Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:9])=[C:6]([CH:8]=1)[NH2:7].[C:10]1([S:16](Cl)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1C=CC=CC=1.CCOC(C)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:9])=[C:6]([NH:7][S:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:18])=[O:17])[CH:8]=1
Reactant: Nc1cc(Br)ccc1Cl
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Br)ccc1Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirring solution of 5-Bromo-2-chloroaniline (100 mg, 0.48 mmol) in DCM (5 ml) is added benzenesulfonyl chloride (280 mg, 202 ul, 1.58 mmol) and pyridine (195 ul, 2.42 mmol). The reaction mixture is stirred at room temperature for 18 hours. EtOAc (20 ml) is added and the reaction mixture is washed with 0.1 m HCl (20 ml), the phases are separated and the organic portion is washed with water (3×), dried over MgSO4, concentrated in vacuo and dried in a vacuum oven to afford the title compound.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[CH:7]([NH:22][CH:23]=[O:24])[CH2:6][CH:5]1[CH3:25])(=[O:3])[CH3:2].[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C(O)(=O)C.C([O-])(O)=O.[Na+]>ClC(Cl)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][N:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:18][CH:19]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:22][CH:23]=[O:24])[CH2:6][C@@H:5]1[CH3:25])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3ccc(C=O)cc3)cc2C(NC=O)CC1C
Reactant: C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CC(=O)N1c2ccc(-c3ccc(CN4CCCCC4)cc3)cc2[C@H](NC=O)C[C@@H]1C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
To a solution of [1-acetyl-6-(4-formylphenyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]formamide (for a preparation see Intermediate 48) (95 g, 0.25 mol) and piperidine (31 g, 0.3 mol) in solution in dichloroethane (2 L) were added at room temperature triacetoxysodiumborohydride (70 g, 0.33 mol) and acetic acid (33 g). After stirring 2 hours a t.l.c monitoring indicated the completion of the reaction and the mixture was poured into a saturated solution of NaHCO3. The organic phase was extracted after addition of DCM (500 mL) and washed with brine (100 mL), dried over Na2SO4, filtered and evaporated to dryness. Trituration of the residue in a mixture of DCM/hexane afforded the title compound (109 g, 95.6%) as an off white solid. LC/MS (Method E) m/z 406 [M+H]+, Rt=2.22 min;
Reaction SMILES: [CH:1]([O:3][CH2:4][CH3:5])=[CH2:2].Cl[CH2:7][CH2:8][C@H:9]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[OH:10].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(Cl)[Cl:35]>>[CH2:1]([O:3][CH:4]([O:10][C@@H:9]([CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([Cl:35])[CH2:12]1)[CH2:8][CH3:7])[CH3:5])[CH3:2]
Reactant: ClCCl
Reactant: O[C@H](CCCl)C1CCCCC1
Reactant: C=COCC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: CCOC(C)O[C@H](CC)C1CCCC(Cl)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97 %

Procedure:
Ethyl vinyl ether (EVE) (10 mL) was added to a stirred, ice-cooled solution of (R)-3-chloro-1-cyclohexyl-1-propanol (4.89 g, 27.7 mmol) and pyridinium p-toluenesulfonate (PPTS) (0.04 g) in 40 mL of dry CH2Cl2. After 10 minutes, 0.20 g of PPTS and 8 mL of EVE were added, and the solution was allowed to warm to RT. After 1 hour, the solution was filtered through a pad of silica, eluting with diethyl ether. Concentration afforded 6.69 g (97%) of (R)-1-(3-chloro-1-cyclohexyl)propyl (1-ethoxyethyl) ether. NMR (CDCl3) δ0.9-2.0 (m, 13H), 1.21 (t, J=7.0, 3H), 1.30 and 1.32 (2 overlapping d, J=5.3, 3H), 3.4-3.8 (m, 5H), 4.7 (2 overlapping q, J=5.3, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][C@@H:10]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[NH:11][C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[C:3]=1[CH3:29].[NH:30]1[CH2:35][CH2:34][CH:33]([C:36]([O:38][CH3:39])=[O:37])[CH2:32][CH2:31]1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>O>[CH3:39][O:38][C:36]([CH:33]1[CH2:34][CH2:35][N:30]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][C@@H:10]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[NH:11][C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[C:3]=2[CH3:29])[CH2:31][CH2:32]1)=[O:37]
Reactant: Cc1c(Cl)ncnc1NC[C@H](NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Reactant: COC(=O)C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C1CCN(c2ncnc(NC[C@H](NC(=O)OCc3ccccc3)C(=O)OC(C)(C)C)c2C)CC1
Yield: 25 %

Procedure:
A mixture of 80 mg (0.19 mmoles) of (1,1-dimethylethyl) 3-[(6-chloro-5-methyl-4-pyrimidinyl)amino]-N-[(phenylmethoxy)carbonyl]alaninate and 3 ml of methyl 4-piperidinylcarboxylate is heated under reflux for 3 hours. After cooling down the reaction medium is taken up in water, ethyl acetate and a saturated solution of sodium bicarbonate. The organic phase is separated and the aqueous phase reextracted with ethyl acetate. The combined organic phases are dried over magnesium sulphate then the solvent eliminated under vacuum. The residue is chromatographed on silicagel eluting with a gradient of heptane (100%) to heptane-ethyl acetate (50-50). 25 mg (Yield=25%) of the expected product is obtained in the form of oil.
Reaction SMILES: CC1(C)CCC(C)(C)C2C=C(O)C(C(O)=O)=CC1=2.[CH3:19][C:20]1([CH3:37])[CH2:29][CH2:28][C:27]([CH3:31])([CH3:30])[C:26]2[C:25]([Br:32])=[C:24]([OH:33])[C:23]([C:34]([OH:36])=[O:35])=[CH:22][C:21]1=2.CC(CC(C1C(O)=CC(O)=C(CC=C(C)C)C=1[O-])=O)C.[CH3:58][O:59][CH2:60]Cl>>[CH3:19][C:20]1([CH3:37])[CH2:29][CH2:28][C:27]([CH3:30])([CH3:31])[C:26]2[C:25]([Br:32])=[C:24]([O:33][CH2:58][O:59][CH3:60])[C:23]([C:34]([OH:36])=[O:35])=[CH:22][C:21]1=2
Reactant: CC1(C)CCC(C)(C)c2c1cc(C(=O)O)c(O)c2Br
Reactant: COCCl
Agent: CC(C)=CCc1c(O)cc(O)c(C(=O)CC(C)C)c1[O-]
Agent: CC1(C)CCC(C)(C)c2cc(C(=O)O)c(O)cc21
Product: COCOc1c(C(=O)O)cc2c(c1Br)C(C)(C)CCC2(C)C

Procedure:
5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-hydroxynaphthalene (Compound H, available in accordance with the publication Krause Synthesis 1972 140), is the starting material in the example shown in Reaction Scheme 2. Compound H is brominated to provide the corresponding 3-bromo compound (Compound I) which is thereafter protected in the hydroxyl function by treatment with methoxymethyl chloride (MOMCl) to yield 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-methoxymethoxy-2-bromonaphthalene (Compound J). Compound J is reacted with t-butyllithium and carbon dioxide to provide the corresponding carboxylic acid (Compound K) from which the methoxymethyl protecting group is removed by acid to give 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-hydroxynaphthalene-3-carboxylic acid (Compound L). Compound L is brominated to yield 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-1-bromo-2-hydroxynaphthalene-3-carboxylic acid (Compound M). Compound L and Compound M serve as reagents in accordance with Formula 6. The hydroxy group of Compound X is protected for further transformations with methoxymethyl chloride (MOMCl) in the presence of base, yielding 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-1-bromo-2-methoxymethoxynaphthalene-3-carboxylic acid (Compound N). ##STR5##
Reaction SMILES: Cl.CC1C(CN2C=C(N)C=N2)=C(C)[O:5]N=1.Br[CH2:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[C:20]#[N:21].C(N(CC)CC)C>CN(C=O)C.O>[C:20]1(=[O:5])[C:19]2[C:18](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:17][NH:21]1
Reactant: N#Cc1ccccc1CBr
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NCc2ccccc21
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 145.1 %

Procedure:
1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine-hydrochloride (100 mg, 0.44 mmol), 2-(bromomethyl)benzonitrile (115 mg, 0.6 mmol), and triethylamine (0.5 mL, 3.5 mmol) in DMF (3 mL) were irradiated and stirred in the microwave reactor at 80° C. for 10 minutes. The reaction was cooled, diluted with H2O (50 mL) and extracted with ethyl acetate (3×, 30 mL). The combined organic extracts were dried over sodium sulfate and concentrated on the rotovap. The residue was dissolved in ethanol (70 mL), H2O (3 mL) and acetic acid (1 mL) and the mixture was refluxed for 2 hours. The solution was concentrated on the rotovap, taken up in methanol (3 mL) and purified by reversed phase HPLC in 3-1 mL aliquots (5 to 95% acetonitrile in H2O: 16 minute gradient). The pure fractions were combined and concentrated on the rotovap. The residue was triturated with ethyl acetate/hexanes (1/9) to afford 2-(1-(3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)isoindolin-1-one (85 mg, 61%) as a pure white solid. 1H NMR (DMSO-d6, 400 MHz): δ2.18 (s, 3H), 2.43 (s, 3H), 4.97 (s, 2H), 5.18 (s, 2H), 7.58-7.68 (m, 3H), 7.77 (s, 1H), 8.10 (d, J=8 Hz, 1H), 8.27 (s, 1H), 9.19 (bs, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 value greater than 30 μM.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:12]=[CH:11][C:10]=1[C@@H:23]1[CH2:28][CH2:27][C@H:26]([NH2:29])[CH2:25][CH2:24]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:30](Cl)(=[O:32])[CH3:31]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[Si:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][Si:16]([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:18])[CH3:17])[CH:12]=[CH:11][C:10]=1[C@@H:23]1[CH2:24][CH2:25][C@H:26]([NH:29][C:30](=[O:32])[CH3:31])[CH2:27][CH2:28]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@@H](N)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)N[C@H]1CC[C@@H](c2ccc(O[Si](C)(C)C(C)(C)C)cc2O[Si](C)(C)C(C)(C)C)CC1
Reaction time: 24 h
Yield: 50 %

Procedure:
trans/cis-4-(2,4-Bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexylamine (27 mg) was dissolved in pyridine (0.5 ml). Acetyl chloride (6 μl) and 4-dimethylaminopyridine (2 mg) were added sequentially and the reaction mixture stirred for 24 hr. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (10 ml) and water (2 ml). The aqueous phase was extracted with ethyl acetate (2×5 ml) and the combined organic phases were washed with brine (10 ml), dried over anhydrous magnesium sulphate, and concentrated to give a brown oil. Purification via flash column chromatography (SiO2 eluting with ethyl acetate:petroleum ether, 7:3 v/v) afforded the title product as a white solid (15 mg, 50%) and a mixture of diastereoisomers. δH (CDCl3): 0.17 (3H, s), 0.19 (3H, s), 0.21 (3H, s), 0.22 (3H, s), 0.96 (9H, s), 1.02 (9H, s), 1.06-1.20 (2H, m), 1.36-1.54 (2H, m), 1.60-1.75 (2H, m), 1.80-1.92 (2H, m), 1.95 (1.5H, s), 2.00 (1.5H, s), 2.75-2.90 (1H, m), 3.76-3.87 (1H, m), 5.34-5.39 (0.5H, d), 5.72-5.77 (0.5H, d), 6.26-6.29 (1H, m), 6.38-6.41 (1H, m), 6.93 (0.5H, d), 6.95 (0.5H, d); m/z (ES+) 478 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:22])[C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([NH:25][CH2:26][CH3:27])[CH3:24].CN1CCOCC1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[N:8]([C@H:9]1[CH2:10][CH2:11][C@H:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:21])[N:25]([CH2:26][CH3:27])[CH2:23][CH3:24])[CH2:13][CH2:14]1)[CH3:22])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](CCCCC(=O)O)CC1
Reactant: CCNCC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCN(CC)C(=O)CCCC[C@H]1CC[C@H](N(C)C(=O)OC(C)(C)C)CC1
Temperature: 0 °C

Procedure:
To 1 g (3.19 mmol) trans-5-[4-(tert-Butoxycarbonyl-methyl-amino)-cyclohexyl]-pentanoic acid in 37 ml CH2Cl2 was added 0.5 ml (4.8 mmol, 1.5 eq) diethylamine and 0.53 ml (4.79 mmol, 1.5 eq) NMM. The solution was cooled to 0° C. and 795 mg (4.15 mmol, 1.3 eq) EDCI and 98 mg (6.4 mmol) HOBT were added. The mixture was stirred at RT over night, partitioned between CH2Cl2 and a saturated aqueous solution of NaHCO3. The organic phase was washed with KHSO4 and brine, dried over Na2SO4 and evaporated. Column chromatography with EtOAc/hexane 1:1 gave 1.05 g (86%) trans-[4-(4-Diethylcarbamoyl-butyl)-cyclohexyl]-methyl-carbamic acid tert-butyl ester as colorless liquid MS: 369 (MH+).
Reaction SMILES: FC(F)(F)C(O)=O.COC1C=C(OC)C=CC=1[CH2:12][N:13](C)[C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:23][C:24]2[S:25][CH:26]=[CH:27][N:28]=2)(=[O:22])=[O:21])=[C:16]([F:29])[CH:15]=1.C(Cl)Cl>>[F:29][C:16]1[CH:15]=[C:14]([NH:13][CH3:12])[CH:19]=[CH:18][C:17]=1[S:20]([NH:23][C:24]1[S:25][CH:26]=[CH:27][N:28]=1)(=[O:22])=[O:21]
Reactant: COc1ccc(CN(C)c2ccc(S(=O)(=O)Nc3nccs3)c(F)c2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNc1ccc(S(=O)(=O)Nc2nccs2)c(F)c1
Reaction time: 1 h
Yield: 43.2 %

Procedure:
Trifluoroacetic acid (1 mL, 0.01 mol) was added to a solution of the 4-[(2,4-dimethoxy-benzyl)-methyl-amino]-2-fluoro-N-thiazol-2-yl-benzenesulfonamide (0.22 g, 0.00050 mol) in methylene chloride (5.0 mL, 0.078 mol). The reaction solution was stirred for one hour then concentrated. The residue was partitioned between sat'd NaHCO3 and EtOAc. Organic layer was separated and the aq phase was extracted with EtOAc (2×). The combined organic layers were washed with water and brine, dried over Na2SO4. Evaporation of the solvent gave the crude product that was purified using Gilson preparative HPLC (reverse phase, Phenomenex 250×30 mm, 15 micron C18 column, 40 mL/min. Gradient, 85% A to 100% B over 25 min. Solvent A: 7800 water/200 acetonitrile/8 TFA. Solvent B: 7200 acetonitrile/800 water/8). Fractions were checked by LC/MS. The appropriate fractions were combined and dried on a lyophilizer to give the desired product as a pale yellow powder (62 mg, 43%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:30][CH3:31])[N:6]2[CH2:16][CH:17]1[CH2:22]CN(C(OC(C)(C)C)=O)[CH2:19][CH2:18]1.FC(F)(F)C(O)=O.C(OC1N=C2C(N=C(OC)N2)=C(N)N=1)CCC.BrC[C@@H]1CCC[N:60]([C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[CH2:59]1>>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:30][CH3:31])[N:6]2[CH2:16][C@@H:17]1[CH2:18][CH2:19][CH2:59][N:60]([C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](CBr)C1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CC3CCN(C(=O)OC(C)(C)C)CC3)c2n1
Agent: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(C[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)c2n1

Procedure:
Prepared similarly to Intermediate 13 from 2-butoxy-8-methoxy-9H-purin-6-amine trifluoroacetate salt and 1,1-dimethylethyl (3R)-3-(bromomethyl)-1-piperidinecarboxylate.
Reaction SMILES: O[O:2][S:3]([O-:5])=O.[K+].[CH2:7]([O:9][C:10](=[O:27])/[C:11](/[C:19]1[CH:24]=[CH:23][C:22](SC)=[CH:21][CH:20]=1)=[CH:12]/[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH3:8].[CH3:28]C(C)=O>O>[CH2:7]([O:9][C:10](=[O:27])/[C:11](/[C:19]1[CH:24]=[CH:23][C:22]([S:3]([CH3:28])(=[O:5])=[O:2])=[CH:21][CH:20]=1)=[CH:12]/[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH3:8]
Reactant: O=S([O-])OO
Reactant: CCOC(=O)/C(=C/C1CCCCC1)c1ccc(SC)cc1
Reactant: CC(C)=O
Agent: [K+]
Solvent: O
Product: CCOC(=O)/C(=C/C1CCCCC1)c1ccc(S(C)(=O)=O)cc1

Procedure:
Add a suspension of oxone ® (33 g, 53 mmol) in water (300 mL) to a solution of (E)-3-cyclohexyl-2-(4-methylsulfanyl-phenyl)-acrylic acid ethyl ester (7.4 g, 24 mmol) in acetone (300 mL). Stir for three h, and then add water. Extract the resulting mixture with dichloromethane (2×500 mL). Combine the extracts, wash them with saturated aqueous sodium chloride solution, dry them over magnesium sulfate, and remove solvent under vacuum. Apply the residue to silica gel column, and elute this with a 15:15:70 mixture of dichloromethane: ethyl acetate: hexane to afford the title compound as an off-white solid (7.35 g). MS (m/e): 337 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]([N:12]=[N+]=[N-])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[I:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[CH3:1][O:2][C:3](=[O:15])[CH:4]([NH2:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[I:11]
Reactant: COC(=O)C(N=[N+]=[N-])c1ccccc1I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(N)c1ccccc1I
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of azido-(2-iodophenyl)-acetic acid methyl ester in THF (100 mL) is added triphenylphosphine (28.5 g, 109 mmol) in portions. The mixture is stirred at RT for 2 h then water (4 mL) is added and is heated to reflux. The solvent is removed under reduced pressure and ether (50 mL) is added followed by 2N HCl until acidic. The aqueous phase is washed with methylene chloride then is concentrated and basified with NaOH/ice until pH 12. The mixture is extracted with methylene chloride (3×200 mL) and the combined organic phases are dried over sodium sulfate. The solvent is removed under reduced pressure to give the title compound.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=CC=1.[CH3:50][N:51]([CH3:55])[CH2:52][CH2:53][NH2:54]>>[NH2:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[C:16]3[CH2:29][CH2:28][N:27]([C:30]4[CH:38]=[CH:37][C:33]([C:34]([NH:54][CH2:53][CH2:52][N:51]([CH3:55])[CH3:50])=[O:35])=[CH:32][CH:31]=4)[C:17]=3[N:18]=[C:19]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[N:20]=2)=[CH:11][N:10]=1
Reactant: CN(C)CCN
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3)cn2)cc1
Product: CN(C)CCNC(=O)c1ccc(N2CCc3c(-c4cnc(N)nc4)nc(N4CCOCC4)nc32)cc1
Yield: 55 %

Procedure:
Using 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-yl)-benzoic acid (53.4 mg) obtained in Step A in Example 1-D-19 and N,N-dimethyl ethylenediamine (18 μl) instead of 3-(aminomethyl)pyridine, in the same manner as Step B in Example 1-D-19, 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-N-(2-dimethylamino-ethyl)-benzamide was obtained as a crude product. Then the PMB groups were removed according to Deprotection method 3, to obtain the desired compound (D-41) as a colorless solid (21.7 mg, 55%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:36][C:15]3[N:16]=[CH:17][N:18]=[C:19]([NH:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]4)[C:14]=3[C:13]=2[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:8][CH:7]=1.N#N.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[O:36][C:15]3[N:16]=[CH:17][N:18]=[C:19]([NH:20][CH2:21][CH2:22][N:23]4[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]4)[C:14]=3[C:13]=2[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[CH:10][CH:11]=1
Reactant: COCCOc1ccc(-c2oc3ncnc(NCCN4CCN(C(=O)OC(C)(C)C)CC4)c3c2-c2ccccc2)cc1
Agent: N#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCOc1ccc(-c2oc3ncnc(NCCN4CCNCC4)c3c2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Tert-butyl 4-(2-(6-(4-(2-methoxyethoxy)phenyl)-5-phenylfuro[2,3-d]pyrimidin-4-ylamino)ethyl)piperazine-1-carboxylate 35 (Prepared in a manner analogous to Steps 1-2 of Example 7; 60 mg, 0.104 mmol) was dissolved in CH2Cl2 (1.5 mL). After purging with N2, TFA (0.37 mL, 4.8 mmol) was added and the mixture was allowed to stir at RT for 4 h. The reaction mixture was concentrated to remove TFA then taken up in CH2Cl2 and washed with saturated NaHCO3. The organic layer was dried over Na2SO4 and concentrated. Preparative TLC (SiO2, 20% MeOH in CH2Cl2) afforded the title compound 36. Mass for C27H31N5O3 found: 474 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C@H:25]([NH:37]C(OC(C)(C)C)=O)[CH2:26][O:27][C:28]3[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=3[I:36])[C:31]#[N:32])=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC(C)C)C(C)C.[C:56]1([S:62](Cl)(=[O:64])=[O:63])[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1.C(OCC)(=O)C>Cl.O1CCOCC1>[C:56]1([S:62]([NH:37][C@@H:25]([CH2:24][C:21]2[CH:20]=[CH:19][C:18]([O:17][CH:14]3[CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[O:10])[CH2:16][CH2:15]3)=[CH:23][CH:22]=2)[CH2:26][O:27][C:28]2[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=2[I:36])[C:31]#[N:32])(=[O:64])=[O:63])[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1
Reactant: CC(C)(C)OC(=O)N[C@H](COc1cc(C#N)ccc1I)Cc1ccc(OC2CCN(C(=O)OCc3ccccc3)CC2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CCN(CC(C)C)CC(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: N#Cc1ccc(I)c(OC[C@H](Cc2ccc(OC3CCN(C(=O)OCc4ccccc4)CC3)cc2)NS(=O)(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.6 g (2.7 mmol) of 3-[(2S)-3-[4-(1-benzyloxycarbonyl-4-piperidyloxy)phenyl]-2-(t-butoxycarbonylamino)propoxy]-4-iodobenzonitrile was dissolved in 4 N solution of hydrogen chloride in dioxane, and the solution was stirred at room temperature overnight. The solvent was distilled off, and the residue was dissolved in dimethylformamide. 1 ml (6 mmol) of N,N-diisobutylethylamine and 0.34 ml (2.7 mmol) of benzenesulfonyl chloride were added to the solution under cooling with ice, and they were stirred for 2 hours. After the isolation process with ethyl acetate as the extractant in the same manner as that of step 1 in Example 1, the crude product was obtained, which was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH:33]=O)[CH:28]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:20][CH2:21][N:22]([CH2:33][C:29]4[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=4)[CH2:23][CH2:24]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:25][CH:26]=1
Reactant: O=Cc1cccnc1
Reactant: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCNCC2)cc1
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCN(Cc3cccnc3)CC2)cc1

Procedure:
Using the general procedure described in Example 3, N1-(4-methoxybenzoyl)-N2-(piperidin-4-ylcarbonyl)-1,2-benzenediamine (0.070 mmol) was reacted with 3-pyridinecarboxaldehyde to provide 47 mg of the title product as the free base. Treatment with hydrochloric acid and concentration in vacuo yielded the salt of the title compound.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.Cl[C:15]([O:17][CH:18]([Cl:20])[CH3:19])=[O:16]>ClCCl>[C:15](=[O:16])([O:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[O:17][CH:18]([Cl:20])[CH3:19]
Reactant: CC(Cl)OC(=O)Cl
Reactant: OC1CCCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(Cl)OC(=O)OC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of cyclohexanol (10.9 g, 10.9 mmol), pyridine (8.62 g, 10.9 mmol) in dichloromethane was added 1-chloroethyl chloroformate (15.59, 10.9 mmol) at ° C. The resulting mixture was stirred at room temperature for 60 min. The mixture was partitioned between hexane and 10% citric acid. The organic phase was separated and dried over MgSO4. Removal of the solvent gave the title compound, which was used in the next reaction without further purification.