Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:23]=[CH:22][CH:21]=[N:20]3)=[CH:15][CH:14]=2)=[C:10]([Cl:24])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:25]([C:37]3[N:41]([CH3:42])[CH:40]=[N:39][CH:38]=3)([C:27]3[CH:28]=[N:29][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:32]=3)[OH:26])[CH:8]=2)[N:3]=1.Cl.[F:44][CH:45]1[CH2:48][NH:47][CH2:46]1.CN(C=O)C>CCOC(C)=O>[Cl:24][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:25]([C:37]3[N:41]([CH3:42])[CH:40]=[N:39][CH:38]=3)([C:27]3[CH:28]=[N:29][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:31][CH:32]=3)[OH:26])[CH:8]=2)[N:3]=[C:2]([N:47]2[CH2:48][CH:45]([F:44])[CH2:46]2)[C:11]=1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH:23]=[CH:22][CH:21]=[N:20]2)=[CH:15][CH:14]=1
Reactant: Cn1cncc1C(O)(c1ccc(C(F)(F)F)nc1)c1ccc2nc(Cl)c(Cc3ccc(-n4cccn4)cc3)c(Cl)c2c1
Reactant: FC1CNC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1cncc1C(O)(c1ccc(C(F)(F)F)nc1)c1ccc2nc(N3CC(F)C3)c(Cc3ccc(-n4cccn4)cc3)c(Cl)c2c1
Temperature: 100 °C

Procedure:
{2,4-Dichloro-3-[4-(1H-pyrazol-1-yl)benzyl]quinolin-6-yl}(1-methyl-1H-imidazol-5-yl)pyrimidin-2-ylmethanol (100 mg, 0.164 mmol, Intermediate 65), 3-fluoroazetidine hydrochloride (183 mg, 1.64 mmol) and DMF (2 mL) were combined in a reaction tube, then sealed and heated to 100° C. and maintained at that temperature for 24 hours. The residue was taken up into EtOAc, transferred to a reparatory funnel and extracted twice with a saturated, aqueous NH4Cl solution. The organic phase was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified via reverse phase chromatography using acetonitrile with ammonium hydroxide in water as eluent to afford the title compound. MS (ESI): mass calcd. for C33H26ClF4N7O, 647.2. m/z found, 648.2 [M+H]+. 1H NMR (600 MHz, CDCl3) δ ppm 8.82 (d, J=1.7 Hz, 1H), 8.09 (d, J=2.0 Hz, 1H), 7.97-7.93 (m, 1H), 7.86 (d, J=2.3 Hz, 1H), 7.76 (d, J=8.8 Hz, 1H), 7.67 (d, J=1.5 Hz, 1H), 7.64 (d, J=8.3 Hz, 1H), 7.59 (d, J=8.6 Hz, 2H), 7.55-7.51 (m, 1H), 7.26 (s, 1H), 7.16 (d, J=8.6 Hz, 2H), 6.46-6.42 (m, 1H), 6.39 (s, 1H), 4.41-4.31 (m, 2H), 4.29 (s, 2H), 4.27-4.18 (m, 3H), 3.44 (s, 3H).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH:11]N1C(=O)C2=CC=CC=C2C1=O.C(OO)(C)(C)C.S(=O)=O.O=O>[O-][V]([O-])([O-])=O.[Na+].[Na+].[Na+].C/C(/O)=C\C(C)=O.C/C(/O)=C\C(C)=O.O=[V].C(O)(=O)C>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=[O:11])[CH2:8]2
Reactant: C1C2CC3CC1CC(C2)C3
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: O=[V]
Agent: O=[V]([O-])([O-])[O-]
Agent: CC(=O)/C=C(\C)O
Solvent: CC(=O)O
Product: O=C1C2CC3CC(C2)CC1C3
Yield: 3 %

Procedure:
A mixture of 2 mmol of adamantane, 0.2 mmol of N-hydroxyphthalimide, 0.01 mmol of vanadyl acetylacetonato [VO(acac) 2 ], 0.02 mmol of TBHP (t-butyl hydroperoxide), and 5 ml of acetic acid was stirred at 25° C. in a sulfur dioxide (SO2) (0.5 atm) and oxygen (0.5 atm) atmosphere for 20 hours. A gas chromatographic analysis of a reaction mixture revealed that the conversion rate of adamantane was 53% and that 2-adamantanone was formed in a yield of 3%. The reaction mixture was extracted with water, was neutralized with an aqueous sodium hydroxide solution, and was adjusted to weak acidity with hydrochloric acid. An aqueous benzyl isothiourea hydrochloride solution in large excess was then added to the mixture to separate S-benzyl thiuronium salt of 1-adamantanesulfonic acid. The yield of this compound was 40%.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.C=O.[OH-].[Na+].[C:15](=O)(O)[O-:16].[Na+]>O.Cl>[OH:16][CH2:15][C:8]1[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([CH3:1])[C:3]2=[CH:10][CH:9]=1
Reactant: O=C([O-])O
Reactant: Cc1nccn2cccc12
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1nccn2c(CO)ccc12
Temperature: 70 °C
Reaction time: 0.67 h
Yield: 48.9 %

Procedure:
3 g (22.7 mmol) of 1-methylpyrrolo[1,2-a]pyrazine prepared in Preparation Example 2 was dissolved in water (15 ml)/concentrated hydrochloric acid (35 ml) mixture while cooling with ice-water. The resulting solution was heated to 70° C.; and 60 ml of formalin was added dropwise thereto over 40 minutes. The resulting solution was stirred at 75° C. for 30 minutes, cooled to 0° C. and then neutralized to pH8.0 with sodium hydroxide and sodium bicarbonate. The reaction mixture was extracted with ethyl acetate (100 ml×3), dried over MgSO4 and then concentrated. The residue was chromatographed over silica gel to obtain 1.8 g of title compound (yield: 48.9%).
Reaction SMILES: C(=O)(O)[O-].[Na+].Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]=[C:16]([C@@H:18]3[CH2:22][CH2:21][CH2:20][N:19]3[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[O:15][N:14]=2)=[CH:9][CH:8]=1.CC1(C)C(C)(C)OB([C:38]2[CH:43]=[CH:42][C:41]([C:44]3[NH:48][C:47]([C@@H:49]4[CH2:53][CH2:52][CH2:51][N:50]4[C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])=[N:46][CH:45]=3)=[CH:40][CH:39]=2)O1>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:26]([O:25][C:23]([N:19]1[CH2:20][CH2:21][CH2:22][C@H:18]1[C:16]1[O:15][N:14]=[C:13]([C:10]2[CH:11]=[CH:12][C:7]([C:38]3[CH:39]=[CH:40][C:41]([C:44]4[N:48]=[C:47]([C@@H:49]5[CH2:53][CH2:52][CH2:51][N:50]5[C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[NH:46][CH:45]=4)=[CH:42][CH:43]=3)=[CH:8][CH:9]=2)[N:17]=1)=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2ccc(Br)cc2)no1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(-c4noc([C@@H]5CCCN5C(=O)OC(C)(C)C)n4)cc3)cc2)c[nH]1
Temperature: 80 °C
Reaction time: 6 h
Yield: 71.6 %

Procedure:
A flask charged with PdCl2(dppf) (0.04 g, 0.051 mmol), sodium bicarbonate (0.37 g, 4.45 mmol), and (5)-tert-butyl 2-(3-(4-bromophenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate (compound 16a, 0.50 g, 1.27 mmol) was flushed with nitrogen. A solution of (S)-tert-butyl 2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (compound 20a, 0.67 g, 1.52 mmol) in 1,2-dimethoxyethane (15 ml) was then added. The reaction mixture was stirred at 80° C. under nitrogen for 6 hours. After cooled to room temperature, the resulting mixture was extracted with ethyl acetate/water, dried over magnesium sulfate, filtered and concentrated to give a crude compound, which was purified with chromatography (ethyl acetate: n-hexane=4:1) to yield product 23a as a white solid (0.57 g).
Reaction SMILES: [F:1][C:2]([F:52])([F:51])[C:3]1[CH:4]=[C:5]([CH:48]=[CH:49][CH:50]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=2[NH:28][C:29]([C:31]2[CH:32]=[C:33]([CH:45]=[CH:46][CH:47]=2)[CH2:34][S:35][CH2:36][CH2:37][C:38]([O:40]C(C)(C)C)=[O:39])=[O:30])[CH:11]=1)=[O:9].FC(F)(F)C(O)=O>ClCCl>[F:51][C:2]([F:1])([F:52])[C:3]1[CH:4]=[C:5]([CH:48]=[CH:49][CH:50]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)[CH:19]=[CH:18][C:17]=2[NH:28][C:29]([C:31]2[CH:32]=[C:33]([CH:45]=[CH:46][CH:47]=2)[CH2:34][S:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:30])[CH:11]=1)=[O:9]
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.7 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of tert-butyl 3-(3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)-benzylthio)propanoate (360 mg, 0.49 mmol, 1.00 equiv) in dichloromethane (2 mL), and 2,2,2-trifluoroacetic acid (2 mL). The resulting solution was stirred for 1 h at room temperature. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum. The crude product was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 217.9 mg (66%) of a white solid. 1H-NMR (300 MHz, DMSO-d6+DCl, ppm): δ 9.06˜9.04 (d, J=5.7 Hz, 1H), 8.86 (s, 1H), 8.75 (s, 1H), 8.74˜8.47 (m, 1H), 8.44˜8.10 (m, 2H), 7.88 (s, 2H), 7.88˜7.84 (d, J=7.8 Hz, 2H), 7.75˜7.48 (m, 4H), 4.60 (s, 2H), 3.86 (s, 2H), 3.78 (s, 4H), 2.63˜2.58 (m, 2H), 2.31˜1.75 (m, 6H). MS (ES, m/z): 677[M+H]+.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][N:10]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27]CC)=[O:26])[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>>[C:1]1([C:7]2[N:8]=[CH:9][N:10]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])[C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCCCCCCn1cnc(-c2ccccc2)c1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCCCCCn1cnc(-c2ccccc2)c1-c1ccccc1
Yield: 19.9 %

Procedure:
Ethyl 8-(4,5-diphenylimidazole-1-yl)octanate (3.25 g) was treated with sodium hydroxide as described in example 10 to give 8-(4,5-diphenyl-imidazol-1-yl)octanoic acid (0.6 g, 20%) as colourless needles, m.p. 129.5°-130° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl.CCOCC>[CH3:21][S:22]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCCCCc1ccccc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCCCCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 6-phenyl-1-hexanol (3.2 g; 18 mmol) dissolved in CH2Cl2 (60 ml) is added Et3N (3.7 ml) and the solution is cooled to 0° C. Methanesulfonyl chloride (1.5 ml; 20 mmol) is added dropwise and then the reaction mixture is allowed to stir for 30 minutes at 0° C. This is then diluted with Et2O and washed with 2N HCl, NaHCO3 solution 2× and brine, dried (MgSO4) and concentrated to dryness to obtain 6-phenylhex-1-yl methylsulfonate as an oil which is used directly in Step E
Reaction SMILES: CC[CH:3]=[CH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CCC=CCCC=CCC>>[CH2:10]1[CH:9]2[CH:5]3[CH:4]=[CH:3][CH:7]([CH:8]2[CH:12]=[CH:11]1)[CH2:6]3
Reactant: CCC=CCCCCCCCC
Agent: CCC=CCCC=CCC
Product: C1=CC2C3C=CC(C3)C2C1

Procedure:
In a nitrogen atmosphere, 50 parts of tetracyclo [4.4.12,8,17,10,0]-dodeca-3-ene (hereinafter abbreviated to “TCD”) and 50 parts of tricyclo[4.3.12,5,01,6]-deca-3,7-diene (trivial name: dicyclopentadiene; hereinafter abbreviated to “DCPD”) were copolymerized by using a knows metathesis ring-opening polymerization catalyst, and the copolymer was hydrogenated by a known procedure to give a hydrogenated TCD/DCPD ring-opened copolymer. The hydrogenated ring-opened copolymer had a number average molecular weight (Mn) of 28,004, a hydrogenation percentage of at least 99.8%, Tg of 135° C., and a melt flow rate of 3 g/10 min. To 100 parts of a pellet of the hydrogenated ring-opened copolymer, 0.05 part of pentaerythrityl-tetrakis[3(3,5-di-tert.-butyl-4-hydroxyphenyl)prapionate] was incorporated and the mixture was kneaded by e twin-screw extruder to give a pellet-form molding material. The pellet was heat-pressed at a resin temperature of 200° C. under a load of 300 kgf/cm2 for 3 minutes into a plate having a size of 20 mm×15 mm×3.0 mm (thickness). The plate was transparent and exhibited a minimum light transmittance of 90.0% at a wavelength of 400 nm to 700 nm.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])C=O)([CH3:3])[CH3:2].S(=O)(=O)(O)[OH:15].OO>CO>[CH:1]([C:4]1[CH:5]=[C:6]([OH:15])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13])([CH3:3])[CH3:2]
Reactant: COc1ccc(C=O)cc1C(C)C
Reactant: O=S(=O)(O)O
Agent: OO
Solvent: CO
Product: COc1ccc(O)cc1C(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-isopropyl-4-methoxybenzaldehyde (12.5 g, 70 mmol) in MeOH(140 mL) was added concentrated sulfuric acid (1.2 mL) followed by dropwise addition of 30% by wt aqueous hydrogen peroxide(6 g, 20 mL, 176 mmol). The mixture was left to stir at ambient room temperature. After 3 hours, the mixture was concentrated in vacuo to about ⅓ of the reaction volume. The concentrate was partitioned between EtOAc (100 mL) and brine (50 mL). The EtOAc extract was washed with brine (50 mL), dried (Na2SO4), filtered and concentrated in vacuo to give 13.5 g of dark oil as crude product. The crude product was purified by chromatography (250 g silica gel, 10% EtOAc in hexane) to afford 10.1 g (86%) of compound 1c as a thick oil that eventually solidified.
Reaction SMILES: [CH:1]1([CH2:6][O:7][C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=[O:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:16](#[N:18])[CH3:17]>>[CH:1]1([CH2:6][O:7][C:8]2[CH:9]=[C:10]([CH:11]([OH:12])[CH2:17][C:16]#[N:18])[CH:13]=[CH:14][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC#N
Reactant: O=Cc1cccc(OCC2CCCC2)c1
Product: N#CCC(O)c1cccc(OCC2CCCC2)c1

Procedure:
Aldol condensation with acetonitrile and 3-(cyclopentylmethoxy)benzaldehyde gave 3-(3-(cyclopentylmethoxy)phenyl)-3-hydroxypropanenitrile as a colorless oil. Yield (0.4 g, 38%): 1H NMR (400 MHz, CDCl3) δ 7.22-7.28 (m, 1H), 6.88-6.94 (m, 2H), 6.82-6.88 (m, 1H), 4.95 (t, J=6.4 Hz, 1H), 3.81 (d, J=6.4 Hz, 2H), 2.83 (brs, 1H), 2.71 (d, J=6.4 Hz, 2H), 2.33 (dddd, J=7.2 Hz, 1H), 1.76-1.88 (m, 2H), 1.50-1.68 (m, 4H), 1.28-1.40 (m, 2H).
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:23][CH2:22][C@@:13]34[C:14]5[CH:15]=[C:16]([OH:21])[CH:17]=[CH:18][C:19]=5[CH2:20][C@@H:7]2[C@@H:8]3[CH2:9][CH2:10][O:11][CH2:12]4)=[O:5])[CH2:3][CH2:2]1.[CH2:24](I)[CH3:25].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:1]1([C:4]([N:6]2[CH2:23][CH2:22][C@@:13]34[C:14]5[CH:15]=[C:16]([O:21][CH2:24][CH3:25])[CH:17]=[CH:18][C:19]=5[CH2:20][C@@H:7]2[C@@H:8]3[CH2:9][CH2:10][O:11][CH2:12]4)=[O:5])[CH2:2][CH2:3]1
Reactant: CCI
Reactant: O=C(C1CC1)N1CC[C@]23COCC[C@H]2[C@H]1Cc1ccc(O)cc13
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1ccc2c(c1)[C@]13CCN(C(=O)C4CC4)[C@H](C2)[C@@H]1CCOC3

Procedure:
A mixture of the product of Step (b) (XXXII) (0.005 m), ethyl iodide (0.006 m) and potassium carbonate (2 g) in 20 ml of acetonitrile is heated at reflux for 18 hours. The mixture is then filtered and the filtrate is concentrated. The residue is treated with water and extracted with ethyl acetate. The extracts are dried (Na2SO4) and concentrated to give the title product.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CC(C)([O-])C.[K+].Br[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1>C1(C)C(C)=CC=CC=1.C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:22]1([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[C:23]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: Brc1cccc2ccccc12
Reactant: C1CNCCN1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1C
Solvent: ClCCl
Product: c1ccc2c(N3CCNCC3)cccc2c1

Procedure:
83.2 g (966 mmol) of piperazine, 38.0 g (339 mmol) of potassium tert-butoxide and 50.0 g (241 mmol) of 1-bromonaphthalene were added to a mixture of 5,4 g (24.2 mmol) of palladium acetate and 14.7 g (48.3 mmol) of tri-o-tolylphosphipe in 500 ml of xylene, and the reaction mixture was heated at reflux for 10 h, while stirring thoroughly and under a nitrogen atmosphere. After that, the mixture was diluted with methylene chloride, the insoluble residues were filtered off and the filtrate was evaporated. The crude product was purified by column chromatography (silica gel, eluent THF/methanol/ammonia 85/13/2). 21.5 g (42%) of product having a m.p. of 84-86° C. were isolated.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9][C@H:8]1[C:17](OC)=[O:18])=[O:6])[CH:2]=[CH2:3].[BH4-].[Na+].S(=O)(=O)(O)O>O1CCCC1.C(O)C>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:14])=[O:15])[CH2:9][C@H:8]1[CH2:17][OH:18])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1C(=O)OC
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CO
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.5 %

Procedure:
To a solution of (2S,4R)-1-allyloxycarbonyl-4-methanesulfonyloxy-2-methoxycarbonylpyrrolidine (27.12 g: 74.0 mmole) in a mixture of tetrahydrofuran (94 ml) and ethanol (140 ml), sodium borohydride (12 g: 31.7 mmole) is added in a nitrogen atmosphere under ice cooling. The mixture is stirred for 4 hours at room temperature. To the reaction mixture concentrated sulfuric acid (8.8 ml: 158.4 mmole) is added dropwise under ice cooling. The reaction mixture is concentrated to half a volume in vacuo, and diluted with ethyl acetate (100 ml) and ice water (100 ml). The organic layer is taken, successively washed with aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, and concentrated in vacuo to give (2S,4R)-1-allyloxycarbonyl-4-methanesulfonyloxypyrrolidine-2-methanol (19.33 g). Yield: 77%. Colorless oil. NMR δ(CDCl3) ppm: 1.9 to 2.1(m, 1H), 2.3 to 2.5(m, 1H), 3.05(s, 3H), 3.5 to 3.7(m, 2H), 3.7 to 4.1(m, 2H), 4.1 to 4.3(m, 1H), 4.6(m, 2H), 5.2 to 5.4(m, 3H), 5.8 to 6.1(m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:23]=[CH:22][CH:21]=[C:6]([C:7]([NH:9][CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:12])=O)[CH:5]=1>O>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:23]=[CH:22][CH:21]=[C:6]([C:7]2[O:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[CH:10][N:9]=2)[CH:5]=1
Reactant: COC(=O)c1cccc(C(=O)NCC(=O)c2ccc(OC)cc2)c1
Solvent: O
Product: COC(=O)c1cccc(-c2ncc(-c3ccc(OC)cc3)o2)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
0.5 g 1.5 mmol) of N-[2-(4-Methoxy-phenyl)-2-oxo-ethyl]-isophthalamic acid methylester from Preparation 2 was dissolved in ˜15 mL of poly phosphoric acid. The mixture was stirred at 80° C. for 2 hours before allowing it to cool to room temperature. Water (60 mL) was added, and the product precipitated upon agitation. The solid was filtered and washed with water. Slurried solid product in hot methanol and filtered. Dried in vacuum oven overnight to obtain 0.38 (80%) desired product.
Reaction SMILES: O([C:8]([NH:10][C:11]1[S:15][N:14]=[N:13][CH:12]=1)=[O:9])C1C=CC=CC=1.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>CC(C)=O>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[NH:16][C:8]([NH:10][C:11]1[S:15][N:14]=[N:13][CH:12]=1)=[O:9]
Reactant: Nc1ccccn1
Reactant: O=C(Nc1cnns1)Oc1ccccc1
Solvent: CC(C)=O
Product: O=C(Nc1ccccn1)Nc1cnns1
Temperature: 25 °C

Procedure:
16.5 g (0.075 mol) 5-phenoxycarbonylamino-1,2,3-thiadiazole are suspended in 150 ml acetone and reacted with 9.4 g (0.1 mol) of 2-aminopyridine. The reaction mass is then refluxed for 3 hours. After cooling to room temperature the formed light brown crystals are removed by suction and dried. They are then recrystallized from ethanol. There is thus obtained the above noted title compound (compound No. 1).
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])=[CH:8][CH:7]=1)[CH:2]=[C:3]([CH3:5])[CH3:4].S(Cl)(Cl)=O.[CH2:21](O)[CH:22]([CH3:24])[CH3:23]>N1C=CC=CC=1.C1C=CC=CC=1>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]([CH3:16])[C:13]([O:15][CH2:21][CH:22]([CH3:24])[CH3:23])=[O:14])=[CH:10][CH:11]=1)[CH:2]=[C:3]([CH3:5])[CH3:4]
Reactant: CC(C)CO
Reactant: CC(C)=CCc1ccc(C(C)C(=O)O)cc1
Solvent: c1ccccc1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CC(C)=CCc1ccc(C(C)C(=O)OCC(C)C)cc1
Temperature: 4 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
To a solution of 21.8 g of 2-(p-prenylphenyl)propionic acid in 17.6 ml of pyridine and 200 ml of benzene was added dropwise a solution of 7.9 ml of thionyl chloride in 15 ml of benzene with stirring at 4° C. After one hour, 14.8 g of isobutyl alcohol was added. The mixture was stirred at room temperature for one hour and then at 60° C. for 2 hours. After cooling, the solution was washed with water, 2 N hydrochloric acid, water, 5% aqueous sodium hydroxide and water successively, and dried over anhydrous magnesium sulfate. The solvent was evaporated to give 20.1 g of isobutyl 2-(p-prenylphenyl)propionate. b.p. 126°-127° C./0.10 mmHg, IR νmaxneat ; 1730 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:3]=1[C:4]([N:6]1[CH2:12][CH2:11][CH:10]=[CH:9][C:8]2[S:13][CH:14]=[CH:15][C:7]1=2)=[O:5].C(N(CC)CC)C.[F:28][C:29]1[CH:30]=[CH:31][C:32]([CH3:38])=[C:33]([CH:37]=1)[C:34](Cl)=[O:35]>ClCCl.O>[S:13]1[C:8]2[CH:9]=[CH:10][CH2:11][CH2:12][N:6]([C:4]([C:3]3[CH:16]=[CH:17][C:18]([NH:20][C:34](=[O:35])[C:33]4[CH:37]=[C:29]([F:28])[CH:30]=[CH:31][C:32]=4[CH3:38])=[CH:19][C:2]=3[Cl:1])=[O:5])[C:7]=2[CH:15]=[CH:14]1
Reactant: Nc1ccc(C(=O)N2CCC=Cc3sccc32)c(Cl)c1
Reactant: Cc1ccc(F)cc1C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)N2CCC=Cc3sccc32)c(Cl)c1
Reaction time: 48 h
Yield: 74.3 %

Procedure:
To a cooled solution of 0.20 g of 4-(2-chloro-4-aminobenzoyl)-5,6-dihydro-4H-thieno[3,2-b]azepine and 137 μl of triethylamine in 3 ml of dichloromethane is added a solution of 0.142 g of 5-fluoro-2-methylbenzoyl chloride in 1 ml of dichloromethane. The mixture is stirred under argon for 2 days and diluted with 30 ml of dichloromethane and 15 ml of H2O. The organic layer is separated and washed with 15 ml each of 2N citric acid, 1M NaHCO3, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate, the filter pad washed with dichloromethane and the filtrate evaporated. The residue is crystallized from ethyl acetate to give 0.215 g of white crystals, m.p. 125°-132° C.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[CH:11][C:12]([O:16][CH3:17])=[C:13]([CH:15]=2)[NH2:14])[CH2:3]1.CN1CCOCC1.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>ClCCl>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:14][C:13]2[CH:15]=[C:9]([N:4]3[CH2:3][C@H:2]([CH3:1])[NH:7][C@H:6]([CH3:8])[CH2:5]3)[CH:10]=[CH:11][C:12]=2[O:16][CH3:17])(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1N
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)aniline (D4) (1.20 g, 5.1 mmol) in dichloromethane (35 ml) was treated with morpholinomethyl-polystyrene HL resin (2.45 g, 4.2 mmol/g loading, 10.29 mmol) followed by 4-bromobenzenesulfonyl chloride (2.60 g, 10.2 mmol). The resulting solution was stirred at room temperature overnight (˜24hours)and then the resin filtered off with methanol and the solvent evaporated in vacuo. The residue was passed through an SCX column eluting first with methanol followed by 2M ammonia in methanol. The relevant fractions were collected, combined and the solvent evaporated in vacuo. The crude product was purified by Flashmaster causing an elution gradient of 0 to 10% methanol in dichloromethane. The relevant fractions were collected, combined and the solvent evaporated to afford the title compound (E106). MS (ES+) m/e 454/456 [M+H]+.