Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:10]1[O:12][C@H:11]1[C:13]([OH:15])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH2:16]([S:24][C:25]1[N:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=2)=[CH:27][N:26]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([C@@H:10]1[O:12][C@H:11]1[C:13]([O:15][C:34]1[CH:33]=[CH:32][C:31]([C:28]2[CH:27]=[N:26][C:25]([S:24][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[N:30][CH:29]=2)=[CH:36][CH:35]=1)=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCSc1ncc(-c2ccc(O)cc2)cn1
Reactant: CCCCCCCCC[C@@H]1O[C@H]1C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCC[C@@H]1O[C@H]1C(=O)Oc1ccc(-c2cnc(SCCCCCCCC)nc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 413 mg (2.0 mmol) of dicyclohexyldicarbodiimide in 10 ml of dry CH2Cl2 is added while stirring at room temperature to 429 mg (2 mmol) of (2R,3S)-3-nonyloxirane-2-carboxylic acid, 633 mg (2 mmol) of 4-(2-n-octylthiopyrimidin-5-yl) phenol and also 20 mg of 4-dimethylaminopyridine. After stirring for 4 hours at room temperature, the reaction solution is evaporated down in vacuo. After chromatographic purification and recrystallization from n-hexane, 120 mg (12%) of colorless crystals are obtained. The substance exhibits the liquid-crystal phase sequence: X 73 SA 93.5 I.
Reaction SMILES: Cl[CH2:2][C@H:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH:5]([CH3:7])[CH3:6].[C:16]([C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)#[N:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:16]([C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[O:24][CH2:2][C@H:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH:5]([CH3:7])[CH3:6])#[N:17]
Reactant: N#Cc1cccc(O)c1
Reactant: CC(C)C[C@H](CCl)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)C[C@H](COc1cccc(C#N)c1)NC(=O)OC(C)(C)C

Procedure:
2.35 g (9.97 mmol) of t-butyl (1R)-2-chloro-1-(2-methylpropyl)ethylcarbamate was reacted with 2.42 g (20.3 mmol)) of 3-cyanophenol and 2.72 g (19.7 mmol) of potassium carbonate in dimethylformamide. After the treatment in an ordinary manner, the title compound was obtained.
Reaction SMILES: [Br-].[CH2:2]([N+:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[C:10]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:22]([S:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:26])=[O:25])=[CH2:23].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>O1CCOCC1>[CH2:2]([N:9]1[C@@H:14]2[C@H:22]([S:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)(=[O:25])=[O:26])[CH2:23][C@@:10]1([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:11](=[O:15])[CH:12]=[CH:13]2)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C=CS(=O)(=O)c1ccccc1
Reactant: Oc1ccc[n+](Cc2ccccc2)c1-c1ccccc1
Agent: O=C([O-])O
Agent: [Br-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C1C=C[C@H]2[C@H](S(=O)(=O)c3ccccc3)C[C@]1(c1ccccc1)N2Cc1ccccc1
Temperature: 25 °C
Yield: 78.8 %

Procedure:
A mixture of N-benzyl-3-hydroxy-2-phenylpyridinium bromide (Description 1; 4.91 g, 14.3 mmol), phenyl vinyl sulphone (4.2 g, 25 mmol), triethylamine (2.8 ml, 20 mmol) and 1,4-dioxane (50 ml) was heated at reflux overnight. After cooling to room temperature, the reaction mixture was poured onto saturated aqueous NaHCO3 and extracted with ethyl acetate (3×100 ml). The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (isohexane:diethyl ether 10-70%) to give the title compound (4.84 g, 78%) as a yellow-orange foam. Crystallisation from iso-hexane:diethyl ether gave the product as yellow rhombs.
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].C(N(C(C)C)CC)(C)C.Cl.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35](Cl)=[O:36]>C(Cl)Cl>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:35]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=2)=[O:36])[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: O=C(Cl)c1ccccn1
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccccn2)CC1
Yield: 80.1 %

Procedure:
To a stirred solution of 1-(2-tert-butylphenyl)piperazine dihydrochloride (0.064 g, 0.22 mmol) and diisopropylethylamine (0.089 g, 0.69 mmol) in methylene chloride stirring at 0° C. was added picolinoyl chloride hydrochloride (0.043 g, 0.24 mmol) at room temperature. After 2 h the reaction mixture was concentrated under reduced pressure and the residue purified by flash column chromatography (silica gel, 95:5 to 90:10 dichloromethane/methanol) to provide (4-(2-tert-butylphenyl)piperazin-1-yl)(pyridin-2-yl)methanone (0.057 g, 80%) as a brown solid, mp 140-145° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[C:4]=1[CH:5]=[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8].CO>[C].[Pd].C(O)(=O)C>[CH3:22][O:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:3]([O:2][CH3:1])[C:4]=1[CH2:5][CH:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(=Cc1c(OC)cccc1OC)C(=O)OCC
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)C(Cc1c(OC)cccc1OC)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.5 %

Procedure:
A mixture of 2.8 g of diethyl (2,6-dimethoxybenzylidene)malonate, 0.6 g of palladium-carbon, 50 ml of methanol and 50 ml of glacial acetic acid was stirred at 25° C. overnight. The solution was filtered and concentrated, and the residue was taken up in ethyl acetate and extracted with 20% NaHCO3 and some ice. Thereafter, the mixture was extracted with 1N, HCl, back-washed with saturated NaCl solution, the organic phase was dried and evaporated under reduced pressure. The crude product was distilled in a high vacuum at 170° C./0.6 mbar. 2.1 g of diethyl (2,6-dimethoxybenzyl)malonate were obtained.
Reaction SMILES: I[C:2]1[C:6]2[C:7]([O:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][CH:9]=[CH:10][C:5]=2[N:4](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:3]=1.N1C=C([C:42]2[C:46]3C(OC4CCOCC4)=NC=C[C:45]=3[N:44]([C:58]([C:71]3[CH:76]=[CH:75]C=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:43]=2)C=N1.BrCC1CC1>>[CH:71]1([CH2:58][N:44]2[CH:45]=[C:46]([C:2]3[C:6]4[C:7]([O:11][CH:12]5[CH2:13][CH2:14][O:15][CH2:16][CH2:17]5)=[N:8][CH:9]=[CH:10][C:5]=4[NH:4][N:3]=3)[CH:42]=[N:43]2)[CH2:76][CH2:75]1
Reactant: Ic1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccnc(OC3CCOCC3)c12
Reactant: c1ccc(C(c2ccccc2)(c2ccccc2)n2nc(-c3cn[nH]c3)c3c(OC4CCOCC4)nccc32)cc1
Agent: BrCC1CC1
Product: c1cc2[nH]nc(-c3cnn(CC4CC4)c3)c2c(OC2CCOCC2)n1
Yield: 71 %

Procedure:
Prepared by a procedure analogous to Example 86 using 3-iodo-4-(tetrahydro-2H-pyran-4-yloxy)-1-trityl-1H-pyrazolo[4,3-c]pyridine as starting material and by reacting 3-(1H-pyrazol-4-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-1-trityl-1H-pyrazolo[4,3-c]pyridine with (bromomethyl)cyclopropane to give the title compound (45.5 mg, 71% over two steps). LC-MS (Method G): m/z=340.1 [M+H]+; 3.63 min. 1H-NMR (400 MHz, DMSO): δ 13.27 (s, 1H), 8.28 (s, 1H), 8.01 (s, 1H), 7.83 (d, J=5.9, 1H), 7.07 (d, J=6.0, 1H), 5.53-5.43 (m, 1H), 4.06 (d, J=7.0, 2H), 3.95-3.85 (m, 2H), 3.53 (t, J=10.3, 2H), 2.20-2.10 (m, 2H), 1.86-1.72 (m, 2H), 1.35-1.24 (m, 1H), 0.62-0.53 (m, 2H), 0.45-0.38 (m, 2H).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[O-]CC.[Na+].[Na].Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29]>C(O)C>[CH3:29][O:28][CH2:27][CH2:26][O:25][CH2:24][O:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: COCCOCOCCCCCBr
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(CCCCCOCOCCOC)C(=O)OCC

Procedure:
A solution of 37.80 of diethyl malonate dissolved in 20 ml of absolute ethanol was added dropwise to a solution of sodium ethoxide prepared by gradually adding 3.00 g of metallic sodium to 30 ml of absolute ethanol. To the mixture was added a solution of 30.01 g of 1-bromo-5-(2-methoxyethoxy)methoxypentane (prepared as described in Preparation 40) dissolved in 10 ml of absolute ethanol. The mixture was heated under reflux for 21 hours, after which it was allowed to cool, and then the solvent was distilled off. The residue was mixed with water, and the mixture was extracted three times with ethyl acetate. The combined extracts were washed with water, dried and concentrated by evaporation under reduced pressure. The residue was subjected to column chromatography through 850 g of silica gel, and 32.78 g of the title compound was obtained from the fractions eluted with a 4:1 by volume mixture of hexane and ethyl acetate, as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Br[CH2:9][CH2:10][N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[C:12]1(=[O:21])[N:11]([CH2:10][CH2:9][O:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]12
Reactant: Oc1ccncc1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1c2ccccc2C(=O)N1CCOc1ccncc1
Temperature: 25 °C
Reaction time: 32 h
Yield: 3.1 %

Procedure:
To a solution of 4.76 g (50 mmol) of 4-hydroxypyridine and 13.97 g (55 mmol) of N-(2-bromoethyl)phthalimide in 80 ml of DMF, 80 ml (55 mmol) of 1,8-diazabicyclo[5.4.0]-7-undecene was added. The mixture was stirred at room temperature for 32 hours. After the solvent was distilled off, the mixture was poured into water and extracted with ethyl acetate. The mixture was washed with water and dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 0.41 g of the desired compound (yield: 3.1%, colorless crystal).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:9](=[CH:15]\[CH3:16])/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C(O)C.[CH3:20][NH:21][CH3:22]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:15]([N:21]([CH3:22])[CH3:20])[CH3:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CNC
Reactant: C/C=C(/C(=O)OCC)c1ccc(Cl)c(Cl)c1
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C(c1ccc(Cl)c(Cl)c1)C(C)N(C)C
Temperature: 50 °C
Reaction time: 10 h

Procedure:
In a Parr bomb containing 45 g. of ethyl 2-(3,4-dichlorophenyl)crotonate in 250 ml. of ethanol add 100 ml. of aqueous 33 percent (w/v) dimethylamine and 0.8 ml. of acetic acid. The mixture is maintained with stirring at 50° C for 10 hours, then the solvent is evaporated in vacuo and the residue, after suspension in water, is extracted several times with ether. After evaporation of the dried organic layer, 60 g. of the title compound is obtained which boils at 124° C/0.2 mm Hg. The product is an approximately 50:50 mixture of the two stereoisomers
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[N:10]=2)=[C:5]([C:22]([NH2:24])=[O:23])[CH:4]=1)#[CH:2].[C:25]([O:31][CH2:32][N:33]=[N+:34]=[N-:35])(=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>CN(C=O)C.O>[C:25]([O:31][CH2:32][N:33]1[CH:2]=[C:1]([C:3]2[S:7][C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]4[CH2:17][CH2:18][O:19][CH2:20][CH2:21]4)[N:10]=3)=[C:5]([C:22]([NH2:24])=[O:23])[CH:4]=2)[N:35]=[N:34]1)(=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27]
Reactant: C#Cc1cc(C(N)=O)c(Nc2cccc(CN3CCOCC3)n2)s1
Reactant: CC(C)(C)C(=O)OCN=[N+]=[N-]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCn1cc(-c2cc(C(N)=O)c(Nc3cccc(CN4CCOCC4)n3)s2)nn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Ethynyl-2-{[6-(morpholin-4-ylmethyl)pyridin-2-yl]amino}thiophene-3-carboxamide (86 mg, 0.25 mmol) and azidomethyl pivalate (59 mg, 0.38 mmol) were combined in DMF (1.0 mL). CuSO4.5H2O (6.3 mg, 0.025 mmol) in water (0.2 mL) and sodium ascorbate (20 mg, 0.10 mmol) in water (0.2 mL) were added, and the reaction mixture was stirred at room temperature overnight. The reaction was concentrated to dryness, combined with MeOH and silica gel, and evaporated. Flash chromatography (dry load, 0-10% MeOH/EtOAc) afforded the title compound as a yellow solid.
Reaction SMILES: [C:1]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17]2[N:21]=[C:20]([CH2:22][N:23]3[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]3)[O:19][N:18]=2)=[O:8])=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:16][O:15][N:14]=[C:12]1[CH2:11][C@@H:10]([C:17]2[N:21]=[C:20]([CH2:22][N:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]3)[O:19][N:18]=2)[N:9]([C:7]([C:4]2[CH:5]=[CH:6][C:1]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:2][CH:3]=2)=[O:8])[CH2:13]1
Reactant: CON=C1C[C@@H](c2noc(CN3CCN(C(=O)OC(C)(C)C)CC3)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CON=C1C[C@@H](c2noc(CN3CCNCC3)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Yield: 85 %

Procedure:
tert-butyl 4-({3-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-5-yl}methyl)-1-piperazinecarboxylate (100 mg, 1.80 mmol) was treated with a 25% TFA/DCM solution at 0° C. for 1 hour. The reaction was then made basic with a sodium carbonate solution (10%) and extracted with DCM. The organic phases were combined and dried over magnesium sulfate and solvent removal afforded a residue, which was purified by flash-chromatography using dichloromethane/methanol as eluent to give the desired product, (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[5-(1-piperazinylmethyl)-1,2,4-oxadiazol-3-yl]-3-pyrrolidinone O-methyloxime, as a mixture of E-/Z-isomers in a 85% yield (94.3% purity by HPLC).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[NH2:9][NH:10][C:11](N)=[O:12].C(OCCO)C.S(=O)(=O)(O)O>O>[N:9]1[NH:10][C:11](=[O:12])[N:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=12
Reactant: Clc1ccccn1
Reactant: NNC(N)=O
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOCCO
Product: O=c1[nH]nc2ccccn12
Reaction time: 0.5 h

Procedure:
A mixture of 50 g. (0.44 mole) of 2-chloropyridine and 98.22 g. (0.88 mole) of semicarbazide hydrocloride in 150 ml. of 2-ethoxyethanol was heated to reflux and then treated with a solution of 1 ml. of concentrated sulfuric acid (36 N) in 5 ml. of 2-ethoxyethanol. The resulting solution was refluxed for 18 hr., cooled to about 60°, and treated with 150 ml. of water. The mixture was stirred, cooled to 0°, and kept 0.5 hr. and the solid was collected on a filter. The solid was washed well with water and dried under reduced pressure, to give 35.0 g. (59%) of product, m.p. 230°-231°, which was sufficiently pure to be used for the next step.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:38])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20]OS(C)(=O)=O)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:26])[C:12]=2[C@H:27]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[I-:39].[Na+]>CC(C)=O.CCOC(C)=O>[CH2:1]([O:4][C:5]1([CH3:38])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][I:39])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:26])[C:12]=2[C@H:27]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: [I-]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(COS(C)(=O)=O)nn23)CC1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CI)nn23)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 84.1 %

Procedure:
To a solution of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-5-methyl-2-(((methylsulfonyl)oxy)methyl)pyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.62 g, 1.122 mmol) in acetone (6 ml) was added sodium iodide (0.673 g, 4.49 mmol) and the mixture was stirred at rt for 45 min. The reaction was diluted with EtOAc and washed with water. The organic phase was dried (Na2SO4), filtered and concentrated. The crude oil was purified by flash chromatography (Biotage; 0%-50% EtOAc/hexane; 20 CV) to give (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(iodomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.5519 g, 0.944 mmol, 84% yield) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 6.53 (s, 1H), 6.16-5.99 (m, 1H), 5.99-5.77 (m, 1H), 5.64-5.39 (m, 1H), 5.32-5.14 (m, 1H), 4.56 (s, 2H), 4.35-4.17 (m, 2H), 4.03 (d, J=4.9 Hz, 2H), 2.59 (s, 3H), 1.93 (br. s., 4H), 1.36 (s, 3H), 1.31-1.18 (m, 12H). 4 piperidine protons not seen. LCMS (M+H) calcd for C25H38IN4O4: 585.19. found: 585.5.
Reaction SMILES: C1CCN(CCCN2CC3C4C=CC(F)=CC=4C(NC=3CC2)=O)CC1.[CH2:26]([N:33]1[C:41]2[CH:40]=[CH:39][CH:38]=[C:37]([C:42]([O:44]C)=[O:43])[C:36]=2[C:35]([CH2:46][CH2:47][NH:48][C@H:49]2[CH:54]3[CH2:55][CH2:56][N:51]([CH2:52][CH2:53]3)[CH2:50]2)=[N:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O.[OH-].[Li+:59]>>[CH2:26]([N:33]1[C:41]2[CH:40]=[CH:39][CH:38]=[C:37]([C:42]([O-:44])=[O:43])[C:36]=2[C:35]([CH2:46][CH2:47][NH:48][C@H:49]2[CH:54]3[CH2:55][CH2:56][N:51]([CH2:52][CH2:53]3)[CH2:50]2)=[N:34]1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1.[Li+:59]
Reactant: COC(=O)c1cccc2c1c(CCN[C@@H]1CN3CCC1CC3)nn2Cc1ccccc1
Agent: O=c1[nH]c2c(c3ccc(F)cc13)CN(CCCN1CCCCC1)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])c1cccc2c1c(CCN[C@@H]1CN3CCC1CC3)nn2Cc1ccccc1
Yield: 100 %

Procedure:
Following general procedure GP-L, (S)-methyl 1-benzyl-3-(2-(quinuclidin-3-ylamino)ethyl)-1H-indazole-4-carboxylate (520 mg, 1.24 mmol) and lithium hydroxide monohydrate (129 mg, 3.07 mmol) were converted lithium (5)-1-benzyl-3-(2-(quinuclidin-3-ylamino)ethyl)-1H-indazole-4-carboxylate (509 mg, quant. yield), which was used in the next step without further purification: MS (ESI+) m/z 405 (M+H).
Reaction SMILES: [CH2:1]([CH2:8][C:9](=O)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[CH3:20])[CH3:13]>>[CH2:12]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1/[CH:20]=[C:9](\[CH3:10])/[CH2:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:13]
Reactant: CCc1cnccc1C
Reactant: CC(=O)CCc1ccccc1
Product: CCc1cnccc1/C=C(\C)CCc1ccccc1
Yield: 69.5 %

Procedure:
The procedure of Example 41 was repeated with the exception that 3.5 g of benzyl acetone in place of cinnamic aldehyde and 2.26 g of 3-ethyl-4-methylpyridine were used in Example 41, to obtain 3.26 g (yield: 59.8%) of (E)-1-(3-ethyl-4-pyridyl)-2-methyl-4-phenyl -1-butene (hereinafter referred to as compound 55) and o.95 g (yield: 17.4%) of (Z)-1-(3-ethyl-4-pyridyl)-2-methyl-4-phenyl-1-butene (hereinafter referred to as compound 56). The analytical results are shown below.
Reaction SMILES: [Mg].[F:2][C:3]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[CH:5][C:4]=1Br.[CH2:12]([C@H:15]1[CH2:20][CH2:19][C@H:18]([CH:21]2[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]2)[CH2:17][CH2:16]1)[CH2:13][CH3:14].Cl>C1COCC1.O>[F:2][C:3]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[CH:5][C:4]=1[C:24]1([OH:27])[CH2:23][CH2:22][CH:21]([C@H:18]2[CH2:19][CH2:20][C@H:15]([CH2:12][CH2:13][CH3:14])[CH2:16][CH2:17]2)[CH2:26][CH2:25]1
Reactant: Fc1ccc(Br)c(F)c1F
Reactant: CCC[C@H]1CC[C@H](C2CCC(=O)CC2)CC1
Agent: Cl
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: CCC[C@H]1CC[C@H](C2CCC(O)(c3ccc(F)c(F)c3F)CC2)CC1
Reaction time: 3 h

Procedure:
Into 7.6 g of magnesium and 20 mL of THF which were stirred while water-cooling in a nitrogen atmosphere, a THF solution (200 mL) containing 60 g of 2,3,4-trifluorobromobenzene was added dropwise for 2 hours, and stirred for 3 hours. Into this, a THF solution (200 mL) containing 70 g of 4-(trans-4-propylcyclohexyl)cyclohexanone was added dropwise for 2 hours, and stirred for 2 hours. After the reaction solution was poured into 10% hydrochloric acid and stirred for a while, an organic layer was separated, and an aqueous layer was extracted with toluene. After the extract and the organic layer were mixed together, washed using water and a saturated saline solution in that order, and dried using anhydrous sodium sulfate, the solvent was evaporated under a reduced pressure to obtain 110 g of 2,3,4-trifluoro-1-[1-hydroxy-4-(trans-4-propylcyclohexyl)cyclohexyl]benzene (unsatisfactorily dried).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1.CCN(CC)CC.CS(Cl)(=O)=O.Cl.[Na+].[I-:27]>C(Cl)Cl>[I:27][CH2:2][CH2:3][CH2:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1
Reactant: N#Cc1ccc(CCCO)cc1
Reactant: [I-]
Agent: CS(=O)(=O)Cl
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(CCCI)cc1

Procedure:
To a solution of 4-(3-hydroxypropyl)benzonitrile (1.8 g, 11.2 mmol) in CH2Cl2 (50 mL) at 0° C., Et3N (1.06 mL, 13.4 mmol) and then MsCl (0.95 mL, 12.5 mmol) were added. Upon completion, the reaction mixture was poured into 0.5M HCl and extracted with EtOAc. The crude mesylate was dissolved in acetone and treated with NaI (3.0 g, 20.0 mmol) in the dark at room temperature. When complete, the reaction was purified by flash chromatography on silica gel eluting with 15% EtOAc in Hexanes to afford the title compound.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[C:9]([O:13][CH3:14])(=[O:12])[C:10]#[CH:11].C(=O)([O-])[O-].[K+].[K+].C1COCC1>O.[Cu]I>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:11]#[C:10][C:9]([O:13][CH3:14])=[O:12])=[N:3][CH:4]=1
Reactant: C#CC(=O)OC
Reactant: Nc1cnc(I)cn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C#Cc1cnc(N)cn1
Temperature: 65 °C
Yield: 38 %

Procedure:
To a 5 mL of microwave vial was added 5-iodopyrazin-2-amine (100 mg, 0.452 mmol), methyl propiolate (161 μL, 1.810 mmol), potassium carbonate (125 mg, 0.905 mmol), copper (I) iodide (3.45 mg, 0.018 mmol), and THF (1508 μL). The reaction mixture was heated at 65° C. for 2 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo. The crude product was purified by flash chromatography (20% EtOAc in DCM) yielding methyl 3-(5-aminopyrazin-2-yl)propiolate (38%). LCMS (m/z): 178.4 (MH+), 0.48 min.
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[NH2:21][C:22]1[CH:26]=[CH:25][S:24][C:23]=1[C:27]([O:29][CH3:30])=[O:28]>ClCCl.N1C=CC=CC=1>[C:11]1([C:12]([NH:21][C:22]2[CH:26]=[CH:25][S:24][C:23]=2[C:27]([O:29][CH3:30])=[O:28])=[O:13])[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=1[S:9][S:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:1]([NH:21][C:22]1[CH:26]=[CH:25][S:24][C:23]=1[C:27]([O:29][CH3:30])=[O:28])=[O:19]
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Reactant: COC(=O)c1sccc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1sccc1NC(=O)c1ccccc1SSc1ccccc1C(=O)Nc1ccsc1C(=O)OC
Temperature: 23 °C
Reaction time: 18 h
Yield: 59 %

Procedure:
A solution of 2,2'-dithiobisbenzoyl chloride (2.00 g, 5.83 mmol) in 50 mL of dichloromethane was added to a solution of methyl 3-amino-2-thiophenecarboxylate (1.82 g, 11.6 mmol) in 14 mL of pyridine at 23° C. The reaction mixture was stirred for 18 hours at 23° C. under nitrogen atmosphere. The precipitate formed was collected by filtration, then triturated with 5% aqueous HCl and washed with water to yield the crude product. The crude material was recrystallized first from ethanol, then from acetonitrile-DMF to yield 2.0 g of the title compound, mp 250-252° C.