Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]1[CH2:15][C@@H:14]2[CH2:16][N:17]([C:19]3[N:24]=[N:23][C:22]([C:25]4[CH:30]=[CH:29][C:28]([C:31]5[CH:32]=[N:33][NH:34][CH:35]=5)=[CH:27][C:26]=4[OH:36])=[CH:21][CH:20]=3)[CH2:18][C@@H:13]2[CH2:12]1)(C(C)(C)C)(C)C.Cl.N>O1CCOCC1.CO>[OH:8][CH2:9][CH2:10][N:11]1[CH2:12][C@@H:13]2[CH2:18][N:17]([C:19]3[N:24]=[N:23][C:22]([C:25]4[CH:30]=[CH:29][C:28]([C:31]5[CH:35]=[N:34][NH:33][CH:32]=5)=[CH:27][C:26]=4[OH:36])=[CH:21][CH:20]=3)[CH2:16][C@@H:14]2[CH2:15]1
Reactant: CC(C)(C)[Si](C)(C)OCCN1C[C@@H]2CN(c3ccc(-c4ccc(-c5cn[nH]c5)cc4O)nn3)C[C@@H]2C1
Agent: Cl
Agent: N
Solvent: C1COCCO1
Solvent: CO
Product: OCCN1C[C@@H]2CN(c3ccc(-c4ccc(-c5cn[nH]c5)cc4O)nn3)C[C@@H]2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
To a solution of 2-(6-((3aR,6aS)-5-(2-((tert-butyldimethylsilyl)oxy)ethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol (20 mg, 0.039 mmol) in dioxane (2 mL) was added 4N HCl in dioxane (1 mL, 4.00 mmol). The reaction mixture was stirred at RT overnight, then basified with 2N NH3 in MeOH and concentrated. The crude product was purified via preparative HPLC to give an off-white solid 2-(6-((3aR,6aS)-5-(2-hydroxyethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol (6.5 mg, 0.016 mmol, 41% yield). LCMS Rt=0.87 min [Method Q]; MS (M+1)=393.1. 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.01 (d, J=9.60 Hz, 1H), 7.93 (s, 2H), 7.69 (d, J=8.08 Hz, 1H), 7.08-7.19 (m, 3H), 3.67-3.77 (m, 4H), 3.56 (d, J=11.12 Hz, 2H), 3.11 (br. s., 2H), 2.97-3.05 (m, 2H), 2.72 (t, J=5.81 Hz, 2H), 2.63-2.70 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[C:7]([C:12](=[O:14])[CH3:13])[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][N:3]=1.I[C:16]1C=CC=C2C=1CCN=C2C.C(OC=C)CCC.CCN(CC)CC.Cl>CS(C)=O.CCOCC.C1COCC1.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]([OH:14])([CH3:16])[CH3:13])[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][N:3]=1
Reactant: CC1=NCCc2c(I)cccc21
Reactant: CC(=O)c1cccc2c1CCN=C2C
Agent: [Pd+2]
Agent: C=COCCCC
Agent: CC(=O)[O-]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC1=NCCc2c1cccc2C(C)(C)O
Temperature: 100 °C
Reaction time: 4 h

Procedure:
1-(1-methyl-3,4-dihydroisoquinolin-5-yl)ethanone. A solution of 5-iodo-1-methyl-3,4-dihydroisoquinoline (2.0 g, 7.38 mmol), Pd(OAc)2 (41 mg, 0.184 mmol) and DPPP (85 mg, 0.207 mmol) in dry DMSO (15 mL) was degassed, and butylvinyl ether (4.80 mL, 36.9 mmol) and Et3N (1.24 mL, 8.85 mmol) were then added in succession. The reaction was heated to 100° C. for 18 h, and then allowed to cool to RT. The mixture was diluted with Et2O and washed with H2O. The organic phase was then dried over Na2SO4, filtered and concentrated in vacuo to give a brown oil that was taken up in THF (50 mL) and treated with a 2N aq. solution of HCl (25 mL). The mixture was stirred at RT for 4 h, and then diluted with AcOEt and washed with H2O. The aq. phase was then neutralized and rendered basic by adding Na2CO3, and then extracted with AcOEt. The combined org. layers were then dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, DCM to DCM/MeOH 9:1) to provide the title compound (1.06 g) as a brown oil, which was used as it is in the next step. UPLC-MS: MS 188.0 (M+H+); UPLC rt 0.45 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([CH3:21])(=[O:20])=[O:19])[C:8]([CH2:22][NH2:23])=[CH:7]2.Cl[C:25]1[N:33]=[CH:32][N:31]=[C:30]2[C:26]=1[NH:27][CH:28]=[N:29]2.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([CH3:21])(=[O:19])=[O:20])[C:8]([CH2:22][NH:23][C:25]1[N:33]=[CH:32][N:31]=[C:30]3[C:26]=1[N:27]=[CH:28][NH:29]3)=[CH:7]2
Reactant: CS(=O)(=O)c1ccccc1-c1nc2c(Cl)cccc2cc1CN
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CS(=O)(=O)c1ccccc1-c1nc2c(Cl)cccc2cc1CNc1ncnc2[nH]cnc12

Procedure:
Prepared according to Procedure H using (8-chloro-2-(2-(methylsulfonyl)phenyl) quinolin-3-yl)methanamine (0.060 g, 0.173 mmol), 6-chloropurine (0.032 g, 0.21 mmol, 1.2 eq) and DIEA (0.34 mmol, 2.0 eq) in n-butanol (3 mL). N-((8-chloro-2-(2-(methylsulfonyl)phenyl)quinolin-3-yl)methyl)-9H-purin-6-amine [PI3Kδ IC50=222 nM] was obtained after purification as a white solid. 1H-NMR (MeOD) δ ppm 8.29 (s, 1H), 8.13 (s, 1H), 8.01-8.09 (m, 2H), 7.78-7.81 (m, 1H), 7.66-7.76 (m, 1H), 7.57-7.65 (m, 1H), 7.46 (d, J=7.83 Hz, 2H), 4.87-4.98 (m, 2 H), 3.28 (s, 3H), Mass Spectrum (ESI) m/e=465 (M+1).
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=1.CC1(C)C(C)(C)OB([C:17]2[CH:18]=[N:19][NH:20][CH:21]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:19]1[CH:18]=[C:17]([C:2]2[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=2)[CH:21]=[N:20]1
Reactant: O=Cc1cnc(Br)s1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=Cc1cnc(-c2cn[nH]c2)s1
Temperature: 70 °C
Yield: 53.7 %

Procedure:
To a solution of 2-bromothiazole-5-carbaldehyde (500 mg, 2.6 mmol) in toluene (15 mL) and ethanol (7 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (606 mg, 3.1 mmol), 2M sodium carbonate solution (7.3 mL) and Pd(PPh3)4 (30 mg, 0.02 mmol). The reaction mixture was purged with argon for 15 min and the resulting mixture was heated at 70° C. for 4 h. The reaction mixture was concentrated, diluted with water (100 mL), and extracted with ethyl acetate (2×200 mL). The combined extracts were washed with brine solution (20 mL), dried over Na2SO4, filtered and concentrated to under vacuum to obtain crude product. The crude product was purified by flash chromatography (60-120μ; 50% ethyl acetate in hexane) to afford 2-(1H-pyrazol-4-yl)thiazole-5-carbaldehyde as yellow solid (250 mg, 54% yield). 1H NMR (400 MHz, DMSO-d6): δ 13.49 (br s, 1H), 10.00 (s, 1H), 8.61 (s, 1H), 8.55 (s, 1H), 8.09 (s, 1H); LC-MS m/z calculated for [M+H]+ 180.02, found 180.1.
Reaction SMILES: [C:1]([C:5]1[CH:44]=[CH:43][C:8]([C:9]([NH:11][C:12]2[C:13]([CH3:42])=[C:14]([C:18]3[N:23]=[C:22]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([CH:31]([N:35]([CH:37]([CH3:39])[CH3:38])[CH3:36])[C:32](O)=[O:33])=[CH:27][CH:26]=4)[C:21](=[O:40])[N:20]([CH3:41])[CH:19]=3)[CH:15]=[CH:16][CH:17]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:45][N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[C:1]([C:5]1[CH:44]=[CH:43][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[N:23]=[C:22]([NH:24][C:25]4[CH:26]=[CH:27][C:28]([CH:31]([N:35]([CH:37]([CH3:38])[CH3:39])[CH3:36])[C:32]([N:49]5[CH2:50][CH2:51][N:46]([CH3:45])[CH2:47][CH2:48]5)=[O:33])=[CH:29][CH:30]=4)[C:21](=[O:40])[N:20]([CH3:41])[CH:19]=3)[C:13]=2[CH3:42])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCNCC1
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cn(C)c(=O)c(Nc2ccc(C(C(=O)O)N(C)C(C)C)cc2)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cn(C)c(=O)c(Nc2ccc(C(C(=O)N3CCN(C)CC3)N(C)C(C)C)cc2)n1
Temperature: 25 °C
Reaction time: 26 h

Procedure:
To a sealed tube equipped with a magnetic stirrer, were charged 29 (100 mg, 0.168 mmol), 1-methylpiperazine (14.6 mg, 0.168 mmol), DMF (3 mL), Hunig's base (65.1 mg, 0.503 mmol), and BOP (74.3 mg, 0.168 mmol). The reaction mixture was stirred at room temperature for 26 hrs. Most solvent was removed by rotary evaporation and the resulting residue was dissolved in ethyl acetate (100 mL). The solution was washed with water (15 mL×3), dried over MgSO4, filtered and solvent removed in vacuo. Silica gel column chromatography (MeOH:CH2Cl2=5:95) afforded 30 as a light yellow solid, 25 mg (22%). 1H NMR (300 MHz, CDCl3) δ8.45 (s, 1 H), 8.09 (s, 1 H), 7.95 (s, 1 H), 7.92 (s, 1 H), 7.85 (m, 2 H), 7.75 (m, 1 H), 7.54 (s, 1 H), 7.51 (s, 1 H), 7.40 (m, 2 H), 7.19-7.23 (m, 2 H), 6.79 (s, 1 H), 5.19 (s, 1 H), 3.62 (s, 3 H), 3.40 (broad s, 2 H), 3.21 (broad s, 2 H), 2.26-2.50 (m, 9 H), 2.18 (s, 3 H), 1.92 (broad s, 2 H), 1.34 (s, 9 H), 1.25-1.31 (m, 6 H) ppm; MS (ESI+) m/z 678.19 (M+H).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N.[Li].Cl.Cl[CH2:17][CH2:18][N:19]([CH3:21])[CH3:20].[Cl-].[NH4+]>CCOCC>[CH3:20][N:19]([CH3:21])[CH2:18][CH2:17][C:1]1([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH2:4][CH:3]=[CH:2]1
Reactant: c1ccc(-c2ccccc2)cc1
Reactant: CN(C)CCCl
Agent: Cl
Agent: N
Agent: [Cl-]
Solvent: CCOCC
Product: CN(C)CCC1(c2ccccc2)C=CCC=C1
Reaction time: 2 h

Procedure:
23.1 g. of biphenyl in 200 ml. of ether are added to 300 ml. of condensed, dry ammonia and then 2.1 g. of lithium wire (about 2 cm long pieces, de-greased with cyclohexane) are subsequently added at -40° C. over a period of 15 minutes. The mixture is then held at boiling temperature (about -33° C.) for 2 hours. Subsequently, 7.2 g. of 2-chloro-N,N-dimethylethylamine hydrochloride are rapidly added portionwise at about -70° C. The mixture is again warmed to boiling temperature and held at this temperature for 0.5 hour. After the subsequent addition of ammonium chloride, distillation of the ammonia and aqueous working-up, an oily product is obtained. After purification by chromatography on a 20-fold amount of silica gel using methylene chloride/methanol (10:1) for the elution, the resulting N,N-dimethyl-1-phenyl-2,5-cyclohexadien-1-ethylamine is converted into the (1:1)-maleate as described in Example 1.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[N:7]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH2:43]=[CH:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-].CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:43](/[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[N:7]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1)=[CH:44]\[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: O=c1c2ccc(Br)cc2nc2n1CCCCC2
Reactant: C=Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: O=c1c2ccc(/C=C/c3ccccc3)cc2nc2n1CCCCC2
Temperature: 120 °C
Reaction time: 2 h

Procedure:
A mixture of 3-bromo-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one (100 mg, 0.34 mmol), Cs2CO3 (132.6 mg, 0.85 mmol), Pd(OAc)2 (30.6 mg, 0.14 mmol), PPh3 (103 mg, 0.34 mmol), Bu4NBr (109.5 mg, 0.34 mmol), and styrene (88.7 mg, 0.85 mmol) in DMF (6 mL) in a sealed tube was stirred at 120° C. for two hours. After it was cooled to room temperature, the reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over Na2SO4. After filtration and concentration, the residue was purified by silica gel chromatography to give the desired product. MS (ESI): 317 (MH+); 1H NMR (300 MHz, CDCl3) δ 8.08-8.05 (d, J=8.19 Hz, 1H), 7.78-7.74 (m, 2H), 7.68-7.66 (m, 2H), 7.54-7.30 (m, 5H), 4.34-4.31 (m, 2H), 3.05 (broad, 2H), 1.73-1.70 (m, 6H). mGluR5 PAM EC50: +++++. Fold shift at 10 μM: ++.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][O:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:32]5[CH:31]=[N:30][C:29]([O:28][CH2:27][CH2:26][O:25][CH3:24])=[CH:34][CH:33]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: COCCOc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: COCCOc1ccc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cn1

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.105 mmol) and 2-(2-methoxy-ethoxy)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 18.1.1, 38 mg, 0.137 mmol) to give the title compound as an off-white foam. (HPLC: tR 2.58 min (Method A); M+H=445 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.96 (s, 1H), 8.32-8.25 (m, 1H), 8.16-8.04 (m, 2H), 7.93-7.86 (m, 1H), 7.81-7.74 (m, 1H), 7.51-7.45 (m, 1H), 6.99-6.92 (m, 1H), 4.45-4.38 (m, 2H), 3.92 (s, 3H), 3.70-3.64 (m, 2H), 3.57 (s, 3H), 3.31 (s, 3H), 1.96 (s, 3H))
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][CH:8]([O:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[C:9]#[CH:10])=[CH:4][CH:3]=1.[CH2:18]([SnH:22]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH3:21]>N(C(C)(C)C#N)=NC(C)(C)C#N>[CH2:27]([Sn:22]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:23][CH2:24][CH2:25][CH3:26])/[CH:10]=[CH:9]/[CH:8]([O:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][O:6][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:17][CH:16]=1)[CH2:28][CH2:29][CH3:30]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C#CC(COc1ccc(F)cc1)O[Si](C)(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCCC[Sn](/C=C/C(COc1ccc(F)cc1)O[Si](C)(C)C)(CCCC)CCCC
Temperature: 140 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
A mixture of 2.52 g (10 mmoles) of 3-trimethylsilyloxy-4-p-fluorophenoxy-1-butyne (Example 158), 2.91 g (10 mmoles) of tri-n-butyl-tin hydride, and 10 mg of azobisisobutyronitrile is heated, under an argon atmosphere, with stirring, for 2 hours at 140° C. After cooling to room temperature, the crude reaction mixture is fractionally distilled at 180°-185° C. (0.05 mm), to give 4.6 g (85%) of the subject product as a colorless liquid.
Reaction SMILES: [C@@H:1]12[CH2:7][C@@H:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[NH:8][C:9]1[S:10][CH:11]([CH2:15][CH2:16][OH:17])[C:12](=[O:14])[N:13]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:29]1[CH:34]=[CH:33][CH2:32][CH2:31][CH2:30]1>C(Cl)Cl>[C@@H:1]12[CH2:7][C@@H:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[NH:8][C:9]1[S:10][CH:11]([CH2:15][CH2:16][O:17][CH:30]2[CH2:31][CH2:32][CH2:33][CH2:34][O:29]2)[C:12](=[O:14])[N:13]=1
Reactant: C1=COCCC1
Reactant: O=C1N=C(N[C@H]2C[C@@H]3CC[C@H]2C3)SC1CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: O=C1N=C(N[C@H]2C[C@@H]3CC[C@H]2C3)SC1CCOC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The mixture of 2-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-ylamino)-5-(2-hydroxyethyl)thiazol-4(5H)-one (3.2 g, 12.6 mmol) and p-toluenesulfonic acid (500 mg) in 3,4-dihydro-2H-pyran (10 mL) was stirred for 2 h at room temperature. The resulting mixture was diluted with CH2Cl2 (100 mL), then washed with sat'd NaH2PO4, and dried over MgSO4. After being filtered and concentrated in vacuo, the crude residue was purified by flash chromatography (3:2; Hexane:EtOAc) to give the title compound as an oil. MS (ES+): 339 (M+H)+.
Reaction SMILES: [N:1]([C:4]1[CH:8]([O:9][CH2:10][CH3:11])[O:7][C:6](=[O:12])[CH:5]=1)=[N+]=[N-].[C:13]1([P:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:26]1([P:19](=[N:1][C:4]2[CH:8]([O:9][CH2:10][CH3:11])[O:7][C:6](=[O:12])[CH:5]=2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCOC1OC(=O)C=C1N=[N+]=[N-]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC1OC(=O)C=C1N=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 65 °C
Yield: 44.6 %

Procedure:
A solution of 4-azido-5-ethoxy-5H-furan-2-one (0.17 g, 1.0 mmol) and triphenylphosphine (0.26 g, 1.0 mmol) in toluene (5 mL) at room temperature under nitrogen was stirred for 1 h, then heated at 60-70° C. for 8 h. The reaction was cooled, was diluted with ethyl acetate, was washed with sodium bisulfate, sodium bicarbonate and brine, was dried over sodium sulfate and was evaporated. Purification by flash chromatography (SiO2) eluted with 1:1 ethyl acetate:hexanes afforded 4-[(triphenylphosphoranylidene)amino]-5-ethoxy-5H-furan-2-one (0.18 g, 45% yield) as an off-white solid. 1H-NMR (500 MHz, CDCl3) δ 7.73 (m, 6H), 7.65 (m, 3H), 7.55• (m, 6H), 5.58 (s, 1H), 4.33 (s, 1H), 3.81 (m, 1H), 3.64 (s, 1H), 1.27 (t, J=7.1 Hz, 3H) ppm. MS (ES+) m/e=404 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[NH:8][C:7]([CH3:14])=[CH:6]2.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH:6]=[C:7]([CH3:14])[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(=O)[nH]c(C)cc2c1
Product: COc1ccc2c(Cl)nc(C)cc2c1

Procedure:
Isoquinoline-1-one 43 was dissolved in POCl3 (2.5 mL) and heated at reflux for 1h. The excess POCl3 was removed in vacuo and the residue was dissolved in CHCl3. The resulting solution was washed with 1N aq. NaOH, water and saturated ag. NaCl. Evaporation of the solvent gave crude 44 which was used directly in the next step.
Reaction SMILES: [CH2:1]([O:6][C:7]1[C:8](=[O:14])[CH:9]=[CH:10][C:11](=[O:13])[CH:12]=1)[CH:2]=[C:3]([CH3:5])[CH3:4].[CH3:15][C:16]1([CH3:24])[C:21]([CH:22]=[CH2:23])=[CH:20][CH2:19][CH2:18][CH2:17]1>CO>[CH2:1]([O:6][C:7]1[C:8](=[O:14])[C:9]2[C:10](=[CH:23][CH:22]=[C:21]3[C:20]=2[CH2:19][CH2:18][CH2:17][C:16]3([CH3:24])[CH3:15])[C:11](=[O:13])[CH:12]=1)[CH:2]=[C:3]([CH3:5])[CH3:4]
Reactant: C=CC1=CCCCC1(C)C
Reactant: CC(C)=CCOC1=CC(=O)C=CC1=O
Solvent: CO
Product: CC(C)=CCOC1=CC(=O)c2ccc3c(c2C1=O)CCCC3(C)C
Yield: 35.5 %

Procedure:
2-Prenyloxy-1,4-benzoquinone (20.0 g, 0.104 M) and 6,6-Dimethyl-1-vinylcyclohexene (56.7 g, 0.416 M) were dissolved in 150 ml of MeOH, and refluxed for 3 hours. 3-Prenyloxy-8,8-dimethyl-5,6,7,8-tetrahydro-1,4-phenanthrenequinone (12.0 g, 0.037 M) was obtained in the same manner as in Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[I:9]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([I:9])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: O=C1CCC(=O)N1I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1ncc(Cl)cc1I
Temperature: 55 °C
Reaction time: 18 h
Yield: 97 %

Procedure:
A mixture of 6.43 g of 5-chloropyridin-2-ylamine and 12.38 g of N-iodosuccinimide in 300 ml of glacial acetic acid is heated at around 55° C. for 6 hours. After returning to a temperature of approximately 20° C., the mixture is agitated for approximately 18 hours and then concentrated to dryness under reduced pressure (13 kPa). The residue is taken up with 400 ml of water; the pH of the suspension obtained is brought back to approximately 8 by adding a saturated aqueous sodium hydrogen carbonate solution. The precipitate is filter-dried, washed with water, and dried at 40° C. under reduced pressure (13 kPa) for approximately 3 hours. 12.35 g of 5-chloro-3-iodopyridin-2-ylamine are obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]([CH:8]([CH3:16])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:4](=[O:17])[CH:3]=1.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1B(O)O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[C:2]1[CH:7]=[CH:6][N:5]([CH:8]([CH3:16])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:4](=[O:17])[CH:3]=1
Reactant: CC(C(=O)OC(C)(C)C)n1ccc(Br)cc1=O
Reactant: OB(O)c1cc(Cl)ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CC(C(=O)OC(C)(C)C)n1ccc(-c2cc(Cl)ccc2Br)cc1=O

Procedure:
856 mg (2.75 mmol) of tert-butyl 2-(4-bromo-2-oxopyridin-1(2H)-yl)propanoate (racemate) and 776 mg (3.3 mmol) of 2-bromo-5-chlorophenylboronic acid in the presence of tetrakis(triphenylphosphine)palladium(0) were reacted according to General Method 2A. Yield: 921 mg (80% of theory)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]([CH3:12])=[N:10][CH:9]=[CH:8][N:7]=1)=[O:5])[CH3:2].[Br:13]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:11]([CH2:12][Br:13])=[N:10][CH:9]=[CH:8][N:7]=1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1nccnc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1nccnc1CBr
Reaction time: 1 h

Procedure:
A mixture of 3-methyl-pyrazine-2-carboxylic acid ethyl ester (Example 1.1) (0.5 g), N-bromosuccinimide (“NBS”) (0.536 g) and 2,2′-azobis(2-methylpropionitrile) (“AIBN”) (0.487 g) in carbon tetrachloride (2.5 ml) was heated to reflux. After 1 hour thin layer chromatography showed a mixture of starting material and the desired product. Further NBS (0.536 g) and AIBN (0.243 g) were added and the reaction mixture heated for a further 1 hour. The percentage of product increased and impurities began to form. The reaction mixture was cooled to ambient temperature and then to 0° C. The cold mixture was filtered and the filtrate concentrated. The residue was purified by chromatography on silica gel (eluent: 0-10% v/v ethyl acetate in iso-hexane) to give 3-bromomethyl-pyrazine-2-carboxylic acid ethyl ester (640 mg) contaminated with 3-methyl-pyrazine-2-carboxylic acid ethyl ester (due to co-elution, ˜3:2). MH+=245, RT=1.26 min (Method A).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=O)=[CH:6][C:5]=1[O:12][CH3:13].[C:16](O[K])([CH3:19])([CH3:18])[CH3:17]>C1COCC1>[CH3:1][O:2][CH:3]([O:14][CH3:15])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:17]/[C:16]2[CH:19]=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:14])=[CH:5][CH:18]=2)=[CH:6][C:5]=1[O:12][CH3:13]
Reactant: COc1cc(C=O)ccc1C(OC)OC
Reactant: CC(C)(C)O[K]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(/C=C/c2ccc(C(OC)OC)c(OC)c2)cc1

Procedure:
The compound was prepared according to the general Horner-Wittig methodology, from 4-formyl-2-methoxybenzaldehyde dimethylacetal (630 mg, 3 mmol), dimethyl-4-carbomethoxylbenzyl phosphonate (775 mg, 1 eq.) using tBuOK (404 mg, 1.2 eq.) as base in anhydrous THF (15 ml); the mixture was heated at 70 C for 90 minutes then worked up as described previously and purified by MPLC with hexanes/ethyl acetate 0-30% gradient. Yield: 795 mg (76%). MS, m/e: 342 (M+) 15%; 311 (M+-MeO, 100%); 294 (5%); 234 (4%); 164 (12%); 139 (10%).
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([NH:12][C:13](=[O:18])[CH2:14][C:15]([OH:17])=O)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[Cl:20][C:21]1[CH:33]=[CH:32][CH:31]=[CH:30][C:22]=1[O:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.CC(C)N=C=NC(C)C>C1COCC1>[Cl:20][C:21]1[CH:33]=[CH:32][CH:31]=[CH:30][C:22]=1[O:23][CH:24]1[CH2:29][CH2:28][N:27]([C:15](=[O:17])[CH2:14][C:13]([NH:12][C:10]2[S:9][N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:11]=2)=[O:18])[CH2:26][CH2:25]1
Reactant: O=C(O)CC(=O)Nc1nc(-c2ccccc2)ns1
Reactant: Clc1ccccc1OC1CCNCC1
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Solvent: C1CCOC1
Product: O=C(CC(=O)N1CCC(Oc2ccccc2Cl)CC1)Nc1nc(-c2ccccc2)ns1
Yield: 36.5 %

Procedure:
To a stirred solution of N-(3-phenyl-[1,2,4]thiadiazol-5-yl)-malonamic acid (0.07 g, 0.00027 mole) in THF (3 mL) was added, 4-(2-chloro-phenoxy)-piperidine hydrochloride (0.072 g, 0.00029 mol) followed by DIC (0.04 g, 0.00031 mole). The resulting mixture was heated to reflux for 4 hours then concentrated. The resulting residue was purified by column chromatography using neutral aluminium oxide (0.5% methanol in dichloromethane) to afford 0.045 g (37%) of 3-[4-(2-chloro-phenoxy)-piperidin-1-yl]-3-oxo-N-(3-phenyl-[1,2,4]thiadiazol-5-yl)-propionamide. LC-MS purity: 457.1 (M+1)+, 84.85% 1H NMR (CDCl3): δ 8.2 (s, 2H), 7.5 (m, 4H), 7.2 (m, 1H), 7.0 (d, 2H), 4.7 (s, 1H), 4.2 (d, 1H), 3.8 (m, 1H), 3.6 (m, 5H), 2.0 (dd, 4H), 2.6 (bs, 3H).