Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:14]([CH2:17][S:18][C:19]3[NH:20][CH:21]=[C:22]([CH2:26][CH3:27])[C:23](=[O:25])[N:24]=3)=[CH:13][C:10]=2[C:11]#[N:12])=[CH:4][C:3]=1[C:28]([F:31])([F:30])[F:29].[CH3:32]CN(C(C)C)C(C)C.CI>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:14]([CH2:17][S:18][C:19]3[N:20]([CH3:32])[CH:21]=[C:22]([CH2:26][CH3:27])[C:23](=[O:25])[N:24]=3)=[CH:13][C:10]=2[C:11]#[N:12])=[CH:4][C:3]=1[C:28]([F:30])([F:29])[F:31]
Reactant: CCc1c[nH]c(SCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)c(C#N)c2)nc1=O
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CI
Product: CCc1cn(C)c(SCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)c(C#N)c2)nc1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.3 %

Procedure:
To a suspension of 2-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-5-{[(5-ethyl-4-oxo-1,4-dihydro-2-pyrimidinyl)thio]methyl}benzonitrile (120 mg, 0.258 mmol) and DIPEA (0.090 ml, 0.515 mmol) in DCM (2 mL) was added MeI (0.02416 ml, 0.386 mmol). The mixture was stirred at room temperature for 2 h. The reaction was then quenched with water, extracted with EA. The combined organic layers were dried with Na2SO4, filtered, concentrated and purified via reverse phase flash chromatography to afford the title compound (40 mg, 32.4% yield). LCMS: rt=3.44 min, [M+H+]=480
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:21]2[S:25][C:24]3[CH:26]=[CH:27][CH:28]=[C:29]([C:30](=[O:35])[NH:31][CH:32]4[CH2:34][CH2:33]4)[C:23]=3[CH:22]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[O:14])=[N:6][CH:7]=1.C=O.[C:38](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CO>[Cl:1][C:2]1[C:3]([C:21]2[S:25][C:24]3[CH:26]=[CH:27][CH:28]=[C:29]([C:30](=[O:35])[NH:31][CH:32]4[CH2:34][CH2:33]4)[C:23]=3[CH:22]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]([CH:15]2[CH2:16][CH2:17][N:18]([CH3:38])[CH2:19][CH2:20]2)=[O:14])=[N:6][CH:7]=1
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(NCCCNC(=O)C4CCNCC4)ncc3Cl)cc12
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCCl
Product: CN1CCC(C(=O)NCCCNc2ncc(Cl)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CC1
Yield: 16.9 %

Procedure:
A stirred suspension of piperidine-4-carboxylic acid {3-[5-chloro-4-(4-cyclopropylcarbamoylbenzo[b]thiophen-2-yl)-pyrimidin-2-ylamino]-propyl}-amide (231 mg, 0.450 mmol) in 1,2-dichloroethane (3 mL) and methanol (3 mL) is treated at room temperature with aqueous 37% formaldehyde (0.200 mL, 3.02 mmol) in the presence of sodium triacetoxyborohydride (165 mg, 0.779 mmol) for 24 hours. The mixture is then concentrated under reduced pressure, and subjected to chromatographic purification on silica gel, eluting with 2 M NH3/MeOH in dichloromethane: 8-15%, to provide the title compound (40 mg, 17% yield). ES+(m/z) 527 (35Cl) and 529 (37Cl) [M+H].
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([OH:10])=[O:9].O[CH2:26][C:27]1[O:28][C:29]2[CH:35]=[C:34]([CH2:36][C:37]3[NH:38][CH:39]=[CH:40][N:41]=3)[CH:33]=[CH:32][C:30]=2[N:31]=1.C1(N=C=NC2CCCCC2)CCCCC1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([O:10][CH2:26][C:27]1[O:28][C:29]2[CH:35]=[C:34]([CH2:36][C:37]3[NH:41][CH:40]=[CH:39][N:38]=3)[CH:33]=[CH:32][C:30]=2[N:31]=1)=[O:9]
Reactant: OCc1nc2ccc(Cc3ncc[nH]3)cc2o1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCc2nc3ccc(Cc4ncc[nH]4)cc3o2)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
332 mg (1 mM) of 1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carboxylic acid together with 229 mg (1 mM) of 2-hydroxymethyl-6-(1-imidazolylmethyl)benzoxazole 248 mg (1.2 mM) of dicyclohexylcarbodiimide and 134 mg (1.1 mM) of 4-N,N-dimethylaminopyridine were dissolved in 5 ml of toluene, while heating, and refluxed for six hours. The solution was cooled to room temperature, and the crystals produced were filtered off. The filtrate was washed with water and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by chromatography on a silica gel column, whereby the captioned compound was obtained. The yield was 542 mg (99.9%).
Reaction SMILES: BrC1C=C2C(=CC=1OCCCCC)C(C)(C)CCC2(C)C.C([Li])(C)(C)C.C(=O)=O.[CH2:30]([O:35][C:36]1[C:37]([C:50]([OH:52])=[O:51])=[CH:38][C:39]2[C:40]([CH3:49])([CH3:48])[CH2:41][CH2:42][C:43]([CH3:47])([CH3:46])[C:44]=2[CH:45]=1)[CH2:31][CH2:32][CH2:33][CH3:34].O[C:54]1[CH:69]=[CH:68][C:57]([C:58]([O:60][CH2:61][C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)=[O:59])=[CH:56][N:55]=1>>[CH2:30]([O:35][C:36]1[C:37]([C:50]([O:52][C:54]2[CH:69]=[CH:68][C:57]([C:58]([O:60][CH2:61][C:62]3[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=3)=[O:59])=[CH:56][N:55]=2)=[O:51])=[CH:38][C:39]2[C:40]([CH3:49])([CH3:48])[CH2:41][CH2:42][C:43]([CH3:46])([CH3:47])[C:44]=2[CH:45]=1)[CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCOc1cc2c(cc1C(=O)O)C(C)(C)CCC2(C)C
Reactant: O=C(OCc1ccccc1)c1ccc(O)nc1
Agent: CCCCCOc1cc2c(cc1Br)C(C)(C)CCC2(C)C
Agent: O=C=O
Agent: [Li]C(C)(C)C
Product: CCCCCOc1cc2c(cc1C(=O)Oc1ccc(C(=O)OCc3ccccc3)cn1)C(C)(C)CCC2(C)C

Procedure:
In analogy to Example 1, by metallating 6-bromo-7-pentoxy-1,1,4,4-tetramethyl-1,2,3,4-tetrahydro-naphthalene with tert.butyl-lithium and reacting with carbon dioxide gas there was prepared 3-pentoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid (m.p. 67°-68° C., from hexane). Reaction of this acid with benzyl 6-hydroxy-nicotinate gave benzyl 6-(3-pentoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-carbonyloxy)-nicotinate as a colorless oil. Subsequent hydrogenation yielded the desired end product 6-(3-pentoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl-carbonyloxy)-nicotinic acid in white crystals, m.p. 132°-133° C. (from diethyl ether/hexane).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:15](O)=[O:16])[CH:5]=[CH:4][C:3]1=2.CC(C)(C)C(Cl)=O.[Cl-].[Li+].[CH3:33][CH:34]([C@@H:36]1[C:40]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[O:39][C:38](=[O:53])[NH:37]1)[CH3:35]>C1COCC1.C(N(CC)CC)C>[CH3:35][CH:34]([C@@H:36]1[C:40]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[O:39][C:38](=[O:53])[N:37]1[C:15](=[O:16])[C@@H:14]([C:6]1[CH:5]=[CH:4][C:3]2[C:2]([CH3:23])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]=2[CH:7]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH3:33]
Reactant: CCCCCC(C(=O)O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: CC(C)[C@H]1NC(=O)OC1(c1ccccc1)c1ccccc1
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCC[C@@H](C(=O)N1C(=O)OC(c2ccccc2)(c2ccccc2)[C@H]1C(C)C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: -30 °C
Reaction time: 2 h
Yield: 89.3 %

Procedure:
2.0 g of (RS)-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-heptanoic acid were dissolved in 30 ml of THF and cooled to −30° C. To the cooled mixture, were added successively, 2.3 ml of triethylamine and 780 μl of trimethylacetyl chloride. The mixture was kept at −30° C. for two hours. 308 mg of lithium chloride were added followed by 978 mg of (R)-4-(1-methylethyl)-5,5-diphenyloxazolidin-2-one (Hintermann T., Seebach D., Helv. Chim. Acta, 1998, 81, 2093). The mixture was allowed to warm to room temperature and was kept at that temperature for 18 hours. The reaction mixture was quenched by the addition of one portion of 30 ml of a saturated aqueous ammonium chloride solution. The resulting mixture was extracted with three portions of 30 ml of ether. The combined organic extracts were washed with two portions of 30 ml of 1N hydrochloric solution, one portion of 30 ml of water and one portion of 30 ml of saturated aqueous sodium chloride solution. The organic phase was dried over MgSO4 and the solvent evaporated. The residual yellow oil was purified by flash chromatography (SiO2, 3% ethyl acetate/hexanes to 20% ethyl acetate/hexanes, dry pack), yielding 1.8 g of the titled compound and 0.8 g of the starting acid, 1H NMR (CDCl3): 7.40-7.20 (m, 6H), 7.15-6.95 (m, 6H), 6.77 (dd, J=8.2, 2.0 Hz, 1H), 5.26 (d, J=3.4 Hz, 1H), 4.92 (dd, J=8.8, 6.2 Hz, 1H), 2.15 (m, 1H), 1.97 (m, 1H), 1.70 (m, 1H), 1.58 (br. s, 4H), 1.35-1.25 (m, 6H), 1.23 (s, 3H), 1.20 (s, 3H), 1.17 (s, 3H), 1.03 (s, 3H), 0.92 (d, J=7.0 Hz, 3H), 0.85 (t, J=6.8 Hz, 3H), 0.80 (d, J=6.8 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:27])=[C:6]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:17]=3[CH:18]=[CH:19][C:20]([CH3:26])=[N:21]4)[CH2:12][CH2:11]2)[CH:7]=1.[C:28]([NH2:31])(=[O:30])[CH3:29]>>[F:27][C:5]1[CH:4]=[CH:3][C:2]([NH:31][C:28](=[O:30])[CH3:29])=[CH:7][C:6]=1[CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[CH:18]=[CH:19][C:20]([CH3:26])=[N:21]3)[CH2:12][CH2:11]1
Reactant: Cc1ccc2c(N3CCN(CCc4cc(Br)ccc4F)CC3)cccc2n1
Reactant: CC(N)=O
Product: CC(=O)Nc1ccc(F)c(CCN2CCN(c3cccc4nc(C)ccc34)CC2)c1
Yield: 66 %

Procedure:
The title compound was prepared in 66% yield according to the general procedure for the preparation of the amides, ureas and carbamates (Method A) starting from 5-{4-[2-(5-bromo-2-fluorophenyl)ethyl]-1-piperazinyl}-2-methylquinoline and acetamide.
Reaction SMILES: [F:1][C:2]([F:35])([CH2:23]OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=2)[CH:6]=[C:5]1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[N-:36]=[N+:37]=[N-:38].[Na+].O>CN(C=O)C>[N:36]([CH2:23][C:2]([F:35])([F:1])[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=2)[CH:6]=[C:5]1[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N+:37]=[N-:38]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)n(CC(F)(F)COS(=O)(=O)c3ccc(C)cc3)c2c1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2cc(C(=O)OCC)n(CC(F)(F)CN=[N+]=[N-])c2c1
Temperature: 95 °C
Yield: 119.5 %

Procedure:
To a solution of diethyl 1-(2,2-difluoro-3-{[(4-methylphenyl)sulfonyl]oxy}propyl)-1H-indole-2,6-dicarboxylate (4.7 g, 59% pure, 5.5 mmol) in DMF (40 mL) is added sodium azide (908 mg, 13.8 mmol). The mixture is heated at 95° C. for 40 h. Water (250 mL) is added and the mixture is extracted with EtOAc (3×250 mL). The organic layers are combined, washed with water (3×250 mL), dried (Na2SO4) and concentrated to afford the title crude compound (2.5 g) which is used in the next step without purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH2:11].S([O-])([O-])(=O)=O.[Na+].[Na+]>[Ag]=O>[CH3:10][O:9][C:5]1[C:6](=[NH:8])[CH:7]=[C:2]([CH3:1])[C:3](=[NH:11])[CH:4]=1
Reactant: COc1cc(N)c(C)cc1N
Agent: O=[Ag]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: COC1=CC(=N)C(C)=CC1=N
Reaction time: 2 h
Yield: 69 %

Procedure:
0.056 mole (8.56 g) 2-methyl-5-methoxy paraphenylenediamine is introduced into 850 cc isopropyl anhydrous ether to which there have been added 0.085 mole (19.7 g) silver oxide and 55 g anhydrous sodium sulfate. The mixture is agitated for two hours, maintaining the temperature thereof between 30° and 40°. After cooling, the sodium sulfate and silver are separated from the reaction mixture by filtration, and the resulting filtrate is evaporated to dryness under vacuum. The dry residue, after recrystallization from a mixture of benzene-hexane, furnishes 5.8 g 2-methoxy-5-methyl benzoquinone diimine, which has a melting point of 96°.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([CH3:15])([CH3:14])[CH2:9][CH2:8][C:7]2([CH3:17])[CH3:16])(=[O:3])[CH3:2].[CH:18]([C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1)=O>[OH-].[Na+].CO>[C:24]([C:23]1[CH:28]=[CH:29][C:20]([CH:18]=[CH:2][C:1]([C:4]2[CH:13]=[CH:12][C:11]3[C:10]([CH3:15])([CH3:14])[CH2:9][CH2:8][C:7]([CH3:17])([CH3:16])[C:6]=3[CH:5]=2)=[O:3])=[CH:21][CH:22]=1)([O:26][CH3:27])=[O:25]
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1ccc(C=CC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.4 %

Procedure:
138 g (0.6 mole) of 6-acetyl-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene and 98.5 g (0.6 mole) of methyl 4-formylbenzoate in a mixture of 16 g of sodium hydroxide and 690 ml of methanol were stirred for 16 hours at room temperature. The precipitated crystals were filtered off under suction and dried to give 132 g of 3-(4-carbomethoxyphenyl)-1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-prop-2-en-1-one of melting point 89°-91° C.
Reaction SMILES: [CH:1]1([OH:5])[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](Br)[N:10]=1>C1(C)C=CC=CC=1>[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)[N:10]=1
Reactant: OC1CCC1
Reactant: Brc1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1cccc(OC2CCC2)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Cyclobutanol (0.470 mL, 6 mmol) was dissolved in toluene (2 mL) and sodium hydride (60% in mineral oil, 0.240 g, 6 mmol) was added. The reaction was stirred at room temperature for 10 minutes then 2,6-dibromo-pyridine (0.710 g, 3 mmol) was added. The reaction was heated to 110° C. for 16 hours then cooled to room temperature, filtered through Celite, and purified on silica gel (0-5% EtOAc in hexanes) to give the title compound.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[S:8][CH:9]=[CH:10][N:11]=1.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]1([CH3:23])[CH2:22][O:21]1.O>CCCCCC.O1CCCC1>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]([OH:21])([CH3:22])[CH2:23][C:9]1[S:8][C:7]([Cl:6])=[N:11][CH:10]=1
Reactant: Clc1nccs1
Reactant: CC1(c2ccc(Cl)cc2Cl)CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CC(O)(Cc1cnc(Cl)s1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76.3 %

Procedure:
Butyl lithium (2.5 M, 12.5 ml) in hexane was added to a solution of 2-chlorothiazole (3.6 g, 30 mmol) in tetrahydrofuran (100 ml) at -78° C. under an atmosphere of nitrogen. After 10 minutes, a solution of 2-(2,4-dichlorophenyl)-2-methyloxirane (5.4 g, 26 mmol) in tetrahydrofuran (40 ml) was added and the mixture was slowly allowed to warm to room temperature and then stirred for a further 3 hours. Water was added and the tetrahydrofuran was then evaporated under reduced pressure. The residue was extracted with ethyl acetate (2×300 ml) and the combined organic extract was washed with saturated sodium chloride solution and then dried. Flash chromatography of the residue on a silica gel column using ethyl acetate-petroleum ether as eluant gave 2-(2,4-dichlorophenyl)-1-(2-chlorothiazol-5-yl)-propan-2-ol (6.4 g) as a white solid, m.pt. 164° C.
Reaction SMILES: C(N(CC)CC)C.FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:28]=[CH:27][CH:26]=[CH:25][C:17]=1[O:18][CH2:19][C@H:20]1[CH2:24][CH2:23][CH2:22][NH:21]1.[NH2:29][C:30]1[N:38]=[C:37]2[C:33]([N:34]=[CH:35][NH:36]2)=[C:32](Cl)[N:31]=1>C(O)CCC>[NH2:29][C:30]1[N:38]=[C:37]2[C:33]([N:34]=[CH:35][NH:36]2)=[C:32]([N:21]2[CH2:22][CH2:23][CH2:24][C@@H:20]2[CH2:19][O:18][C:17]2[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=2[Cl:15])[N:31]=1
Reactant: Nc1nc(Cl)c2nc[nH]c2n1
Reactant: Clc1ccccc1OC[C@H]1CCCN1
Solvent: CCCCO
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: Nc1nc(N2CCC[C@@H]2COc2ccccc2Cl)c2nc[nH]c2n1
Reaction time: 2.5 h
Yield: 57.2 %

Procedure:
7.1 93.84 μl of triethylamine are added dropwise to a mixture of 75 mg of (R)-2-(2-chlorophenoxymethyl)pyrrolidine trifluoroacetate and 39.5 mg of 2-amino-6-chloro-9H-purine in 1 ml of n-butanol. The reaction mixture is stirred at 100° for 2.5 hours. The mixture is cooled, the deposited precipitate is separated off, and the filtrate is chromatographed directly on a 12 g RP18 column. The isolated product fractions are subjected to conventional purification, giving 45.4 mg of 2-amino-6-[(R)-2-(2-chlorophenoxymethyl)-pyrrolidin-1-yl]-9H-purine (“A36”); HPLC retention time 2.77 minutes; gradient P2; [M+H]+ 345.
Reaction SMILES: Cl[C:2](=[O:7])[C:3]([O:5][CH3:6])=[O:4].[Br:8][C:9]1[CH:24]=[CH:23][C:12]([NH:13][CH2:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[CH:16]=2)=[CH:11][CH:10]=1.C(N(CC)CC)C.ClCCl>O>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([N:13]([CH2:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[CH:16]=2)[C:2](=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[CH:23][CH:24]=1
Reactant: Cc1cc(C)cc(CNc2ccc(Br)cc2)c1
Reactant: COC(=O)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)C(=O)N(Cc1cc(C)cc(C)c1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
Methyl chloroglyoxylate (0.566 ml, 6.16 mmol) was added dropwise to a mixture of 4-bromo-N-(3,5-dimethylbenzyl)aniline (1.49 g, 5.13 mmol), triethylamine (1.08 ml, 7.70 mmol) and dichloromethane (20 ml) at 0°, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=3:1) to give the title compound (1.66 g, 86%) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]([NH2:26])=[N:11][C:12](=[O:25])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20](OC)[CH:21]=3)[NH:16][CH:15]=2)[CH:5]=[C:4]([Cl:27])[C:3]=1[NH:28][C:29](=[O:31])[CH3:30].[F:32]C1C=C2C(C(CC(O)=O)=CN2)=CC=1.C(NC1C(Cl)=CC(CN)=CC=1Cl)(=O)C>>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]([NH2:26])=[N:11][C:12](=[O:25])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][C:19]([F:32])=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH:5]=[C:4]([Cl:27])[C:3]=1[NH:28][C:29](=[O:31])[CH3:30]
Reactant: COc1ccc2[nH]cc(CC(=O)N=C(N)NCc3cc(Cl)c(NC(C)=O)c(Cl)c3)c2c1
Reactant: O=C(O)Cc1c[nH]c2cc(F)ccc12
Agent: CC(=O)Nc1c(Cl)cc(CN)cc1Cl
Product: CC(=O)Nc1c(Cl)cc(CNC(N)=NC(=O)Cc2c[nH]c3cc(F)ccc23)cc1Cl

Procedure:
In a manner similar to that used in the preparation of the compound of example 2, but using 2-(6-fluoro-1H-indol-3-yl)acetic acid in step 16 (A) and 4-acetamido-3,5-dichloro-benzylamine (preparation B) in step 16 (B), the title compound was prepared. MS (ESI) (M+H)+=450.08 1H-NMR(500 MHz, CD3OD) δ 7.52 (dd, J=8.55, 5.19 Hz, 1 H), 7.42 (s, 2 H), 7.28 (s, 1 H), 7.09 (dd, J=9.77, 2.14 Hz, 1 H), 6.77-6.95 (m, 1 H), 4.50 (s, 2 H), 3.95 (s, 2 H), 2.19 (s, 3 H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:17][CH3:18])[C:11]=2[CH:15]=O)[CH:6]=1)=[O:4].[F:19][C:20]([F:31])([F:30])[O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1.CC(O)=O.C([BH3-])#N.[Na+]>CCO>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:17][CH3:18])[C:11]=2[CH2:15][NH:27][CH2:26][C:25]2[CH:28]=[CH:29][C:22]([O:21][C:20]([F:19])([F:30])[F:31])=[CH:23][CH:24]=2)[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(C=O)c(OC)ccc2c1
Reactant: NCc1ccc(OC(F)(F)F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(CNCc3ccc(OC(F)(F)F)cc3)c(OC)ccc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.7 %

Procedure:
To a stirred solution of 6-methoxy-5-formyl-2-naphthoic acid methyl ester (1.09 g, 4.46 mmol) in EtOH (40 mL) at room temperature was added 4-trifluoromethoxy-benzyl amine (0.749 mL, 4.91 mmol) followed by HOAc (0.255 mL, 4.46 mmol). After 10 min. at this temperature, sodium cyanoborohydride (0.420 g, 6.69 mmol) was added, and reaction was continued stirring at rt for 4 h. After 1 h at this temperature, the reaction was heated to 45° C. for 2 h. The solution was quenched with sat. aq. NaHCO3 (20 mL) and then extracted with EtOAc (200 mL). The organic layer was washed with brine (20 mL) and dried (MgSO4). After concentration, the residue was purified by flash chromatography (0 to 10% MeOH:CHCl3 gradient) to afford the product (0.780 g, 42%) as a solid; 1H NMR (DMSO-d6) δ3.77 (s, 2H), 3.86 (s, 3H), 3.88 (s, 3H), 4.07 (s, 2H), 7.26 (d, J =8.0 Hz, 2H), 7.44 (d, J=8.6 Hz, 2H), 7.48 (d, J=9.2 Hz, 1H), 7.88 (dd, J=1.9, 8.9 Hz, 1H), 8.06 (d, J=5.2 Hz, 1H), 8.08 (d, J=5.3 Hz, 1H), 8.52 (d, J=1.7 Hz, 1H); mass spectrum [(+) El], m/z 420 (M+H)+.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[OH:13][C@H:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C@@H:15]1[O:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[C:32](=[O:33])[C:31]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([C:41]4[C:42]([C:47]#[N:48])=[CH:43][CH:44]=[CH:45][CH:46]=4)=[CH:37][CH:36]=3)=[C:30]([CH2:49][CH2:50][CH3:51])[N:29]=[C:28]2[CH3:52])=[CH:23][CH:22]=1>O.C(OCC)(=O)C>[OH:13][C@H:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C@@H:15]1[O:20][C:21]1[CH:22]=[CH:23][C:24]([N:27]2[C:32](=[O:33])[C:31]([CH2:34][C:35]3[CH:36]=[CH:37][C:38]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=4[C:47]4[NH:3][C:4](=[O:7])[O:5][N:48]=4)=[CH:39][CH:40]=3)=[C:30]([CH2:49][CH2:50][CH3:51])[N:29]=[C:28]2[CH3:52])=[CH:25][CH:26]=1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCc1nc(C)n(-c2ccc(O[C@H]3CCCC[C@@H]3O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc(O[C@H]3CCCC[C@@H]3O)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 7.4 %

Procedure:
A mixture of hydroxylammonium chloride (1.46 g), sodium hydrogen carbonate (2.21 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[1-(4-{[(1S,2S)-2-hydroxycyclohexyl]oxy}phenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.94 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.34 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.31 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.077 g, 45%).