Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:20][CH2:21][OH:22])[CH:5]=[C:6]([Cl:19])[C:7]=1[S:8][C:9]1[N:10]=[N:11][C:12]([Cl:18])=[C:13]([CH:15]([CH3:17])[CH3:16])[CH:14]=1.CC(C)=[O:25].OS(O)(=O)=O.O=[Cr](=O)=O.CC(O)C>CC(C)=O.C(OCC)(=O)C.O>[Cl:19][C:6]1[CH:5]=[C:4]([CH2:20][C:21]([OH:25])=[O:22])[CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[N:10]=[N:11][C:12]([Cl:18])=[C:13]([CH:15]([CH3:17])[CH3:16])[CH:14]=1
Reactant: CC(C)c1cc(Sc2c(Cl)cc(CCO)cc2Cl)nnc1Cl
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)O
Product: CC(C)c1cc(Sc2c(Cl)cc(CC(=O)O)cc2Cl)nnc1Cl
Temperature: 0 °C
Reaction time: 1.25 h
Yield: 90.8 %

Procedure:
A solution of 2-[3,5-dichloro-4-(6-chloro-5-isopropyl-pyridazin-3-ylsulfanyl)-phenyl]-ethanol (74) (100 mg, 0.26 mmol) in acetone (2.0 mL) cooled to 0° C. was treated with a 2.7M solution of Jones reagent (0.21 mL, 0.57 mmol, prepared via standard method). The reaction was stirred at 0° C. for 1.25 h. At this time, the reaction was treated with 2-propanol until the red solution turned green. This mixture was then diluted with ethyl acetate (50 mL) and water (25 mL). The organics were separated, dried with magnesium sulfate, filtered, and concentrated under vacuum to afford [3,5-dichloro-4-(6-chloro-5-isopropyl-pyridazin-3-ylsulfanyl)-phenyl]-acetic acid (75) (92.5 mg, 89%) as an off-white foam. This material was used without further purification; LRMS-APCI for C15H13Cl3N2O2S (M+H)+ at m/z=390. Exact Mass=389.9763; Molecular weight=391.71
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[C:5]([N:13]2[CH2:18][C@H:17]([CH3:19])[O:16][C@H:15]([CH3:20])[CH2:14]2)=[C:4]([F:21])[C:3]=1[F:22].CN(C)CCN(C)C.CN(C)[CH:33]=[O:34]>O1CCCC1.C(OC(=O)C)C>[CH3:19][C@@H:17]1[CH2:18][N:13]([C:5]2[C:6]([CH:8]3[O:12][CH2:11][CH2:10][O:9]3)=[CH:7][C:2]([CH:33]=[O:34])=[C:3]([F:22])[C:4]=2[F:21])[CH2:14][C@H:15]([CH3:20])[O:16]1
Reactant: CN(C)C=O
Reactant: C[C@@H]1CN(c2c(C3OCCO3)cc(Br)c(F)c2F)C[C@H](C)O1
Agent: CN(C)CCN(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@@H]1CN(c2c(C3OCCO3)cc(C=O)c(F)c2F)C[C@H](C)O1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a solution of (2R,6S)-4-(4-bromo-6-(1,3-dioxolan-2-yl)-2,3-difluorophenyl)-2,6-dimethylmorpholine (previously described in WO2004031195, page 81, 0.500 g, 1.32 mmol) and tetramethylethylene-diamine (0.12 mL, 2.12 mmol) in tetrahydrofuran (12 mL) at −78° C. is added t-buthyllithium (1.94 mL, 3.31 mmol). The reaction is stirred at −78° C. for 1.5 h and dimethylformamide is added. The reaction is stirred at −78° C. for an additional 30 min and warmed to rt. Mixture is diluted with ethylacetate (50 mL) and washed with saturated aqueous NH4Cl. (50 ml) and brine (30 mL). Dried over Na2SO4 and concentrated to give the title compound (433 mg): LCMS (M+H) 327.1.
Reaction SMILES: [CH3:1][C@@:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[CH2:4][C:3]2=[O:13].C(N(CC)CC)C.[Cl:21][C:22]1[CH:23]=[C:24]([N:29]=[C:30]=[O:31])[CH:25]=[CH:26][C:27]=1[Cl:28].Cl>CN(C)C1C=CN=CC=1.ClCCl>[Cl:21][C:22]1[CH:23]=[C:24]([NH:29][C:30]([CH:4]2[C:5](=[O:12])[CH:6]3[C:9]([CH3:10])([CH3:11])[C@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:13])=[O:31])[CH:25]=[CH:26][C:27]=1[Cl:28]
Reactant: CC1(C)C2CC[C@]1(C)C(=O)CC2=O
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C2CC[C@]1(C)C(=O)C(C(=O)Nc1ccc(Cl)c(Cl)c1)C2=O
Temperature: 30 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
To an ice-cooled solution of (1S)-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.18 g, 1.0 mmole), triethylamine (0.10 g, 1.0 mmole) and 4-(dimethylamino)pyridine (0.12 g, 1.0 mmole) in dry dichloromethane (25 mL) was added a solution of 3,4-dichlorophenyl isocyanate (0.19 g, 1.0 mmole) in dry dichloromethane (5 mL). The resulting mixture was allowed to stir overnight under a nitrogen atmosphere, during which time it came up to room temperature, and then was heated at 30° C. for 7 hours. The reaction mixture was treated with 2N aqueous HCl and the layers separated. The acidic aqueous layer was extracted with two additional portions of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to give a yellow oil, which was purified by chromatography on silica gel (10% ethyl acetate/hexane) to yield a yellow oil, which was crystallized from 95% ethanol to yield the title compound as a tan solid (0.21 g, 57% yield), mp=88–90° C.; MS (−) ESI m/z=366 (M−H)−; [α]D25=−24.8° (c=1, EtOH).
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:11]([O:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][C:20]=1[Cl:26])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CN1CCCC1=O>CO>[CH2:11]([O:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:2]2[C:3]3[NH:10][CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:21][C:20]=1[Cl:26])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Nc1ccc(OCc2ccccc2)c(Cl)c1
Reactant: Clc1ncnc2cc[nH]c12
Solvent: CO
Solvent: CN1CCCC1=O
Product: Clc1cc(Nc2ncnc3cc[nH]c23)ccc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 49.5 %

Procedure:
A mixture of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (200 mg), 4-(benzyloxy)-3-chloroaniline (365 mg) and 1-methyl-2-pyrrolidone (3 mL) was stirred at 80° C. for 4 hrs. Methanol and activated carbon were added to the reaction mixture and the mixture was stirred. The activated carbon was filtered off, aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent, methanol:ethyl acetate=0:100→15:75) and recrystallized from ethanol-ethyl acetate to give the title compound (226 mg) as a pale-brown powder.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:12][C:13]3[N:14]=[C:15]([N:22]4[CH2:27][CH2:26][CH:25]([CH2:28][C:29]([OH:31])=O)[CH2:24][CH2:23]4)[C:16]4[CH:21]=[CH:20][NH:19][C:17]=4[N:18]=3)[CH:8]=2)[NH:3]1.C1C=CC2N(O)N=[N:38]C=2C=1.C(Cl)CCl.N>CN(C=O)C>[O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:12][C:13]3[N:14]=[C:15]([N:22]4[CH2:27][CH2:26][CH:25]([CH2:28][C:29]([NH2:38])=[O:31])[CH2:24][CH2:23]4)[C:16]4[CH:21]=[CH:20][NH:19][C:17]=4[N:18]=3)[CH:8]=2)[NH:3]1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)CC1CCN(c2nc(Nc3ccc4c(c3)CCC(=O)N4)nc3[nH]ccc23)CC1
Agent: N
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: NC(=O)CC1CCN(c2nc(Nc3ccc4c(c3)CCC(=O)N4)nc3[nH]ccc23)CC1
Reaction time: 0.67 h
Yield: 76.9 %

Procedure:
To a solution of 2-(1-(2-(2-oxo-1,2,3,4-tetrahydroquinolin-6-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-yl)acetic acid (26 mg, 0.062 mmol) and HOBt (35 mg, 0.23 mmol) in DMF (2 mL), EDC (40 mg, 0.21 mmol) was added. After being stirred for 40 min, NH3 (0.5 M in dioxane, 1.00 mL, 0.500 mmol) was added. The mixture was stirred for 20 h. It was then purified by HPLC to give the titled compound (20 mg). MS 420.3 (M+H); UV 201.8, 279.8 nm.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].Cl[C:13]1([C:24]2[C:25]([O:30][CH2:31][CH3:32])=[N:26][CH:27]=[CH:28][CH:29]=2)[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=2)[NH:15][C:14]1=[O:23].Cl>CN(C)C=O.ClCCl>[Cl:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:23])[C:13]2([CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])[C:24]1[C:25]([O:30][CH2:31][CH3:32])=[N:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)CC(=O)OC
Reactant: CCOc1ncccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOc1ncccc1C1(C(C(=O)OC)C(=O)OC)C(=O)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.7 %

Procedure:
11.2 ml (98 mmol) of dimethyl malonate were slowly added dropwise to a suspension, cooled to 10° C., of 3.56 g (89 mmol) of sodium hydride (60% dispersion in mineral oil) in 150 ml of dimethylformamide, and the mixture was then stirred at room temperature for 30 minutes. Subsequently, 9.6 g (30 mmol) of 3,5-dichloro-3-(2-ethoxypyridin-3-yl)-1,3-dihydroindol-2-one from example 1.1 were added in portions, and the mixture was stirred at room temperature for 15 min. To work up the reaction it was stirred into cold 1N HCl, and dichloromethane was added. The phases were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phase was washed with water and saturated sodium chloride solution and dried over magnesium sulfate, and the solvent was removed in vacuo. The residue was recrystallized from dichloromethane/pentane. 9.01 g of the title compound were obtained as a yellowish solid.
Reaction SMILES: [CH2:1]([CH2:4]OC)OC.[C:7]1(=[O:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.O=[CH:15][C@@H:16]([C@H:18]([C@@H:20]([C@@H:22]([CH2:24][OH:25])[OH:23])[OH:21])[OH:19])[OH:17].Cl>O1CCOCC1.C1C=CC=CC=1>[CH2:10]1[CH2:11][CH2:12][C:7]2([O:17][CH:16]([C@H:18]3[O:19][C@@H:24]4[O:25][C:4]5([CH2:1][CH2:9][CH2:8][CH2:7][CH2:12]5)[O:23][C@@H:22]4[C@H:20]3[OH:21])[CH2:15][O:13]2)[CH2:8][CH2:9]1
Reactant: COCCOC
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: O=C1CCCCC1
Agent: Cl
Solvent: c1ccccc1
Solvent: C1COCCO1
Product: O[C@@H]1[C@H]2OC3(CCCCC3)O[C@H]2O[C@@H]1C1COC2(CCCCC2)O1
Temperature: 95 °C
Reaction time: 7 h
Yield: 82.1 %

Procedure:
To a mixed solution of 150 ml of dimethoxyethane and 50 ml of cyclohexanone were added 10.0 g of D-glucose, 150 mg of cupric hydroxide and 1 ml of a 2 mole/l solution of hydrogen chloride in dioxane, and the mixture was stirred for 7 hours under reflux in an oil bath at 95° C. The refluxing solvent was continuously dried with 20 g of molecular sieve 3A which was placed between the reaction vessel and the cooling tube. After the conclusion of the reaction, the reaction solution was diluted with benzene, washed with aqueous sodium hydrogencarbonate and water, and dried over anhydrous magnesium sulfate. When the solvent and cyclohexanone were distilled off under reduced pressure, there was obtained 15.5 g (82.1%) of 1,2:5,6-di-O-cyclohexylidene-α-D-glucofuranose as a residue. The compound, when recrystallized from ligroin, showed a melting point of 133° to 135° C.
Reaction SMILES: [NH2:1][C@H:2]([CH2:7][OH:8])[C:3]([CH3:6])([CH3:5])[CH3:4].[CH2:9]([C@@:12]1([CH3:33])[CH2:17][C@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)[C@H:15]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[O:14][C:13]1=[O:32])[CH:10]=[CH2:11]>C(OCC)(=O)C>[Cl:24][C:20]1[CH:19]=[C:18]([C@H:16]([C@H:15]([C:25]2[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=2)[OH:14])[CH2:17][C@:12]([CH3:33])([CH2:9][CH:10]=[CH2:11])[C:13]([NH:1][C@@H:2]([C:3]([CH3:6])([CH3:5])[CH3:4])[CH2:7][OH:8])=[O:32])[CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)[C@H](N)CO
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@H](c2ccc(Cl)cc2)OC1=O
Solvent: CCOC(C)=O
Product: C=CC[C@@](C)(C[C@H](c1cccc(Cl)c1)[C@@H](O)c1ccc(Cl)cc1)C(=O)N[C@H](CO)C(C)(C)C
Temperature: 100 °C
Reaction time: 48 h

Procedure:
(S)-tert-leucinol (0.937 g, 7.99 mmol) and (3S,5R,6R)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyltetrahydro-2H-pyran-2-one (1 g, 2.66 mmol; Example 261, Step F) were combined in a reaction flask and heated to 100° C. After 2 d, the reaction mixture was cooled to RT and dissolved in ethyl acetate. The organic phase was washed with 3×10 mL 1N HCl and 1×10 mL brine, dried over MgSO4, filtered and concentrated to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][C@H:9]([C@H:12]([O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)[N:8]2[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:4][CH:3]=1.[S:37]1[CH:41]=[C:40]([CH:42]([CH3:46])[C:43](O)=[O:44])[N:39]=[CH:38]1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C>[Si:21]([O:20][C@H:12]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[C@@H:9]1[CH2:10][CH2:11][C@H:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:43](=[O:44])[CH:42]([C:40]3[N:39]=[CH:38][S:37][CH:41]=3)[CH3:46])=[CH:36][CH:35]=2)[N:8]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])([C:24]([CH3:27])([CH3:25])[CH3:26])([CH3:23])[CH3:22]
Reactant: CC(C(=O)O)c1cscn1
Reactant: CC(C)(C)OC(=O)N1C(Cc2ccc(N)cc2)CC[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)c1cccc(F)c1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C(=O)Nc1ccc(C[C@H]2CC[C@@H]([C@H](O[Si](C)(C)C(C)(C)C)c3cccc(F)c3)N2C(=O)OC(C)(C)C)cc1)c1cscn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 50 mg (0.10 mmol) of tert-butyl(5R)-2-(4-aminobenzyl)-5-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(3-fluorophenyl)methyl]pyrrolidine-1-carboxylate (i-4c) and 2-(1,3-thiazol-4-yl)propanoic acid (15 mg, 0.10 mmol) in 3 mL anhydrous DMF was added a 0.5 M solution of HOAt in DMF (0.2 mL, 0.10 mmol) followed by EDC (25 mg, 0.15 mmol) and DIEA (16.5 μL, 0.1 mmol). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 16 h. The mixture was washed with water and extracted with dichloromethane (2×5 mL). The organics were combined, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was purified by preparative TLC plate (500 uM) eluting with 5% MeOH in dichloromethane to yield the product as a mixture of diastereomers. The two diastereomers were then separated by chiral HPLC employing a Daicel CHIRALPAK® AD® column (eluent: 40% IPA in Heptane). The first eluting diastereomer was designated as Isomer 1 and is a colorless solid. LC-MS: m/z (ES) 655 (MH)+, 677 (MNa)+. The second eluting diastereomer was designated as Isomer 2 and is also a colorless solid. m/z (ES) 654 (MH)+, 676 (MNa)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][CH:20]=3)=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:27]([OH:29])=O)[CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1)[CH3:2].Cl.[CH3:31][O:32][NH2:33].CCN(CC)CC>S(Cl)(Cl)=O.C(Cl)Cl>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:18]([C:19]3[CH:20]=[CH:21][C:22]([CH2:25][CH3:26])=[CH:23][CH:24]=3)=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:27]([NH:33][O:32][CH3:31])=[O:29])[CH:15]=3)[N:10]=2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(-c2nc3ccc(C(=O)O)cc3nc2-c2ccc(CC)cc2)cc1
Reactant: CON
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCc1ccc(-c2nc3ccc(C(=O)NOC)cc3nc2-c2ccc(CC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.3 %

Procedure:
A solution of 2,3-bis(4-ethylphenyl)quinoxaline-6-carboxylic acid (150 mg, 0.39 mmol, 1.00 equiv) in thionyl chloride (20 mL) was heated under reflux for 3 h in a oil bath. The resulting solution was concentrated under vacuum and diluted with 20 ml of CH2Cl2. The resulting solution was added to a solution of O-methyl-hydroxylamine hydrochloride (326 mg, 3.93 mmol, 10.00 equiv) and NEt3 (396 mg, 3.92 mmol, 10.00 equiv) in CH2Cl2 (20 mL) at 0° C. and stirred overnight at room temperature. The reaction mixture was concentrated under vacuum, and the crude product (100 mg) was purified by Prep-HPLC yielding 15 mg (7%) of 2,3-bis(4-ethylphenyl)-N-methoxyquinoxaline-6-carboxamide as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH:25]2[CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26]2)[N:5]=[C:6]2[C:11](=[O:12])[NH:10][C:9]([C:13]3[C:14]([O:21][CH2:22][CH2:23][CH3:24])=[N:15][CH:16]=[C:17](C#C)[CH:18]=3)=[N:8][C:7]=12)[CH3:2].S(=O)(=O)(O)O.[CH3:41][C:42](C)=[O:43]>>[C:42]([C:17]1[CH:18]=[C:13]([C:9]2[NH:10][C:11](=[O:12])[C:6]3[C:7](=[C:3]([CH2:1][CH3:2])[N:4]([CH:25]4[CH2:26][NH:27][CH2:28]4)[N:5]=3)[N:8]=2)[C:14]([O:21][CH2:22][CH2:23][CH3:24])=[N:15][CH:16]=1)(=[O:43])[CH3:41]
Reactant: C#Cc1cnc(OCCC)c(-c2nc3c(CC)n(C4CN(C(=O)OC(C)(C)C)C4)nc3c(=O)[nH]2)c1
Reactant: CC(C)=O
Agent: O=S(=O)(O)O
Product: CCCOc1ncc(C(C)=O)cc1-c1nc2c(CC)n(C3CNC3)nc2c(=O)[nH]1
Temperature: 25 °C

Procedure:
The product from stage g) (1.44 g, 3.0 mmol) in acetone (50 ml) and sulphuric acid (1N, 3 ml) was treated with mercuric sulphate (268 mg, 9.0 mmol) and heated to reflux for 6 h. The reaction mixture was concentrated to ˜20 ml in vacuo, poured into sodium bicarbonate (sat. aq., 20 ml) and extracted into methylene chloride (6×20 ml). Combined organics were washed with brine (20 ml), dried over MgSO4, and concentrated to a brown oil which was taken up in 40% trifluoroacetic acid in methylene chloride (50 ml) and water (1 ml) and stirred for 1 hat room temperature. After evaporation in vacuo, the residue was purified by column chromatography (eluting with 95:5:1 methylene chloride:methanol:0.88 ammonia) to afford the title compound as a white hydroscopic foam ( 1.65 g); m.p. 128.5-130.0° C.; 1H NMR (400MHz, MeOD): δ=1.00 (t, 3H), 1.30 (t, 3H), 1.79-1.90 (m, 2H), 2.60 (s, 3H), 3.00-3.10 (q, 2H), 4.50 (t, 2H), 4.60-4.70 (m, 4H), 5.65-5.78 (m, 1H), 8.65 (s, 1 H), 8.90 (s, 1H); LRMS (TSP—positive ion) 397 (MH+).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7](C#C)=[CH:6][CH:5]=1)[CH2:2][CH3:3].[CH2:12](SC1C=CC(I)=CC=1)[CH2:13][CH2:14][CH2:15][CH3:16]>C(NCC)C.[Cu]I>[C:4]1([C:1]#[C:2][C:3]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCCCCSc1ccc(I)cc1
Reactant: C#Cc1ccc(CCC)cc1
Agent: [Cu]I
Solvent: CCNCC
Product: C(#Cc1ccccc1)c1ccccc1
Temperature: 20 °C
Reaction time: 16 h
Yield: 123.4 %

Procedure:
The product from step 2.4 (2.82 g) and the product from step 2.2 (6.0 g) were mixed in diethylamine (44 ml). Copper (I) iodide (0.026 g) and dichloro di(triphenylphosphine) palladium (0) (0.193 g) were then added and the mixture was then stirred at 20° C. under argon for 16 hrs. Purification by chromatography gave 4.3 g of tolane product, mpt. 43° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:20]#[N:21])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.S(=O)(=O)(O)[OH:24].C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:20]([NH2:21])=[O:24])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: N#CC1(c2ccccc2)CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: NC(=O)C1(c2ccccc2)CCN(Cc2ccccc2)CC1

Procedure:
(a′) 1-benzyl-4-cyano-4-phenylpiperidine, prepared in situ via neutralization of its hydrochloride, is treated with 94-96% sulfuric acid and acetic acid in toluene at 80-100° C. and the 1-benzyl-4-phenyl-4-piperidinecarboxamide thus obtained is treated with bromine in the presence of sodium methoxide; and then
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[O:12]=[C:13]1[NH:17][CH:16]([CH2:18][OH:19])[CH2:15][O:14]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:19][CH2:18][CH:16]2[CH2:15][O:14][C:13](=[O:12])[NH:17]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1NC(CO)CO1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2COC(=O)N2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
p-Toluenesulfonyl chloride (1.01 g, 0.0053 mole) was added to a stirred solution of 2-oxo-1,3-oxazolidin-4-methanol (0.619 g, 0.0053 mole) and 4-dimethylaminopyridine (1.30 g, 0.0106 mole) in 60 ml. methylene chloride at 0° C. under an atmosphere of nitrogen. After 1 hour at 0° C., 0.121 g. more p-toluenesulfonyl chloride was added and the reaction mixture was stirred at 0° C. for 30 min. and at 25° C. for 1 hour. The reaction solution was then washed with two 50 ml. portions of 1N aqueous hydrochloric acid solution, 50 ml. water, 50 ml. saturated aqueous sodium bicarbonate solution and 50 ml. saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo to a white solid of the title compound (1.22 g, 85% yield). NMR (CDCl3): 2.45 (s, 3H); 3.87-4.54 (c, 5H); 6.18 (b, 1H); 7.3 (d, 2H); and 7.73 (d, 2H)ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]([O:14][CH2:15][CH:16]2[CH2:18][O:17]2)=[CH:12][C:6]2[CH:7]=[CH:8][C:9](=[O:11])[O:10][C:5]=2[CH:4]=1.[OH:19][C:20]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.Cl>C(O)(C)C>[OH:17][CH:16]([CH2:18][N:23]1[CH2:24][CH2:25][C:20]([OH:19])([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:21][CH2:22]1)[CH2:15][O:14][C:13]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[O:10][C:9](=[O:11])[CH:8]=[CH:7][C:6]=2[CH:12]=1
Reactant: COc1cc2oc(=O)ccc2cc1OCC1CO1
Reactant: OC1(c2ccccc2)CCNCC1
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2oc(=O)ccc2cc1OCC(O)CN1CCC(O)(c2ccccc2)CC1
Yield: 69 %

Procedure:
Method C (3 d at 40° C.); starting materials: 7-methoxy-6-(oxiranylmethoxy)-2H-1-benzopyran-2-one and 4-hydroxy-4-phenylpiperidine; yield 69%; fusion point 155°-157° C. (from isopropanol). Hydrochloride: method G; yield 88%; fusion point 202°-203° C. (from isopropanol).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH2:13]([CH:15]([C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)[C:16]([OH:18])=[O:17])[CH3:14].CI>CN(C=O)C.C1COCC1>[CH2:13]([C:15]([C:19]1[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=1)([CH3:1])[C:16]([OH:18])=[O:17])[CH3:14]
Reactant: CC(C)NC(C)C
Reactant: CCC(C(=O)O)c1ccncc1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: CI
Solvent: C1CCOC1
Product: CCC(C)(C(=O)O)c1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.6 %

Procedure:
To dry THF at −78° C. was added diisopropylamine(5.05 g 48 mmol, 7 mL) and then n-butyl lithium. The reaction mixture was stirred for 0.5 h and then ethyl 4-pyridyl acetic acid (7.85 g, 46 mmol) was added, and after sirring for 0.5 h at that −78° C. the reaction temperature was raised to room temperature. DMF (20 mL was added and the reaction mixture cooled to −78° C. again. Methyl iodide(7.07 g, 50.2 mmol, 3.15 mL) was added and the reaction mixture stirred at that temperature for 1 h and then at room temperature overnight. All the volatiles were then stripped off and the reaction mixture was partitioned between water-CH2Cl2. The aqueous phase was washed twice with CH2Cl2. The combined CH2Cl2 phases were dried and evaporated. The crude product was chromatographed on silica gel eluting with 80% EtOAc hexane to give the title compound (7.88 g, MH+ 179).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](Cl)=[N:7][N:6]=[CH:5]2.[CH2:13]1[CH:22]2[CH:17]([CH2:18][CH2:19][CH2:20][CH2:21]2)[CH2:16][CH2:15][NH:14]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:14]1[CH2:15][CH2:16][CH:17]3[CH:22]([CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:13]1)=[N:7][N:6]=[CH:5]2
Reactant: C1CCC2CNCCC2C1
Reactant: Clc1nncc2cc(Br)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Brc1ccc2c(N3CCC4CCCCC4C3)nncc2c1
Temperature: 180 °C
Yield: 105.4 %

Procedure:
A mixture of 6-bromo-1-chlorophthalazine (Example 1, 0.1 g, 411 μmol), decahydroisoquinoline (114 mg, 821 μmol), potassium carbonate (57 mg, 411 μmol) and 5 mL acetonitrile was added to a glass microwave reaction vessel. The reaction mixture was stirred and heated in a Smith Synthesizer® microwave reactor (Personal Chemistry, Inc., Upssala, Sweden) at 180° C. for 20 min. The mixture was concentrated under vacuum and purified via flash chromatography (silica gel) eluting with a gradient of 2% 2 M ammonia in MeOH/DCM to 6% 2M ammonia in MeOH/DCM to give 6-bromo-1-(octahydroisoquinolin-2(1H)-yl)phthalazine (0.15g) as a yellow solid. Found MS (ES+): 346, 348(M+H)+.