Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([S:5]([CH2:8][CH:9]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2]>[OH-].[Na+]>[C:1]([S:5]([CH2:8][C@H:9]([CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:7])=[O:6])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C(Cc1ccccc1)CS(=O)(=O)C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)[C@@H](Cc1ccccc1)CS(=O)(=O)C(C)(C)C
Yield: 36.8 %

Procedure:
54 g of calcium chloride were added to 97 l of tap water to give a 5 mM solution. The solution was thermostatized to 39°-40° C. while stirring. 6.50 kg of molten ethyl (RS)-α-[(tert-butylsulfonyl)methyl]hydrocinnamate (87% GC) were poured slowly into the warm solution while stirring. The pH value of the emulsion was 7.9. The hydrolysis was started by the addition of 300 g of Optimase M 440 and the pH value was held constant at 7.5 by dosing-in 1N sodium hydroxide solution using automatic titration while stirring. After a consumption of 9.6 l of 1N sodium hydroxide solution (after 22.5 hours), 3 g of DICALITE Speedex and 10 l of ethyl acetate were added to the reaction mixture while stirring and the suspension was filtered. The filtrate was subsequently extracted with 40, 30 and 20 l of ethyl acetate (total amount 90 l). For the rapid phase separation, 2, 0.5 and, respectively, 0.2 kg of sodium sulfate (total amount 2.7 kg) were added each time. The three organic phases were dried over magnesium sulfate and evaporated at 1200 Pa/40° C., whereby 2.39 kg of ethyl (R)-α-[(tert-butylsulfonyl)methyl]hydrocinnamate were obtained. The aqueous phase was adjusted to pH 2.2 with 1.5 l of 25% hydrochloric acid and extracted with 25 and 20 l (total amount 45 l) of ethyl acetate. The first phase separation was accelerated by the addition of 0.2 kg of sodium sulfate. The two organic phases were dried over magnesium sulfate and evaporated at 1200 Pa/40° C., whereby there were obtained 2.22 kg (7.716 mol) of (S)-α-[(tert-butylsulfonyl)methyl]hydrocinnamic acid, which had an enantiomeric excess and a gas-chromatographical purity of, in each case, >99%.
Reaction SMILES: [Cl:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:15])[C:6]=2[CH:5]=[C:4]([O:16]C)[CH:3]=1.CN1CCCC1=O.Cl.N1C=CC=CC=1>O>[Cl:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:15])[C:6]=2[CH:5]=[C:4]([OH:16])[CH:3]=1
Reactant: COc1cc(Cl)c2c(c1)C(=O)c1ccccc1-2
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: c1ccncc1
Solvent: O
Product: O=C1c2ccccc2-c2c(Cl)cc(O)cc21
Temperature: 90 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
Under an argon atmosphere, to 4-chloro-2-methoxy-9H-fluoren-9-one (92.0 g) were added N-methylpyrrolidone (120 ml) and pyridine hydrochloride (144 g). The reaction mixture was stirred at an oil bath temperature of 200° C. for 3 hr with removing water by a Dean-Stark apparatus. The reaction mixture was cooled to 90° C., water (600 ml) was added dropwise, and the mixture was stirred at room temperature for 2 hr. The precipitated solid was collected by filtration, and washed with water (400 ml). The obtained solid was air-dried for 3 days, a mixed solvent of hexane and ethyl acetate (hexane:ethyl acetate 1:1, 300 ml) was added, and the mixture was stirred at room temperature for 1 hr. The solid was collected by filtration, and washed with a mixed solvent of hexane and ethyl acetate (hexane:ethyl acetate=1:1, 500 ml). The obtained solid was dried under reduced pressure at 50° C. for 3 hr to give the title compound (48.6 g).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][O:16][C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:3]1.Cl[CH2:44][C:45]1[CH:46]=[C:47]([O:55][CH2:56][O:57][CH2:58][CH2:59][Si:60]([CH3:63])([CH3:62])[CH3:61])[C:48]2[C:53]([CH:54]=1)=[CH:52][CH:51]=[CH:50][CH:49]=2>>[CH3:61][Si:60]([CH3:62])([CH3:63])[CH2:59][CH2:58][O:57][CH2:56][O:55][C:47]1[C:48]2[C:53](=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH:54]=[C:45]([CH2:44][O:1][CH:2]2[CH:7]([C:8]3[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][O:16][C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[CH:10][CH:9]=3)[CH2:6][CH2:5][N:4]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:3]2)[CH:46]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CCOC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)C(O)C1
Reactant: C[Si](C)(C)CCOCOc1cc(CCl)cc2ccccc12
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(CCOC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)C(OCc2cc(OCOCC[Si](C)(C)C)c3ccccc3c2)C1

Procedure:
(α) In an analogous manner to that described in Example 1 (g), by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-[4-(2-trityloxy-ethyl)-phenyl]-piperidine-1-carboxylate [Example 29 (t)] with 3-chloromethyl-1-(2-trimethylsilanyl-ethoxymethoxy)-naphthalene [Example 5 (c)] there was obtained tert-butyl (3RS,4RS)-3-[4-(2-trimethylsilanyl-ethoxymethoxy)-naphthalen-2-ylmethoxy]-4-[4-(2-trityloxy-ethyl)-phenyl]-piperidine-1-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:24]CC3C=CC=CC=3)=[CH:5][C:4]=2[N:3]=1.Cl>C(=O)([O-])[O-].[Na+].[Na+]>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([OH:18])([CH3:19])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([OH:24])=[CH:5][C:4]=2[N:3]=1
Reactant: CCOCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOCc1nc2c(N)nc3cc(O)ccc3c2n1CC(C)(C)O

Procedure:
(4-Amino-7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol was debenzylated using the general method of Example 5. Upon completion of the reaction, the catalyst was removed by filtration through a polytetrafluoroethylene (PTFE) membrane and the filtrate was concentrated under reduced pressure to give a tan solid. The solid was slurried in 1% aqueous sodium carbonate. This formed a gooey slurry. The pH was lowered to 1 with the addition of concentrated hydrochloric acid. When a homogenous solution was formed, the pH was adjusted back to 5 with the addition of 1% aqueous sodium carbonate. A solid precipitated and was collected by filtration. The solid was dried under a stream of air to give 4-amino-2-ethoxymethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-ol as an off-white solid.
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH:12](O)[C:11]3[CH:14]=[C:15]([C:18]([OH:20])=[O:19])[CH:16]=[CH:17][C:10]=3[O:9][CH2:8]2)[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[NH4+]>C(O)(=O)C.S(=O)(=O)(O)O>[N:1]1([CH2:6][C:7]2[CH2:8][O:9][C:10]3[CH:17]=[CH:16][C:15]([C:18]([OH:20])=[O:19])=[CH:14][C:11]=3[CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(O)c1ccc2c(c1)C(O)C(Cn1ccnc1)CO2
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=C(O)c1ccc2c(c1)C=C(Cn1ccnc1)CO2
Yield: 53.5 %

Procedure:
A solution of 3,4-dihydro-3(1H-imidazol-1-ylmethyl)-4-hydroxy-2H-1-benzopyran-6-carboxylic acid (3.0 g) in glacial acetic acid (60 ml) and concentrated sulfuric acid (30 ml) is heated at 80° C. for 3 hours. After cooling, the reaction mixture is poured into crushed ice, neutralized with ammonium hydroxide and extracted with methylene chloride. The organic layer is dried over sodium sulfate and evaporated to dryness. The resulting residue is treated with ethyl ether to give 1.5 g of 3-(1H-imidazol-1-ylmethyl)-2H-1-benzopyran-6-carboxylic acid, m.p. 258°-259°.
Reaction SMILES: [C:1]1([C:7]2[O:8][CH:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:10]([OH:13])[CH2:11][N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1.O>O1CCCC1>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([O:13][CH:10]2[CH:9]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[O:8][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:12][CH2:11]2)=[O:31])=[CH:25][CH:24]=1
Reactant: OC1CN=C(c2ccccc2)OC1c1ccccc1
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)cc1)OC1CN=C(c2ccccc2)OC1c1ccccc1
Reaction time: 0.5 h
Yield: 41 %

Procedure:
A solution of (5RS, 6SR)-2,6-diphenyl-5,6-dihydro-4H-1,3-oxazin-5-ol (1.52 g) in anhydrous tetrahydrofuran (10 cc) is added at a temperature in the region of 20° C. to an oily suspension (50% by weight; 0.31 g), maintained under an argon atmosphere, of sodium hydride in anhydrous tetrahydrofuran (20 cc). The mixture is stirred for 30 minutes at the same temperature. A solution of 4-chlorophenyl isocyanate (1 g) in anhydrous tetrahydrofuran (10 cc) is then added dropwise and stirring is continued for 3 hours at a temperature in the region of 20° C. Distilled water (25 cc) is then added and the mixture is extracted with dichloromethane (3×50 cc). The organic phases are combined, washed with distilled water (3×20 cc), dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The residue is purified by chromatography on silica (0.063-0.2 mm; 50 g) contained in a column 2 cm in diameter [eluent: ethyl acetate/cyclohexane (2:3 by volume)], collecting 20-cc fractions. Fractions 4 to 6 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization in diisopropyl ether, (5RS, 6SR)-5-(4-chlorophenylcarbamoyloxy)-2,6-diphenyl-5,6-dihydro-4H-1,3-oxazine (1 g), m.p. 124° C. is obtained.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[C:9]([OH:11])=[N:10][C:5]2=[N:4][CH:3]=1.[CH3:17][S-:18].[Na+]>CN1CCCC1=O>[CH3:17][S:18][C:2]1[N:7]=[C:6]2[N:8]([CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[C:9]([OH:11])=[N:10][C:5]2=[N:4][CH:3]=1
Reactant: CCC(CC)n1c(O)nc2ncc(Br)nc21
Reactant: C[S-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCC(CC)n1c(O)nc2ncc(SC)nc21

Procedure:
The title compound was prepared by reacting 6-bromo-1-(pentan-3-yl)-1H-imidazo[4,5-b]pyrazin-2-ol (1.0 equiv), sodium thiomethoxide (1.4 equiv), and N-methylpyrrolidone (5.9 volume equivalents) in a manner analagous to Example 1(c). LCMS m/z (APCI)=253.0 (M+H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C@H:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:15][CH:16]=3)[C@@H:11]3[CH2:28][CH2:29][CH2:30][N:10]3[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:31][Si:32]([C:35]#[CH:36])([CH3:34])[CH3:33].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(CC)CC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[N:22]1([CH2:21][CH2:20][CH2:19][O:18][C:14]2[CH:13]=[C:12]3[C:17]([C@H:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([C:36]#[C:35][Si:32]([CH3:34])([CH3:33])[CH3:31])[CH:3]=4)[CH2:9][N:10]4[CH2:30][CH2:29][CH2:28][C@H:11]43)=[CH:16][CH:15]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: C#C[Si](C)(C)C
Reactant: Ic1cccc([C@@H]2CN3CCC[C@H]3c3cc(OCCCN4CCCCC4)ccc32)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1cccc([C@@H]2CN3CCC[C@H]3c3cc(OCCCN4CCCCC4)ccc32)c1
Temperature: 25 °C
Yield: 69.3 %

Procedure:
To a high-pressure reaction vial was added cis-6-(3-iodo-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline (Example 32, 40.0 mg, 0.08 mmol), trimethylsilylacetylene (9.0 mg, 0.093 mmol), Pd(PPh3)2Cl2 (6.0 mg, 0.008 mmol), Cul (2.0 mg, 0.008 mmol), PPh3 (4.0 mg, 0.016 mmol), Et2NH (0.12 mL, 1.2 mmol), and DMF (0.1 mL). The sealed vial was placed in a 120° C. preheated oil bath for 30 min, cooled to rt, concentrated under a stream of nitrogen, and purified by reverse-phase HPLC to give 27.0 mg (47%) of the desired product as a TFA salt. MS: exact mass calcd for C31H42N2OSi, 486.3; m/z found, 487.6 [M+H]+. 1H NMR (acetone-d6): 7.46 (m, 2H), 7.36 (m, 2H), 6.97 (d, J=2.5, 1H), 6.80 (dd, J=2.6, 8.7, 1H), 6.65 (d, J=8.7, 1H), 4.92 (m, 1H), 4.63 (m, 1H), 4.14 (t, J=6.0, 2H), 3.95 (m, 1H), 3.66 (m, 3H), 3.51 (m, 1H), 3.41 (m, 1H), 3.31 (m, 2H), 2.95 (m, 3H), 2.32 (m, 5H), 1.89 (m, 5H), 1.50 (m, 1H), 0.22 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([SH:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31]Cl>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:31][C:30]2[CH:33]=[CH:34][CH:35]=[C:28]([O:27][CH3:26])[CH:29]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1cccc(CCl)c1
Reactant: Nc1nc(S)nc2c1nc(O)n2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(CSc2nc(N)c3nc(O)n(Cc4ccccc4)c3n2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.8 %

Procedure:
Crude 6-amino-9-benzyl-8-hydroxy-2-mercaptopurine (134 mg, 0.49 mmol) was suspended in dimethylformamide (60 ml). To the suspension were added potassium carbonate (100 mg, 0.72 mmol) and 3-methoxybenzyl chloride (0.1 ml, 0.7 mmol) in order. The mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (5% methanol/chloroform) to give the subject compound (94 mg, yield 49%).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:5][C:6]2[C:11]([C:12]=1[C:13]([OH:15])=O)=[CH:10][CH:9]=[CH:8][CH:7]=2.C(N(CC)CC)C.S(Cl)(Cl)=O.[C:33]1([C@@H:39]([NH2:42])[CH2:40][CH3:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CCOC(C)=O.O>[CH3:1][S:2][C:3]1[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:5][C:6]2[C:11]([C:12]=1[C:13]([NH:42][C@H:39]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:40][CH3:41])=[O:15])=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: CSc1c(-c2ccccc2)nc2ccccc2c1C(=O)O
Reactant: CC[C@H](N)c1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC[C@H](NC(=O)c1c(SC)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
To a solution of 3-(methylthio)-2-phenylquinoline-4-carboxylic acid (150 mg, 0.51 mmol) and triethylamine (0.17 mL, 1.22 mmol) in EtOAc (2.5 mL) at 5° C. was added thionyl chloride (0.043 mL, 0.61 mmol). The cooling bath was removed and the suspension allowed to stir for 0.5 h, then (S)-(−)-1-phenylpropylamine (76 mg, 0.56 mmol) was added and reaction allowed to stir for another 0.5 h. Water (2 mL) and EtOAc (2 mL) were then added, the layers shaken together, then separated, the organics dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting material was purified by silica gel chromatography (0-20% EtOAc/CH2Cl2) to give the desired product (150 mg, 70% yield) as a solid. 1H NMR (300 MHz, CDCl3) δ 8.11 (d, J=8.4 Hz, 1H), 7.78-7.67 (m, 4H), 7.55-7.27 (m, 9H), 6.12 (d, J=8.5 Hz, 1H), 5.30 (q, J=7.6 Hz, 1H), 2.16-1.91 (m, 5H), 1.06 (t, J=7.4 Hz, 3H); HRMS m/z 413.1669, calcd 413.1688.
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11](Cl)[CH:10]=2)[N:6]=[C:5]2[CH2:17][CH2:18][CH2:19][C:4]=12.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](N)=[O:29])=[CH:23][CH:22]=1>>[ClH:2].[Cl:15][C:13]1[CH:14]=[C:9]([C:7]2[N:6]=[C:5]3[CH2:17][CH2:18][CH2:19][C:4]3=[C:3]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][OH:29])=[CH:23][CH:22]=3)[CH:8]=2)[CH:10]=[CH:11][C:12]=1[Cl:1]
Reactant: Clc1cc(Cl)cc(-c2cc(Cl)c3c(n2)CCC3)c1
Reactant: NC(=O)Cc1ccc(N)cc1
Agent: Cl
Product: OCCc1ccc(Nc2cc(-c3ccc(Cl)c(Cl)c3)nc3c2CCC3)cc1
Yield: 16.7 %

Procedure:
Following General Procedure A1, 4-chloro-2-(3,5-dichlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride (0.100 g, 0.33 mmol) was reacted with 2-(4-aminophenyl)acetamide (0.060 g, 0.40 mmol), followed by the formation of the hydrochloride salt to afford the title compound (0.024 g, 18%) as a tan solid. MW=448.77. 1H NMR (DMSO-d6, 500 MHz) δ 14.12 (s, 1H), 9.53 (s, 1H), 7.89 (d, J=2.0 Hz, 2H), 7.81 (s, 1H), 7.36 (s, 4H), 7.13 (s, 1H), 3.73 (s, 2H), 3.63 (s, 2H), 3.11 (t, J=7.6 Hz, 2H), 2.91 (t, J=7.6 Hz, 2H), 2.30-2.14 (m, 2H); APCI MS m/z 412 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[NH:11]1[CH:15]=[N:14][CH:13]=[N:12]1.FC1C=CC(C=O)=CC=1OC.N1C=CC=N1>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:11]1[CH:15]=[N:14][CH:13]=[N:12]1)[CH:5]=[O:6]
Reactant: c1nc[nH]n1
Reactant: O=Cc1ccc(F)c(F)c1
Agent: COc1cc(C=O)ccc1F
Agent: c1cn[nH]c1
Product: O=Cc1ccc(-n2cncn2)c(F)c1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 5 by substituting 3,4-difluorobenzaldehyde and 1,2,4-triazole, respectively, for the 4-fluoro-3-methoxybenzaldehyde and pyrazole of Reference Example 5. MS 192 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=3)[C:11]([O:21][CH3:22])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:23](=[O:25])[CH3:24])[CH:15]=3)[C:11]([O:21][CH3:22])=[CH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1cnc(-c2ccc(F)cc2)nc1-c1cccc(O)c1
Agent: O=S(=O)(O)O
Product: COc1cnc(-c2ccc(F)cc2)nc1-c1cccc(OC(C)=O)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 73 %

Procedure:
One drop of 96% sulfuric acid was added to a mixture of 1.2 g of 2-(4-fluorophenyl)-4-(3-hydroxyphenyl)-5-methoxypyrimidine and 0.5 g of acetic anhydride, and the resulting mixture was stirred for 20 hours at room temperature. After completion of the reaction, ice-cold water was added to mixture. Subsequently, the mixture was extracted with ethyl acetate. The solvent was evaporated off, and the residue was purified by column chromatography on silica gel thereby obtaining 1.0 g of 2-(4-fluorophenyl)-4-(3-acetoxyphenyl)-5-methoxypyrimidine (Compound 55).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:12]2[C:7](=[CH:8][C:9]([Cl:14])=[CH:10][C:11]=2[Cl:13])[NH:6][C@@H:5]([C:15]([O:17][CH3:18])=[O:16])[CH2:4]1.C(N(CC)CC)C.[C:26]1([N:32]=[C:33]=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl>[Cl:13][C:11]1[CH:10]=[C:9]([Cl:14])[CH:8]=[C:7]2[C:12]=1[C@@H:3]([NH:2][C:33]([NH:32][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:34])[CH2:4][C@H:5]([C:15]([O:17][CH3:18])=[O:16])[NH:6]2
Reactant: O=C=Nc1ccccc1
Reactant: COC(=O)[C@H]1C[C@H](N)c2c(Cl)cc(Cl)cc2N1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1C[C@H](NC(=O)Nc2ccccc2)c2c(Cl)cc(Cl)cc2N1
Yield: 73.1 %

Procedure:
To a suspension of trans-4-amino-5,7-dichloro-2-methoxycarbonyl-1,2,3,4-tetrahydroquinoline hydrochloride (0.200 g, 0.642 mmol) in anhydrous dichloromethane (20 ml) under an atmosphere of nitrogen was added dry triethylamine (0.098 ml, 0.706 mmol) and the mixture was stirred until dissolution was complete. To this solution was then added phenyl isocyanate (0.077 ml, 0.706 mmol) and the resulting mixture was stirred at room temperature for 2 h. The solvent was removed under vacuum and the residue was partitioned between ethyl acetate (150 ml) and 1M aqueous citric acid (75 ml). The organic layer was successively washed with 1M aqueous citric acid (1×75 ml), saturated sodium bicarbonate solution (2×75 ml) and saturated brine (1×75 ml), then dried (MgSO4) and evaporated. The crude product was recrystallised from methanol to give the title compound as colourless crystals (0.185 g), m.p. 228°-229° C. (dec). δ (DMSO, 360 MHz) 1.67 (1H, ddd, J=12.7, 12.4 and 3.5 Hz, CHACHBHCCHD), 2.34 (1H, dm, J=12.7 Hz, CHACHBHCCHD), 3.73 (3H, s, CO2CH3), 4.00 (1H, dd, J=12.4 and 2.9 Hz, CH ACHBHCCHD), 4.94 (1H, m, CHACHBHCCHDNHCO), 6.53 (1H, d, J=6.4 Hz, CHDNHCONAr), 6.72 (1H, d, J=2.0 Hz, 6-H or 8-H), 6.88-6.93 (3H, m, 6-H or 8-H, ArH and ArNH), 7.20-7.25 (2H, m, ArH) 7.39 (2H, d, J=8.0 Hz, ArH), 8.15 (1H, s, CHDNHCONHAr); m/e 393 (M+), 198 (100%, M-NHCONHPh, CO2CH3 and H); Found C, 54.76; H, 4.39; N, 10.48; C18H17Cl2N3O3 requires C, 54.84; H, 4.35; N, 10.66%.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.C([Li])CCC.[CH2:13]([O:16][C:17]([N:19]1[CH2:23][C@H:22]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:21][C@H:20]1[CH:32]=[O:33])=[O:18])[CH:14]=[CH2:15].Cl>O1CCCC1.C(OCC)C.CCCCCC.C(OCC)(=O)C.O>[CH2:13]([O:16][C:17]([N:19]1[CH2:23][C@H:22]([O:24][Si:25]([C:28]([CH3:30])([CH3:29])[CH3:31])([CH3:26])[CH3:27])[CH2:21][C@H:20]1[CH:32]([C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1)[OH:33])=[O:18])[CH:14]=[CH2:15]
Reactant: Brc1cncnc1
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(O)c1cncnc1
Temperature: 0 °C
Yield: 66.6 %

Procedure:
Under nitrogen atmosphere to a solution of 5-bromopyrimidine (18.3 g) in tetrahydrofuran (360 ml) and diethyl ether (360 ml) was slowly dropped 1.56 mol/l n-butyllithium in hexane solution (73.6 ml) at -90° C. to -95° C. The reaction mixture was stirred at the same temperature for an hour, and then the solution of (2S,4R)-1-allyloxycarbonyl-4-(t-butyldimethylsilyloxy)-2-formylpyrrolidine (30.0 g) in tetrahydrofuran (60 ml) and ether (60 ml) was dropped into the reaction mixture below -85° C. The reaction mixture was stirred at -50° C. for an hour, then water (150 ml) was dropped thereto below -10° C. The reaction mixture was poured into ethyl acetate (500 ml) and ice-water (300 ml) and adjusted to pH 7.0 with concentrated hydrochloric acid. Insoluble material was removed by filtration and washed with ethyl acetate (200 ml). The organic layer was separated, washed with water (300 ml) and brine (300 ml), and then dried over magnesium sulfate, and evaporated. The residue was subjected to column chromatography on silica gel (360 g) [solvent; hexane:ethyl acetate=4:1 to 2:1 to 1:3] to give 1-{(2S,4R)-1-allyloxycarbonyl-4-(t-butyldimethyl-silyloxy) pyrrolidin-2-yl}-1-(pyrimidin-5-yl)methanol (25.1 g) as an oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N-:4][C:5](=O)[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1.B.[Na].C(O)(=O)C.Cl>O1CCCC1.O>[OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=1
Reactant: O=C(CCc1ccc([N+](=O)[O-])cc1)[N-]CCO
Agent: B
Agent: Cl
Agent: [Na]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(CCCNCCO)cc1
Reaction time: 1 h

Procedure:
50 g of the previously obtained N-(2-hydroxyethyl)-3-(4-nitrophenyl)propionylamide and 31.8 g of sodium boron hydride were suspended in 500 ml of tetrahydrofuran, and 50.5 g of acetic acid was added dropwise thereto under ice cooling conditions. After completion of the addition, the solution was heated under reflux for 2 hours and then ice-cooled again, and 500 ml of water was added dropwise thereto. Afterward, 4N hydrochloric acid was added to the solution so as to adjust its pH to a level of from 5 to 6, and tetrahydrofuran was then distilled off under reduced pressure. Next, 425 ml of 4N hydrochloric acid was added to the resultant aqueous solution, and the solution was stirred at 60°-70° C. for 1 hour and then allowed to stand for cooling, so that the temperature of the solution was returned to room temperature. After washed with chloroform, the aqueous solution was adjusted to a pH of 11 by the use of a 16% aqueous sodium hydroxide solution, and extraction was carried out twice with 500 ml of chloroform. The chloroform extracts were joined and concentrated under reduced pressure, and the resultant residue was crystallized from 900 ml of toluene to obtain 38.6 g of crystalline N-(2-hydroxyethyl)-3-(4-nitrophenyl)propylamine, which had a melting point of from 82.5° to 84.5° C.