Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=1.O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=CC=CC=1C(OC)=O>>[O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:31][CH:32]=1
Reactant: COC(=O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1
Agent: COC(=O)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Product: O=C(O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1

Procedure:
Following the procedure as described in EXAMPLE 11.30 and making non-critical variations using methyl 4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoate to replace methyl 2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoate, 4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid was obtained (95%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ12.93 (s, 1H), 7.90 (d, J=8.1 Hz, 2H), 7.43 (d, J=8.1 Hz, 2H), 7.22 (dd, J=7.4 Hz, 1H), 7.16 (d, J=7.4 Hz, 1H), 7.00 (dd, J=7.4 Hz, 1H), 6.94 (d, J=7.4 Hz, 1H), 6.45 (s, 1H), 6.40 (s, 1H), 4.98 (ABq, 2H), 4.77 (ABq, 2H), 4.47 (t, J=8.9 Hz, 2H), 3.01-2.85 (m, 2H); MS (ES+) m/z 414.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([CH:22]=[O:23])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:24]([F:27])([F:26])[F:25].O.Cl>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:15]2[C:16]([CH:22]=[O:23])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:24]([F:25])([F:27])[F:26]
Reactant: COCN(c1cc(Cl)cnc1C=O)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 80 °C

Procedure:
The unpurified aldehyde from the previous reaction was magnetically stirred in dioxane (20 mL), water (20 mL), and 4N HCl in dioxane (40 mL); and heated at 80° C. (oil bath) overnight. LCMS indicated complete reaction; the reaction was concentrated and the residue was neutralized (pH 6) with aqueous sodium bicarbonate and extracted with ethyl acetate (3×80 mL). The extracts were dried (Na2SO4), filtered, and purified by flash column chromatography on silica gel using ethyl acetate-hexane to provide 4-chloro-N-(5-chloro-2-formyl-pyridin-3-yl)-3-trifluoromethyl-benzenesulfonamide. MS: (M+H)/z=398.9.
Reaction SMILES: [H-].[Na+].[C:3]([N:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:9][C:8](=[O:18])[CH:7]1[CH:19]([CH3:21])[CH3:20])(=[O:5])[CH3:4].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[C:3]([N:6]1[CH:11]=[C:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:9]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:8](=[O:18])[CH:7]1[CH:19]([CH3:21])[CH3:20])(=[O:5])[CH3:4]
Reactant: CC(=O)N1C=C(c2ccccc2)NC(=O)C1C(C)C
Reactant: CCOC(=O)CBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CN1C(=O)C(C(C)C)N(C(C)=O)C=C1c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under ice cooling, 60% sodium hydride (27.9 mg) is added to a solution of (3RS)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazine (150 mg, Reference compound No. 49-1) in tetrahydrofuran (1 ml), and the mixture is stirred for 30 minutes. Ethyl bromoacetate (77 μl) is added to the mixture, then the temperature is raised to room temperature, and the whole is stirred for one hour. The reaction mixture is diluted with ethyl acetate, and a saturated aqueous ammonium chloride solution is added thereto. The diluted solution is washed with 0.1 N hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution and saturated brine successively and dried over anhydrous magnesium sulfate. The diluted solution is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography to give the titled reference compound (195 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)[N:3]=1.[Na].[CH3:14][OH:15]>>[N:8]1([C:4]2[N:3]=[C:2]([O:15][CH3:14])[CH:7]=[CH:6][N:5]=2)[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: CO
Reactant: Clc1ccnc(-n2ccnc2)n1
Agent: [Na]
Product: COc1ccnc(-n2ccnc2)n1

Procedure:
Following the procedure of Example 15, 180 mg of 4-chloro-2-(1-imidazolyl)pyrimidine were reacted with 23 mg of sodium metal and 2 ml of anhydrous methanol was carried out to yield 134 mg of 2-(1-imidazolyl)-4-methoxypyrimidine, having a melting point of 78°-79° C., recrystallized from a mixture of n-hexane and ethyl acetate.
Reaction SMILES: CN(C)S([N:6]1[CH:10]=[C:9]([CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])[CH3:12])[N:8]=[C:7]1[Si](C(C)(C)C)(C)C)(=O)=O.N>Cl>[F:20][C:14]1[C:15]([F:19])=[CH:16][CH:17]=[CH:18][C:13]=1[CH:11]([C:9]1[N:8]=[CH:7][NH:6][CH:10]=1)[CH3:12]
Reactant: CC(c1cn(S(=O)(=O)N(C)C)c([Si](C)(C)C(C)(C)C)n1)c1cccc(F)c1F
Agent: Cl
Agent: N
Product: CC(c1c[nH]cn1)c1cccc(F)c1F
Yield: 47.4 %

Procedure:
(+)-2-(tert-Butyl-dimethyl-silanyl)-4-[1-(2,3-difluoro-phenyl)-ethyl]-imidazole-1-sulfonic acid dimethylamide (350 mg, 0.81 mmol) was dissolved in 10 ml 1.5N hydrochloric acid and refluxed for 1 h. The cooled solution was adjusted to pH>8 with 25% aqueous ammonia and the solution was extracted with dichloromethane (2 times). The combined organic layers are dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (silica gel, dichloromethane/methanol/aqueous conc. ammonia=90:10:1) to yield 80 mg (47%) of 4-[1-(2,3-difluoro-phenyl)-ethyl]-1H-imidazole (Enantiomer 1) as off-white solid: MS (ISP): 208.9 ((M+H)+.), chiral HPLC (Reprosil Chiral-NR; heptane/ethanol=90:10): tR=9.9 min. 4-[1-(2,3-Difluoro-phenyl)-ethyl]-1H-imidazole (Enantiomer 2) was obtained by the same procedure from (−)-2-(tert-butyl-dimethyl-silanyl)-4-[1-(2,3-difluoro-phenyl)-ethyl]-imidazole-1-sulfonic acid dimethylamide in 73% yield; colourless oil, MS (ISP): 208.9 ((M+H)+.), chiral HPLC (Reprosil Chiral-NR; heptane/ethanol=90:10): tR=11.1 min.
Reaction SMILES: C(OC(NC(C1C=CC=CC=1)C(O)=O)=O)(C)(C)C.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.N12CCC(CC1)[C@@H](O)C2.C(OC([NH:60][CH:61]([C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1)[C:62]([O:64][C@@H:65]1[CH:70]2[CH2:71][CH2:72][N:67]([CH2:68][CH2:69]2)[CH2:66]1)=[O:63])=O)(C)(C)C.O1CCOCC1.[ClH:85].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>C1COCC1.C(Cl)Cl>[ClH:85].[ClH:85].[NH2:60][CH:61]([C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1)[C:62]([O:64][C@@H:65]1[CH:70]2[CH2:69][CH2:68][N:67]([CH2:72][CH2:71]2)[CH2:66]1)=[O:63]
Reactant: CC(C)(C)OC(=O)NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)(C)OC(=O)NC(C(=O)O)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97 %

Procedure:
A mixture of 2-(tert-butoxycarbonylamino)-2-phenylacetic acid (0.90 g, 4.18 mmol), HOBt (0.68 g, 12.5 mmol), DCC (1.29 g, 6.27 mmol) and 3(R)-quinuclidinol (1.59 g, 12.5 mmol) in dry THF (50 mL) is stirred at room temperature for 16 hours (LC-MS monitoring: complete conversion). The solvent is removed under reduced pressure, the residue is taken up with EtOAc and washed twice with 2M K2CO3. The organic phase is dried over Na2SO4, filtered and evaporated to dryness. The compound is triturated with hexane to give (R)-quinuclidin-3-yl 2-(tert-butoxycarbonylamino)-2-phenylacetate as a white solid (1.46 g; 97% yield, mixture of diastereoisomers). This compound is dissolved in DCM (50 mL) and 4N HCl dioxane (5 mL) is added. The reaction is stirred at room temperature for 1 hour (LC-MS monitoring: complete conversion) and then solvent is separated. The gummy solid is triturated with hexane to give C25 as a white solid (1.26 g, 94% yield, di hydrochloride, mixture of diastereoisomers).
Reaction SMILES: S(=O)(=O)(O)O.[O-]S([O-])(=O)=O.[Mg+2].[Br:12][CH:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14]([OH:16])=[O:15].[C:23](O)([CH3:26])([CH3:25])[CH3:24].C([O-])(O)=O.[Na+]>ClCCl.O>[Br:12][CH:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14]([O:16][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:15]
Reactant: O=C(O)C(Br)c1ccccc1
Reactant: CC(C)(C)O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)C(Br)c1ccccc1
Reaction time: 0.25 h

Procedure:
Concentrated sulphuric acid (0.55 mL; 10 mmol) was added to a stirred suspension of anhydrous MgSO4 (4.8 g; 40 mmol) in dry dichloromethane (40 mL) at ambient temperature. After 15 min stirring, α-bromophenylacetic acid (2.15 g; 10.0 mmol) was added, followed by t-butyl alcohol (4.8 mL; 50 mmol). The reaction flask was closed with a stopper and the mixture was stirred 7 days at ambient temperature. Saturated NaHCO3 solution (75 mL) and water (75 mL) was added to the reaction mixture. After separating, the aqueous layer was extracted with dichloromethane (2×15 mL). The combined organic layers were washed with water and dried (MgSO4). After filtration and evaporation 2.39 g (88%) product was obtained (colourless oil).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:9]([CH2:10][NH2:11])=[CH:8][CH:7]=[C:6]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[N:5]=1.[CH3:18][O:19][C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([CH3:31])[N:30]=1)[C:25](O)=[O:26])=[O:21]>>[CH3:2][O:3][C:4]1[C:9]([CH2:10][NH:11][C:25]([C:24]2[CH:28]=[C:29]([CH3:31])[N:30]=[C:22]([C:20]([O:19][CH3:18])=[O:21])[CH:23]=2)=[O:26])=[CH:8][CH:7]=[C:6]([O:12][CH2:13][C:14]([F:17])([F:15])[F:16])[N:5]=1
Reactant: COc1nc(OCC(F)(F)F)ccc1CN
Reactant: COC(=O)c1cc(C(=O)O)cc(C)n1
Agent: Cl
Product: COC(=O)c1cc(C(=O)NCc2ccc(OCC(F)(F)F)nc2OC)cc(C)n1

Procedure:
The title compound is prepared from (2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine hydrochloride (Amine-24) and 2-(methoxycarbonyl)-6-methylisonicotinic acid by the similar manner in Step-1 of Example 8.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][N:8]([CH2:10][C:11]([OH:13])=O)[CH:9]=1)=[O:4].S(Cl)(Cl)=O.[NH2:18][C:19]1[CH:24]=[C:23]([Cl:25])[C:22]([C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:28][CH:27]=2)=[CH:21][C:20]=1[C:38]([O:40][CH3:41])=[O:39]>C1(C)C=CC=CC=1.ClCCl>[Cl:25][C:23]1[CH:24]=[C:19]([NH:18][C:11](=[O:13])[CH2:10][N:8]2[CH:9]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=[N:7]2)[C:20]([C:38]([O:40][CH3:41])=[O:39])=[CH:21][C:22]=1[C:26]1[CH:27]=[CH:28][C:29]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:30][CH:31]=1
Reactant: COC(=O)c1cc(-c2ccc(N3CCCCC3)cc2)c(Cl)cc1N
Reactant: COC(=O)c1cnn(CC(=O)O)c1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)c1cnn(CC(=O)Nc2cc(Cl)c(-c3ccc(N4CCCCC4)cc3)cc2C(=O)OC)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
To a solution of 2-(4-(methoxycarbonyl)-1H-pyrazol-1-yl)acetic acid (ChemCollect GmbH, 401 mg, 2.175 mmol) in toluene (10 mL) was added thionyl chloride (0.317 mL, 4.35 mmol) and the reaction mixture was stirred at 90° C. for 2 h. The solvent was removed under reduced pressure and the residue was added to a solution of methyl 4-amino-6-chloro-4′-(piperidin-1-yl)-[1,1′-biphenyl]-3-carboxylate (Intermediate 48) (500 mg, 1.45 mmol) in dichloromethane (10 mL). The reaction mixture was stirred at room temperature overnight. Solvent was removed under reduced pressure and water was added. Precipitate was observed, solid was filtered and dried to give the title compound methyl 1-(2-((2-chloro-5-(methoxycarbonyl)-4′-(piperidin-1-yl)-[1,1′-biphenyl]-4-yl)amino)-2-oxoethyl)-1H-pyrazole-4-carboxylate (720 mg, 1.409 mmol, 97% yield) as a cream solid. LCMS: (M+H)+=511; Rt=4.04 min.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[N:13]=[C:14]([CH2:37][O:38][CH2:39][CH3:40])[N:15]([CH2:16][C:17]3([O:30][CH2:31][CH2:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)[C:11]=2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]=1>C(O)C>[CH2:39]([O:38][CH2:37][C:14]1[N:15]([CH2:16][C:17]2([O:30][CH2:31][CH2:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[C:3]([NH2:2])[C:12]=2[N:13]=1)[CH3:40]
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CC1(OCCS(C)(=O)=O)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCO
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CC1(OCCS(C)(=O)=O)CCNCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.3 %

Procedure:
A solution of HCl in ethanol (4.2 M, 0.8 mL, 3.56 mmol) was added to a suspension of tert-butyl 4-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}-4-[2-(methylsulfonyl)ethoxy]piperidine-1-carboxylate (0.40 g, 0.71 mmol) in ethanol (4 mL) at rt. The resulting yellow solution was heated at reflux for 1.5 h. The reaction was stirred at rt for 16 h, then was concentrated under reduced pressure. The resulting solid was dissolved in water (20 mL) and 20% aqueous NaOH was added until the pH=13. The solution was extracted with dichloromethane (3×50 mL). The organic layers were combined, washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to provide a solid that was crystallized from acetonitrile. The crystals were dried under vacuum at 65° C. to provide 2-(ethoxymethyl)-1-({4-[2-(methylsulfonyl)ethoxy]piperidin-4-yl}methyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.25 g, 76%) as crystalline plates, mp 212-214° C. 1H NMR (300 MHz, DMSO-d6) δ 8.26 (d, J=8.1 Hz, 1H), 7.61 (d, J=8.1 Hz, 1H), 7.44 (t, J=8.1 Hz, 1H), 7.26 (t, J=8.1 Hz, 1H), 6.61 (bs, 2H), 4.85 (s, 2H), 4.81 (s, 2H), 3.70 (t, J=5.6 Hz, 2H), 3.55 (q, J=7.5 Hz, 2H), 3.19 (t, J=5.6 Hz, 2H), 2.92 (s, 3H) 2.66-2.58 (m, 4H), 1.84 (bs, 1H), 1.70-1.66 (m, 2H), 1.48-1.38 (m, 2H), 1.16 (t, J=7.5 Hz, 3H); MS (APCI) m/z 462 (M+H)+; Anal. Calcd for C22H31N5O4S: C, 57.25; H, 6.77: N, 15.17. Found: C, 57.48; H, 7.05; N, 15.57.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1.[Br:18]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:18][CH:10]([C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:16])([F:17])[F:1])=[CH:9][CH:8]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)Cc1ccc(OC(F)(F)F)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(Br)c1ccc(OC(F)(F)F)cc1
Yield: 103.2 %

Procedure:
A mixture of ethyl 2-(4-(trifluoromethoxy)phenyl)acetate (1.99 g, 8.00 mmol), N-bromosuccinimide (NBS) (1.57 g, 8.80 mmol) and 2,2′-azobis(2-methylpropionitrile) (AIBN) (66 mg, 0.400 mmol) in carbon tetrachloride (10 ml) was heated under reflux for 5 hours. The reaction mixture was concentrated in vacuo, diluted with diethyl ether (200 ml), washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo to give ethyl 2-bromo-2-(4-(trifluoromethoxy)phenyl)acetate (65) (2.70 g, quantitative yield) as yellow oil.
Reaction SMILES: Cl.[C:2]([C:5]1[CH:6]=[CH:7][C:8]([O:31][CH2:32][CH:33]2[CH2:35][CH2:34]2)=[C:9]([C:11]2[C:12]3[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][C@H:24]4[CH2:29][CH2:28][C@H:27]([NH2:30])[CH2:26][CH2:25]4)=[O:22])[C:13]=3[N:14]=[CH:15][N:16]=2)[CH:10]=1)(=[O:4])[CH3:3].[CH3:36][O:37][CH2:38][C:39](Cl)=[O:40]>>[C:2]([C:5]1[CH:6]=[CH:7][C:8]([O:31][CH2:32][CH:33]2[CH2:34][CH2:35]2)=[C:9]([C:11]2[C:12]3[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][C@H:24]4[CH2:29][CH2:28][C@H:27]([NH:30][C:39](=[O:40])[CH2:38][O:37][CH3:36])[CH2:26][CH2:25]4)=[O:22])[C:13]=3[N:14]=[CH:15][N:16]=2)[CH:10]=1)(=[O:4])[CH3:3]
Reactant: CC(=O)c1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c1
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(C)=O)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[5-acetyl-2-(cyclopropylmethoxy)phenyl]-N-(trans-4-aminocyclohexyl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f56) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [OH-].[K+].[C:3]([C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]([NH:27][C@@H:28]([CH:33]([CH3:35])[CH3:34])[C:29]([O:31]C)=[O:30])=[O:26])=[CH:20][C:19]=3[Cl:36])=[CH:14][CH:13]=2)[C:9]([CH3:37])=[N:8][C:7]=1[CH3:38])(=[O:5])[NH2:4]>CC(O)(C)C>[C:3]([C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]([NH:27][C@@H:28]([CH:33]([CH3:34])[CH3:35])[C:29]([OH:31])=[O:30])=[O:26])=[CH:20][C:19]=3[Cl:36])=[CH:14][CH:13]=2)[C:9]([CH3:37])=[N:8][C:7]=1[CH3:38])(=[O:5])[NH2:4]
Reactant: COC(=O)[C@@H](NC(=O)Cc1ccc(-c2ccc(-c3nc(C(N)=O)c(C)nc3C)cc2)c(Cl)c1)C(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: Cc1nc(C)c(-c2ccc(-c3ccc(CC(=O)N[C@H](C(=O)O)C(C)C)cc3Cl)cc2)nc1C(N)=O
Temperature: 45 °C
Reaction time: 5 h
Yield: 29.4 %

Procedure:
Potassium hydroxide (108 mg, 1.93 mmol) was added in one portion to (S)-methyl 2-(2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)acetamido)-3-methylbutanoate (Intermediate 17-1; 327.4 mg, 0.64 mmol) in t-BuOH (4150 μL) at RT. The resulting solution was stirred at 45° C. for 5 hours a precipitate formed. The reaction mixture was quenched with 2M HCl (5 mL), The reaction mixture was evaporated to dryness and redissolved in water (10 mL), and filtered through nylon, washed with water and dried under vacuum. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 50 mm diameter, 150 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford (S)-2-(2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)acetamido)-3-methylbutanoic acid (93 mg, 29.1%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl.[OH-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5]
Reactant: N#Cc1ccc(Cl)cc1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NCc1ccc(Cl)cc1Br

Procedure:
13.9 ml of borane-THF complex are provided with ice cooling. Slowly a solution of 2.0 g of 2-bromo-4-chlorobenzonitrile (Example 1A) in 60 ml of THF is added. Thereafter the reaction mixture is heated under reflux for 1 h, cooled, and 20 ml of 1N hydrochloric acid are added dropwise, with ice cooling. The mixture is heated under reflux for 1 h and allowed to cool. For the work-up, the solution is rendered alkaline using a 1N sodium hydroxide solution and extracted with dichloromethane. The organic phase is dried over sodium sulfate and concentrated on a rotary evaporator. The crude product is reacted further without purification.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH2:15][CH2:16][O:17][CH3:18])[CH:8]=1.[B:19](OC(C)C)([O:24]C(C)C)[O:20]C(C)C.Cl>O1CCCC1>[CH3:18][O:17][CH2:16][CH2:15][CH2:14][O:13][C:9]1[CH:8]=[C:7]([B:19]([OH:24])[OH:20])[CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COCCCOc1cccc(Br)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCCCOc1cccc(B(O)O)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
6.71 ml of n-butyllithium solution (1.6M in hexane) are added dropwise to a solution of 2.5 g of 1 -bromo-3-(3-methoxypropoxy)benzene in 14 ml of dry tetrahydrofuran at −78° C. After stirring at this temperature for 15 minutes, 2.78 ml of triisopropyl borate are added, and the mixture is then slowly warmed to room temperature, 20 ml of 1N ,HCl and 5 ml of conc. HCl are added to the reaction mixture, and the organic solvents are evaporated off in vacuo. The precipitate which has separated out is filtered off with suction and washed twice with ice-water. Drying under high vacuum affords 0.987 g of the title compound as a yellowish brown solid. Rt=3.04.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]2[N:19]=[CH:18][N:17]=[C:16]3[C:12]=2[N:13]=[C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[N:15]3[C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[CH2:5][CH2:4]1.[CH3:34][S:35](Cl)(=[O:37])=[O:36].C(N(CC)CC)C>C1COCC1>[Cl:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:14]1[N:15]([C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)[C:16]2[C:12]([N:13]=1)=[C:11]([NH:10][CH2:9][CH:6]1[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][S:35]([CH3:34])(=[O:37])=[O:36])[CH2:4][CH2:5]1)[N:19]=[CH:18][N:17]=2
Reactant: CS(=O)(=O)Cl
Reactant: NCC1CCC(CNc2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)NCC1CCC(CNc2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71 %

Procedure:
To a solution of N-{[4-(aminomethyl)cyclohexyl]methyl}-8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-amine (6 mg, 0.013 mmol, 1 eq.) in 5 mL of THF was added methanesulfonyl chloride (0.02 mL) and triethylamine (0.05 mL) The reaction was stirred at room temperature 16 h. The reaction was concentrated in vacuo. The crude material was purified by silica gel column chromatography using 0-100% ethyl acetate/hexanes to yield 5 mg (71%) of N-{[4-({[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]amino}methyl)cyclohexyl]methyl}methanesulfonamide. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.82-1.16 (m, 2 H) 1.33-1.75 (m, 6 H) 1.77-2.02 (m, 2 H) 2.84-3.00 (m, 4 H) 3.00-3.16 (m, 1 μl) 3.43-3.80 (m, 2 H) 4.40-4.63 (m, 1 H) 5.89-6.18 (m, 1 H) 7.08-7.60 (m, 8 H) 8.44 (s, 1H), [M+H]+ 559.6.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][NH:4][C:5](=S)[NH:6][C:7]1[CH:12]=[N:11][CH:10]=[C:9]([Cl:13])[N:8]=1.[NH3:17]>>[F:1][C:2]([F:16])([F:15])[CH2:3][N:4]=[C:5]([NH2:17])[NH:6][C:7]1[CH:12]=[N:11][CH:10]=[C:9]([Cl:13])[N:8]=1
Reactant: FC(F)(F)CNC(=S)Nc1cncc(Cl)n1
Reactant: N
Product: NC(=NCC(F)(F)F)Nc1cncc(Cl)n1
Temperature: 25 °C

Procedure:
To a solution of 2-[3-(2,2,2-trifluoroethyl)-thioureido]-6-chloropyrazine (0.7 g.) in alcoholic ammonia (35 ml.) was added red mercuric oxide (0.65 g.) with stirring at room temperature. After stirring overnight, the black mixture was filtered and the black solid washed with alcohol. The resulting yellow filtrate was evaporated to give a yellow solid (0.7 g.). Recrystallisation from hot toluene diluted with petroleum ether (b.p. 60°-80°) yielded colourless needles (0.5 g.) of 2-[2-(2,2,2-trifluoroethyl)guanidino]-6-chloropyrazine m.p. 139°-140°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([F:9])[CH:3]=1.[F:10][C:11]([F:22])([F:21])[C:12]1[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][NH2:20])=[N:16][CH:17]=1>>[F:9][C:4]1[CH:3]=[C:2]([NH:20][CH2:19][CH2:18][C:15]2[CH:14]=[CH:13][C:12]([C:11]([F:22])([F:10])[F:21])=[CH:17][N:16]=2)[CH:7]=[CH:6][C:5]=1[CH3:8]
Reactant: NCCc1ccc(C(F)(F)F)cn1
Reactant: Cc1ccc(Br)cc1F
Product: Cc1ccc(NCCc2ccc(C(F)(F)F)cn2)cc1F

Procedure:
In analogy to the procedure described for the synthesis example 71 (step 1), the title compound (3-fluoro-4-methyl-phenyl)-[2-(5-trifluoromethyl-pyridin-2-yl)-ethyl]-amine (MS m/e: 299.3 [M+H]+) was prepared from 4-bromo-2-fluorotoluene instead of 6-bromo-2,3-dihydro-benzofuran and 2-(5-trifluoromethyl-pyridin-2-yl)-ethylamine instead of 2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine.