Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+:3].[C:4]1([O:14][CH2:15][CH2:16][NH:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=2)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1>CO>[C:4]1([O:14][CH2:15][CH2:16][NH:17][C:18]2[CH:19]=[CH:20][C:21]([C:22]([O-:24])=[O:23])=[CH:25][CH:26]=2)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1.[Na+:3]
Reactant: O=C(O)c1ccc(NCCOc2cccc3ccccc23)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C([O-])c1ccc(NCCOc2cccc3ccccc23)cc1

Procedure:
To a solution of 1.42 g. sodium methoxide in 250 ml. methanol is added 8.0 g. of 4-[2-(1-naphthyloxy)ethylamino]benzoic acid. After one-half hour, the mixture is concentrated under vacuum to a solid which is washed with methanol and then CH2Cl2. This solid is immediately dried in a vacuum oven to minimize absorption of moisture from the air.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[Cl:9][C:10]1[CH:26]=[CH:25][C:13]([C:14]([C:16]2([N:19]3[CH:23]=[N:22][C:21]([Cl:24])=[N:20]3)[CH2:18][CH2:17]2)=[O:15])=[CH:12][CH:11]=1.O>CS(C)=O>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]2([C:16]3([N:19]4[CH:23]=[N:22][C:21]([Cl:24])=[N:20]4)[CH2:17][CH2:18]3)[CH2:4][O:15]2)=[CH:25][CH:26]=1
Reactant: C[S+](C)(C)=O
Reactant: O=C(c1ccc(Cl)cc1)C1(n2cnc(Cl)n2)CC1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Clc1ccc(C2(C3(n4cnc(Cl)n4)CC3)CO2)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
60 ml of absolute dimethyl sulphoxide are added dropwise at 10° C. under a nitrogen atmosphere to a stirred mixture of 2.5 g (83 mmol) of sodium hydride (80 per cent of substance) and 17.6 g (80 mmol) of trimethyl sulphoxonium iodide. Stirring is continued for one hour at 20° C., and a solution of 20 g (71 mmol) of 1-(4-chlorobenzoyl)-1-(3-chloro-1,2,4-triazol-1-yl)-cyclopropane in 30 ml of dimethyl sulphoxide is subsequently added at 10° C. After the reaction mixture has been stirred for 48 hours at 20° C., it is warmed for another hour at 40° C. and then poured into water. The mixture is extracted several times using ethyl acetate, and the combined organic phases are washed with water, dried over sodium sulphate and concentrated by stripping off the solvent under reduced pressure. This procedure gives 21 g (100% of theory) of 2-(4-chlorophenyl)-2-[1-(3-chloro-1,2,4-triazol-1-yl)-cyclopropyl]-oxirane in the form of an oil. 1H-NMR (200 MHz, CDCl3): δ=0.8-1.4 (m, 4H); 2.92 (d, 1H); 3.15 (d, 1H); 7.10 (d, 2 H); 7.38 (d, 2H); 7.75 (s, 1H). ##STR18##
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1N.S(=O)(=O)(O)[OH:13].N([O-])=O.[Na+]>O>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[OH:13]
Reactant: Cc1cccc(C(=O)O)c1N
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cccc(C(=O)O)c1O
Temperature: 0 °C

Procedure:
3-methylanthranilic acid (12.5 g) was added slowly with stirring to sulfuric acid (61 ml: 7.5M) cooled to 0° C. A solution of sodium nitrite (5.7 g) in water (19 ml) was added dropwise maintaining the temperature below 5° C. The mixture was stirred for half an hour at room temperature and heated at 79-80° C. for one hour then cooled. Water was added and the mixture allowed to stand over the weekend. The mixture was filtered and the precipitate collected and washed with water. It was dissolved in ethyl acetate and the solution washed with water, stirred with barium chloride for 2 hours to remove any residual sulfuric acid, filtered, washed with water, dried and evaporated under reduced pressure to give 3-methylsalicylic acid, m.p. 160-2° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([Sn](CCCC)(CCCC)CCCC)=[CH:7][CH:6]=1)[CH3:2].FC(F)(F)S(O[C:31]1[CH:36]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:35][CH2:34][CH2:33][CH:32]=1)(=O)=O>>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:6]=[CH:7][C:8]([C:35]2[CH:36]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:31][CH2:32][CH2:33][CH:34]=2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CC(C)(C)C1CCCC=C1OS(=O)(=O)C(F)(F)F
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C(=O)OCC)cc1
Product: CCOC(=O)c1ccc(C2=CCCCC2C(C)(C)C)cc1
Yield: 66.8 %

Procedure:
4-(Tri-n-butyl-stannyl)-benzoic acid ethyl ester of Example 15, Step A (2.00 g, 4.55 mmol) and 6-tert-butyl-cyclohex-1-en-1-yl trifluoromethanesulfonate (1.43 g, 5.01 mmol) were reacted by the procedure described in Example 15, Step B. Purification by flash column chromatography on silica gel, eluting with a solvent gradient of from 0 to 10% ethyl acetate in hexane followed by recrystallization from methanol (0° C.) afforded the title compound (0.870 g) as white crystals, m.p. 50° C.
Reaction SMILES: Cl.Cl.O[C:4]1[CH:5]=[CH:6][C:7]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][CH2:9][C:8]=2[N:21]=1.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:4]1[CH:5]=[CH:6][C:7]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][CH2:9][C:8]=2[N:21]=1
Reactant: Oc1ccc2c(n1)CCN(Cc1ccccc1)CC2
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Product: Clc1ccc2c(n1)CCN(Cc1ccccc1)CC2

Procedure:
Prepared by reacting 2-hydroxy-7-benzyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine dihydrochloride with phosphorus oxychloride at 140° C.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[N:17]=[CH:16][N:15]=[C:14]2[C:10]=1[N:11]=[CH:12][N:13]2[C@H:18]1[C@@H:22]2[O:23]C(C)(C)[O:25][C@@H:21]2[C@@H:20]([CH2:28][N:29]([CH3:47])[CH2:30][CH2:31][CH2:32][NH:33][C:34]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([C:43]([CH3:46])([CH3:45])[CH3:44])=[CH:39][CH:38]=2)=[O:35])[CH2:19]1>O>[NH2:8][C:9]1[N:17]=[CH:16][N:15]=[C:14]2[C:10]=1[N:11]=[CH:12][N:13]2[C@@H:18]1[CH2:19][C@H:20]([CH2:28][N:29]([CH3:47])[CH2:30][CH2:31][CH2:32][NH:33][C:34]([NH:36][C:37]2[CH:38]=[CH:39][C:40]([C:43]([CH3:45])([CH3:46])[CH3:44])=[CH:41][CH:42]=2)=[O:35])[C@@H:21]([OH:25])[C@H:22]1[OH:23]
Reactant: CN(CCCNC(=O)Nc1ccc(C(C)(C)C)cc1)C[C@H]1C[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@H]12
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CN(CCCNC(=O)Nc1ccc(C(C)(C)C)cc1)C[C@H]1C[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O
Reaction time: 0.5 h
Yield: 103.4 %

Procedure:
A cooled (ice bath) solution of trifluoroacetic acid (5.2 mL, 67 mmol) in water (0.60 mL) was added to the precooled (ice bath) flask of 1-(3-((((3aR,4R,6R,6aS)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)(methyl)amino)propyl)-3-(4-(tert-butyl)phenyl)urea (0.10 g, 0.18 mmol). The reaction mixture was stirred for 30 min, the cold bath was removed, and the clear, pale yellow reaction mixture was stirred at rt for 1 h; HPLC indicated complete consumption of starting material. The reaction mixture was concentrated in vacuo and diluted with MeOH and concentrated (2×10 mL). The resultant residue was taken up in 10% MeOH/CH2Cl2 (60 mL) and washed with 10% aqueous NH4OH (1×18 mL). The separated aqueous layer was extracted with 10% MeOH/CH2Cl2 (3×18 mL) and the cloudy combined organics (pH>7) were diluted with MeOH (5 mL) to afford a clear solution, which was dried (Na2SO4) and concentrated in vacuo to afford the title compound (95 mg, quant) as a slightly off-white gum/foam: MS (ESI+) for C26H38N8O3 m/z 511.4 [M+H]+; MS (ESI−) for C26H38N8O3 m/z 509.3 [M−H]−, 555.3 [M+CO2H]−; HPLC purity>95% (ret. time, 2.701 min); 1H NMR (400 MHz, d4-MeOH) δ 8.17 (s, 1H), 8.16 (s, 1H), 7.27-7.20 (m, 4H), 4.78 (dt, J=10.7, 8.14 Hz, 1H), 4.52 (dd, J=8.5, 6.01 Hz, 1H), 4.01 (dd, J=5.8, 4.15 Hz, 1H), 3.31-3.23 (m, 2H), 2.78-2.70 (m, 1H), 2.67-2.55 (m, 3H), 2.48-2.31 (m, 2H), 2.39 (bs, 3H), 1.95-1.87 (m, 1H), 1.81-1.74 (m, 2H), 1.28 (s, 9H).
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH:3]=[CH:2]1.[C:7]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)#[N:8]>C(#N)C.O.O.O.O.O.O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>[O:6]=[C:1]1[CH2:5][CH2:4][CH:3]([C:12]2[C:11]3[C:15](=[CH:16][CH:17]=[C:9]([C:7]#[N:8])[CH:10]=3)[NH:14][CH:13]=2)[CH2:2]1
Reactant: O=C1C=CCC1
Reactant: N#Cc1ccc2[nH]ccc2c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: CC#N
Product: N#Cc1ccc2[nH]cc(C3CCC(=O)C3)c2c1
Yield: 69.1 %

Procedure:
2-Cyclopenten-1-one (4.1 g, 4.2 mL, 50 mMol) was added to a stirred solution of 5-cyanoindole (1.42 g, 10 mMol) and ytterbium triflate hexahydrate (124 mg, 0.2 mMol) in acetonitrile (15 mL). After stirring at room temperature for 7d, the reaction was concentrated to an oil and diluted with ether. The red oily mixture was filtered through celite and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (35 g) using a gradient of 20–35% ethyl acetate in hexane. Pure product fractions were concentrated and dried under high vacuum to give 3-(3-oxocyclopentyl)-1H-indole-5-carbonitrile (1.55 g, 69%). 1H NMR (500 MHz, CDCl3) δ 8.41 (1 H, bs), 7.99 (1 H, s), 7.45 (2 H, m), 7.12 (1 H, dd, J=2.44, 0.92 Hz), 3.72 (1 H, m), 2.77 (1 H, dd, J=7.63, 18.31 Hz), 2.56 (1 H, m), 2.40 (3 H, m), 2.10 (1 H, m). MS m/e 223.2 (M−H)+. Anal. calcd. for C14H12N2O: C, 74.98; H, 5.39; N, 12.49. Found: C, 74.75; H, 5.50; N, 12.23.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:14])=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].[Br:19]Br>C(Cl)(Cl)Cl>[Br:19][CH:10]1[C:9](=[O:14])[CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:15]([F:16])([F:17])[F:18])[CH:4]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: O=C1CCCCC1c1ccc(Cl)c(C(F)(F)F)c1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: O=C1C(Br)CCCC1c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 82.8 %

Procedure:
2-(4-Chloro-3-trifluoromethyl-phenyl)-cyclohexanone (50 mg, 0.18 mmol) was dissolved in chloroform (1 mL). To this solution bromine (30.3 mg, 0.19 mmol) in chloroform (0.5 mL) was added drop wise at room temperature. The reaction was stirred for 1½ hours at room temperature. The solvent was removed under reduced pressure to yield the crude title compound (53 mg) which was used directly in the next step without further purification.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([OH:25])=O)=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH3:49][NH:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:51]([N:50]([CH3:49])[C:23]([C:18]1[NH:19][C:20]2[C:16]([CH:17]=1)=[CH:15][C:14]([C:12]([N:9]1[CH2:8][CH2:7][N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:11][CH2:10]1)=[O:13])=[CH:22][CH:21]=2)=[O:25])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: O=C(O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Reactant: CNCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(Cc1ccccc1)C(=O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), methylbenzylamine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=O)[NH:5][CH:6]=[CH:7][CH:8]=1.P(Cl)(Cl)([Cl:12])=O.C(N(CC)C1C=CC=CC=1)C>O>[Cl:12][C:4]1[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc[nH]c1=O
Solvent: CCN(CC)c1ccccc1
Solvent: O
Product: COc1cccnc1Cl

Procedure:
3-methoxy-2-(1H)pyridone, 10 g. (0.08 mole), 12.3 g. (0.08 mole) of phosphorus oxychloride, and 11.9 g. (0.08 mole) of N,N-diethylaniline are combined in a suitable reaction vessel and heated at reflux for 20 hrs. The reaction mixture was allowed to cool, and was then mixed with 200 ml. of water and ice. The aqueous mixture was extracted with ether and the extracts dried over magnesium sulfate. The drying agent was then removed by filtration and the solvent was removed from the filtrate by distillation in vacuo. The residue was extracted with 160 ml. of boiling hexane and the hexane extracts decanted from the residue while still hot. The hexane solution was cooled in ice resulting in precipitation of the desired produce, weight 7.5 g., m.p. 46°-48°.
Reaction SMILES: Cl.[Br:2][C:3]1[C:4]([C@@H:9]([NH2:23])[C@H:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=2[F:22])[CH2:11][CH2:12][CH:13]=[CH2:14])=[N:5][CH:6]=[CH:7][N:8]=1.[C:24]([O:28][C:29](OC([O-])=O)=[O:30])([CH3:27])([CH3:26])[CH3:25].C(N(CC)CC)C>C(Cl)Cl>[Br:2][C:3]1[C:4]([C@@H:9]([NH:23][C:29](=[O:30])[O:28][C:24]([CH3:27])([CH3:26])[CH3:25])[C@H:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=2[F:22])[CH2:11][CH2:12][CH:13]=[CH2:14])=[N:5][CH:6]=[CH:7][N:8]=1
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: C=CCC[C@@H](c1cccc(F)c1F)[C@H](N)c1nccnc1Br
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCC[C@@H](c1cccc(F)c1F)[C@H](NC(=O)OC(C)(C)C)c1nccnc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
In a 250 mL round-bottomed flask was (R)—N-((1S)-1-(3-bromopyrazin-2-yl)-2-(2,3-difluorophenyl)hex-5-enyl)-2-methylpropane-2-sulfinamide (1.96 g, 4.16 mmol) in methanol (17 mL) to give a tan solution. HCl (4M in dioxane, 4.2 mL, 17 mmol) was added, and the mixture was stirred at rt for 1 h. Volatiles were removed in vacuo and the tan residue was diluted with ether and concentrated. The remaining tan foam was directly used in the next reaction. In the same round-bottomed flask was dissolved (1S,2S)-1-(3-bromopyrazin-2-yl)-2-(2,3-difluorophenyl)hex-5-en-1-amine (1.532 g, 4.16 mmol) (crude HCl salt) and t-butylpyrocarbonate (1.449 mL, 6.24 mmol) in methylene chloride (22 mL) to give a tan solution. triethylamine (1.28 mL, 9.15 mmol) was added dropwise, and the mixture was stirred at rt for 2 h. LCMS showed complete conversion. It was concentrated to dryness, and directly subject to flash column chromatography up to 40% ethyl acetate/hexane to afford the desired product (1.80 g, 92% for 2 steps) as colorless oil: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.27 (d, J=17.07 Hz, 2H) 6.92-7.14 (m, 3H) 5.69 (dd, J=10.29, 5.77 Hz, 1H) 5.63 (dd, J=9.41, 5.90 Hz, 1H) 5.41 (d, J=9.54 Hz, 1H) 4.84-4.95 (m, 2H) 3.65 (br. s., 1H) 1.88-2.08 (m, 3H) 1.81 (br. s., 1H) 1.30-1.41 (m, 9H). A slightly more polar diastereomer (generally <10% if there was minimum epimerization at the aldehyde stage) could be removed at this stage: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.46 (d, J=2.26 Hz, 1H) 8.20 (d, J=2.51 Hz, 1H) 6.88-7.11 (m, 3H) 5.66-5.81 (m, 1H) 5.60 (t, J=8.91 Hz, 1H) 5.51 (d, J=9.29 Hz, 1H) 4.83-5.00 (m, 2H) 3.55 (d, Hz, 1H) 1.87-2.06 (m, 3H) 1.73-1.86 (m, 1H) 1.44 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[CH:12]1(O)[CH2:16][CH2:15][CH:14]=[CH:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C(Cl)Cl>[CH:16]1([O:8][C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[N+:9]([O-:11])=[O:10])[CH2:15][CH2:14][CH:13]=[CH:12]1
Reactant: OC1C=CCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)cc1OC1C=CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-fluoro-2-nitrophenol (1.48 g), 2-cyclopenten-1-ol (662 mg) and triphenylphosphine (2.47 g) in THF (25.0 ml) diethylazodicarboxylate (1.48 ml) was added at 0° C. After stirring at room temperature overnight the reaction mixture was diluted with methylene chloride and washed with 10% aq. KHSO4. The organic layer was passed through a hydrophobic frit and concentrated in vacuo. The residue was purified by chromatography to give the desired product.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.[CH3:10][NH:11][C:12]1[NH:20][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][C:14]=2[N:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[F:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:17]2[CH:18]=[CH:19][C:14]3=[N:13][C:12]([NH:11][CH3:10])=[N:20][C:15]3=[CH:16]2)=[CH:4][CH:5]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: CNc1nc2ccncc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNc1nc2ccn(Cc3ccc(F)cc3)cc-2n1
Temperature: 60 °C

Procedure:
A mixture of 5.6 parts of 1-(chloromethyl)-4-fluorobenzene, 5.2 parts of N-methyl-3H-imidazo[4,5-c]pyridine-2-amine, 4.2 parts of sodium carbonate and 90 parts of N,N-dimethylformamide was stirred and heated first for 3 hours at 90°-100° C. and further overnight at 60° C. The reaction mixture was poured onto water and the product was extracted four times with dichloromethane. The combined extracts were dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (92.5:7.5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was boiled in 2-propanone, yielding 6 parts of 5-[(4-fluorophenyl)methyl]-N-methyl-5H-imidazo[4,5-c]pyridin-2-amine; mp. 209.5° C. (intermediate 97).
Reaction SMILES: [Li]CCCC.CCCCCC.[C:12]([C:14]1([OH:22])[CH:19]2[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]2)[CH2:15]1)#[CH:13].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([C:33]2[S:34][CH:35]=[CH:36][CH:37]=2)=[O:32])=[CH:27][CH:26]=1>C1COCC1>[OH:32][C:31]([C:28]1[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=1)([C:33]1[S:34][CH:35]=[CH:36][CH:37]=1)[C:13]#[C:12][C:14]1([OH:22])[CH:19]2[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]2)[CH2:15]1
Reactant: C#CC1(O)CN2CCC1CC2
Reactant: COc1ccc(C(=O)c2cccs2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(C(O)(C#CC2(O)CN3CCC2CC3)c2cccs2)cc1
Reaction time: 0.5 h

Procedure:
A 1.6 N solution of BuLi in hexane (1.12 ml, 1.79 mmol) was added dropwise to a solution of 3-ethynyl-1-azabicyclo[2.2.2]octan-3-ol 47 (123 mg, 0.81 mmol) in THF (5 ml) at room temperature. After stirring for 30 minutes, (4-methoxyphenyl)(2-thienyl)methanone (231 mg, 1.06 mmol, commercial) in THF (1 ml) was added slowly. After 2 hours, the reaction was quenched by addition of saturated aqueous NH4Cl solution and diluted with AcOEt. The organic phase was washed with brine, dried over Na2SO4 and evaporated. The yellowish oil was purified by chromatography on silica gel (CH2Cl2/MeOH 85/15) and 3-[3-hydroxy-3-(4-methoxyphenyl)-3-(2-thienyl)-1-propynyl]quinuclidin-3-ol 152 was obtained as a white solid (41 mg, 14%, mixture of diastereomers).
Reaction SMILES: [ClH:1].[CH2:2]([O:4]CC)[CH3:3].[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])#[N:8]>C(O)C>[ClH:1].[CH2:12]([O:11][C:9]([C:7](=[NH:8])[O:4][CH2:2][CH3:3])=[O:10])[CH3:13]
Reactant: CCOC(=O)C#N
Reactant: CCOCC
Agent: Cl
Solvent: CCO
Product: CCOC(=N)C(=O)OCC

Procedure:
A hydrogen chloride gas was introduced into a diethyl ether solution of an equimolar mixture of ethyl cyanoformate and ethanol at 0° C. or lower, and a precipitated crystal was filtered out and washed with diethyl ether to obtain ethyl ethoxycarbonylformimidate hydrochloride [H5C2O2CC(OC2H5)=NH.HCl]. 5.4 g of this hydrochloride, 40 ml of acetic acid, 5.0 g of phenacylamine hydrochloride (the same as used in Synthesis Example 2) and 4.85 g of anhydrous sodium acetate were mixed and reacted with stirring at 90° to 100° C. for 4 hours.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[ClH:14].[H][H]>C(O)C.[Pd]>[ClH:14].[NH2:2][CH2:1][C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: [H][H]
Reactant: CCOC(=O)c1cccnc1C#N
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cccnc1CN
Reaction time: 12 h

Procedure:
To a solution of ethyl 2-cyano-3-pyridinecarboxylate (2.5 g) and conc. HCl (5 mL) in 150 mL ethanol was added 10% Pd/C (wet, 250 mg) and the reaction mixture was hydrogenated using a hydrogen balloon and stirred for 12 h. The reaction was filtered through celite and ethanol was evaporated to give ethyl 2-(aminomethyl)-3-pyridinecarboxylate HCl as a white solid which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH:11]=[O:12].[CH2:13](O)[CH2:14][OH:15]>C1C=CC=CC=1.C([O-])(O)=O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH:11]1[O:15][CH2:14][CH2:13][O:12]1
Reactant: OCCO
Reactant: O=Cc1oc2ccccc2c1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: Brc1c(C2OCCO2)oc2ccccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 100.5 %

Procedure:
3-bromo-1-benzofuran-2-carbaldehyde (5.49 g, 24.4 mmol) is combined with para-toluene sulfonic acid hydrate (232 mg, 1.2 mmol) and ethylene glycol (2.44 ml, 43.9 mmol) in benzene (75 ml). The reaction is refluxed with a Dean-Stark trap for 5 h. The mixture is cooled to rt and diluted with saturated NaHCO3 solution (20 ml) and left to stir for an additional 12 h. The layers are allowed to separate, and the organic layer is dried over Na2SO4, filtered, and concentrated to afford 6.6 g (100%) of 3-bromo-2-(1,3-dioxolan-2-yl)-1-benzofuran as a dark brown oil. HRMS (FAB) calcd for C11H9BrO3+H: 268.9814, found 268.9821.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32](O)=[O:33])[C:27]2=[O:35])=[CH:22][CH:21]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CC#N.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:32]([C:28]3[C:27](=[O:35])[N:26]([C:23]4[CH:22]=[CH:21][C:20]([F:19])=[CH:25][CH:24]=4)[CH:31]=[CH:30][CH:29]=3)=[O:33])=[CH:16][CH:17]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1
Reactant: O=C(O)c1cccn(-c2ccc(F)cc2)c1=O
Reactant: Nc1ccc(Nc2cc(Cl)nn3ccnc23)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Nc2cc(Cl)nn3ccnc23)cc1)c1cccn(-c2ccc(F)cc2)c1=O
Temperature: 50 °C
Reaction time: 12 h
Yield: 9.8 %

Procedure:
To a 2 dram vial was added N1-(6-chloroimidazo[1,2-b]pyridazin-8-yl)benzene-1,4-diamine (0.078 g, 0.3 mmol, prepared as described in Example XV1, step 1a), 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (0.10 g, 0.45 mmol, prepared as described in Example XVII, step 1e2), EDCI (0.086 g, 0.45 mmol), HOBt (0.061 g, 0.45 mmol), TEA (0.12 ml, 0.9 mmol), DMF (0.8 ml) and CH3CN (1.5 ml). The reaction was allowed to stir around 50° C. for 12 hrs. Upon cooling, the solvent was removed in vacuo and diluted with methanol (2 ml). The solution was purified by HPLC (20-100% methanol gradient), which yielded 0.014 g of the title compound as a TFA salt. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 11.88 (1H, s), 8.70 (1H, dd, J=7.12, 2.03 Hz), 7.71-7.91 (3H, m), 7.67 (1H, s), 7.50-7.63 (1H, m), 7.10-7.43 (5H, m), 6.64 (1H, s), 6.56 (1H, t, J=7.12 Hz). LC/MS, m/e 475 (M+1). HPLC Rt, 2.82 min. YMC ODSC18 column (4.6×50 mm). 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4 mL/min.