Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[N:11]=[CH:10][C:9]([C:12]3[CH:23]=[CH:22][C:15]([C:16]([NH:18][CH:19]4[CH2:21][CH2:20]4)=[O:17])=[CH:14][CH:13]=3)=[CH:8][C:6]=2[N:7]=1.[C:30]([O:34][C:35]([NH:37][C:38]1[N:43]=[CH:42][C:41](B(O)O)=[CH:40][N:39]=1)=[O:36])([CH3:33])([CH3:32])[CH3:31].P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(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.O>[CH:19]1([NH:18][C:16]([C:15]2[CH:22]=[CH:23][C:12]([C:9]3[CH:10]=[N:11][C:5]4[C:4]([N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)=[N:3][C:2]([C:41]5[CH:42]=[N:43][C:38]([NH:37][C:35](=[O:36])[O:34][C:30]([CH3:32])([CH3:31])[CH3:33])=[N:39][CH:40]=5)=[N:7][C:6]=4[CH:8]=3)=[CH:13][CH:14]=2)=[O:17])[CH2:21][CH2:20]1
Reactant: O=C(NC1CC1)c1ccc(-c2cnc3c(N4CCOCC4)nc(Cl)nc3c2)cc1
Reactant: CC(C)(C)OC(=O)Nc1ncc(B(O)O)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ncc(-c2nc(N3CCOCC3)c3ncc(-c4ccc(C(=O)NC5CC5)cc4)cc3n2)cn1
Temperature: 95 °C
Reaction time: 1 h
Yield: 48.9 %

Procedure:
To a 50 mL sealed tube, 4-(2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)-N-cyclo-propylbenzamide (0.15 g, 0.00036 mol), (2-((tert-butoxycarbonyl)amino)pyrimidin-5-yl)boronic acid (0.113 g, 0.00047), potassium phosphate (0.155 g, 0.00072 mol), DMF (10 mL) and water (2 mL) were added. The reaction mixture was degassed with N2 for 5-10 minutes. To the same reaction mixture, Pd(PPh3)4 (0.022 g, 0.000018 mol) was added and degassed with N2 for 5-10 minutes. The reaction mixture was stirred at 95° C. for 1 hour. The reaction mass was cooled to room temperature and added ice cold water. A precipitate was obtained and the solid was collected by filtration. The solid was dissolved in chloroform, dried over anhydrous sodium sulfate and evaporated under reduced pressure to provide the crude product. The crude product was purified by flash column chromatography (2% methanol in chloroform) to provide the title compound (0.1 g, 48%). 1H NMR (300 MHz, DMSO-d6): δ 10.41 (br s, 1H), 9.47 (s, 1H), 9.19 (d, J=1.8 Hz, 1H), 6.59 (d, J=4.2 Hz, 1H), 8.51 (d, J=1.8 Hz, 1H), 7.98-8.08 (m, 4H), 4.57 (br s, 4H), 3.83 (s, 4H), 2.88-2.89 (m, 1H), 1.48 (s, 9H), 0.73 (d, J=5.4 Hz, 2H), 0.61 (d, J=3.0 Hz, 2H): LC-MS (ESI): Calculated mass: 568.2; Observed mass [M+H]+: 569.2. (RT=1.57 min).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]([CH2:13][C:14]([O:16]CC)=O)[CH2:7][NH:8]2)([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+].Cl.C([O-])(O)=O.[Na+]>O.CCO>[NH:8]1[C:9]2[C:5]3[CH:6]([CH2:13][C:14](=[O:16])[NH:1][C:4]=3[CH:12]=[CH:11][CH:10]=2)[CH2:7]1
Reactant: CCOC(=O)CC1CNc2cccc([N+](=O)[O-])c21
Agent: Cl
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Solvent: CCO
Solvent: O
Product: O=C1CC2CNc3cccc(c32)N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of ethyl (4-nitro-2,3-dihydro-1H-indol-3-yl)acetate, enantiomer B, from Step B (1.50 g, 5.99 mmol) in H2O (50 mL) and EtOH (42 mL) was added sodium hydrosulfite (ca. 85%; 4.91 g, 24 mmol). The reaction mixture was stirred at ambient temperature for 1 h, then 3 N hydrochloric acid (14 mL, 42 mmol) was added and the solution was heated to 100° C. for 3 h. The cooled mixture was adjusted to pH 8 with saturated aqueous NaHCO3, then extracted with CH2Cl2 (6×200 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=175 (M+1).
Reaction SMILES: COC1C=C2C(=CC=1OC)CC(/C=C/C#N)=C2.[ClH:18].[OH:19][NH:20][C:21](=[NH:37])/[CH:22]=[CH:23]/[C:24]1[CH2:25][C:26]2[C:31]([CH:32]=1)=[CH:30][C:29]([O:33][CH3:34])=[C:28]([O:35][CH3:36])[CH:27]=2>>[ClH:18].[OH:19][NH:20][C:21](=[NH:37])[CH:22]=[CH:23][C:24]1[CH2:25][C:26]2[C:31]([CH:32]=1)=[CH:30][C:29]([O:33][CH3:34])=[C:28]([O:35][CH3:36])[CH:27]=2
Reactant: COc1cc2c(cc1OC)CC(/C=C/C(=N)NO)=C2
Agent: COc1cc2c(cc1OC)CC(/C=C/C#N)=C2
Agent: Cl
Product: COc1cc2c(cc1OC)CC(C=CC(=N)NO)=C2

Procedure:
Using the procedure described in Example 1 (E)-3-(5,6-dimethoxy-1H-indene-2-yl)-2-propenenitrile was converted into (E)-N-hydroxy-3-(5,6-dimethoxy-1H-indene-2-yl)-prop-2-ene-imidamide hydrochloride, m.p. 170° C. (dec.).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:12]([N:14]([CH3:39])[C@H:15]([C:19]([N:21]([CH3:38])[C@H:22]([C:35]([NH2:37])=[O:36])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:25]=1)=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([F:11])[CH:5]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:1][C@H:2]([C:12]([N:14]([CH3:39])[C@H:15]([C:19]([N:21]([CH3:38])[C@H:22]([C:35]([NH2:37])=[O:36])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([C:31]([CH3:32])([CH3:34])[CH3:33])[CH:25]=1)=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([F:11])[CH:5]=1
Reactant: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)N(C)C(=O)[C@H](Cc1ccc(O)c(F)c1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)N(C)C(=O)[C@@H](N)Cc1ccc(O)c(F)c1
Reaction time: 0.25 h
Yield: 84.9 %

Procedure:
To a solution of Boc-Tyr(3-F)-N-Me-Val-N-Me-Tyr(3-tBu)-NH2 (0.19 g, 0.294 mmol) in methylene chloride (3 ml), TFA (1.5 ml) was added and stirred for 15 min. The reaction mixture was concentrated under reduced pressure, mixed with a saturated aqueous NaHCO3 solution, and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate. The resultant was evaporated to remove the solvent under reduced pressure, giving the titled compound (136 mg, 85%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([CH3:14])[CH:7]=1)(O)[CH3:4].Cl[CH2:18]Cl>[Ti](Cl)(Cl)(Cl)Cl>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([C:3]([CH3:18])([CH3:4])[C:2]([F:16])([F:15])[F:1])=[CH:7][C:8]=1[CH3:14]
Reactant: COc1ccc(C(C)(O)C(F)(F)F)cc1C
Reactant: ClCCl
Agent: Cl[Ti](Cl)(Cl)Cl
Product: COc1ccc(C(C)(C)C(F)(F)F)cc1C
Temperature: -70 °C
Reaction time: 2 h

Procedure:
To an ice-cold solution of 1,1,1-trifluoro-2-(4-methoxy-3-methylphenyl)-propane-2-ol (440 mg) in dichloromethane (20 ml) were added titanium tetrachloride (357 mg). Under the same temperature, it was stirred for 2 hours. Ice-cold water and dichloromethane were added to the organic layer and the organic layer was separated. The obtained organic layer was washed with saturated sodium bicarbonate solution and dried over anhydrous potassium carbonate. After removing the drying agent, the organic layer was concentrated under reduced pressure. After the residue was dissolved in dichloro methane (15 ml), it was cooled at −70° C. and titanium tetrachloride (302 mg) and dimethylzinc (1M, n-hexane solution, 3.18 ml) was added. The mixture was brought back to room temperature and stirred for 3 hours. Ice-cold water and dichloromethane were added to the solution and the organic layer was separated. The obtained organic layer was washed with saturated sodium bicaronate solution and then dried over anhydroous magnesium sulfate. After removing the drying agent, the organic layer was concentrated under reduced pressure.
Reaction SMILES: F[C:2]1[CH:7]=C[C:5]([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[CH:4][CH:3]=1.CC1[S:43]C(B2OC(C)(C)C(C)(C)O2)=CC=1>>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]2[N:24]=[C:20]([CH:17]3[CH2:18][CH2:19][N:14]([C:13]4[N:12]=[CH:11][N:10]=[C:9]([NH2:37])[C:8]=4[C:5]4[S:43][C:2]([CH3:7])=[CH:3][CH:4]=4)[CH2:15][CH2:16]3)[N:21]([CH3:36])[CH:22]=2)=[CH:26][C:27]=1[C:32]([F:35])([F:34])[F:33]
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Product: Cc1ccc(-c2c(N)ncnc2N2CCC(c3nc(-c4ccc(F)c(C(F)(F)F)c4)cn3C)CC2)s1

Procedure:
The title compound was prepared in an analogous manner as 5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine using 5-methylthiophene-2-boronic acid pinacol ester instead of 4-fluorophenylboronic acid. LC-MS: (M+1=517, obsd.=517).
Reaction SMILES: C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)[C:14]2[N:15]=[CH:16]C=CC=2N=N1.F[P-](F)(F)(F)(F)F.[F:34][C:35]1[CH:40]=[CH:39][C:38]([N:41]2[C:45]3[CH:46]=[C:47]4[C@:52]([C:54](=[O:61])[C:55]5[CH:60]=[CH:59][CH:58]=[CH:57][N:56]=5)([CH2:53][C:44]=3[CH:43]=[N:42]2)[CH2:51][N:50]([S:62]([C:65]2[CH:66]=[C:67]([CH:71]=[CH:72][CH:73]=2)[C:68]([OH:70])=O)(=[O:64])=[O:63])[CH2:49][CH2:48]4)=[CH:37][CH:36]=1.CNC.C(N(CC)CC)C>ClCCl>[F:34][C:35]1[CH:36]=[CH:37][C:38]([N:41]2[C:45]3[CH:46]=[C:47]4[C@:52]([C:54](=[O:61])[C:55]5[CH:60]=[CH:59][CH:58]=[CH:57][N:56]=5)([CH2:53][C:44]=3[CH:43]=[N:42]2)[CH2:51][N:50]([S:62]([C:65]2[CH:66]=[C:67]([CH:71]=[CH:72][CH:73]=2)[C:68]([N:15]([CH3:16])[CH3:14])=[O:70])(=[O:64])=[O:63])[CH2:49][CH2:48]4)=[CH:39][CH:40]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCC3=Cc4c(cnn4-c4ccc(F)cc4)C[C@]3(C(=O)c3ccccn3)C2)c1
Agent: CNC
Agent: C[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)c1cccc(S(=O)(=O)N2CCC3=Cc4c(cnn4-c4ccc(F)cc4)C[C@]3(C(=O)c3ccccn3)C2)c1
Yield: 11.7 %

Procedure:
2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate Methanaminium (HATU) (42.7 mg, 0.112 mmol) was added to a solution of (R)-3-((1-(4-fluorophenyl)-4a-picolinoyl-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinolin-6(4H)-yl)sulfonyl)benzoic acid (57 mg, 0.102 mmol), dimethylamine (51.0 μl, 0.102 mmol) and triethylamine (28.4 μl, 0.204 mmol) in dichloromethane (3 mL). The resultant mixture was stirred at room temperature for 1 hour. The reaction was diluted with dichloromethane (5 mL) and washed with a saturated solution of sodium hydrogen carbonate (aqueous, 5 mL). The organic phase was passed through a phase separator and solvent removed to give a yellow solid. The crude product was purified by chromatography on silica gel (gradient: 0-100% ethyl acetate in isohexane) to afford (R)-3-((1-(4-fluorophenyl)-4a-picolinoyl-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinolin-6(4H)-yl)sulfonyl)-N,N-dimethylbenzamide (7 mg) as a white solid. LCMS (Method F, ES-API): RT 2.24 min, m+H=586.1; 1H NMR (400 MHz, CDCl3): δ 8.68 (1H, ddd, J=4.7, 1.7, 0.9 Hz), 7.90 (1H, dt, J=7.9, 1.2 Hz), 7.84 (1H, td, J=7.7, 1.7 Hz), 7.74-7.71 (2H, m), 7.61 (1H, dt, J=7.7, 1.4 Hz), 7.57-7.39 (4H, m), 7.28 (1H, s), 7.20-7.13 (2H, m), 6.47 (1H, d, J=2.0 Hz), 5.52 (1H, dd, J=12.1, 2.0 Hz), 4.27 (1H, d, J=16.9 Hz), 3.86-3.77 (1H, m), 3.14 (3H, s), 2.94-2.76 (5H, m), 2.70 (1H, d, J=12.1 Hz), 2.50-2.43 (2H, m).
Reaction SMILES: [S:1](Br)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].CCN(CC)CC.[C:19]([C:23]1[CH:28]=[C:27]([O:29][CH2:30][CH2:31][O:32][CH2:33][O:34][CH3:35])[C:26]([CH3:36])=[CH:25][C:24]=1[SH:37])([CH3:22])([CH3:21])[CH3:20]>C(Cl)C(Cl)Cl.CCOC(C)=O>[C:19]([C:23]1[CH:28]=[C:27]([O:29][CH2:30][CH2:31][O:32][CH2:33][O:34][CH3:35])[C:26]([CH3:36])=[CH:25][C:24]=1[S:37][S:1]([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2])([CH3:22])([CH3:21])[CH3:20]
Reactant: Cc1ccc(S(=O)(=O)Br)cc1
Reactant: COCOCCOc1cc(C(C)(C)C)c(S)cc1C
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCC(Cl)Cl
Product: COCOCCOc1cc(C(C)(C)C)c(SS(=O)(=O)c2ccc(C)cc2)cc1C
Reaction time: 13 h

Procedure:
A solution of tosyl bromide (21.0 g; 89.32 mmol), 50 mL of trichloroethane and 20 mL of NEt3 was cooled to 0° C. To this solution was added slowly a solution of 12.4 mmol of 2-tert-butyl-4-(2-methoxymethoxy-ethoxy)-5-methyl-benzenethiol (prepared in Example AAAA) in 100 mL of trichloroethane. After 13 hours, the reaction mixture was diluted with EtOAc and washed with brine. The product was purified by flash silica gel chromatography, eluting with EtOAc:hexane (5:95, then switching to 3:7).
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[F:23][C:24]1[CH:32]=[C:31]2[C:27]([C:28]([CH:33]3[CH2:38][CH2:37][N:36]([CH2:39][C:40](O)=[O:41])[CH2:35][CH2:34]3)=[N:29][NH:30]2)=[CH:26][CH:25]=1.[NH2:43][CH2:44][C:45]1[NH:46][C:47](=[O:55])[C:48]2[CH2:54][O:53][CH2:52][CH2:51][C:49]=2[N:50]=1.CCN(CC)CC>CN(C=O)C.[Cl-].[Na+].O>[F:23][C:24]1[CH:32]=[C:31]2[C:27]([C:28]([CH:33]3[CH2:38][CH2:37][N:36]([CH2:39][C:40]([NH:43][CH2:44][C:45]4[NH:46][C:47](=[O:55])[C:48]5[CH2:54][O:53][CH2:52][CH2:51][C:49]=5[N:50]=4)=[O:41])[CH2:35][CH2:34]3)=[N:29][NH:30]2)=[CH:26][CH:25]=1
Reactant: O=C(O)CN1CCC(c2n[nH]c3cc(F)ccc23)CC1
Reactant: NCc1nc2c(c(=O)[nH]1)COCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(CN1CCC(c2n[nH]c3cc(F)ccc23)CC1)NCc1nc2c(c(=O)[nH]1)COCC2
Temperature: 25 °C
Reaction time: 15 h
Yield: 19 %

Procedure:
To a solution of EDCl (0.22 g, 1.17 mmol), HOBT (0.16 g, 1.17 mmol) in 10 mL of DMF were added [4-(6-fluoro-1H-indazol-3-yl)-piperidin-1-yl]-acetic acid (0.27 g, 1.0 mmol), 2-aminomethyl-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (0.19 g, 1.1 mmol), and Et3N (0.40 g, 3.9 mmol). The reaction mixture was stirred at ambient temperature for 15 hours then poured into a separatory funnel containing brine. After separation, the aqueous layer was extracted with DCM (50 mL). The combined organic layers were washed with saturated aqueous NaHCO3 solution, dried over Na2SO4, filtered and concentrated in vacuo to yield an oily liquid. Purification by flash chromatography gave the title compound (89.0 mg, 0.19 mmol, 20% yield) as a yellow solid. MS (ESI) m/z 440.8 (M+H+); HPLC (Novapak 150×3.9 mm C-18 column: mobile phase: 35-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 2 min.) t 0.96 min. 1H NMR (400 MHz, MeOD) δ ppm 1.94-2.27 (m, 4H), 2.36-2.56 (m, 2H), 2.64 (br. s., 2H), 2.98-3.46 (m, 4H), 3.90 (br. s., 2H), 4.27-4.59 (m, 2H), 4.72-5.01 (m, 3H), 6.91 (br. s., 1H), 7.14 (br. s., 1H), 7.82 (br. s., 1H). HRMS calculated for C22H26FN6O3: 441.2050 (M+H). found (ESI, [M+H]+): 441.2067.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH:19]=O)[CH:6]=1.[NH2:22][CH2:23][C@@H:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[OH:25]>>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19][NH:22][CH2:23][C@H:24]([OH:25])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=1
Reactant: NC[C@H](O)c1ccccc1
Reactant: COC(=O)Cc1cccc(Oc2ccc(Br)cc2C=O)c1
Product: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CNC[C@H](O)c2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 45, Step 3, using the following starting materials: [3-(4-bromo-2-formyl-phenoxy)-phenyl]-acetic acid methyl ester and (R)-(−)-2-amino-1-phenylethanol.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:10]Cl)=[N:4][CH:5]=[C:6]([O:8][CH3:9])[N:7]=1.[NH:12]1[CH:16]=[CH:15][N:14]=[C:13]1[C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[C:3]([CH2:10][N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[C:17]2[N:18]=[CH:19][CH:20]=[CH:21][N:22]=2)=[N:4][CH:5]=[C:6]([O:8][CH3:9])[N:7]=1
Reactant: COc1cnc(CCl)c(Cl)n1
Reactant: c1cnc(-c2ncc[nH]2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cnc(Cn2ccnc2-c2ncccn2)c(Cl)n1
Temperature: 45 °C
Reaction time: 16 h
Yield: 55.1 %

Procedure:
A mixture of 3-chloro-2-chloromethyl-5-methoxy pyrazine (141 mg, 0.73 mmol), 2-(1H-imidazol-2-yl)-pyrimidine (105 mg, 0.72 mmol) and K2CO3 (307 mg, 2.22 mmol) in DMF (10 mL) is stirred at 45° C. for 16 hours. On cooling, the reaction is quenched with saturated NH4Cl (5 mL) and extracted with DCM (3×15 mL). The combined organic layers are dried and solvent removed. PTLC separation (silica gel; 10% MeOH in DCM) gives 120 mg of 2-[1-(3-chloro-5-methoxy-pyrazin-2-ylmethyl)-1H-imidazol-2-yl]-pyrimidine as an oil. 1H NMR (CDCl3) 8.98 (d, 2H), 7.98 (s, 1H), 7.27 (s, 1H), 7.14–7.18 (m, 2H), 6.05 (s, 2H), 3.97 (s, 3H). H. 2-[1-(3,5-Dimethoxy-pyrazin-2-ylmethyl)-1H-imidazol-2-yl]-pyrimidine (Compound 9)
Reaction SMILES: [SH:1][C:2]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([N:6]([CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)[CH2:7][C:8](O)=[O:9])=[O:5].C(N(CC)CC)C.ClC(OCC)=O>C(Cl)Cl>[CH:11]1([N:6]2[C:4](=[O:5])[C:3]3[CH:16]=[CH:17][CH:18]=[C:19]([O:20][CH3:21])[C:2]=3[S:1][C:8](=[O:9])[CH2:7]2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COc1cccc(C(=O)N(CC(=O)O)C2CCCC2)c1S
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc2c1SC(=O)CN(C1CCCC1)C2=O
Reaction time: 2 h

Procedure:
N-(2-mercapto-3-methoxybenzoyl)-N-cyclopentylglycine (14.5 g, 0.0469 m) and triethylamine (4.7 g, 0.0469 m) in methylene chloride (500 ml) were cooled to 0° C., and ethyl chloroformate (5.1 g, 0.0469 m) was added over one minute. The mixture was stirred 2 hours at 0°-10° C., washed (water, then brine), dried (Na2SO4) and concentrated. HPLC purification using hexane/ethyl acetate (1/1) as eluent gave the desired product. Recrystallization from ethyl acetate provided 5.4 g analytically pure material (yield: 35%).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]([OH:19])([CH3:18])[CH3:17])=[CH:10][C:3]=1[CH2:4][NH:5][C:6](=[O:9])[O:7][CH3:8].[Cl-].[Ca+2].[Cl-].Cl.[CH3:24][O-].[Na+]>C1(C)C=CC=CC=1.CO.[Cu]I.[Cu].O>[Cl:1][C:2]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]([O:19][CH3:24])([CH3:17])[CH3:18])=[CH:10][C:3]=1[CH2:4][NH:5][C:6](=[O:9])[O:7][CH3:8]
Reactant: C[O-]
Reactant: COC(=O)NCc1cc(C#CC(C)(C)O)ccc1Cl
Agent: [Cu]
Agent: [Cu]I
Agent: Cl
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)NCc1cc(C#CC(C)(C)OC)ccc1Cl
Temperature: 0 °C
Reaction time: 5 h
Yield: 82.6 %

Procedure:
0.60 g of methyl N-[2-chloro-5-(3-hydroxy-3-methyl-1-butynyl)benzyl]carbamate was dissolved in 10 ml of toluene. This solution was added at 0° C. to a mixture comprising 0.12 g of calcium chloride, 0.08 g of copper(I) iodide, 0.01 g of copper and 10 ml of concentrated hydrochloric acid, followed by stirring at 0° C. for 5 hours. This solution was poured into water and extracted with ethyl acetate, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude product was dissolved in 10 ml, of methanol. To this solution, 0.50 g of sodium methylate (28 wt % methanol solution) was added at room temperature, followed by stirring at room temperature for 24 hours. The reaction mixture was poured into water and extracted with ethyl acetate, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified with silica gel column chromatography to obtain 0.52 g of methyl N-[2-chloro-5-(3-methoxy-3-methyl-1-butynyl)benzyl]carbamate as a brown viscous liquid.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=[O:22])[C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:8]=1)(=O)[CH3:2].CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC.ClC(Cl)C>>[CH3:2][C:1]1[O:22][C:6]([C:7]2[CH:8]=[C:9]([N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)[CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=2)=[N:5][N:4]=1
Reactant: CC(=O)NNC(=O)c1cc(N2CCOCC2)cc([N+](=O)[O-])c1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: CC(Cl)Cl
Product: Cc1nnc(-c2cc(N3CCOCC3)cc([N+](=O)[O-])c2)o1
Temperature: 120 °C

Procedure:
A 10 mL microwave vessel equipt with a stirbar was charged with N′-acetyl-3-morpholino-5-nitrobenzohydrazide (0.250 g, 0.811 mmol), Burgess reagent (0.97 g, 4.05 mmol), and dichloroethane (4 mL). The red solution was heated in a microwave at 120° C. for 20 minutes, then concd. The resulting residue was partitioned between EtOAc and water, and the organic layer washed with 1 N HCl, 1 N sodium hydroxide, and brine, then dried over magnesium sulfate and concd. This afforded a crude material that was purified by column chromatography (silica; 0-75% EtOAc in hexanes), providing 4-(3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-nitrophenyl)morpholine as a yellow amorphous solid. Mass Spectrum (ESI) m/e=291.1 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH:11]([NH2:13])[C:10]2=[N:14][C:15]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[CH:16][C:17](=[O:18])[N:9]2[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:25][O:26][C:27]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:28]=1[C:29](O)=[O:30].ClC1C=CC(C(O)=O)=C(OC)C=1>>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH:11]([NH:13][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][C:34]([O:36][CH3:37])=[CH:35][C:27]=2[O:26][CH3:25])[C:10]2=[N:14][C:15]([C:19]3[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=3)=[CH:16][C:17](=[O:18])[N:9]2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: COc1ccc(C(=O)O)c(OC)c1
Reactant: CCOC(=O)N1CCn2c(nc(-c3ccncc3)cc2=O)C(N)C1
Agent: COc1cc(Cl)ccc1C(=O)O
Product: CCOC(=O)N1CCn2c(nc(-c3ccncc3)cc2=O)C(NC(=O)c2ccc(OC)cc2OC)C1

Procedure:
By analogy with the method described in example 1 (step 1.8), using 9-amino-4-oxo-2-pyridin-4-yl-5,6,8,9-tetrahydro-4H-1,4a,7-triaza-benzocycloheptene-7-carboxylic acid ethyl ester and 2,4-dimethoxy-benzoic acid in place of (+/−)-9-amino-4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-1,4a,7-triaza benzocycloheptene-7-carboxylic acid ethyl ester hydrobromide (1:1) and 4-chloro-2-methoxy-benzoic acid, the compound, 0.103 g (76%), was obtained as a white powder.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][CH2:8][C:7]2([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[C:6]1=O)=O.[NH2:23][NH2:24]>C1(C)C=CC=CC=1>[C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][C:7]2([C:6]3[NH:24][NH:23][C:3](=[O:2])[C:5]=3[CH2:9][CH2:8]2)[CH2:10][CH2:11]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: NN
Reactant: COC(=O)C1CCC2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC2(CCc3c2[nH][nH]c3=O)CC1
Yield: 61.4 %

Procedure:
To a solution of tert-butyl 2-(methoxycarbonyl)-1-oxo-8-azaspiro[4.5]decane-8-carboxate from Procedure 1, Step F (0.448 g, 1.46 mmol) in toluene (15 mL) was added hydrazine (0.084 mL, 1.72 mmol). The reaction mixture was refluxed for 12 h, concentrated and the residue was purified by flash chromatography eluting with 5% MeOH/dichloromethane and 0.1% triethylamine to give the title compound (0.263 g). MS/EI (acetonitrile/water): m/z 294.3 retention time=2.0 min.
Reaction SMILES: [C:1]([CH:4]([CH2:17][C:18]#[C:19][C:20]1([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH2:5][CH2:6][CH2:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)(=[O:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pt]>[C:1]([CH:4]([CH2:17][CH2:18][CH2:19][C:20]1([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1)[CH2:5][CH2:6][CH2:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)C(CC#CC1(O)CCCCC1)CCCc1ccc(C(=O)O)cc1
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CC(=O)C(CCCc1ccc(C(=O)O)cc1)CCCC1(O)CCCCC1

Procedure:
4-[4-Acetyl-7-(1-hydroxycyclohexyl)-6-heptyn-1-yl]benzoic acid (5.1 g., 0.014 mole) in ethyl acetate (55 ml.) is hydrogenated over 2.0 g. of a 5% Pt on charcoal catalyst at 1 atmosphere pressure and room temperature. The theoretical amount of hydrogen (0.028 mole) is absorbed in 25 minutes. The catalyst is filtered off, the solvent is evaporated and the residue (5 g.) is chromatographed on 75 g. of silica gel with 2% methanol in chloroform as eluant. The title compound is obtained as a colorless viscous oil.