Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[CH3:19][O:20][C:21]([C:23]1([C:26](O)=[O:27])[CH2:25][CH2:24]1)=[O:22].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(#N)C>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:26]([C:23]2([C:21]([O:20][CH3:19])=[O:22])[CH2:25][CH2:24]2)=[O:27])[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Reactant: COC(=O)C1(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)C1(C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.9 %

Procedure:
A suspension of 1-(2-tert-butylphenyl)piperazine dihydrochloride (Reference Example 1, 0.500 g, 1.72 mmol), 1-(methoxycarbonyl)cyclopropanecarboxylic acid (0.297 g, 2.06 mmol), EDCI (0.395 g, 2.06 mmol), HOBt (0.278 g, 2.06 mmol) and triethylamine (719 μl, 5.16 mmol) in acetonitrile (10 mL) was stirred at room temperature for 16 h. The reaction mixture was poured into saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated sodium hydrogen carbonate solution and brine, dried over MgSO4, and the solvent was evaporated under reduced pressure to give the crude product. The product was purified by flash column chromatography (silica gel, n-hexane/ethyl acetate=90:10 to 65:35) to provide methyl 1-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}cyclopropanecarboxylate (0.485 g, 82%) as a white solid.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH:19]=[C:20]2[CH2:28][S:29]/[CH:30]=[CH:31]/[CH2:32][C:33]([O:36][Si](CC)(CC)CC)([CH3:35])[CH3:34])[CH2:12][C@@H:11]([O:44][Si](C(C)(C)C)(C)C)[CH2:10]1)(C(C)(C)C)(C)C.O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[OH:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH:19]=[C:20]2[CH2:28][S:29]/[CH:30]=[CH:31]/[CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])[CH2:12][C@@H:11]([OH:44])[CH2:10]1
Reactant: CC[Si](CC)(CC)OC(C)(C)C/C=C/SCC1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(O)C/C=C/SCC1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 99.7 %

Procedure:
1α,3β-Bis(tert-butyldimethylsilyloxy)-17-{4-triethylsilyloxy-4-methyl-(2E)-pentenylthiomethyl}androsta-5,7,16-triene (115 mg, 0.149 mmol) and a 1M tetra-n-butylammonium fluoride tetrahydrofuran solution (4 ml) were subjected to reaction using a procedure similar to that of Example 5(2) (3 hours), worked up and purified by column chromatography (ethyl acetate) to give the titled compound (64 mg, 100%) as a pale yellow foam.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH:10][C:11]([NH:13][C@H:14]([C:25]([O:27]C)=[O:26])[CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1)=[O:12].[OH-].[Na+:32]>CO>[F:30][C:2]([F:1])([F:29])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH:10][C:11]([NH:13][C@H:14]([C:25]([O-:27])=[O:26])[CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1)=[O:12].[Na+:32]
Reactant: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C=Cc1ccccc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(C=Cc1ccccc1C(F)(F)F)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)[O-]
Yield: 46 %

Procedure:
The same procedures as in Example 60 were carried out from the compound obtained in Example 10 (3.4 g), 1 mol/L of an aqueous sodium hydroxide solution (12 mL), and methanol (120 mL), to give the captioned compound (1.6 g, 46%) as crystals.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH:16]1[CH2:25][CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:26][CH3:27])[CH:22]=2)[C:17]1=[O:28].Cl>CN(C=O)C>[CH3:3][C:4]([CH:16]1[CH2:25][CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:26][CH3:27])[CH:22]=2)[C:17]1=[O:28])([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: COc1ccc2c(c1)CCC(Br)C2=O
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C(=O)OCC)C1CCc2cc(OC)ccc2C1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
To 6 L of ice cold DMF was added 183 grams of NaH; the mixture stirred and a solution of 811.2 grams diethyl methylmalonate in 1.5 L DMF was added dropwise. The temp was kept at 0-5° C. for 2 hrs, and then cooled below −3° C., and 650 grams bromo-6-methoxy-3,4-dihydronaphthalen-1(2H)-one was added. The reaction was followed by HPLC until the starting material disappeared. The mixture was poured onto ice water, adjusted to pH 4-5 with HCl, and extracted with ethyl acetate. The organic layer was washed with brine, dried, decolorized and concentrated. To the residue was added ether, the mixture cooled, filtered, and the residue washed with petroleum ether to get 745 g of diethyl 2-methyl-2-(6-methoxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)malonate, M=348.2, purity 96.57%.
Reaction SMILES: Cl.[CH3:2][C:3]1[O:4][C:5]2[C:14]3[CH:13]([CH2:15][CH2:16][NH2:17])[CH2:12][CH2:11][C:10]=3[CH:9]=[CH:8][C:6]=2[N:7]=1.C(N(CC)CC)C.[C:25]([O:28][CH:29]([CH3:33])[C:30](Cl)=[O:31])(=[O:27])[CH3:26]>O1CCCC1>[C:25]([O:28][CH:29]([CH3:33])[C:30]([NH:17][CH2:16][CH2:15][CH:13]1[C:14]2[C:5]3[O:4][C:3]([CH3:2])=[N:7][C:6]=3[CH:8]=[CH:9][C:10]=2[CH2:11][CH2:12]1)=[O:31])(=[O:27])[CH3:26]
Reactant: Cc1nc2ccc3c(c2o1)C(CCN)CC3
Reactant: CC(=O)OC(C)C(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)OC(C)C(=O)NCCC1CCc2ccc3nc(C)oc3c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
2-(2-Methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethanamine hydrochloride (150 mg, 0.593 mmol) and triethylamine (166 μL, 1.19 mmol) were dissolved in tetrahydrofuran (5 mL), 2-chloro-1-methyl-2-oxoethyl acetate (108 mg, 0.712 mmol) was added, and the mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=70/30→100/0) to give the title compound (78.4 mg, yield 40%).
Reaction SMILES: C[O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][NH:8][C:9]2=[O:12])=[CH:5][CH:4]=1.B(Br)(Br)Br.CO>C(Cl)Cl>[OH:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][NH:8][C:9]2=[O:12])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(=O)NC2
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: O=C1NCc2ccc(O)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.6 %

Procedure:
A mixture of 6-methoxy-2,3-dihydro-isoindol-1-one (167 mg, 1.0 mmol) and boron tribromide (1 M in CH2Cl2, 3.6 mL, 3.6 mmol) in CH2Cl2 (8 mL) at −78° C. was stirred for 18 h at RT. The mixture was then cooled to −78° C. and MeOH (20 mL) was added. After 2 h at −78° C. the mixture was evaporated and the residue purified by chromatography (SiO2, CH2Cl2:2N NH3-MeOH 9:1) to afford the title product (147 mg, 100%) as a white solid. MS m/e=148.0 (M−H+).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:18][C:17](=[O:19])[NH:16][C@@H:15]([CH3:20])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+].Br[CH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][C:35]=1[I:36])[CH2:32][CH2:31][CH2:30]2>>[F:22][C:2]([F:1])([F:21])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:18][C:17](=[O:19])[N:16]([CH2:26][C:27]3[CH:28]=[C:29]4[C:33](=[CH:34][C:35]=3[I:36])[CH2:32][CH2:31][CH2:30]4)[C@@H:15]([CH3:20])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: BrCc1cc2c(cc1I)CCC2
Reactant: C[C@H]1C[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1
Agent: [H-]
Agent: [Na+]
Product: C[C@H]1C[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc2c(cc1I)CCC2

Procedure:
(4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazinan-2-one (Intermediate 22; 104 mg; 0.318 mmol) was treated with sodium hydride (60% in oil; 11.9 mg; 0.297 mmol) and 5-(bromomethyl)-6-iodoindane (Intermediate 24; 100 mg; 0.297 mmol) as described for Intermediate 23 to afford (4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-3-[(6-iodo-2,3-dihydro-1H-inden-5-yl)methyl]-4-methyl-1,3-oxazinan-2-one as a white solid. LCMS=583.8 (M+1)+. 1H NMR (CDCl3, 500 MHz): δ 7.90 (s, 2H), 7.87 (s, 1H), 7.72 (s, 1H), 7.19 (s, 1H), 5.43 (dd, J=11.8, 1.7 Hz, 1H), 4.96 (d, J=15-8 Hz, 1H), 4.47 (d, J=16 Hz, 1H), 3.69-3.62 (m, 1H), 2.90-2.86 (m, 4H), 2.43-2.38 (m, 1H), 2.12-2.05 (m, 2H), 2.00-1.92 (m, 1H), 1.25 (d, J=6.2 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[OH:13].[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]=O>CO.C(O)=O>[O:13]([C:3]1[C:4]([C:9]([CH3:10])([CH3:12])[CH3:11])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1/[N:1]=[CH:20]/[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccn1
Reactant: Cc1cc(N)c(O)c(C(C)(C)C)c1
Solvent: CO
Solvent: O=CO
Product: Cc1cc(/N=C/c2ccccn2)c(Oc2ccccc2)c(C(C)(C)C)c1
Reaction time: 2 h
Yield: 107.2 %

Procedure:
To a slurry of 2-amino-4-methyl-6-tertbutylphenol (0.70 g, 3.90 mmol) in 5 mL methanol, a methanol solution of pyridine-2-carbaldehyde (0.418 g, 3.90 mmol) was slowly added, forming a dark orange solution. Two drops formic acid were added, quickly forming a yellow precipitate. This was stirred for 2 hr, then collected on a frit, washed with cold methanol and dried under vacuum to yield 0.72 g of 12 (69%).
Reaction SMILES: C([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22][CH2:23][C:24]=1[C:25]1[S:29][C:28]([NH:30][C:31]([O:33][CH3:34])=[O:32])=[N:27][CH:26]=1)[CH:20]([NH:35][C:36](=[O:43])[CH2:37][C:38]1[S:39][CH:40]=[CH:41][CH:42]=1)[C:19]2=[O:44])=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1>C(O)=O>[C:15]([C:17]1[N:18]2[CH:21]([S:22][CH2:23][C:24]=1[C:25]1[S:29][C:28]([NH:30][C:31]([O:33][CH3:34])=[O:32])=[N:27][CH:26]=1)[CH:20]([NH:35][C:36](=[O:43])[CH2:37][C:38]1[S:39][CH:40]=[CH:41][CH:42]=1)[C:19]2=[O:44])([OH:16])=[O:14]
Reactant: COC(=O)Nc1ncc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)Cc4cccs4)C3SC2)s1
Solvent: O=CO
Product: COC(=O)Nc1ncc(C2=C(C(=O)O)N3C(=O)C(NC(=O)Cc4cccs4)C3SC2)s1
Yield: 66.6 %

Procedure:
2-Benzhydryloxycarbonyl-3-(2-methoxycarbonylaminothiazol-5-yl)-8-oxo-7-(thien-2-yl-acetamido)-5-thia-1-azabicyclo[4.2.0]oct-2-ene (1.82 g) is treated with formic acid (20 cc) in accordance with the working method described in Example 1. 2-Carboxy-3-(2-methoxycarbonylaminothiazol-5-yl)-8-oxo-7-(thien-2-yl-acetamido)-5-thia-1-azabicyclo[4.2.0]oct-2-ene (0.9 g) is obtained in the form of a yellow solid.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:42]=[CH:41][C:16]([CH2:17][N:18]([CH2:28][C:29]3[CH:40]=[CH:39][C:32]([O:33][CH2:34][C:35]([O:37]C)=[O:36])=[CH:31][CH:30]=3)[C:19]([C:21]3[CH:22]=[N:23][C:24]([OH:27])=[CH:25][CH:26]=3)=[O:20])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO.C1COCC1>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:42]=[CH:41][C:16]([CH2:17][N:18]([CH2:28][C:29]3[CH:30]=[CH:31][C:32]([O:33][CH2:34][C:35]([OH:37])=[O:36])=[CH:39][CH:40]=3)[C:19]([C:21]3[CH:22]=[N:23][C:24]([OH:27])=[CH:25][CH:26]=3)=[O:20])=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(OCC(=O)OC)cc3)C(=O)c3ccc(O)nc3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(OCC(=O)O)cc3)C(=O)c3ccc(O)nc3)cc2)cc1

Procedure:
The titled compound was prepared following the procedure F using methyl [4-({{4-[(4-butylphenyl)ethynyl]benzyl}[(6-hydroxypyridin-3-yl)carbonyl]amino}methyl)phenoxy]acetate and NaOH 1N in the presence of MeOH/THF as a white powder (47%). 1H NMR (DMSO-d6, 300 MHz) δ 7.57-7.43 (m, 6H), 7.26-7.09 (m, 6H), 6.89 (d, J=8.7 Hz, 2H), 6.33 (d, J=9.4 Hz, 1H), 4.65 (s, 2H), 4.52 (2H), 4.48 (s, 2H), 2.60 (t, J=7.5 Hz, 2H), 1.55 (m, 2H), 1.30 (m, 2H), 0.89 (t, J=7.3 Hz, 3H). M− (ESI): 547.3; M+ (ESI): 549.4. HPLC, Rt: 4.48 min (Purity: 76.9%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])[N:9]=2)=[CH:4][CH:3]=1.[OH-].[K+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
560 mg (1.67 mmol) of ethyl 3-[3-(4-chlorophenyl)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-propionate from Example 87A are placed in 1.5 ml methanol, treated with 0.5 ml 20% aqueous potassium hydroxide and stirred for 2 hrs at room temperature. The methanol is removed in vacuo, the aqueous residue acidified to pH 1 with 2 N hydrochloric acid and the resulting precipitate isolated by filtration. 439 mg (73% of theory) of the target compound are thus obtained.
Reaction SMILES: [C:1](/[N:9]=[C:10]1/[N:11]([C@@H:28]2[CH2:33][CH2:32][C@H:31]([C:34]([O:36]C)=[O:35])[CH2:30][CH2:29]2)[C:12]2[CH:17]=[C:16]([O:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[N:15]=[CH:14][C:13]=2[NH:27]/1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[C:1](/[N:9]=[C:10]1/[N:11]([C@@H:28]2[CH2:29][CH2:30][C@H:31]([C:34]([OH:36])=[O:35])[CH2:32][CH2:33]2)[C:12]2[CH:17]=[C:16]([O:18][CH2:19][CH2:20][N:21]3[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]3)[N:15]=[CH:14][C:13]=2[NH:27]/1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccccc3)[nH]c3cnc(OCCN4CCCCC4)cc32)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(/N=c1\[nH]c2cnc(OCCN3CCCCC3)cc2n1[C@H]1CC[C@@H](C(=O)O)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of cis-methyl 4-((E)-2-(benzoylimino)-6-(2-(piperidin-1-yl)ethoxy)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarboxylate (0.052 g, 0.103 mmol) in MeOH (1.0 mL) was added 1N aqueous NaOH (1.028 mL, 1.028 mmol), and the resulting mixture was stirred at RT for 48 hours. The reaction mixture was concentrated under vacuum to remove MeOH and neutralized with 2 N HCl. The product was extracted with DCM (5-20 mL) to afford cis-4-((E)-2-(benzoylimino)-6-(2-(piperidin-1-yl)ethoxy)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarboxylic acid as an off-white solid (50 mg, 99% yield). MS m/z=492.2 [M+H]. Calc'd for C27H33N5O4: 491.3.
Reaction SMILES: C([N:8]1[C:13]([CH3:15])([CH3:14])[CH2:12][N:11]([CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[N:20]=[C:19]3[N:30]([CH:34]4[CH2:39][CH2:38][CH2:37][CH2:36][O:35]4)[N:31]=[C:32]([CH3:33])[C:18]=23)[C:10]([CH3:41])([CH3:40])[CH2:9]1)C1C=CC=CC=1>CO>[CH3:33][C:32]1[C:18]2[C:19](=[N:20][C:21]([C:23]3[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=3)=[CH:22][C:17]=2[CH2:16][N:11]2[CH2:12][C:13]([CH3:14])([CH3:15])[NH:8][CH2:9][C:10]2([CH3:41])[CH3:40])[N:30]([CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][O:35]2)[N:31]=1
Reactant: Cc1nn(C2CCCCO2)c2nc(-c3ccc(O)cc3)cc(CN3CC(C)(C)N(Cc4ccccc4)CC3(C)C)c12
Solvent: CO
Product: Cc1nn(C2CCCCO2)c2nc(-c3ccc(O)cc3)cc(CN3CC(C)(C)NCC3(C)C)c12
Reaction time: 0.5 h
Yield: 71.7 %

Procedure:
250 mg 4-[4-(4-benzyl-2,2,5,5-tetramethyl-piperazin-1-ylmethyl)-3-methyl-1-(tetra-hydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl]-phenol was dissolved in 20 ml methanol and purged with argon. 25 mg Palladium (10% on charcoal) were added and the mixture was hydrogenated at r.t. for 30 min. The catalyst was filtered off and the solvents were evaporated. 150 mg (72%) of the title compound were obtained.
Reaction SMILES: Cl.O[CH2:3][CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl.ClCCNCC1C=CC=CC=1>>[CH2:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:3][CH2:4][NH:5]1
Reactant: OCCNCc1ccccc1
Agent: Cl
Agent: ClCCNCc1ccccc1
Product: c1ccc2c(c1)CCNC2

Procedure:
The reactions of Examples 1 and 2 are repeated with equimolar quantities of N-hydroxyethylbenzylamine hydrochloride or N-chloroethylbenzylamine hydrochloride to give 1,2,3,4-tetrahydroisoquinoline. The use of N-chloroethyl-2,3-dichlorobenzylamine as the base gives good yields of 7,8-dichlorol,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C@@H:7]2[O:13][C@H:12]([CH2:14][OH:15])[C@@H:10]([OH:11])[C@H:8]2[OH:9])[CH:5]=[N:4][C:3]=1[C:16]([NH2:18])=[O:17].[C:19]([OH:23])(=O)[CH2:20][CH3:21]>>[NH2:1][C:2]1[N:6]([C@@H:7]2[O:13][C@H:12]([CH2:14][O:15][C:19](=[O:23])[CH2:20][CH3:21])[C@@H:10]([O:11][C:16](=[O:17])[CH2:3][CH3:2])[C@H:8]2[O:9][C:8](=[O:9])[CH2:10][CH3:12])[CH:5]=[N:4][C:3]=1[C:16]([NH2:18])=[O:17]
Reactant: NC(=O)c1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1N
Reactant: CCC(=O)O
Product: CCC(=O)OC[C@H]1O[C@@H](n2cnc(C(N)=O)c2N)[C@H](OC(=O)CC)[C@@H]1OC(=O)CC

Procedure:
A method for producing N2 -phenyl-2,6-diaminonebularine, which comprises reacting 5-amino-1-β-D-ribofuranosylimidazole-4-carboxamide with a reactive derivative of propionic acid to yield 5-amino-1-(2,3,5,-tri-O-propionyl-β-D-ribofuranosyl)imidazole-4-carboxamide, dehydrating 5-amino-1-(2,3,5-tri-O-propionyl-β-D-ribofuranosyl)imidazole-4-carboxamide to yield 5-amino-4-cyano-1-(2,3,5-tri-O-propionyl-β-D-ribofuranosyl)imidazole, treating 5-amino-4-cyano-1-(2,3,5-tri-O-propionyl-β-D-ribofuranosyl)imidazole with aqueous ammonia or alkali metal alkoxide to yield 5-amino-1-β-D-ribofuranosyl-4-cyanoimidazole and reacting 5-amino-1-β-D-ribofuranosyl-4-cyanoimidazole with phenylcyanamide in the presence of ammonia to yield N2 -phenyl-2,6-diaminonebularine.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH:5]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH:22]2[CH2:24][CH2:23]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1)[O:6][CH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)C.[OH-].[Li+].C1COCC1.CO>O>[CH:22]1([S:19]([C:16]2[CH:15]=[CH:14][C:13]([CH:5]([O:6][CH:7]3[CH2:8][CH2:9][O:10][CH2:11][CH2:12]3)[C:4]([OH:25])=[O:3])=[CH:18][CH:17]=2)(=[O:21])=[O:20])[CH2:24][CH2:23]1
Reactant: CCOC(=O)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.4 %

Procedure:
To (4-cyclopropanesulfonyl-phenyl)-[(tetrahydro-pyran-4-yloxy)]-acetic acid ethyl ester (23.2 g, 62.87 mmol) was added a solution of lithium hydroxide (13.0 g, 314.36 mmol) in water (150 mL) followed by THF (200 mL) and methanol (10 mL) and stirred for 2 hours at 25° C. Organic solvents were evaporated from the reaction mixture and aqueous layer was acidified 1N HCl, extracted with ethyl acetate (3×200 mL), organic layer was washed with brine solution, dried over anhydrous sodium sulfate, and washed concentrated under reduced pressure to provide (4-cyclopropanesulfonyl-phenyl)-[(tetrahydro-pyran-4-yloxy)]-acetic acid (18.49 g)
Reaction SMILES: ClC(Cl)C(=O)C(C)(C)C.[Cl:10][C:11]1[N:16]=[C:15]([OH:17])[CH:14]=[CH:13][CH:12]=1.N1C=NC=N1.C(=O)([O-])[O-].[K+].[K+].[N:29]1([CH:34](N2C=NC=N2)[C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])[CH:33]=[N:32][CH:31]=[N:30]1.ClC1N=C(OC(OC2C=CC=C(Cl)N=2)C(=O)C(C)(C)C)C=CC=1>CC(C)=O>[Cl:10][C:11]1[N:16]=[C:15]([O:17][CH:34]([N:29]2[CH:33]=[N:32][CH:31]=[N:30]2)[C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])[CH:14]=[CH:13][CH:12]=1
Reactant: Oc1cccc(Cl)n1
Reactant: CC(C)(C)C(=O)C(n1cncn1)n1cncn1
Agent: CC(C)(C)C(=O)C(Cl)Cl
Agent: CC(C)(C)C(=O)C(Oc1cccc(Cl)n1)Oc1cccc(Cl)n1
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Product: CC(C)(C)C(=O)C(Oc1cccc(Cl)n1)n1cncn1

Procedure:
33.8 g (0.2 mol) of 1,1-dichloro-3,3-dimethyl-butan-2-one, 26 g (0.2 mol) of 6-chloro-2-hydroxy-pyridine, 21 g (0.3 mol) of 1,2,4-triazole and 56 g (0.4 mol) of potassium carbonate were heated under reflux in 250 ml of acetone for 12 hours, while stirring. Thereafter, the mixture was allowed to cool, the salt which had precipitated was filtered off and the filtrate was concentrated in vacuo. Isopropanol was added to the oily residue, it being possible to isolate successively three crystal fractions. The first two contained mainly 1,1-bis-(1,2,4-triazol-1-yl)-3,3-dimethylbutan-2-one of melting point 157°-158° C. and 1,1-bis-(6-chloropyridin-2-yl-oxy)-3,3-dimethyl-butan-2-one of melting point 102°-104° C. 4 g of 1-(6-chloropyridin-2-yl-oxy)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-butan-2-one of melting point 102° C. were obtained from the third fraction.
Reaction SMILES: [CH:1]1([CH2:4][NH2:5])[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl.[F:14][C:15]([F:49])([F:48])[C:16]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[N:19]=[C:18]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([C:38]3[CH:39]=[C:40]([S:44](Cl)(=[O:46])=[O:45])[CH:41]=[CH:42][CH:43]=3)[CH:33]=2)[N:17]=1>C1COCC1>[CH:1]1([CH2:4][NH:5][S:44]([C:40]2[CH:41]=[CH:42][CH:43]=[C:38]([C:34]3[CH:33]=[C:32]([C:18]4[N:17]=[C:16]([C:15]([F:14])([F:48])[F:49])[CH:21]=[C:20]([C:22]5[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][CH:23]=5)[N:19]=4)[CH:37]=[CH:36][N:35]=3)[CH:39]=2)(=[O:45])=[O:46])[CH2:3][CH2:2]1
Reactant: NCC1CC1
Reactant: O=S(=O)(Cl)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S(=O)(NCC1CC1)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Temperature: 0 °C
Yield: 91.8 %

Procedure:
To a cooled (ice-water bath) and stirred mixture of cyclopropylmethylamine (0.21 g, 2.96 mmol), triethylamine (0.28 ml, 2.0 mmol) and THF (4 ml) was added drop wise a solution of 3-{4-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonyl chloride hydrochloride (example I.1) (0.56 g, 0.96 mmol) in THF (6 ml). The mixture was allowed to stir at room temperature for 16 h. Purification of the reaction mixture by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (dichloromethane/MeOH/hexane) yielded the title compound as a white solid (0.51 g, 97%). MS (ISP) 578.6 [(M+H)+]; mp 133.5° C.
Reaction SMILES: C(C1C=CC([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:19]=[C:18]([C:20]([NH2:22])=[O:21])[CH:17]=[C:16]([C@@H:23]([OH:26])[CH2:24][OH:25])[N:15]=3)=[CH:10][CH:9]=2)=CC=1C(F)(F)F)#N.CC1(C)C(C)(C)OB(C2C=CC(O[C:48]3[CH:53]=[CH:52][C:51]([C:54]([F:57])([F:56])[F:55])=[CH:50][CH:49]=3)=CC=2)O1>>[OH:26][C@H:23]([C:16]1[N:15]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([O:7][C:48]3[CH:53]=[CH:52][C:51]([C:54]([F:57])([F:56])[F:55])=[CH:50][CH:49]=3)=[CH:9][CH:10]=2)[N:19]=[C:18]([C:20]([NH2:22])=[O:21])[CH:17]=1)[CH2:24][OH:25]
Reactant: CC1(C)OB(c2ccc(Oc3ccc(C(F)(F)F)cc3)cc2)OC1(C)C
Reactant: N#Cc1ccc(Oc2ccc(-c3nc(C(N)=O)cc([C@@H](O)CO)n3)cc2)cc1C(F)(F)F
Product: NC(=O)c1cc([C@@H](O)CO)nc(-c2ccc(Oc3ccc(C(F)(F)F)cc3)cc2)n1

Procedure:
(R)-6-(1,2-dihydroxyethyl)-2-(4-(4-(trifluoromethyl)phenoxy)phenyl) pyrimidine-4-carboxamide (Compound Example No. 18) was prepared a similarly to (R)-2-(4-(4-cyano-3-(trifluoromethyl)phenoxy)phenyl)-6-(1,2-dihydroxyethyl) pyrimidine-4-carboxamide (Compound Example No. 12) using 4,4,5,5-tetramethyl-2-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1,3,2-dioxaborolane. 1H NMR (400 MHz, DMSO-d6): 8.75-8.67 (2 H, m), 8.65-8.59 (1 H, m), 8.05-8.01 (1 H, m), 8.01-7.94 (1 H, m), 7.83-7.75 (2 H, m), 7.31-7.22 (4 H, m), 5.84-5.79 (1 H, m), 4.87-4.79 (1 H, m), 4.73-4.67 (1 H, m), 3.86-3.77 (1 H, m), 3.74-3.64 (1 H, m); LC/MS: m/z=420 [M+H]+.