Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[O:22]1[CH2:27][CH2:26][CH:25]([C:28](O)=[O:29])[CH2:24][CH2:23]1>>[CH:18]1([CH2:17][NH:16][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[C:5]([CH3:21])=[CH:4][CH:3]=[C:2]([NH:1][C:28]([CH:25]4[CH2:26][CH2:27][O:22][CH2:23][CH2:24]4)=[O:29])[CH:7]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20][CH2:19]1
Reactant: O=C(O)C1CCOCC1
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Product: Cc1ccc(NC(=O)C2CCOCC2)cc1-c1ccc(C(=O)NCC2CC2)cc1

Procedure:
N-(4′-{[(Cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)tetrahydropyran-4- carboxamide was prepared from 5′-amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4- carboxamide and tetrahydropyran-4-carboxylic acid using method D. NMR; δH [2H6]—DMSO 9.89,(1H, s), 8.61,(1H, t), 7.91,(2H, d), 7.52-7.48,(2H, m), 7.40,(2H, d), 7.21,(1H, d), 3.89,(2H, m), 3.37,(1H, m), 3.16,(2H, t), 2.56,(2H, m), 2.16,(3H, s), 1.65,(3H, m), 1.04,(1H, m), 0.43,(2H, m), 0.24,(2H, m). LCMS: retention time 2.94 min, MH+393.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([C:7](=[O:10])[CH2:8]Br)=[CH:3][CH:2]=1.CCO.[N-:20]=[N+]=[N-].[Na+].[BH4-].[Na+]>CO>[NH2:20][CH2:8][CH:7]([C:4]1[CH:5]=[CH:6][C:1]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:2][CH:3]=1)[OH:10]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(CBr)c1ccc(-c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: NCC(O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a solution consisting of 1-biphenyl-4-yl-2-bromo-ethanone (412 mg. 1.5 mmol) and EtOH (6 mL) was added NaN3 (107 mg, 1.6 mmol) at rt. The mixture was stirred at rt for 2 h and then cooled to 0° C. NaBH4 (61 mg, 1.6 mmol) was added and the mixture stirred for 45 min. A mixture (black slurry) of CuSO4.5H2O (37 mg)/NaBH4 (28 mg) in MeOH 2 mL) was prepared by adding the NaBH4 to CuSO4.5H2O in MeOH at 0° C. This slurry was poured into the reaction mixture. The reaction vessel was allowed to gradually warm to rt. An additional amount of NaBH4 (28 mg) was added 30 min after the addition of the slurry. The reaction was stirred at rt for 2 h. The mixture was filtered through a pad of celite, adhered to silica gel (7-8 g) and purified (FCC) to give the title compound (256 mg, 80%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:23](O)=[O:24])=[N:11][CH:12]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:27]([O:31][C:32](=[O:35])[CH2:33][NH2:34])([CH3:30])([CH3:29])[CH3:28].C(N(C(C)C)CC)(C)C>CN(C=O)C.ON1C2C=CC=CC=2N=N1>[C:27]([O:31][C:32](=[O:35])[CH2:33][NH:34][C:23]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:14][C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][N:11]=1)=[O:24])([CH3:30])([CH3:29])[CH3:28]
Reactant: O=C(O)c1ncc(OCc2ccccc2)cc1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNC(=O)c1ncc(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 99 %

Procedure:
To a solution of 3,5-bis-benzyloxy-pyridine-2-carboxylic acid, 2, (2.36 g, 6.36 mmol) in DMF (20 mL) at room temperature under N2 is added 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide (EDCI) (1.83 g, 9.54 mmol) and 1-hydroxybenzo-triazole (HOBt) (0.086 g, 0.64 mmol). The mixture is stirred for 15 minutes after which time glycine tert-butyl ester hydrochloride (1.60 g, 9.54 mmol) and diisopropylethylamine (DIPEA) (3.32 ml, 19.08 mmol) are added. The resulting solution is stirred at room temperature for 48 hours then concentrated under reduced pressure. The resulting brown oil is purified over silica (EtOAc) to afford 3.04 g (99% yield) of the desired compound as a yellow solid. 1H NMR (250 MHz, CDCl3) δ ppm 8.19 (1H, t, J=5.2 Hz), 8.01-8.08 (2H, m), 7.27-7.54 (9H, m), 6.97 (1H, d, J=2.4 Hz), 5.24 (2H, s), 5.13 (2H, s), 4.17 (2H, d, J=5.2 Hz), 1.51 (9H, s). HPLC-MS: m/z 449 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:17]1[NH:21][C:20]2[CH:22]=[CH:23][C:24]([C:26]#[N:27])=[CH:25][C:19]=2[N:18]=1)([C:5]1[C:13]([O:14][CH3:15])=[CH:12][C:11]([CH3:16])=[C:10]2[C:6]=1[CH:7]=[CH:8][NH:9]2)[CH3:4].C([BH3-])#N.[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3]([C:17]1[NH:21][C:20]2[CH:22]=[CH:23][C:24]([C:26]#[N:27])=[CH:25][C:19]=2[N:18]=1)([C:5]1[C:13]([O:14][CH3:15])=[CH:12][C:11]([CH3:16])=[C:10]2[C:6]=1[CH2:7][CH2:8][NH:9]2)[CH3:4]
Reactant: COc1cc(C)c2[nH]ccc2c1C(C)(OC)c1nc2cc(C#N)ccc2[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cc(C)c2c(c1C(C)(OC)c1nc3cc(C#N)ccc3[nH]1)CCN2
Reaction time: 1 h

Procedure:
(±)-2-(1-Methoxy-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile (Example 27-B) (0.213 g, 0.591 mmol) was dissolved in acetic acid (1.970 mL), and sodium cyanoborohydride (0.12 g, 1.910 mmol) was added at room temperature. The reaction was stirred at the same temperature for 1 hour. The reaction was placed in an ice bath and quenched with 1N aq. NaOH (20 mL) until pH>7. EtOAc was added and the organic layer was removed, dried over MgSO4 and concentrated. The resulting residue was purified by flash chromatography (0-100% EtOAc in heptanes) to give the title compound. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.11 (s) 7.84 (m) 7.65 (s) 7.43-7.54 (m, 1H) 7.34-7.42 (m) 6.43 (s, 1H) 3.50-3.59 (m, 2H) 3.27-3.36 (m, 2H) 3.24 (s, 3H) 3.12 (s, 3H) 2.13 (s, 3H) 2.05 (s, 3H). HRMS calcd. for C21H22N4O2 (M+H)+, 303.1604. found 303.1615
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:13]=[CH2:14]>C(Cl)Cl.CCOCC>[CH2:12]([CH:13]1[O:9][CH2:14]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C=CCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOCC
Product: c1ccc(CC2CO2)cc1
Reaction time: 5 h
Yield: 74.5 %

Procedure:
A solution of m-chloroperbenzoic acid (mCPBA; 17 g, 0.1 mol) in 120 mL of methylene chloride was added (at ambient temperature) dropwise to a solution of allyl benzene (10 g, 85 mmol) in 200 mL of methylene chloride. After the reaction mixture was stirred for 5 h with a mechanical stirrer, 5 additional grams of m-CPBA were added and the reaction mixture stirred for another 2 h. The reaction mixture was then diluted with 200 mL of ether, washed with 2×100 mL of aqueous sodium bisulfite solution, 1×100 mL of aqueous sodium bicarbonate solution and 1×100 mL of brine. The organic solution was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by bulb-to-bulb distillation (60° C., 0.1 mm) to give 8.5 g (77% yield) of 1-benzyl ethylene oxide as a clear colorless liquid.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=O.C[Si](C)(C)CCOCN1C=CN=C1C=O.[CH2:28]([N:32]([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH2:35][NH2:36])[CH2:29][CH2:30][CH3:31]>>[CH2:28]([N:32]([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH2:35][NH:36][CH2:1][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)[CH2:29][CH2:30][CH3:31]
Reactant: CCCCN(CCCC)CCCN
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: C[Si](C)(C)CCOCn1ccnc1C=O
Product: CCCCN(CCCC)CCCNCc1ccc(C(=O)OC)cc1

Procedure:
The same procedure as a series of reactions of Example 1 was carried out, except that methyl 4-formylbenzoate was used in place of 1-({[2-(trimethylsilyl)ethyloxy]methyl}-1H-imidazole-2-carboaldehyde and N,N-dibutyl-1,3-propanediamine was used in place of {[4-(methyloxy)phenyl]methyl}amine, to obtain methyl 4-({[3-(dibutylamino)propyl]amino}methyl)benzoate (compound 11-a). The same procedure as a series of reactions of Example 4→Example 5→Example 6→Example 9→Example 10 was carried out, except that the compound 11-a was used in place of the compound 3 in the process of Example 4, to obtain the title compound having the following physical properties.
Reaction SMILES: [CH2:1]([O:4][C@H:5]([C@H:12]([CH2:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([N:27]2[C:31]([CH3:32])=[CH:30][CH:29]=[C:28]2[CH3:33])[N:21]=1)[C:13](OC(C)C)=[O:14])[C:6](OC(C)C)=[O:7])[CH:2]=[CH2:3].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([O:4][C@H:5]([C@H:12]([CH2:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([N:27]2[C:31]([CH3:32])=[CH:30][CH:29]=[C:28]2[CH3:33])[N:21]=1)[CH2:13][OH:14])[CH2:6][OH:7])[CH:2]=[CH2:3]
Reactant: C=CCO[C@@H](C(=O)OC(C)C)[C@H](Cc1cc(C)cc(-n2c(C)ccc2C)n1)C(=O)OC(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCO[C@@H](CO)[C@@H](CO)Cc1cc(C)cc(-n2c(C)ccc2C)n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 85.7 %

Procedure:
To a solution of 10 (300 mg, 0.70 mmol) in THF (15 mL) at 0° C. was added LiAlH4 (55 mg, 1.4 mmol) in several portions. The reaction mixture was allowed to stir at 0° C. for 20 min then carefully quenched with H2O (50 μL). The solvent was removed by rotary evaporation, and the crude product was purified by flash column chromatography (EtOAc/hexanes, 1:2-1:1) to give 11 (205 mg, 0.60 mmol, 86%) as a colorless oil: 1H NMR (500 MHz, CDCl3) δ 2.10 (s, 6H), 2.30-2.38 (br s, 1H), 2.39 (s, 3H), 2.83-2.88 (dd, J=4.0, 13.5 Hz, 1H), 2.90-2.94 (dd, J=5.5, 14.0 Hz, 1H), 3.40-3.57 (m, 3H), 3.62-3.67 (m, 2H), 3.74-3.78 (dd, J=5.0, 11.5 Hz, 1H), 4.00-4.04 (dd, J=6.0, 12.5 Hz, 1H), 4.10-4.15 (dd, J=5.0, 13.5 Hz, 1H), 5.15-5.18 (dd, J=1.5, 11.5 Hz, 1H), 5.24-5.28 (dd, J=1.5, 17.5 Hz, 1H), 6.88 (s, 1H), 7.05 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 13.3, 14.4, 21.2, 21.3, 36.0, 43.0, 60.6, 61.8, 61.9, 71.5, 77.1, 77.3, 77.6, 81.5, 106.9, 117.4, 120.9, 124.0, 128.7, 135.0, 150.5, 151.7, 160.3, 171.4; LCQ-MS (M+H+) calcd for C20H29N2O3 345. found 345; LC-TOF-MS (M+H+) calcd for C20H29N2O3 345.21782. found 345.21772.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH2:16])=[S:15])=[CH:9][CH:8]=2)[S:4][N:3]=1.Br[CH:18]1[CH2:23][CH2:22][CH2:21][CH:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19]1=O>C(O)C>[CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]3[S:15][C:26]4[CH2:27][CH2:28][CH2:29][CH:24]([C:20]5[CH:21]=[CH:22][CH:23]=[CH:18][CH:19]=5)[C:25]=4[N:16]=3)=[CH:11][CH:12]=2)[S:4][N:3]=1
Reactant: O=C1C(Br)CCCC1c1ccccc1
Reactant: Cc1nsc(-c2ccc(NC(N)=S)cc2)n1
Solvent: CCO
Product: Cc1nsc(-c2ccc(Nc3nc4c(s3)CCCC4c3ccccc3)cc2)n1
Temperature: 25 °C
Yield: 9.9 %

Procedure:
A solution of [4-(3-methyl-[1,2,4]thiadiazol-5-yl)-phenyl]-thiourea (75 mg, 0.3 mmol) and 2-bromo-6-phenyl-cyclohexanone (84 mg, 0.33 mmol) in ethanol (3 ml) was heated to reflux over night. The precipitated solid, unreacted thiourea, was filtered off after cooling to room temperature and washed with ethanol. The filtrate was evaporated under reduced pressure and the residue was purified on silica gel using heptane/ethyl acetate (4:1 v/v) as the eluent to yield the title compound (12 mg, 10%) as a yellow solid. MS ISP (m/e): 405.2 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=10.51 (br s, 1H, NH), 7.82 (d, 2H), 7.58 (d, 2H), 7.28 (t, 2H), 7.19 (t, 1H), 7.13 (d, 1H), 4.07 (m, 1H), 2.72 (m, 2H), 2.58 (s, 3H), 2.13 (m, 1H), 1.70-1.90 (m, 3H).
Reaction SMILES: N[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:3]=1.[N+]([O-])(OC(C)(C)C)=O.C(=O)(O)[O-].[Na+].C(Cl)(Cl)[Cl:34]>[Cu](Cl)Cl>[CH2:13]([O:12][C:4]1[CH:3]=[C:2]([Cl:34])[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClC(Cl)Cl
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(N)n1
Agent: Cl[Cu]Cl
Agent: CC(C)(C)O[N+](=O)[O-]
Agent: O=C([O-])O
Product: COC(=O)c1cc(OCc2ccccc2)cc(Cl)n1
Reaction time: 6 h

Procedure:
To a solution of 258 mg of methyl 6-amino4-(benzyloxy)pyridine-2-carboxylate dissolved in 5 ml of chloroform, 170 mg of tert-butyl nitrate and 210 mg of copper(II) chloride were added, and the mixture was stirred for 6 hours with the light being shut out. Then saturated sodium bicarbonate was added to the resulting reaction mixture, and then the mixture was extracted with ethyl acetate. The organic layer was concentrated under a reduced pressure. The resulting residue was purified by flash chromatography (eluent: hexane/ethyl acetate) to yield the title compound.
Reaction SMILES: [C:1]1([C:14]2[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=2[C:16]([O:18][CH3:19])=[O:17])[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C1C(=O)N([Br:31])C(=O)C1.O>CN(C=O)C>[Br:31][C:3]1[CH:2]=[C:1]([C:14]2[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=2[C:16]([O:18][CH3:19])=[O:17])[C:13]2[NH:12][C:11]3[C:6]([C:5]=2[CH:4]=1)=[CH:7][CH:8]=[CH:9][CH:10]=3
Reactant: COC(=O)c1ccccc1-c1cccc2c1[nH]c1ccccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccccc1-c1cc(Br)cc2c1[nH]c1ccccc12
Reaction time: 6 h

Procedure:
62 g (207 mmol) of methyl 2-(9H-carbazolyl)benzoate are cooled to −10° C. in 2 l of DMF, and 37.3 g (207 mmol) of NBS are added in portions. The solution is then brought to room temperature and stirred at this temperature for 6 h. 500 ml of water are subsequently added to the mixture, which is then extracted with CH2Cl2. The organic phase is dried over MgSO4, and the solvents are removed in vacuo. The product is washed by stirring with hot toluene, and the solid is isolated.
Reaction SMILES: [N:1]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]=[S:3].[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>C1COCC1>[CH2:7]([O:6][C:4](=[O:5])[NH:1][C:2]([N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[S:3])[CH3:8]
Reactant: CCOC(=O)N=C=S
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: CCOC(=O)NC(=S)N1CCOCC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 99.5 %

Procedure:
Ethyl isothiocyanatoformate (5 g, 38.2 mmol) was dissolved in THF (50 mL) and cooled to 0° C. Morpholine (3.99 mL, 45.8 mmol) was added dropwise over 2 min. The reaction mixture was stirred for 3 h. The solvent was evaporated to give (morpholin-4-yl-carbothioyl)carbamic acid ethyl ester (8.3 g, 38 mmol) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[OH:34][CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[OH:34][CH:35]1[CH2:40][CH2:39][N:38]([C:1](=[NH:2])[C:3]2[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]3[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([S:29](=[O:31])(=[O:32])[NH2:30])=[CH:25][CH:24]=4)(=[O:20])=[O:19])=[CH:14][CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[CH2:37][CH2:36]1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Reactant: OC1CCNCC1
Product: N=C(c1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1)N1CCC(O)CC1
Yield: 42 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide following procedure C and using 1.3 equivalents of 4-hydroxy-piperidine as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][N:6]1[C:14]([NH2:15])=[N:13][C:12]2[C:7]1=[N:8][C:9]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])=[N:10][C:11]=2[I:16])C.O.[OH-].[Li+].Cl>O1CCCC1.O>[CH2:20]([O:19][C:17]([C:9]1[N:8]=[C:7]2[C:12]([N:13]=[C:14]([NH2:15])[N:6]2[CH2:5][C:4]([OH:27])=[O:3])=[C:11]([I:16])[N:10]=1)=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)Cn1c(N)nc2c(I)nc(C(=O)OCc3ccccc3)nc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Nc1nc2c(I)nc(C(=O)OCc3ccccc3)nc2n1CC(=O)O
Reaction time: 0.5 h
Yield: 104.1 %

Procedure:
To a suspension of [2-(benzyloxycarbonyl)-amino-6-iodo-purine-9-yl]-acetic acid ethyl ester (10.02 g, 20.8 mmol) in tetrahydrofuran (50 mL) and water (50 mL) was added lithium hydroxide hydrate (2.83 g, 20.8 mmol) at 10° C. The resulting reaction mixture was stirred for 30 min. Then the mixture was acidified to pH=3 by adding 1N HCl. The precipitated solid was filtered off, washed with water and ethyl ether, and dried in vacuo to give the title compound (9.81 g). 1H-NMR (500 MHz; DMSO-d6) δ 10.75 (s, 1H), 8.44 (s, 1H), 7.50˜7.30 (m, 5H), 5.17 (s, 2H), 4.97 (s, 2H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:9]1.[CH3:30][NH:31][CH3:32]>CN(C)C(=O)C>[CH3:30][N:31]([CH3:32])[CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:9]1
Reactant: CN(C[C@H]1CC[C@H](COCCCCBr)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: CNC
Solvent: CC(=O)N(C)C
Product: CN(C)CCCCOC[C@H]1CC[C@H](CN(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1

Procedure:
In analogy to the method described in example 12.1, trans-N-[4-(4-bromo-butoxymethyl)-cyclohexylmethyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide was reacted with dimethyl-amine in N,N-dimethylacetamide at room temperature to yield trans-N-[4-(4-dimethylamino-butoxymethyl)-cyclohexylmethyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide as colorless solid, MS: 465 (MH+).
Reaction SMILES: CC1(C)[O:6][CH:5]([CH2:7][NH:8][C:9]([O:11][CH:12]([O:14][C:15](=[O:55])[C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([C@H:25]3[C@H:29]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=4[F:37])[C@:28]([C:40]4[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][C:41]=4[F:47])([C:38]#[N:39])[C@H:27]([CH2:48][C:49]([CH3:52])([CH3:51])[CH3:50])[NH:26]3)=[O:24])=[C:18]([O:53][CH3:54])[CH:17]=2)[CH3:13])=[O:10])[CH2:4][O:3]1.Cl.CCOCC>C(#N)C>[OH:6][CH:5]([CH2:4][OH:3])[CH2:7][NH:8][C:9]([O:11][CH:12]([O:14][C:15](=[O:55])[C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C@H:25]2[C@H:29]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=3[F:37])[C@:28]([C:40]3[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][C:41]=3[F:47])([C:38]#[N:39])[C@H:27]([CH2:48][C:49]([CH3:51])([CH3:50])[CH3:52])[NH:26]2)=[O:24])=[C:18]([O:53][CH3:54])[CH:17]=1)[CH3:13])=[O:10]
Reactant: COc1cc(C(=O)OC(C)OC(=O)NCC2COC(C)(C)O2)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Agent: Cl
Solvent: CC#N
Solvent: CCOCC
Product: COc1cc(C(=O)OC(C)OC(=O)NCC(O)CO)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reaction time: 1.17 h
Yield: 51.2 %

Procedure:
A solution of 1-((2,2-dimethyl-1,3-dioxolan-4-yl)methylcarbamoyloxy)ethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (Example 15, 75.7 mg, 0.092 mmol) in acetonitrile (4 mL) was treated with a 2M solution of hydrochloric acid in ether (Sigma Aldrich, 0.5 mL, 1.00 mmol) and stirred for 70 min. The reaction mixture was concentrated, diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate, brine, dried and concentrated. The crude material was then purified by flash chromatography (methylene chloride/methanol) to give 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 1-(2,3-dihydroxy-propylcarbamoyloxy)-ethyl ester as a white solid (36.6 mg, 50% yield). MS (ES+) m/z calcd. for C37H40Cl2F2N4O8: [(M+H)+]: 777 found: 777
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:16][C:17](C)([O-])[CH3:18].[K+].C(Br)C=C>C1COCC1>[CH2:18]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)[CH:17]=[CH2:16]
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCOc1ccc(-c2ccc(C#N)cc2)cc1
Temperature: 25 °C
Yield: 65 %

Procedure:
The crude phenol 2i [4-(4-hydroxyphenyl)-benzonitrile] was dissolved in 250 mL of anh THF and added to a 500-mL 3-neck round-bottom flask and stirred at 25° C. Potassium tert-butoxide (0. 89 g, 8 mmol) was added to the solution, which turned yellow. Allyl bromide was added in excess (5.0 mL, 40 mmol) and the mixture was refluxed overnight. The THF and allyl bromide were removed by rotoevaporation. The resultant sludge was extracted 5 times with mL of hexane. This material was purified chromatographically (200 mesh Kieselgel 60, 2 % EtOAc 98% in hexane) to afford 1.0 g of white crystalline material (65%): mp 68°-69° C.; IR 3083, 3013, 2884, 2225, 1604, 1492, 1455, 1291, 1249, 1180, 995, 940, 824, 533 cm-1 ; 1H NMR δδ 7.6-7.8 (m, 4H), 7.4-7.5 (d, 2H), 6.9-7.0 (d, 2 H), 5.9-6.0 (m, 1 H), 5.2-5.4 (m, 2 H), 4.5 (d, 2 H); MS m/e 235 (M+), 220, 207, 166. Anal. Calcd for C14H11NO: C, 81.68; H, 5.56. Found C, 81.56; H, 5.68.
Reaction SMILES: CC(C)([O-])C.[K+].C(COC)OC.[N:13]12[CH2:20][CH2:19][CH:16]([CH2:17][CH2:18]1)[C:15](=O)[CH2:14]2.S([CH2:32][N:33]=C=O)(C1C=CC(C)=CC=1)(=O)=O>C(O)C>[C:32]([CH:15]1[CH:16]2[CH2:19][CH2:20][N:13]([CH2:18][CH2:17]2)[CH2:14]1)#[N:33]
Reactant: O=C1CN2CCC1CC2
Reactant: Cc1ccc(S(=O)(=O)CN=C=O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCO
Product: N#CC1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
A solution of potassium tert-butoxide (18.27 ml) in 1:1 (v/v) mixture of dimethoxyethane and ethanol (100 ml) was added slowly to a stirred mixture of 3-quinuclidinone (8.14 g), tosylmethylisocyanate (16.53 g) in dry ethanol (6.5 ml), and dry dimethoxyethane (228 ml) under an atmosphere of argon whilst maintaining the temperature below 10° C. The reaction mixture was allowed to warm to ambient temperature and stirred at this temperature for 30 minutes. The reaction mixture was then stirred at 40° C. for 3 hours. The reaction mixture was cooled, filtered and the filtrate evaporated. The residue was purified by flash column chromatography on alumina (Brockmann Grade I) using a 2:98 (v/v) mixture of methanol/ethyl acetate as eluant to give 3-cyanoquinuclidine (6.6 g), microanalysis, found: C, 67.6; H, 8.5; N, 18.7%; C8H12N2 requires: C, 70.6; H, 8.8; N, 20.6%; NMR (CDCl3): 1.4-1.7 (3H, m), 1.85-2.0 (1H, m) 2.0-2.1 (1H, m) and 2.6-3.4 (7H, m); m/z 137 (M+H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([OH:11])=[CH:3][C:2]=1[OH:12].C(O)(=O)C.[N+:17]([O-])([OH:19])=[O:18]>O>[N+:17]([C:3]1[C:2]([OH:12])=[N:1][C:10]2[C:5]([C:4]=1[OH:11])=[CH:6][CH:7]=[CH:8][CH:9]=2)([O-:19])=[O:18]
Reactant: Oc1cc(O)c2ccccc2n1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1c(O)nc2ccccc2c1O
Temperature: 105 °C
Reaction time: 0.17 h
Yield: 78.2 %

Procedure:
To a 50 mL round bottom flask were sequentially added quinoline-2,4-diol (2 g, 12.4 mmol), glacial acetic acid 12.5 mL, and concentrated nitric acid 3.25 mL, stirred for 30 min at room temperature, and then stirred for 10 min in an oil bath of 105° C., followed by cooling to room temperature. 25 mL water was added to form precipitates, which were filtrated through an air pump, washed sequentially with water and ethyl ether. The solid was dried under vacuum to afford 2 g titled product with a yield of 78.2%.