(=O)OCc1ccccc1
Reactant: C[C@@H]1O[C@@H](OCCNCCO[C@@H]2O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]2O)[C@@H](O)[C@H](O)[C@@H]1O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: C[C@@H]1O[C@@H](OCCN(CCO[C@@H]2O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]2O)C(=O)CCCCC(=O)OCc2ccccc2)[C@@H](O)[C@H](O)[C@@H]1O
Reaction time: 16 h

Procedure:
To a solution of 6-(benzyloxy)-6-oxohexanoic acid (40 mg, 0.169 mmol), EDC (114 mg, 0.593 mmol) and HOBt (2.59 mg, 0.017 mmol) in DMF (5 mL) at rt was added 2-({2-[(α-L-fucopyranosyl)oxy]ethyl}amino)ethyl α-L-fucopyranoside (190 mg, 0.478 mmol). After stirring for 16 hr, the reaction mixture was concentrated and the residue was purified by flash chromatography on C18 reverse phase silica gel (50 g), eluting with 5-40% AcCN in water to give the title compound. UPLC Method B: m/e=616.2923 [M+1]; Rt=3.114 min. 1H NMR (CD3OD) δ 1.24 (6H, d, J=6.58), 1.72-1.64 (4H, m), 2.45 (2H, t, J=7.11), 2.53 (2H, t, J=7.32), 3.91-3.55 (17H, m), 4.78-4.75 (2H, m), 5.14 (2H, s), 7.38-7.37 (5H, m).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C@@H:6]([NH2:14])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[F:15][C:16]([F:31])([F:30])[C:17]1[C:25]2[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=2[N:19]([CH2:26][C:27](O)=[O:28])[N:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C@@H:6]([NH:14][C:27](=[O:28])[CH2:26][N:19]1[C:20]2[CH2:21][CH2:22][CH2:23][CH2:24][C:25]=2[C:17]([C:16]([F:30])([F:15])[F:31])=[N:18]1)[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)Cn1nc(C(F)(F)F)c2c1CCCC2
Reactant: N[C@@H](Cc1ccccc1)c1ncc[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cn1nc(C(F)(F)F)c2c1CCCC2)N[C@@H](Cc1ccccc1)c1ncc[nH]1
Reaction time: 0.25 h

Procedure:
To (S)-1-(1H-imidazol-2-yl)-2-phenylethanamine from the previous reaction was added DMF (10 mL), 2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acid (288 mg, 1.18 mmol), and HATU (530 mg, 1.4 mmol). Diisopropylethylamine (452 μL, 2.6 mmol) was added and the reaction was stirred for 15 min. The reaction was partitioned between EtOAc and H2O. The organics were separated, washed with saturated aqueous NaHCO3, and saturated aqueous NaCl. Solvents were removed in vacuo and the residue purified by column chromatography on silica to provide the desired product: MS (m/z) 418.3 [M+H]+.
Reaction SMILES: C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:29]([Br:33])(Br)(Br)Br.OC[CH2:36][CH2:37][N:38]1[C:46]2[C:41](=[N:42][C:43]([O:47][CH3:48])=[CH:44][CH:45]=2)[CH2:40][C:39]1=[O:49]>ClCCl>[Br:33][CH2:29][CH2:36][CH2:37][N:38]1[C:46]2[C:41](=[N:42][C:43]([O:47][CH3:48])=[CH:44][CH:45]=2)[CH2:40][C:39]1=[O:49]
Reactant: COc1ccc2c(n1)CC(=O)N2CCCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc2c(n1)CC(=O)N2CCCBr
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Under argon and in an anhydrous medium, 1.50 g (3.76 mmol) of 1,2-bis-diphenylphosphinoethane are added at 0° C. to a solution of 1.25 g (3.76 mmol) of carbon tetrabromide in 20 ml of dichloromethane. After 10 minutes at 0° C., 417 mg (1.88 mmol) of the compound obtained in Step D dissolved in 10 ml of dichloromethane are added to the mixture. The mixture is stirred for 30 minutes at 0° C., and then for 3 hours at room temperature. After hydrolysis of the reaction mixture, the organic phase is dried over magnesium sulphate, filtered and concentrated. Purification by flash chromatography over silica gel (eluant: petroleum ether/ethyl acetate, 8:2) yields the title compound in the form of a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[OH:14])[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].N1C=CC=CC=1.[Br:21]Br.Cl>C(Cl)Cl>[C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([Br:21])[C:13]=1[OH:14])[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(O)c(C(C)=O)c1
Reactant: BrBr
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cc(Br)c(O)c(C(C)=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a stirred solution of methyl 3-acetyl-4-hydroxybenzoate (240 g, 1236 mmol) in DCM (2 L) was added pyridine (0.400 L, 4944 mmol) followed by a dropwise addition of dibromine (0.070 L, 1360 mmol) at 0° C. The reaction mixture was stirred at RT for 2 hrs then cooled to 5° C. and HCl 4N (0.927 L, 3708 mmol) was added dropwise. The organic phase was separated, dried over magnesium sulfate, filtered and concentrated to afford a brown solid which was stirred in ether/petroleum ether (1:1, 1 L) for 1 hr. The solid was collected by filtration and dried to afford methyl 3-acetyl-5-bromo-4-hydroxybenzoate (270 g, 80%) as a beige powder.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[SH:11].B(O)(O)O.[CH:16](O)=O>O>[CH3:10][O:9][C:7]1[CH:6]=[CH:5][C:4]2[S:11][CH:16]=[N:2][C:3]=2[CH:8]=1
Reactant: O=CO
Reactant: COc1ccc(S)c(N)c1
Agent: Cl
Agent: OB(O)O
Solvent: O
Product: COc1ccc2scnc2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 15 %

Procedure:
A mixture of intermediate 23 (1.33 g, 6.9 mmol), boric acid (2.3 g, 37.2 mmol) and formic acid (17 mL) was heated to reflux and stirred for 6 h. The reaction mixture was cooled to rt and diluted with water. The solution was made alkaline and extracted with ethyl acetate. Further purification by column chromatography (elution with PE/EtOAc=3:1) gave 5-methoxybenzo[d]thiazole (intermediate 24) (290 mg, 15%). HPLC: 99%, RI 2.646 min. MS (ESI) m/z 166.0 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=2[NH2:16])[C:9]([O:11][CH3:12])=[O:10])[CH2:3][CH2:2]1.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>N1C=CC=CC=1>[CH3:12][O:11][C:9](=[O:10])[C:8]1[CH:13]=[CH:14][C:15]([NH:16][S:18]([CH3:17])(=[O:20])=[O:19])=[C:6]([O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)[CH:7]=1
Reactant: COC(=O)c1ccc(N)c(OCC2CC2)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NS(C)(=O)=O)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl 3-(cyclopropylmethoxy)-4-aminobenzoate (8.86 g) was dissolved in pyridine (80 mL) at room temperature under N2 atmosphere. Methanesulfonyl chloride (4.04 mL) was added and the mixture was stirred at r.t. for 18 hours. The reaction mixture was evaporated to dryness, the crude was treated with 1N HCl (500 mL) and extracted with CH2Cl2 (3×200 mL). The organic layer was dried over Na2SO4 and the solvent was evaporated off to yield 11.7 g of the desired intermediate.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:9]2[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8].[C:16]1([CH2:22][CH2:23][SH:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([C:4]2[C:3]([CH2:2][S:24][CH2:23][CH2:22][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:7]([CH3:8])[O:6][N:5]=2)=[CH:10][CH:11]=1
Reactant: SCCc1ccccc1
Reactant: Cc1onc(-c2ccc(Br)cc2)c1CBr
Product: Cc1onc(-c2ccc(Br)cc2)c1CSCCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 34, Step 4, using 4-bromomethyl-3-(4-bromo-phenyl)-5-methyl-isoxazole and 2-phenyl-ethanethiol.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]2[CH2:8][CH2:9][CH2:10][C:11](=[O:13])[NH:12][C:6]=2[CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:23][CH2:24][O:25][CH3:26]>CN(C)C=O>[CH3:26][O:25][CH2:24][CH2:23][N:12]1[C:11](=[O:13])[CH2:10][CH2:9][CH2:8][C:7]2[CH:14]=[CH:15][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]1=2
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc2N1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCCN1C(=O)CCCc2ccc([N+](=O)[O-])cc21
Temperature: 50 °C
Yield: 78.3 %

Procedure:
To a mixture of 8-nitro-1,3,4,5-tetrahydro-1-benzazepin-2-one (1.000 g, 4.850 mmol) and cesium carbonate (3.160 g, 9.699 mmol) in N,N-dimethylformamide (20 mL) was added, 1-bromo-2-methoxyethane (0.9 mL, 9.7 mol). The reaction was heated to at 50° C., O/N. The reaction mixture was filtered and the filtrate evaporated to afford a residue that was extracted into DCM and washed with water, brine and dried by passing through a funnel filled with MgSO4. The filtrate was evaporated and the residue purified by chromatography (silica gel eluted with 3:1 EtOAc:hexane) to provide 1-(2-methoxy-ethyl)-8-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (1.004 g, 78%) as pale yellow crystals that had the following properties: 1H-NMR (CDCl3, 400 MHz) δ 8.33 (s, 1H), 8.05 (d, J=8.3, 1H), 7.38 (d, J=8.3, 1H), 4.05 (br s, 2H), 3.62 (m, 2H), 3.32 (s, 3H). 2.86 (br s, 2H), 2.35 2.10 (m, 4H).
Reaction SMILES: [CH3:1][Si:2]([CH3:25])([CH3:24])[CH2:3][CH2:4][O:5][C:6](=[O:23])[C:7]1[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:8]=1[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].[CH3:26][C:27]1[O:31][C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[N:29][C:28]=1[CH2:38][CH2:39]OS(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:25][Si:2]([CH3:24])([CH3:1])[CH2:3][CH2:4][O:5][C:6](=[O:23])[C:7]1[CH:12]=[C:11]([O:13][CH2:39][CH2:38][C:28]2[N:29]=[C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:31][C:27]=2[CH3:26])[CH:10]=[CH:9][C:8]=1[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17]
Reactant: CC(C)(C)OC(=O)CCc1ccc(O)cc1C(=O)OCC[Si](C)(C)C
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(C(=O)OCC[Si](C)(C)C)c1
Temperature: 55 °C
Reaction time: 12 h
Yield: 78.1 %

Procedure:
To a solution of 2-(2-tert-butoxycarbonyl-ethyl)-5-hydroxy-benzoic acid 2-trimethylsilanyl-ethyl ester (4.30 g, 11.7 mmol) and toluene-4-sulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl ester (4.61 g, 12.9 mmol) in DMF (30 mL) was added Cs2CO3 (4.59 g, 14.1 mmol). The suspension was stirred at 55° C. for 12 h. The reaction mixture was quenched with H2O (200 mL) and extracted with EtOAc (3×100 mL). The combined organics were dried (Na2SO4) and concentrated to a residue, which was purified using silica gel chromatography (hexanes/EtOAc 9/1 to 8/2) to afford the title compound as a colorless oil (5.04 g, 78%). 1H NMR (400 MHz, CDCl3): δ 0.06 (s, 9H), 1.11 (t, 2H, J=8.8 Hz), 1.40 (s, 9H), 2.36 (s, 3H), 2.51 (t, 1H, J=7.8 Hz), 2.97 (t, 2H, J=6.8 Hz), 3.12 (t, 1H, J=7.8 Hz), 4.24 (t, 2H, J=6.8 Hz), 4.35 (t, 2H, J=8.8 Hz), 6.88 (dd, 1H, J=3.0, 8.3 Hz), 7.15 (d, 1H, J=8.3 Hz), 7.37-7.44 (m, 4H), 7.97 (d, 2H, J=7.8 Hz).
Reaction SMILES: C([O:4][CH2:5][CH2:6][S:7][C:8]([F:26])([F:25])[C:9]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[F:24])([OH:16])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1)(=O)C.O.[OH-].[Li+]>C(O)C>[F:24][C:18]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=1[C:9]([OH:16])([CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1)[C:8]([F:26])([F:25])[S:7][CH2:6][CH2:5][OH:4]
Reactant: CC(=O)OCCSC(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: OCCSC(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 27 %

Procedure:
To a solution of 1-(2-acetoxyethyl)thio-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (14.3 g, 0.12 mol) in ethanol (200 ml), a 10% aqueous solution (20 ml) of lithium hydroxide monohydrate was added and they were stirred at room temperature for one hour. After the completion of the reaction, the reaction mixture was distilled off under reduced pressure. Water was added to the residue so obtained, followed by extraction with chloroform. The chloroform solution was washed with water, dried over magnesium sulfate and then distilled off under reduced pressure, whereby 2-(2,4-difluorphenyl)-1,1-difluoro-1-(2-hydroxyethyl)thio-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (11.4 g, yield: 89.8%) was obtained as colorless crystals.
Reaction SMILES: [C:1]1([P:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]2[N:13]=[C:12]([NH2:14])[CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:28](OC(=O)C)(=[O:30])[CH3:29]>ClCCl.CN(C1C=CN=CC=1)C>[C:15]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[N:13]=[C:12]([NH:14][C:28](=[O:30])[CH3:29])[CH:11]=[CH:10][CH:9]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Nc1cccc(P(c2ccccc2)c2ccccc2)n1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cccc(P(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.9 %

Procedure:
0.10 g (0.36 mmol) of 6-(diphenylphosphino)-2-aminopyridine from example 14.3.1 was dissolved in 2.0 ml of dichloromethane and admixed with 0.05 ml (0.04 g, 0.40 mmol) of triethylamine and a spatula-tip of DMAP. After 0.04 ml (0.04 g, 0.40 mmol) of acetic anhydride had been added, the mixture was stirred at room temperature for 2 h and then the solvent was removed under reduced pressure. The residue was purified by column chromatography with cyclohexane/ethyl acetate (1:1). 0.074 g (0.23 mmol, 63.9%) of 6-(diphenylphosphino)-2-acetylaminopyridine was obtained as a beige-colored solid.
Reaction SMILES: N1(C2C=CC(O[CH:11]3[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]3)=CC=2)C=CN=C1.CO.[CH3:21][O:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([CH:33]=O)=[CH:25][CH:24]=1>C(Cl)Cl>[CH3:21][O:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([CH2:33][N:13]2[CH2:14][CH2:15][CH2:16][CH2:11][CH2:12]2)=[CH:25][CH:24]=1
Reactant: COc1ccc(C=O)c2ccccc12
Reactant: c1cn(-c2ccc(OC3CCCNC3)cc2)cn1
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(CN2CCCCC2)c2ccccc12
Reaction time: 8 h
Yield: 16.8 %

Procedure:
To a mixture of 3-[4-(imidazol-1-yl)phenoxy]piperidine (308 mg, 1.26 mmol), methanol (6.0 mL) was added 4-methoxy-1-naphthaldehyde (1.25 eq, 298 mg), followed by borane pyridine complex (0.196 mL, 1.25 eq.). The resulting mixture was stirred overnight. The methanol was evaporated, and the residue diluted with ethyl acetate, washed with water and brine. Evaporation of the solvent in vacuo gave a crude product. Flash column chromatography on silical gel with 1-2% methanol in methylene chloride afforded 3-[4-(imidazol-1-yl)phenoxy]-]-1-[(4-methoxynaphth-1-yl)methyl]piperidine (54 mg), 1H NMR(CDCl3) 8.30 (m, 2), 7.70 (s, 1), 7.50 (m, 2), 7.30 (s, 1), 7.20 (m, 4), 6.90 (m, 2), 6.70 (d, 2), 4.30 (m, 1), 4.00 (s, 3), 3.90 (AB q , 2), 3.10 (m, 1), 2.80 (m, 1), 2.10-2.30 (m, 3), 1.80 (m, 1), 1.40-1.70 (m, 2) ppm.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][C@H:12]2[C@@H:16]([OH:17])[CH2:15][N:14]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[CH2:13]2)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].N[C@H]1[C@H](O)CN(C(OCC2C=CC=CC=2)=O)C1>>[CH2:1]([C:3]1[C:4]([NH:11][C@H:12]2[C@H:16]([OH:17])[CH2:15][N:14]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[CH2:13]2)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2]
Reactant: CCc1cnc(CC)c(N[C@@H]2CN(C(=O)OCc3ccccc3)C[C@@H]2O)n1
Agent: N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1O
Product: CCc1cnc(CC)c(N[C@@H]2CN(C(=O)OCc3ccccc3)C[C@H]2O)n1

Procedure:
Following the procedure for the preparation of benzyl (3R,4S)-3-[(3,6-diethylpyrazin-2-yl)amino]-4-hydroxypyrrolidine-1-carboxylate but substituting benzyl (trans)-3-amino-4-hydroxypyrrolidine-1-carboxylate and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ) 7.78, 7.39, 6.41, 6.22, 5.18, 4.51-3.95, 3.40, 2.65, 1.31-1.26; (MS/CI) calcd for C20H26N4O3+H 371.4, found 370.9.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][O:8][C:9](=[O:22])[C:10]1C(=[CH:15][CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20])C(O)=O>C(Cl)Cl.CN(C=O)C>[CH3:7][O:8][C:9](=[O:22])[C:10]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:1]=1[C:2]([Cl:4])=[O:3]
Reactant: COC(=O)c1c(C(=O)O)cccc1[N+](=O)[O-]
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1c(C(=O)Cl)cccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Oxalyl chloride (5.4 mL, 62.4 mmol) was added to a suspension of 3-nitro-phthalic acid 2-methyl ester (11.7 g, 52.0 mmol, Step A) in 150 mL of anhydrous CH2Cl2 at RT. A few drops of DMF were added, then the mixture was heated to reflux for 2 h, and cooled to RT. The mixture was washed with NaHCO3 (aq), brine, dried over MgSO4, filtered, and condensed to give the titled compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Cl:8])[CH:3]=1.ClCCl.[C:12]([NH:19][C:20](=[N:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])SC)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>C(N(CC)CC)C.[Hg](Cl)Cl>[C:27]([O:26][C:24](=[O:25])[NH:23]/[C:20](/[NH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Cl:8])[CH:3]=1)=[N:19]\[C:12](=[O:13])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:30])([CH3:28])[CH3:29]
Reactant: Nc1ccnc(Cl)c1
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: Cl[Hg]Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)/N=C(\NC(=O)OC(C)(C)C)Nc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 75 %

Procedure:
20.22 g (0.157 mol) of 4-amino-2-chloropyridine were diluted in triethylamine (67 ml) and dichloromethane (600 ml) at 0-5° C. 47 g of Mercury(II) chloride (0.173 mol) and 50.24 g (0.173 mol) of N,N′-bis(boc)-S-methyl-isothiourea were added to the reaction mixture, which was then stirred at room temperature for 4 days, filtered on a fritted funnel, concentrated in vacuo and chromatographed on silica (Heptane90/AcOEt10) to yield 43.67 g of di-tert-butyl{(Z)-[(2-chloropyridin-4-yl)amino]methylylidene}biscarbamate (yield=71%).
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]([CH2:12][C:13]([OH:15])=O)[CH:10]=[N:11][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2].[NH2:16][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2([C:31]#[N:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1)[CH3:18].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC#N>[C:1]([C:3]1[C:8]2[N:9]([CH2:12][C:13]([NH:16][CH:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4([C:31]#[N:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]4)=[CH:21][CH:20]=3)[CH3:18])=[O:15])[CH:10]=[N:11][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(N)c1ccc(C2(C#N)CCCCC2)cc1
Reactant: N#Cc1cccc2ncn(CC(=O)O)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(NC(=O)Cn1cnc2cccc(C#N)c21)c1ccc(C2(C#N)CCCCC2)cc1

Procedure:
2-(7-Cyano-1H-benzimidazol-1-yl)-N-{1-[4-(1-cyanocyclohexyl)phenyl]ethyl}acetamide is synthesized according to example 5 by mixing (7-cyano-1H-benzimidazol-1-yl)acetic acid (216 mg, 1.08 mmol) prepared according to scheme 3, 1-[4-(1-aminoethyl)phenyl]cyclohexanecarbonitrile (246 mg, 1.08 mmol) prepared according to scheme 11, Et3N (328 mg, 3.24 mmol, 0.452 mL) and HATU (411 mg, 1.08 mmol) in MeCN (10.0 mL). The product is purified by HPLC: Gilson prep pumps, Flow rate: 30 ml/min, Column: Gemini (5μ) 21.2×50 mm, Mobile phase: A=water (10 mM NH4CO3) B=MeCN, (443 mg, 1.08 mmol, quantitative). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.22-1.36 (m, 1H) 1.39 (d, J=6.84 Hz, 3H) 1.53-1.68 (m, 2H) 1.68-1.77 (m, 1H) 1.77-1.89 (m, 4H) 1.98-2.08 (m, 2H) 4.88-5.02 (m, 1H) 5.24 (dd, J=24.61, 17.77 Hz, 2H) 7.35 (t, J=7.91 Hz, 1H) 7.40 (d, J=8.40 Hz, 2 H) 7.46 (d, J=8.40 Hz, 2H) 7.72 (d, J=7.62 Hz, 1H) 8.01 (dd, J=8.20, 0.78 Hz, 1H) 8.35 (s, 1 H) 8.85 (d, J=7.81 Hz, 1H); MS [M+H], calcd: 412.0. found: 412.3.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6][C:7]2[CH:19]=[CH:18][C:10]([C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.O[C:21]1C=CC(C(OC)=O)=CC=1.C1(CCCO)CC1>>[CH:3]1([CH2:1][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])=[CH:18][CH:19]=2)[CH2:2][CH2:21]1
Reactant: O=C(O)CNC(=O)c1ccc(OCCC2CC2)cc1
Reactant: COC(=O)c1ccc(O)cc1
Agent: OCCCC1CC1
Product: O=C(O)CNC(=O)c1ccc(OCCCC2CC2)cc1
Yield: 51 %

Procedure:
The same reactions as in Example 9 (9a) and (9b) were conducted using methyl 4-hydroxybenzoate (6.09 g, 40.0 mmol) and 3-cyclopropylpropan-1-ol (which is the compound disclosed in Helv. Chim. Acta, (2003), 86, 865-893, 4.41 g, 44.0 mmol) to give 5.74 g of the title compound (white powder, yield: 51%).