Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].[CH3:12][C:13]1[CH:23]=[CH:22][C:16]([C:17]([N:19]=[C:20]=[S:21])=[O:18])=[CH:15][CH:14]=1>CCOCC>[CH3:7][NH:6][C:4](=[O:5])[C:3]1[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=1[NH:1][C:20]([NH:19][C:17](=[O:18])[C:16]1[CH:22]=[CH:23][C:13]([CH3:12])=[CH:14][CH:15]=1)=[S:21]
Reactant: Cc1ccc(C(=O)N=C=S)cc1
Reactant: CNC(=O)c1ccccc1N
Solvent: CCOCC
Product: CNC(=O)c1ccccc1NC(=S)NC(=O)c1ccc(C)cc1
Yield: 98 %

Procedure:
To a stirred mixture of 8.0 g of 2-amino-N-methylbenzamide and 200 ml of ether was added dropwise, a solution of 10 g of 4-methylbenzoyl isothiocyanate in 100 ml of ether over 1 hour. After stirring several hours, the solid was collected, giving 17.1 g of the desired product as white crystals, mp 198°-200° C. (dec.).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:27])[C:12]3[CH:17]=[CH:16][C:15]([O:18][CH:19]4[CH2:24][CH2:23][CH2:22][NH:21][CH:20]4[CH2:25][CH3:26])=[CH:14][CH:13]=3)=[C:9]([C:28]3[CH:33]=[CH:32][C:31]([O:34]C)=[CH:30][CH:29]=3)[S:8][C:7]=2[CH:36]=1.C(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:27])[C:12]3[CH:13]=[CH:14][C:15]([O:18][CH:19]4[CH2:24][CH2:23][CH2:22][NH:21][CH:20]4[CH2:25][CH3:26])=[CH:16][CH:17]=3)=[C:9]([C:28]3[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=3)[S:8][C:7]=2[CH:36]=1
Reactant: CCC1NCCCC1Oc1ccc(C(=O)c2c(-c3ccc(OC)cc3)sc3cc(OC)ccc23)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Product: CCC1NCCCC1Oc1ccc(C(=O)c2c(-c3ccc(O)cc3)sc3cc(O)ccc23)cc1
Yield: 89.9 %

Procedure:
6-Methoxy-2-(4-methoxyphenyl)-3-(4-[2-ethylpiperidin-3-oxy]benzoyl)benzo[b]thiophene (226 mg, 0.451 mmol), ethane thiol (2.25 mmol), and aluminum chloride (360 mg, 2.70 mmol) were converted to 192 mg (90%) of the title compound by the procedure of Example 16. MS(FD) 474(M+). IR (CHCl3) ν max 3380, 2970, 1597, 1467, 1255, 1165.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][O:9][CH2:10][C:11]#[CH:12]>C(NCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[CH3:8][O:9][CH2:10][C:11]#[C:12][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Brc1ccccn1
Reactant: C#CCOC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Product: COCC#Cc1ccccn1
Temperature: 40 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
To a solution of 2-bromopyridine (20 g) dissolved in diethylamine (100 mL) was added 3-methoxy-1-propyne (11.8 g), dichlorobis(triphenylphosphine)palladium(II) (888 mg) and copper iodide (121 mg), and the reaction mixture was stirred for 1 hour at 40° C. under a nitrogen stream. After the reaction mixture was filtered through celite to remove insoluble residue, the filtrate was evaporated under reduced pressure, the residue was purified by silica gel column chromatography and the title compound (16.8 g) was obtained as a light orange oil from the n-hexane:ethyl acetate (5:1) fraction.
Reaction SMILES: [CH3:1][N:2]([CH3:39])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([C@@H:9]1[CH2:23][C@H:22]2[C@@H:12]([CH2:13][C:14]3[C:24]4[C:17](=[CH:18][CH:19]=[CH:20][C:21]2=4)[N:16]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:15]=3)[N:11]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:10]1)=[O:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:59]([N:61]=[C:62]=[O:63])[CH3:60]>ClCCl.[Cu]Cl>[CH3:39][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][N:6]([C:62]([NH:61][CH2:59][CH3:60])=[O:63])[C:7]([C@@H:9]1[CH2:23][C@H:22]2[C@@H:12]([CH2:13][C:14]3[C:24]4[C:17](=[CH:18][CH:19]=[CH:20][C:21]2=4)[N:16]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:15]=3)[N:11]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:10]1)=[O:8]
Reactant: CCN=C=O
Reactant: CN(C)CCCNC(=O)[C@@H]1C[C@@H]2c3cccc4c3c(cn4C(=O)OC(C)(C)C)C[C@H]2N(C(=O)OC(C)(C)C)C1
Agent: Cl[Cu]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCNC(=O)N(CCCN(C)C)C(=O)[C@@H]1C[C@@H]2c3cccc4c3c(cn4C(=O)OC(C)(C)C)C[C@H]2N(C(=O)OC(C)(C)C)C1
Temperature: 35 °C
Reaction time: 4 h
Yield: 96.4 %

Procedure:
To a solution of 15.5 g (28.67 mmol) of N-[3-(dimethylamino)propyl]-1,6-di(tert-butoxycarbonyl)-ergoline-8β-carboxamide (XVII, R2=tert-butyl) in 350 ml of dichloro-methane 0.8 g of triphenylphosphine, 0.3 g of copper(I) chloride and 6.8 ml (86 mmol) of ethyl isocyanate was sequentially added, and the reaction mixture was stirred at 35° C. for 4 hours. The reaction mixture was concentrated in vacuum and the product was purified on a silica plug to give 16.9 g (96.4%) of the title compound.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:26])[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:32][C:33]1[CH:37]=[CH:36][N:35]([CH2:38][C:39]([CH3:42])([OH:41])[CH3:40])[N:34]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:26])[CH:13]=[N:12]2)[C:8]([NH:32][C:33]2[CH:37]=[CH:36][N:35]([CH2:38][C:39]([OH:41])([CH3:42])[CH3:40])[N:34]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2ccccc2C(=O)N2CCCC2)cc1=O
Reactant: CC(C)(O)Cn1ccc(N)n1
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(Oc3ccccc3C(=O)N3CCCC3)cc2=O)n1
Yield: 19 %

Procedure:
Using the method described in Example 17, 3-cyclopentyl-2-{6-oxo-4-[2-(pyrrolidine-1-carbonyl)-phenoxy]-6H-pyridazin-1-yl}-propionic acid (Intermediate 27) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-{6-oxo-4-[2-(pyrrolidine-1-carbonyl)-phenoxy]-6H-pyridazin-1-yl}-propionamide as a light yellow solid (24.6 mg, 19%); ES+-HRMS m/e calcd for C30H38N6O5 [M+H+] 563.2977 found 563.2974. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.03-1.08 (m, 7H) 1.25-2.03 (m, 13H) 2.19-2.40 (m, 1H) 3.21 (t, J=6.2 Hz, 2H) 3.28-3.36 (m, 2H) 3.89 (s, 2H) 4.67 (s, 1H) 5.47 (dd, J=11.1, 4.3 Hz, 1H) 5.79 (d, J=2.8 Hz, 1H) 6.40 (d, J=2.1 Hz, 1H) 7.38 (d, J=8.1 Hz, 1H) 7.41 (t, J=7.5 Hz, 1H) 7.49-7.54 (m, 2H) 7.54-7.61 (m, 1H) 8.07 (d, J=2.8 Hz, 1H) 10.80 (s, 1H).
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])[OH:2].[S:6]([O-:10])([O-:9])(=[O:8])=[O:7].[Ca:11].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[F-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2]>>[OH2:2].[S:6]([O-:10])([O-:9])(=[O:8])=[O:7].[Ca+2:11].[Ca+2:11].[S:1]([O-:5])([O-:4])(=[O:3])=[O:2]
Reactant: O=S(=O)(O)O
Reactant: [Ca]
Agent: O=P([O-])([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Product: O

Procedure:
Sulfuric acid is added in amounts such that the sulfate content of the added acid and the sulfate content of the added rock is equivalent to about 90% to about 100% (more preferred 93-99.5%) of the stoichiometric amount of sulfate required to react with calcium added in the phosphate rock to form calcium sulfate hemihydrate.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:11][CH2:12][CH2:13][OH:14])([CH3:10])([CH3:9])[CH3:8].[Cl:15][C:16]1[CH:17]=[C:18]([CH:22]2[CH2:24][O:23]2)[CH:19]=[CH:20][CH:21]=1>C(OCC)(=O)C>[Cl:15][C:16]1[CH:17]=[C:18]([CH:22]([OH:23])[CH2:24][O:14][CH2:13][CH2:12][O:11][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:19]=[CH:20][CH:21]=1
Reactant: Clc1cccc(C2CO2)c1
Reactant: CC(C)(C)OCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OCCOCC(O)c1cccc(Cl)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
5.1 g of potassium tert-butoxide was added to 105 ml of ethylene glycol mono-tert-butyl ether. The mixture was heated to 80° C. Thereto was dropwise added 35.0 g of 2-(3-chlorophenyl)oxirane over 1 hour. The mixture was stirred for 2 hours at the same temperature. The reaction mixture was added to a mixture of 100 ml of ice water and 100 ml of ethyl acetate. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was subjected to further distillation under reduced pressure to obtain 37.7 g of colorless oily 1-(3-chlorophenyl)-2-(2-tert-butoxyethoxy)ethanol having a boiling point of 140°-146° C./0.9 mm Hg.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:17][C:18]([C:20]2[N:24]([CH3:25])[N:23]=[CH:22][C:21]=2[C:26]([OH:28])=O)=[O:19])=[CH:4][C:5]2[N:6]([N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.CCCP(=O)=O.C(N(C(C)C)CC)(C)C>O1CCCC1>[F:1][C:2]1[C:3]([NH:17][C:18]([C:20]2[N:24]([CH3:25])[N:23]=[CH:22][C:21]=2[C:26]([N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)=[O:28])=[O:19])=[CH:4][C:5]2[N:6]([N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1cc2nc(-c3ccccc3)nn2cc1F
Reactant: C1CCNC1
Agent: CCCP(=O)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(C(=O)N2CCCC2)c1C(=O)Nc1cc2nc(-c3ccccc3)nn2cc1F
Temperature: 70 °C
Reaction time: 60 h
Yield: 52.8 %

Procedure:
A mixture of 5-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (138 mg, 363 μmol), pyrrolidine (240 μl, 2.9 mmol), propylphosphonic anhydride (50% in ethyl acetate, 534 μl, 907 μmol) and diisopropylethylamine (190 μl, 1.09 mmol) in tetrahydrofuran (10 ml) was stirred for 2.5 days at 70° C. The solvent was evaporated; the residue was triturated with saturated aqueous sodium hydrogencarbonate solution and the precipitated solid was filtered off and dried in vacuo. The material was applied on silica and purified by flash chromatography over a 20 g silica column using heptane/EtOAc 10-100% as eluent, affording N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(pyrrolidine-1-carbonyl)-1H-pyrazole-5-carboxamide (83 mg, 52.8%) as white solid. Mp. 250-251° C. MS: m/z=434.4 (M+H+).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([CH3:17])=[O:16])=[C:10]([N+:18]([O-])=O)[CH:9]=2)=[N:5][NH:4][C:3]1=[O:21].C(O)(=O)C>C(O)C>[CH3:1][CH:2]1[CH2:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([CH3:17])=[O:16])=[C:10]([NH2:18])[CH:9]=2)=[N:5][NH:4][C:3]1=[O:21]
Reactant: CC(=O)Nc1ccc(C2=NNC(=O)C(C)C2)cc1[N+](=O)[O-]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(C2=NNC(=O)C(C)C2)cc1N

Procedure:
2.9 gm of 4-methyl-6-(3'-nitro-4'-acetamino-phenyl)-4,5-dihydro-3(2H)-pyridazinone were hydrogenated in 80 ml of ethanol and 20 ml of glacial acetic acid at room temperature and 5 atmospheres in the presence of 1.5 gm of palladizedcoal. The catalyst was then filtered off, the filtrate was evaporated, and the residue was used as such in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].S(Cl)([Cl:16])=O>ClCCl>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:16])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: Nc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Nc1ccc(C(=O)Cl)cc1[N+](=O)[O-]

Procedure:
A mixture of 4-amino-3-nitro-benzoic acid (12.0 g, 65.9 mmol) in 300 mL dichloromethane with 12 mL thionyl chloride was refluxed for 2.5 h, and concentrated to dryness i. vac. The residue was further reacted without further purification.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([CH:7]=[O:8])[CH2:3]1.[O:9]1[CH:14]=[CH:13][CH2:12][CH2:11][CH2:10]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[O:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[O:1][CH:2]1[CH2:6][CH2:5][N:4]([CH:7]=[O:8])[CH2:3]1
Reactant: C1=COCCC1
Reactant: O=CN1CC[C@@H](O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=CN1CCC(OC2CCCCO2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
The (R)-3-hydroxypyrrolidine-1-carbaldehyde (31 g) was treated with dihydropyran (36.8 ml) and p-toluenesulphonic acid (1 g). The mixture was stirred at room temperature for approximately one hour, during which time the colour changed from yellow to dark purple. GC analysis showed the reaction was complete. The reaction was quenched by addition of saturated sodium bicarbonate solution (90 ml). The aqueous phase was extracted with DCM (3×90 ml). The combined organic phase was washed with saturated sodium chloride solution (90 ml), then dried over MgSO4 and concentrated at below 30° C. The product, 3-(tetrahydropyran-2-yloxy)pyrrolidine-1-carbaldehyde, was obtained in 100% yield, 54.5 g. GC analysis showed two adjacent peaks, RT 14.45 and 14.83 min, 49.7 and 47.1% respectively. δH (CDCl3) 8.22 and 8.27 (1H, 2×s), 4.60-4.75 (1H, m), 4.35-4.50 (1H, m), 3.80-3.95 (1H, m), 3.40-3.70 (5H, m), 1.40-2.20 (8H, m).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([CH2:16][OH:17])[CH:13]=[C:12]([C:18]([O:20]C)=[O:19])[CH:11]=1)#[N:2].[OH-].[Li+].[NH4+].[Cl-].CCOC(C)=O>O1CCOCC1.O>[C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([CH2:16][OH:17])[CH:13]=[C:12]([C:18]([OH:20])=[O:19])[CH:11]=1)#[N:2]
Reactant: COC(=O)c1cc(CO)cc(-c2ccc(C)cc2C#N)c1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ccc(-c2cc(CO)cc(C(=O)O)c2)c(C#N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of methyl 2′-cyano-5-(hydroxymethyl)-4′-methylbiphenyl-3-carboxylate (220 mg, 0.78 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was added lithium hydroxide (60 mg, 2.5 mmol). The reaction mixture was stirred at rt for 8 h, and then treated with aq. NH4Cl and EtOAc. The organic layer was separated, dried over anhydrous MgSO4, and concentrated. The residue was purified by silica gel chromatography to afford the title compound. 1H NMR (acetone-d6, 400 MHz): 8.16 (m, 1H), 8.11 (m, 1H), 7.81 (m, 1H), 7.73 (m, 1H), 7.65-7.61 (m, 1H), 7.56 (d, 1H, J=8.0 Hz), 4.81 (s, 2H), 2.46 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH3:10])[CH:5]=[CH:4][N:3]=1.OS(O)(=O)=O.[Br:16]N1C(=O)CCC1=O>CC(=O)OCC>[Br:16][C:5]1[C:6]([O:8][CH2:9][CH3:10])=[CH:7][C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: CCOc1ccnc(Cl)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CCOc1cc(Cl)ncc1Br
Temperature: 80 °C
Reaction time: 3 h
Yield: 41.3 %

Procedure:
2-Chloro-4-ethoxypyridine (100 g, 0.63 mol) was added to H2SO4 (500 mL) slowly. Then 1-bromopyrrolidine-2,5-dione (124.2 g, 0.70 mol) was added into above mixture at rt. The mixture was stirred at 80° C. for 3 h. TLC (PE/EA=10:1, Rf=0.5) showed the reaction was finished. The reaction mixture was poured into ice-water (2 L), and extracted with EA (1 L×3). The organic layer was washed with saturated Na2CO3 solution (1 L×2), dried over Na2SO4 and concentrated. The residue was purified by silica column chromatography (PE/EA=60:1-30:1). All fractions found to contain product by TLC (PE/EA=10:1, Rf=0.5) were combined and concentrated to yield 5-bromo-2-chloro-4-ethoxypyridine (60.9 g, 0.26 mol, 40% yield): 1H NMR (400 MHz, CD3OD) δ 8.31 (s, 1H), 7.14 (s, 1H), 4.32-4.10 (m, 2H), 1.58-1.35 (m, 3H); ES-LCMS m/z 237 (M+2).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([C@H:5]1[C@H:12]2[C@H:8]([O:9][C:10]([CH3:14])([CH3:13])[O:11]2)[C:7]([CH2:15][O:16][C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:6]1)[OH:4].[Cl:36][C:37]1[C:42](Cl)=[N:41][CH:40]=[CH:39][N:38]=1.C(N(CC)CC)C>CN(C=O)C>[Cl:36][C:37]1[C:42]([NH:1][CH2:2][C@H:3]([C@H:5]2[C@H:12]3[C@H:8]([O:9][C:10]([CH3:13])([CH3:14])[O:11]3)[C:7]([CH2:15][O:16][C:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:6]2)[OH:4])=[N:41][CH:40]=[CH:39][N:38]=1
Reactant: CC1(C)O[C@H]2[C@H]([C@H](O)CN)C=C(COC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@H]2O1
Reactant: Clc1nccnc1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(C)O[C@H]2[C@H]([C@H](O)CNc3nccnc3Cl)C=C(COC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@H]2O1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
(S)-2-amino-1-((3aS,4S,6aR)-2,2-dimethyl-6-(trityloxymethyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)ethanol (1-5) (2 g, 3.82 mmol, 1.0 eq) was dissolved in DMF (15.3 mL). 2,3-Dichloropyrazine (1.20 g, 7.63 mmol, 2 equiv) was added followed by triethylamine (2.13 mL, 15.3 mmol, 4 equiv). The reaction was stirred 20 hours at 60° C. Over a period of 52 hours 2,3-dichloropyrazine (299 mg, 1.91 mmol, 0.5 equiv) was added every 3 hours. The reaction was concentrated and purified via flash chromatography on silica gel column (ethyl acetate/hexanes) to yield (S)-2-(3-chloropyrazin-2-ylamino)-1-((3aS,6aR)-2,2-dimethyl-6-(trityloxymethyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)ethanol (1-6) as a white foam. 1H NMR (500 MHz, CDCl3) δ 7.91 (d, 1H, J=1.5 Hz), 7.62 (d, 1H, J=1.5 Hz), 7.21-7.48 (m, 15H), 5.84 (2 s, 1H), 5.62 (m, 1H), 4.97 (t, 1H, J=6 Hz), 4.60-4.77 (2 d, 1H, J=7 Hz), 3.95 (d, 1H, J=14 Hz), 3.75 (m, 2H), 3.31 (m, 1H), 2.57-2.88 (m, 2H), 1.36 (s, 3H), 1.32 (s, 3H).
Reaction SMILES: C([O:3][C:4](=[O:41])[C:5]([NH:7][C:8]1[C:9](=[O:40])[N:10]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:25]4[O:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[C:24]=4[CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH:13]=1)=[O:6])C.[OH-].[Na+].Cl>O1CCOCC1>[CH2:33]([N:10]1[CH:11]=[C:12]([C:14]2[CH:15]=[CH:16][C:17]([C:20]3[C:25]4[O:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[C:24]=4[CH:23]=[CH:22][CH:21]=3)=[CH:18][CH:19]=2)[CH:13]=[C:8]([NH:7][C:5](=[O:6])[C:4]([OH:41])=[O:3])[C:9]1=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CCOC(=O)C(=O)Nc1cc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cn(Cc2ccccc2)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)C(=O)Nc1cc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cn(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 98 %

Procedure:
A solution of N-[1-benzyl-5-(4-dibenzofuran-4-yl-phenyl)-2-oxo-1,2-dihydro-pyridin-3-yl]-oxalamic acid ethyl ester (110 mg, 0.203 mmol) in 1,4-dioxane (4 mL) was treated with NaOH (24 mg, 3 equiv., 0.6 mmol) and stirred at room temperature. After 4 h, the solution was acidified with 10% HCl to pH<5. The resulting precipitate was filtered and washed with ether (2×2 mL) to give N-[1-benzyl-5-(4-dibenzofuran-4-yl-phenyl)-2-oxo-1,2-dihydro-pyridin-3-yl]-oxalamic acid as a white solid (102.4 mg, 99%). Mp 220-223° C.; Rf 0.63 (50% methanol in ethyl acetate), 1H NMR (DMSO-d6, 300 MHz) δ 10.36 (s, 1H), 8.74 (d, J=2.4 Hz, 1H), 8.20-7.99 (m, 5H), 7.72, (dd, J1=10.2 Hz, J2=8.1 Hz, 4H), 7.53-7.28 (m, 7H), 5.28 (s, 2H) ); ESI-LCMS m/z calcd for C32H22N2O5: 514; found 515 (M+1)+.
Reaction SMILES: [I-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[CH2:28]([C:35]1[N:40]=[N:39][C:38]([N:41]2[CH2:46][CH2:45][N:44]([C:47]3[CH:52]=[N:51][C:50]([C:53](=O)[CH3:54])=[CH:49][N:48]=3)[C@H:43]([CH3:56])[CH2:42]2)=[C:37]([CH3:57])[C:36]=1[CH3:58])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[CH2:28]([C:35]1[N:40]=[N:39][C:38]([N:41]2[CH2:46][CH2:45][N:44]([C:47]3[CH:52]=[N:51][C:50]([C:53]([CH3:2])=[CH2:54])=[CH:49][N:48]=3)[C@H:43]([CH3:56])[CH2:42]2)=[C:37]([CH3:57])[C:36]=1[CH3:58])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(=O)c1cnc(N2CCN(c3nnc(Cc4ccccc4)c(C)c3C)C[C@H]2C)cn1
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C)c1cnc(N2CCN(c3nnc(Cc4ccccc4)c(C)c3C)C[C@H]2C)cn1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 37.3 %

Procedure:
Methyltriphenylphosphonium iodide (410 mg, 1.010 mmol) is added to THF (5.5 mL) and cooled to 5° C. Potassium tert-butoxide (1.1 mL, 1M in THF, 1.1 mmol) is added dropwise and the reaction is stirred for 30 min. 1-[(R)-4-(6-Benzyl-4,5-dimethyl-pyridazin-3-yl)-2-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-yl]-ethanone (350 mg, 0.841 mmol) in THF (1.5 mL) is added to the reaction. The reaction is allowed to stir 1 h at 5° C., and then the ice bath is removed and the reaction is allowed to stir an additional 16 h at room temperature. Remove THF in vacuo. The residue is purified by flash chromatography on silica gel (60-90% EtOAc/heptane) to afford the title compound (130 mg, 37%).
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]([CH:15]3[CH:19]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=4[CH3:27])[C:18]([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=4[F:37])([C:28]#[N:29])[CH:17]([CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])[NH:16]3)=[O:14])=[CH:8][CH:7]=2)=[N:4][N:3]=[N:2]1.[C:43](=O)(O)[O-].[Na+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:43][N:3]1[NH:2][N:1]=[C:5]([C:6]2[CH:7]=[CH:8][C:9]([NH:12][C:13]([CH:15]3[CH:19]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=4[CH3:27])[C:18]([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=4[F:37])([C:28]#[N:29])[CH:17]([CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])[NH:16]3)=[O:14])=[CH:10][CH:11]=2)[NH:4]1
Reactant: Cc1c(Cl)cccc1C1C(C(=O)Nc2ccc(-c3nnn[nH]3)cc2)NC(CC(C)(C)C)C1(C#N)c1ccc(Cl)cc1F
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: Cc1c(Cl)cccc1C1C(C(=O)Nc2ccc(C3=NNN(C)N3)cc2)NC(CC(C)(C)C)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 55.2 %

Procedure:
To a stirred solution of rac (2R,3R,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-methyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(1H-tetrazol-5-yl)-phenyl]-amide (32 mg, 0.0524 mmol) in acetone (5 mL), sodium bicarbonate (45 mg, 0.6 mmol) and dimethyl sulfate (0.11 mmol) was added and the mixture was stirred at rt for 5 hrs. The solvent was removed and the residue was suspended in 3 mL of methylene chloride. The mixture was filtered and the filtrate was loaded on a silica gel column. Eluting with 35-70% EtOAc/Hexanes on an ISCO machine gave the desired product (18 mg) and the other regioisomer (3 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=1[CH:5]=[C:6]1[C:10](=[O:11])O[C:8]([CH3:12])=[N:7]1.[CH2:17]([NH2:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:17]([N:19]1[C:10](=[O:11])[C:6](=[CH:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]=2[O:2][CH3:1])[N:7]=[C:8]1[CH3:12])[CH3:18]
Reactant: CCN
Reactant: COc1ccccc1C=C1N=C(C)OC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCN1C(=O)C(=Cc2ccccc2OC)N=C1C
Temperature: 80 °C

Procedure:
4-(2′-Methoxybenzylidene)-2-methyl-4H-oxazol-5-one (5 g) was dissolved in ethanol (100 ml) and an aqueous ethylamine solution (15 ml) and potassium carbonate (7 g) were added thereto. The mixture was heated at 80° C. for 5 hr. After cooling, the solvent was evaporated under reduced pressure and the precipitated yellow crystals were collected by filtration to give the title compound (1.2 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]([CH2:20][C:21]([OH:23])=O)[S:10]([C:13]2[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1.[CH2:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[CH3:25]>>[CH2:24]([N:26]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[C:21](=[O:23])[CH2:20][N:9]([C:6]1[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[S:10]([C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:11])=[O:12])[CH3:25]
Reactant: CCNCc1ccccn1
Reactant: COc1ccc(N(CC(=O)O)S(=O)(=O)c2ccccc2C)cn1
Product: CCN(Cc1ccccn1)C(=O)CN(c1ccc(OC)nc1)S(=O)(=O)c1ccccc1C

Procedure:
prepared by reaction of [(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-acetic acid with ethyl-pyridin-2-ylmethyl-amine