Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[N:7][N:6]2[CH:9]=[C:10]([C:13](Cl)=[O:14])[C:11]([CH3:12])=[C:5]2[C:4]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)#[N:2].CCN(CC)CC.Cl.[CH3:38][O:39][NH:40][CH3:41]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH3:38][O:39][N:40]([CH3:41])[C:13]([C:10]1[C:11]([CH3:12])=[C:5]2[C:4]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:19][CH:18]=3)=[C:3]([C:1]#[N:2])[CH:8]=[N:7][N:6]2[CH:9]=1)=[O:14]
Reactant: Cc1c(C(=O)Cl)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c2c1C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
To a solution of 3-cyano-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-6-carbonyl chloride (Example 412B) (181 mg, 0.45 mmol) in CH2Cl2 (3 ml) was added Et3N (160 μl, 1.13 mmol) followed by O,N-dimethylhydroxyamine hydrochloride (44 mg, 0.45 mmol) in one portion. The mixture was stirred overnight, diluted with CHCl3 (20 ml), washed with water (2×20 ml), dried with Na2SO4. Concentrated in vacuo and purified by prep. TLC to give the title compound (138 mg, 72%) (50% EtOAc—hexanes). It has a retention time of 6.45 min (standard LCl method, 8 min run). LCMS Found: (M+H)+=428.1
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[O:6][C@@H:5]([CH2:7][NH:8][C:9]([CH3:27])([CH3:26])[CH2:10][C:11]([NH:13][C@@H:14]2[CH2:20][CH2:19][C:18]3[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=3[NH:16][C:15]2=[O:25])=[O:12])[CH2:4][O:3]1.[CH3:29][NH:30][C:31]([NH:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]1[CH:46]=[CH:45][C:44]([CH2:47]O)=[CH:43][CH:42]=1)=[O:32]>>[CH3:1][C:2]1([CH3:28])[O:6][C@@H:5]([CH2:7][NH:8][C:9]([CH3:27])([CH3:26])[CH2:10][C:11]([NH:13][C@@H:14]2[CH2:20][CH2:19][C:18]3[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=3[N:16]([CH2:47][C:44]3[CH:43]=[CH:42][C:41]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=4[CH2:34][NH:33][C:31]([NH:30][CH3:29])=[O:32])=[CH:46][CH:45]=3)[C:15]2=[O:25])=[O:12])[CH2:4][O:3]1
Reactant: CNC(=O)NCc1ccccc1-c1ccc(CO)cc1
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2NC1=O)NC[C@H]1COC(C)(C)O1
Product: CNC(=O)NCc1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)CC(C)(C)NC[C@H]3COC(C)(C)O3)CCc3ccccc32)cc1

Procedure:
Prepared from 3-[[2,2-dimethyl-1,3-dioxolan-4(S)-yl]-methyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-3(R)-yl]butanamide (Step B) and 2'-[[(methylamino)carbonyl]amino]methyl-1,1'-biphenyl-4-methanol, methanesulfonate ester (Example 48, Step I) according to the procedure described in Example 35, Step H.1H NMR (200 MHz, CD3OD): δ 1.14 (s, 6H), 1.28 (s, 3H), 1.34 (s, 3H), 2.07 (m, 1H), 2.20-2.42 (m, 3H), 2.48-2.76 (m, 4H), 2.64 (s, 3H), 3.64 dd; 8, 6 Hz; 1H), 4.05 (dd; 8, 6 Hz; 1H), 4.14 (s, 2H), 4.20 (m, 1H), 4.40 (dd; 12, 8 Hz; 1H), 4.94 (d, 15 Hz, 1H), 5.27 (d, 15 Hz, 1H), 7.10-7.40 (m, 12H). FAB-MS: calculated for C37H46N5O5 641; found 642 (M+H, 80%).
Reaction SMILES: [O-][CH2:2][CH3:3].[Na+].[CH2:5]([C:9]([NH2:11])=[O:10])[C:6]([NH2:8])=[NH:7].Cl.BrCC([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)=O>C(O)C>[NH2:7][C:6]1[NH:8][C:2]([C:19]2[CH:18]=[CH:17][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)=[CH:3][C:5]=1[C:9]([NH2:11])=[O:10]
Reactant: CC[O-]
Reactant: O=C(CBr)c1cccc2ccccc12
Reactant: N=C(N)CC(N)=O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1cc(-c2ccc3ccccc3c2)[nH]c1N
Reaction time: 0.33 h
Yield: 29.8 %

Procedure:
Under ice-cooling, sodium ethoxide (2.7 g, 40 mmol) was added to a suspension of malonamamidine hydrochloride (5.5 g, 40 mmol) in dehydrated ethanol (130 mL), and then the mixture was stirred for 20 minutes. 2-Bromoacetylnaphthalene (5.0 g, 20 mmol) was added thereto, and the whole was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo, and the obtained residue was purified by silica gel column chromatography to give the title reference compound (1.5 g) as a black solid (Yield 30%).
Reaction SMILES: N[C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[C:13]([N:23]4[CH:28]=[CH:27][C:26](=[O:29])[NH:25][C:24]4=[O:30])[CH:14]=[C:15]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:16]=3[O:17][CH3:18])[CH:8]=[CH:7][C:5]=2[N:6]=1.N(OCCC(C)C)=O>O1CCOCC1>[S:3]1[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[C:13]([N:23]4[CH:28]=[CH:27][C:26](=[O:29])[NH:25][C:24]4=[O:30])[CH:14]=[C:15]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:16]=3[O:17][CH3:18])[CH:8]=[CH:7][C:5]=2[N:6]=[CH:2]1
Reactant: COc1c(-c2ccc3nc(N)sc3c2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Agent: CC(C)CCON=O
Solvent: C1COCCO1
Product: COc1c(-c2ccc3ncsc3c2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Yield: 48.4 %

Procedure:
To a solution of the product from Example 53 (30 mg, 0.071 mmol) in anhydrous 1,4-dioxane (3 mL) under N2 was added isoamyl nitrite (19 μL, 0.142 mmol). The resulting mixture was stirred at reflux for 1 h, and concentrated in vacuo. The crude product was purified by C-18 reverse-phase HPLC using an acetonitrile:H2O (0.1% TFA) gradient to give the title compound (14 mg, 48%). 1H NMR (300 MHz, DMSO-d6) δ 11.42 (d, J=1.84 Hz, 1 H) 9.44 (s, 1 H) 8.34 (d, J=1.47 Hz, 1 H) 8.19 (d, J=8.46 Hz, 1 H) 7.79 (d, J=7.72 Hz, 1 H) 7.73 (dd, J=8.46, 1.84 Hz, 1 H) 7.32-7.37 (m, 2 H) 5.65 (dd, J=7.91, 2.39 Hz, 1 H) 3.24 (s, 3 H) 1.42 (s, 9 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:16]=[C:15]([Cl:17])[N:14]=[C:13]([NH:18][CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)[CH:12]=3)=[CH:9][N:8](S(C3C=CC=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[OH-].[Li+]>O1CCCC1.CO.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:16]=[C:15]([Cl:17])[N:14]=[C:13]([NH:18][CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)[CH:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cc(Cl)nc(NC3CCCCC3)c2)c2cc(Br)cnc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Clc1cc(-c2c[nH]c3ncc(Br)cc23)cc(NC2CCCCC2)n1
Yield: 83.2 %

Procedure:
A solution of Example 171a (0.100 g, 0.16 mmol) in 9 mL tetrahydrofuran/methanol (2:1) was treated with 1N lithium hydroxide (0.024 g, 1.00 mmol) in 1 mL water at room temperature for 16 hours. The material was diluted with water and resulting precipitate collected by filtration. Trituration with dimethyl sulfoxide/methanol and filtration afforded 54 mg of the title compound. 1H NMR (300 MHz, DMSO-d6) ppm 1.11-1.44 (m, 5H) 1.54-1.66 (m, 1H) 1.67-1.80 (m, 2H) 1.87-1.99 (m, 2H) 3.62-3.77 (m, 1H) 6.78 (d, J=7.93 Hz, 1H) 6.86 (d, J=4.36 Hz, 2H) 8.23 (s, 1H) 8.37 (s, 1H) 8.49 (s, 1H) 12.41 (s, 1H). MS (ESI−) m/z 405.1 (M−H)−.
Reaction SMILES: [C:1]([CH:4]([O:6][C:7]1[N:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[N:8]=1)[CH3:5])([OH:3])=[O:2].S(Cl)(Cl)=O.[C:24]1(C)[CH:29]=CC=C[CH:25]=1>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[N:9]1[CH:10]=[N:11][C:7]([O:6][CH:4]([C:1]([O:3][CH:24]([CH3:29])[CH3:25])=[O:2])[CH3:5])=[N:8]1
Reactant: CC(Oc1ncn(-c2ccc(Cl)cc2Cl)n1)C(=O)O
Reactant: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CC(C)OC(=O)C(C)Oc1ncn(-c2ccc(Cl)cc2Cl)n1

Procedure:
Three g of the compound of Example 23 was added to 50 ml of toluene, and 5 ml of thionyl chloride was then added. The mixture was heated under reflux for 2 hours, and was then cooled and evaporated under vacuum. Fifty ml of additional toluene was added and removed under vacuum, and then 50 ml of isopropanol was added to the residue. The mixture was heated under reflux for 2 hours, and was then cooled and evaporated under vacuum. The residue was recrystallized from isopropanol to obtain 2.6 g of the desired product, m.p. 55°-57°.
Reaction SMILES: O[CH:2]([C:11]1[CH:20]=[CH:19][C:18]2[C:17]([CH3:22])([CH3:21])[CH2:16][CH2:15][C:14]([CH3:24])([CH3:23])[C:13]=2[CH:12]=1)[C:3]1[CH:4]=[C:5]([CH:9]=[O:10])[O:6][C:7]=1[CH3:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:8][C:7]1[O:6][C:5]([CH:9]=[O:10])=[CH:4][C:3]=1[CH2:2][C:11]1[CH:20]=[CH:19][C:18]2[C:17]([CH3:22])([CH3:21])[CH2:16][CH2:15][C:14]([CH3:24])([CH3:23])[C:13]=2[CH:12]=1
Reactant: Cc1oc(C=O)cc1C(O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1oc(C=O)cc1Cc1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A solution containing 4-[hydroxy-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)methyl]-5-methyl-2-furaldehyde (3.6 g, 11 mmol), triethylsilane (3.8 g, 33.1 mmol) and anhydrous methylene chloride (50 mL) was cooled to 0° C. To this mixture was added trifluoroacetic acid (˜1.3 g, 11.4 mmol) and the reaction was allowed to stir at RT for 16 hours. The reaction was quenched with saturated NaHCO3 and the organics were separated and dried over MgSO4. The resulting oil was used without further purification (the product appears to quickly decompose).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][C:7]([O:9]C)=O)[CH2:2]1.[NH2:11][NH2:12].O>CO>[O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][C:7]([NH:11][NH2:12])=[O:9])[CH2:2]1
Reactant: NN
Reactant: COC(=O)CC1CCOC1
Solvent: CO
Solvent: O
Product: NNC(=O)CC1CCOC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a round-bottom flask was added a solution of methyl 2-(tetrahydrofuran-3-yl)acetate (compound 130.3, 1.50 g, 10.4 mmol, 1.00 equiv) and NH2NH2. H2O (1.04 g, 20.8 mmol, 2.00 equiv) in methanol (15 mL). The resulting mixture was stiffed overnight at 80° C. in an oil bath. After cooling to ambient temperature, the mixture was concentrated in vacuo to yield 1.20 g (80%) of the title compound as a yellow oil.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([N-]C(C)C)(C)C.[Li+].[CH:32]([C:34]1[CH:35]=[C:36]([C:39]([O:41][CH3:42])=[O:40])[NH:37][CH:38]=1)=O.O>O1CCCC1>[CH3:2][O:3][CH:4]=[CH:32][C:34]1[CH:35]=[C:36]([C:39]([O:41][CH3:42])=[O:40])[NH:37][CH:38]=1
Reactant: COC(=O)c1cc(C=O)c[nH]1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COC=Cc1c[nH]c(C(=O)OC)c1
Reaction time: 1 h
Yield: 50 %

Procedure:
Into a solution of 200 g (0.58 mol) of methoxymethyltriphenylphosphonium chloride in 1.5 liter of tetrahydrofuran, was added dropwise 220 ml of a tetrahydrofuran solution (2.01 mol concentration) containing 0.44 mol of lithium diisopropylamide under stirring and cooling with ice. After one-hour stirring at room temperature, 400 ml of a tetrahydrofuran solution of 57.6 g (0.38 mol) of methyl 4-formylpyrrole-2-carboxylate was added to the mixture at 5° to 8° C. under cooling with ice. The reaction was carried out for one hour at room temperature, and the reaction mixture was added with water and extracted with ethyl acetate. The organic layer was collected, washed with a saturated solution of sodium chloride, dried over anhydrous magnesium sulfate and evaporated to obtain a residue. The residue was purified by a silica-gel column chromatography (eluent:ethyl acetate/hexane=1/4) to obtain 34.4 g of methyl 4-methoxyvinylpyrrole-2-carboxylate as a mixture of E-isomer and Z-isomer. The yield was 50%.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5](N)=[CH:4][CH:3]=1.[C:9]([N:12]1[C:21]2[C:16](=[CH:17][C:18]([F:22])=[CH:19][CH:20]=2)[C@@H:15]([OH:23])[CH2:14][C@@H:13]1[CH3:24])(=[O:11])[CH3:10].FC1C=CC(O)=CC=1>>[C:9]([N:12]1[C:21]2[C:16](=[CH:17][C:18]([F:22])=[CH:19][CH:20]=2)[C@H:15]([O:23][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:14][C@@H:13]1[CH3:24])(=[O:11])[CH3:10]
Reactant: Nc1ccc(F)cc1
Reactant: CC(=O)N1c2ccc(F)cc2[C@@H](O)C[C@@H]1C
Agent: Oc1ccc(F)cc1
Product: CC(=O)N1c2ccc(F)cc2[C@H](Oc2ccc(F)cc2)C[C@@H]1C
Yield: 61 %

Procedure:
Trans-1-acetyl-6-fluoro-4-hydroxy-2-methyl-1,2,3,4-tetrahydroquinoline was obtained in the same manner as in Example 17, using 4-fluoroaniline. A compound was produced in the same manner as in Example 17, using 60 mg of trans-1-acetyl-6-fluoro-4-hydroxy-2-methyl-1,2,3,4-tetrahydroquinoline and 112 mg of 4-fluorophenol, and thus 58 mg (61%) of the title compound was obtained as a colorless oily substance.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[CH:10]C(OCC)=O)[CH2:3]1.[Li][CH3:18].[NH4+].[Cl-].C([O:23][CH2:24][CH3:25])C>>[CH3:18][C:24]([OH:23])([CH3:25])[CH:10]=[C:4]1[CH2:3][C:2]([CH3:16])([CH3:1])[CH2:7][C:6]([CH3:8])([CH3:9])[CH2:5]1
Reactant: CCOC(=O)C=C1CC(C)(C)CC(C)(C)C1
Reactant: [Li]C
Reactant: CCOCC
Agent: [Cl-]
Agent: [NH4+]
Product: CC(C)(O)C=C1CC(C)(C)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
A solution of acetate 2 (2.14 g, 10 mmol) in diethyl ether (20 ml) was added to 1.6 M MeLi solution in diethyl ether (26 ml, 40 mmol), while cooling in an ice bath. The reaction mixture was stirred at room temperature for 1 h. It was then cooled in an ice bath and saturated aqueous NH4Cl (20 ml) was added dropwise. The aqueous phase was extracted with diethyl ether (230 ml). The combined organic phases were washed with brine (30 ml), dried over MgSO4, filtered and evaporated. The residue was purified by Kugelrohr short path distillation (100° C./4 mm Hg) to give 29 (1.86 g, 86%) as a colorless oil. 1H-NMR: (CDCl3, TMS): 0.91 and 0.96 (total 12H, both s, c-Hex-3,5-CH3); 1.25 (2H, s, c-Hex-4-CH2); 1.38 (6H, s, —C(CH3)2O); 1.79 and 2.23 (both 2H, both s, c-Hex-2,6-CH2) and 5.39 ppm (1H, s, ═CH—).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]3[O:14][C:15]([S:18][CH3:19])=[N:16][N:17]=3)[CH:12]=[C:6]2[C:5]=1[NH:20][C@@H:21]1[CH2:25][CH2:24][C@@:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:26])[C:22]1([CH3:36])[CH3:35])(=[O:3])[NH2:2].[OH:37]OS([O-])=O.[K+]>CC(C)=O.O.CCOC(C)=O>[C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]3[O:14][C:15]([S:18]([CH3:19])=[O:37])=[N:16][N:17]=3)[CH:12]=[C:6]2[C:5]=1[NH:20][C@@H:21]1[CH2:25][CH2:24][C@@:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:26])[C:22]1([CH3:36])[CH3:35])(=[O:3])[NH2:2]
Reactant: CSc1nnc(-c2cc3c(N[C@@H]4CC[C@](C)(NC(=O)OC(C)(C)C)C4(C)C)c(C(N)=O)cnn3c2)o1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)c1nnc(-c2cc3c(N[C@@H]4CC[C@](C)(NC(=O)OC(C)(C)C)C4(C)C)c(C(N)=O)cnn3c2)o1
Reaction time: 2 h
Yield: 22.5 %

Procedure:
A solution of tert-butyl ((1S,3R)-3-((3-carbamoyl-6-(5-(methylthio)-1,3,4-oxadiazol-2-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-1,2,2-trimethylcyclopentyl)carbamate (805 mg, 1.561 mmol) in acetone (16 mL) was added oxone (1.920 g, 3.12 mmol) in water (16.00 mL) and stirred for 2 hrs. The reaction mixture was diluted with 150 mL of EtOAc which was washed with 50 mL of 10% LiCl solution, 50 mL of brine and dried over Na2SO4. Filtration and concentration yielded a crude product which was purified on silica gel column with EtOAc to give tert-butyl ((1S,3R)-3-((3-carbamoyl-6-(5-(methylsulfinyl)-1,3,4-oxadiazol-2-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-1,2,2-trimethylcyclopentyl)carbamate (186.6 mg, 23% yield). HPLC retention time=2.993 min. LC-MS: M+1 532.3. 1H-NMR (400 MHz, methanol-d4) δ 8.30 (d, J=1.8 Hz, 1H), 8.26 (s, 1H), 7.51 (d, J=1.8 Hz, 1H), 4.50 (d, J=9.0 Hz, 1H), 3.31 (s, 3H, under MeOH peak), 2.51-2.32 (m, 1H), 2.29-2.13 (m, 1H), 2.12-1.95 (m, 1H), 1.83-1.63 (m, 1H), 1.49 (s, 3H), 1.46 (s, 9H), 1.13 (s, 3H), 1.09 (s, 3H).
Reaction SMILES: [N+]([O-])([O-])=O.[Ag+:5].C(N(CC)CC)C.[NH2:13][C:14]1[C:27]2[C:26](=[O:28])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19](=[O:29])[C:18]=2[C:17]([NH2:30])=[CH:16][CH:15]=1>C(#N)C>[Ag:5].[NH2:13][C:14]1[C:27]2[C:26](=[O:28])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19](=[O:29])[C:18]=2[C:17]([NH2:30])=[CH:16][CH:15]=1
Reactant: [Ag+]
Agent: Nc1ccc(N)c2c1C(=O)c1ccccc1C2=O
Agent: O=[N+]([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: [Ag]

Procedure:
Silver (I) nitrate (0.71g) is dissolved in acetonitrile (25 ml). Triethylamine (0.3 ml) and 1,4-diamino anthraquinone (0.5 g) are added and a precipitate forms immediately. The precipitate is collected and washed with acetonitrile, dimethylformamide, acetonitrile, and finally methylene chloride before drying. The yield is 0.22 g of a dark blue-black powder having a conductivity of 7.9×10-3S/cm. Analysis shows a composition of C--38.6 percent, H--2.06 percent, N--6.12 percent and Ag--40.1 percent.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].[C:24](Cl)(=[O:28])[CH:25]([CH3:27])[CH3:26]>CCCCCC.[Cl-].[NH4+].O1CCCC1>[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH:18]([C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)Cc1ccco1
Reactant: CC(C)C(=O)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(C(=O)C(C)C)c1ccco1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 327 %

Procedure:
To 60 mL of tetrahydrofuran and 9.3 mL (66 mmol) of diisopropylamine, 38 mL (60 mmol) of 1.57 M n-butyllithium in n-hexane was added dropwise under a nitrogen atmosphere under cooling with ice, and the reaction mixture was warmed to room temperature and stirred for 30 minutes. After the stirring, the reaction mixture was cooled to −78° C., and after dropwise addition of 4.62 g (30.0 mmol) of ethyl 2-(furan-2-yl)acetate, stirred at the same temperature for 1 hour. After the stirring, 3.8 mL (36 mmol) of isobutyryl chloride was added at −78° C., and the reaction mixture was gradually warmed and then stirred at room temperature for 15 hours. After completion of the reaction, the reaction mixture was diluted with saturated aqueous ammonium chloride under cooling with ice and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and with saturated aqueous sodium chloride successively, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by intermediate pressure silica gel column chromatography (silica gel 30 g, ethyl acetate:hexane=1:10) to give 22 g of the desired product as an orange liquid.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[C:7]3[CH:13]=[C:12]([C:14]4[N:15]([CH2:19][C:20]([OH:22])=O)[CH:16]=[CH:17][CH:18]=4)[NH:11][C:8]3=[N:9][CH:10]=[C:5]2[CH:4]=[N:3]1.C(Cl)(=O)C([Cl:26])=O.CN(C=O)C>C(Cl)Cl>[CH3:1][N:2]1[C:6]2=[C:7]3[CH:13]=[C:12]([C:14]4[N:15]([CH2:19][C:20]([Cl:26])=[O:22])[CH:16]=[CH:17][CH:18]=4)[NH:11][C:8]3=[N:9][CH:10]=[C:5]2[CH:4]=[N:3]1
Reactant: Cn1ncc2cnc3[nH]c(-c4cccn4CC(=O)O)cc3c21
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1ncc2cnc3[nH]c(-c4cccn4CC(=O)Cl)cc3c21
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a flask was added 2-(2-(1-methyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-7-yl)-1H-pyrrol-1-yl)acetic acid (0.125 g, 0.423 mmol, Example #AN.1.2) and oxalyl chloride (0.275 mL, 0.550 mmol) in DCM (4 mL) followed by a drop of DMF. The mixture was stirred for about 40 min at rt and then concentrated to dryness to afford 2-(2-(1-methyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-7-yl)-1H-pyrrol-1-yl)acetyl chloride. The mixture was used immediately in the next step. Analytics were performed by quenching a sample with MeOH and methyl ester is the observed (M+H)+: LC/MS (Table 2, Method c) Rt=1.30 min; MS m/z 310 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[CH3:7][CH:8]1[CH:13]=[C:12]([CH3:14])[CH2:11][CH2:10][CH:9]1[CH2:15][OH:16].[OH2:17]>N1C=CC=CC=1>[CH3:7][CH:8]1[CH:13]=[C:12]([CH3:14])[CH2:11][CH2:10][CH:9]1[CH2:15][O:16][C:1](=[O:5])[C:2]([O:17][CH2:15][CH:9]1[CH2:10][CH2:11][C:12]([CH3:14])=[CH:13][CH:8]1[CH3:7])=[O:3]
Reactant: O
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC1=CC(C)C(CO)CC1
Solvent: c1ccncc1
Product: CC1=CC(C)C(COC(=O)C(=O)OCC2CCC(C)=CC2C)CC1
Temperature: 25 °C
Yield: 85 %

Procedure:
Oxalyl chloride (10 ml, 116 mmol) was added dropwise to a stirred solution of (±)-(2,4-dimethylcyclohex-3-en-1-yl)methanol (32.48 g, 233 mmol, cis/trans ca. 4:1) in pyridine (270 ml) at 0° C. over a period of 15 min. The solution was allowed to warm up to room temperature and, after 21 h, was poured onto cold water, extracted with diethyl ether (2×), H2SO4 (10%) (2×), NaHCO3 (sat.) and NaCl (sat.). The organic layer was dried (Na2SO4) and concentrated. Column chromatography (SiO2, heptane/ether 8:2) gave 32.85 g (85%) of (±)-bis[(2,4-dimethyl-3-cyclohexen-1-yl)methyl]oxalate as a slightly yellow oil (mixture of cis/trans-isomers ca. 4:1).
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[F:9][C:10]([F:33])([F:32])[C:11]1[CH:12]=[C:13]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:14][O:15][CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18]>CS(C)=O.C(OCC)(=O)C>[F:9][C:10]([F:32])([F:33])[C:11]1[CH:12]=[C:13]([CH:25]=[C:26]([C:28]([F:30])([F:31])[F:29])[CH:27]=1)[CH2:14][O:15][CH2:16][C:17]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:2][O:18]1
Reactant: C[S+](C)(C)=O
Reactant: O=C(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: FC(F)(F)c1cc(COCC2(c3ccccc3)CO2)cc(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
Trimethylsulfoxonium iodide (185 mg, 0.84 mmol) was dissolved in anhydrous dimethylsulfoxide (2 ml). Sodium hydride (60 wt % in mineral oil, 36 mg, 0.9 mmol) was added to the solution and followed by addition of (2-(3,5-bis(trifluoromethyl)benzyloxy)-1-phenylethanone). After stirred for 1 hour, the reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried with magnesium sulfate, concentrated, and the residue was purified by flash chromatography on silica gel to give the desired product. 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 7.76 (s, 1 H) 7.69 (s, 2 H) 7.40–7.45 (m, 2 H) 7.34–7.39 (m, 2 H) 7.30–7.34 (m, 1 H) 4.65–4.72 (m, 2 H) 4.23 (d, J=11.90 Hz, 1 H) 3.79 (d, J=11.60 Hz, 1 H) 3.11 (d, J=5.19 Hz, 1 H) 2.82 (d, J=5.19 Hz, 1 H); LRMS [ESI, MNa+] m/z calcd for C18H14O2F6Na 399.08, found 398.97.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[SH:6].Br[CH2:8][CH2:9][CH2:10][C:11]#[N:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6][CH2:8][CH2:9][CH2:10][C:11]#[N:12]
Reactant: N#CCCCBr
Reactant: Sc1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCCCSc1cccs1
Yield: 93.7 %

Procedure:
2.3 g of thiophen-2-thiol, 3.0 g of 4-bromobutyronitrile and 5.5 g of potassium carbonate were stirred in N,N-dimethylformamide at room temperature to give 3.4 g of 4-(2-thienylsulfanyl)butane nitrile. 3.4 g of 4-(2-thienylsulfanyl)butane nitrile was reacted with 5.4 g of N-iodosuccinimide in N,N-dimethylformamide, whereby 5.5 g of the title compound was obtained as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](OS(C(F)(F)F)(=O)=O)=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][N:7]=[CH:6]2.[C:22]1([C:28]#[CH:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.O>CN(C=O)C>[CH3:1][O:2][C:3]1[C:4]([C:29]#[C:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][N:7]=[CH:6]2
Reactant: COc1ccc2c(=O)[nH]ncc2c1OS(=O)(=O)C(F)(F)F
Reactant: C#Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(=O)[nH]ncc2c1C#Cc1ccccc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 79.9 %

Procedure:
A mixture under N2 of trifluoro-methanesulfonic acid 6-methoxy-1-oxo-1,2-dihydrophthalazin-5-yl ester (1 g, 3.08 mmoles), prepared as described in example 59, phenylacetylene (0.507 ml, 4.62 mmoles), bis(triphenylphosphine)PdCl2 (108 mg, 0.154 mmole), triethylamine (1.71 ml, 12.32 mmoles) in DMF (20 ml) was heated at 90° C. under stirring for 3 hours, then cooled, poured into water and extracted with CH2Cl2. The extract was washed with water, anhydrified over Na2SO4 and brought to dryness. The residue was taken up in ethyl ether and filtered to give 680 mg of the title compound (yield: 80%).