Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[CH2:3]1.[OH-].[K+].[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1>O>[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][CH:5]2[C:6](=[O:8])[CH2:7][C:2]([CH3:10])([CH3:1])[CH2:3][C:4]2=[O:9])=[CH:16][CH:15]=1
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: ClCc1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC1(C)CC(=O)C(Cc2ccc(Cl)cc2)C(=O)C1
Temperature: 59 °C
Yield: 42 %

Procedure:
449 g (3.21 mols) dimedone (5,5-dimethylcyclohexane-1,3-dione) were added to a solution of aqueous potassium hydroxide comprising 166 g of 85% potassium hydroxide (2.52 moles) in 700 ml of water. The mixture was then warmed and a clear orange solution was obtained at 47° C. The solution was then heated to 59° C. and 544 g (3.21 mols) molten 4-chlorobenzyl chloride were added over a period of 1 hour with further heating to 85° C. Heating was continued for a further 21/2 to 3 hours up to a temperature of 100° C. The mixture was then cooled, the solid product filtered off, washed with water and dried in a vacuum oven at 50° C. The crude solid (815 g) was then dissolved in 2400 ml methanol at reflux and 200 ml water added to produce a permanent cloudiness. The mixture was then allowed to cool to room temperature overnight with stirring The solid so obtained was filtered, washed with about 400 ml cold methanol and dried in a vacuum oven to produce 340 g 2-(4-chlorobenzyl)-5,5-dimethylcyclohexane-1,3-dione as a white solid, m.pt. 188°-190° C. Yield: 42%.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=1.[CH:24]([NH2:27])([CH3:26])[CH3:25]>>[CH:24]([NH:27][C:21]([C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:20][N:19]=1)=[O:23])([CH3:26])[CH3:25]
Reactant: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)O)nc1
Reactant: CC(C)N
Product: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)NC(C)C)nc1
Yield: 80 %

Procedure:
As described for example 6f, 5-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridine-2-carboxylic acid (81.6 mg, 0.26 mmol) was converted, using isopropylamine instead of 4-aminotetrahydropyran, to the title compound (74 mg, 80%), after 1 h instead of overnight, which was obtained as a white solid after purification by chromatography (silica, heptane:ethyl acetate=4:1 to 0:1). MS: m/e=353.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.[I:12]NC(=O)CCC(N)=O.O>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([C:6]([OH:8])=[O:7])=[C:9]([I:12])[CH:10]=1
Reactant: NC(=O)CCC(=O)NI
Reactant: Cc1cc(Cl)ccc1C(=O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Cl)cc(I)c1C(=O)O
Temperature: 100 °C

Procedure:
A mixture of 4-chloro-2-methyl-benzoic acid (3.40 g, 20 mmol,), N-iodosuccinamide (4.4 g, 22 mmol) and palladium (II) acetate (0.448 g, 2 mmol) in dry DMF (35 mL) was heated at 100° C. for 36 h under nitrogen atmosphere. After this time, the reaction mixture was cooled to ambient temperature and poured into water. The aqueous solution was extracted with ethyl acetate (2×100 mL) and the combined organic extracts were washed with aqueous sodium thiosulphate (30 mL) and brine (30 mL). The organic solution was dried over anhydrous MgSO4, filtered and concentrated to afford 4-chloro-2-iodo-6-methyl-benzoic acid. The product was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=[O:12])=[CH:5]2.Cl.[CH3:15]O>>[OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH3:15])=[O:12])=[CH:5]2
Reactant: O=C(O)c1cc2cc(O)ccc2[nH]1
Reactant: CO
Agent: Cl
Product: COC(=O)c1cc2cc(O)ccc2[nH]1

Procedure:
A 4 N hydrogen chloride-methanol solution (80 mL) of 5-hydroxyindole-2-carboxylic acid (3.0 g) was heated overnight under reflux. The solvent was evaporated off from the reaction liquid under reduced pressure, aqueous saturated sodium hydrogencarbonate solution was added to the resulting residue, and extracted with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate, and the solvent was evaporated off under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane/ethyl acetate=4/1 to 3/2) to obtain methyl 5-hydroxy-1H-indole-2-carboxylate (2.3 g) as a pale brown solid.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[C:17]([OH:18])=[CH:16][CH:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][C:12]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:13]3)=[O:7])=[CH:4][CH:3]=1.CI.[C:27](=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[F:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[C:17]([O:18][CH3:27])=[CH:16][CH:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][C:12]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:13]3)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CS(=O)(=O)c1ccc2c(C(=O)c3ccc(F)cc3)c(O)ccc2c1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2cc(S(C)(=O)=O)ccc2c1C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.2 %

Procedure:
A mixture of 5-(4-fluorobenzoyl)-6-hydroxy-2-methylsulfonylnaphthalene (1.0 g, 2.9 mmol), [prepared as described in step 3 above], methyl iodide (0.65 ml, 10.45 mmol), and potassium carbonate (0.64 g, 4.65 mmol) in N,N-dimethylformamide (10 ml) was stirred at room temperature. After 16 h, the reaction mixture was diluted with water and extracted into ethyl acetate. The organic layer was separated, washed with brine, and dried over sodium sulfate. The solvent was removed in vacuo and the crude product was purified by flash chromatography (gradient elution 40-100% ethyl acetate/hexanes) to give 1.0 g of 5-(4-fluorobenzoyl)-6-methoxy-2-methylsulfonylnaphthalene as a solid (96% yield).
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]([CH2:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([CH3:27])[CH2:23][CH2:22]3)[C:9]([N:11]3[CH2:16][CH2:15][O:14][C@@H:13]4[CH2:17][CH2:18][CH2:19][C@@H:12]34)=[N:10][C:6]=2[CH:5]=[C:4]([Cl:28])[N:3]=1.[CH2:29]([O:36][C:37]1[C:42](B(O)O)=[CH:41][C:40]([Cl:46])=[CH:39][N:38]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([O-])([O-])=O.[Na+].[Na+].O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CCOC(C)=O>[CH2:29]([O:36][C:37]1[C:42]([C:2]2[C:7]3[N:8]([CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([CH3:27])[CH2:23][CH2:22]4)[C:9]([N:11]4[CH2:16][CH2:15][O:14][C@@H:13]5[CH2:17][CH2:18][CH2:19][C@@H:12]45)=[N:10][C:6]=3[CH:5]=[C:4]([Cl:28])[N:3]=2)=[CH:41][C:40]([Cl:46])=[CH:39][N:38]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: OB(O)c1cc(Cl)cnc1OCc1ccccc1
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCO[C@@H]4CCC[C@H]43)nc3cc(Cl)nc(Cl)c32)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@H]1CC[C@H](Cn2c(N3CCO[C@@H]4CCC[C@H]43)nc3cc(Cl)nc(-c4cc(Cl)cnc4OCc4ccccc4)c32)CC1
Temperature: 90 °C

Procedure:
4,6-dichloro-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine (racemic, 460 mg, 1.08 mmol), (2-(benzyloxy)-5-chloropyridin-3-yl)boronic acid (purchased from Combi-Blocks Inc.; 372 mg, 1.41 mmol) and 2M aqueous Na2CO3 (5 mL, 10 mmol) were added to degassed 1,2-dimethoxyethane (15 mL), followed by the addition of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (159 mg, 0.2 mmol). The reaction was heated at 90° C. for 6 hours. Water and EtOAc were added. The aqueous layer was extracted several times with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified on a silica gel column (0 to 30% EtOAc/hexanes) to afford 4-[2-(benzyloxy)-5-chloropyridin-3-yl]-6-chloro-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine (racemic). MS ES calc'd. for C33H37Cl2N5O2 [M+H]+ 606. found 606.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[CH:22][CH:21]=4)[CH:18]=3)[N:13]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:12]=2)[CH:8]=[N:7]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.Br[CH2:57][CH2:58][OH:59]>O>[F:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:27][CH2:28][N:29]([CH2:57][CH2:58][OH:59])[CH2:30][CH2:31]5)=[CH:22][CH:21]=4)[CH:18]=3)[N:13]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:33])=[O:34])[CH:12]=2)[CH:8]=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)cc4)cnc32)cc1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(CCO)CC5)cc4)cnc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a stirred solution of 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(4-(piperazin-1-yl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (product of step 1 of example 124) (75 mg, 0.123 mmol), potassium carbonate (24 mg, 0.185 mmol) and DMF (5 ml) was added 2-bromoethanol (24 mg, 0.185 mmol) and the mixture stirred at RT for overnight. Then water was added, this was then extracted into 10% methanol in DCM, organic portion was dried over sodium sulfate and concentrated to give 60 mg (75% yield) of the titled compound. MS: m/z=651.2 (M+1).
Reaction SMILES: [CH:1]12[CH2:11][CH:7]([C:8](=[O:10])[CH2:9]1)[CH:6]1[CH:2]2[CH2:3][CH2:4][CH2:5]1.[BH4-].[Na+].Cl.O>CO>[CH2:3]1[CH:2]2[CH:6]([CH:7]3[CH2:11][CH:1]2[CH2:9][CH:8]3[OH:10])[CH2:5][CH2:4]1
Reactant: O=C1CC2CC1C1CCCC21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OC1CC2CC1C1CCCC21
Reaction time: 8 h

Procedure:
25 g of tricyclo[5.2.1.0 (2,6)]decan-8-one (Aldrich) were dissolved in 100 ml of methanol and, at room temperature and with slight cooling and stirring, admixed a little at a time with 6.3 g of solid sodium borohydride over a period of 2 h. The mixture was then stirred for another 2 h and allowed to stand overnight. With cooling, about 40 ml of 2 N HCl were then added dropwise, followed by 20 ml of water. The mixture was concentrated, the residue was admixed with ethyl acetate, and the ethyl acetate phase was washed once with water and once with sodium bicarbonate solution. The ethyl acetate phase was dried using magnesium sulfate and then filtered and concentrated. This gave 26 g of an oil which was purified by distillation under reduced pressure. This gave 20.7 g of an oily liquid (bp0.5 76° C.).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].S=[C:6]1[NH:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[CH2:9][N:8]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:7]1>C(OC(=O)C)C>[C:20]([O:19][C:17]([N:8]1[CH2:9][C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=[C:6]([NH:1][CH2:2][CH2:3][OH:4])[CH2:7]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: NCCO
Reactant: CC(C)(C)OC(=O)N1CC(=S)Nc2ccccc2C1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(NCCO)=Nc2ccccc2C1
Temperature: 25 °C
Yield: 90 %

Procedure:
2-aminoethanol (3.5 mL, 10 mL/mmol) was added to a solution of tert-butyl 2-thioxo-2,3-dihydro-1H-benzo[e][1,4]diazepine-4(5H)-carboxylate (100 mg, 0.35 mmol), [prepared as described in Example 6, Step 6] and the reaction mixture was heated to reflux for 24 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature, diluted with ethylacetate (50 mL) and washed with water (20 mL). The organic layer was separated, dried over anhydrous sodium sulphate and concentrated to give the desired compound as viscous oil (100.0 mg, 90%) which was used as such for the next step.
Reaction SMILES: C(N(CC)C(C)C)(C)C.O[C@H:11]1[CH2:15][CH2:14][NH:13][C:12]1=[O:16].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[Cl:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][CH:42]=1)[NH:39][CH2:38][CH2:37][CH2:36]2>C(Cl)Cl>[Cl:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][CH:42]=1)[N:39]([C@@H:11]1[CH2:15][CH2:14][NH:13][C:12]1=[O:16])[CH2:38][CH2:37][CH2:36]2
Reactant: O=C1NCC[C@@H]1O
Reactant: Clc1ccc2c(c1)CCCN2
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1NCC[C@H]1N1CCCc2cc(Cl)ccc21
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 12 %

Procedure:
Prepared using general procedure 57. Under an N2 atmosphere at −20° C., N,N-diisopropylethylamine (1.74 mL, 10.0 mmol) was added dropwise to a solution of (S)-3-hydroxypyrrolidin-2-one (500 mg, 5.0 mmol) in CH2Cl2 (8 mL). Trifluoromethanesulfonic anhydride (0.88 mL, 5.25 mmol) was added dropwise to this solution. Upon completion of addition, the mixture was stirred at −20° C. for 30 min. 6-Chloro-1,2,3,4-tetrahydroquinoline (1.26 g, 7.5 mmol) was added in one portion. The reaction was allowed to warm up to RT overnight. After 18 h, the reaction mixture was washed with saturated aqueous sodium bicarbonate (2×20 mL), brine (20 mL), dried over magnesium sulfate, and concentrated. Purification via silica gel chromatography using 0-30% ethyl acetate in hexane gave (R)-3-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)pyrrolidin-2-one as a colorless oil (150 mg, 12%). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=251.3; tR=2.77 min.
Reaction SMILES: [CH2:1](P(=O)(OCC)OCC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]1([S:22]([C:25]([CH3:37])([CH3:36])[CH2:26][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][CH2:32][C:31](=O)[CH2:30]2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[H-].[Na+]>CN1CCN(C)C1=O>[C:16]1([S:22]([C:25]([CH3:37])([CH3:36])[CH2:26][CH2:27][CH2:28][N:29]2[CH2:30][CH2:31][CH2:32]/[C:33](=[CH:1]/[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)/[CH2:34]2)(=[O:24])=[O:23])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOP(=O)(Cc1ccccc1)OCC
Reactant: CC(C)(CCCN1CCCC(=O)C1)S(=O)(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCN(C)C1=O
Product: CC(C)(CCCN1CCC/C(=C/c2ccccc2)C1)S(=O)(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of diethyl benzylphosphonate (0.53 ml, 2.54 mmol) and 1-(4-benzenesulfonyl-4-methylpentyl)-3-piperidinone (0.7 g, 2.17 mmol) in 1,3-dimethylimidazolidin-2-one (5 ml) was added dropwise to a stirred slurry of sodium hydride (60% dispersion in mineral oil, 117 mg, 2.93 mmol) in 1,3-dimethylimidazolidin-2-one (3 ml). The reaction was stirred for 30 minutes then quenched by the addition of water. The mixture was extracted with dichloromethane. The combined organic layers were dried (MgSO4) and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with 20–75% ethyl acetate/chloroform, followed by preparative HPLC.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@@H:4]([O:14][CH2:15][CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[CH3:13].Cl[CH2:19][C:20]1[N:21]=[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])[O:23][C:24]=1[CH3:25].FC1C=CC=CC=1C=O.O=P(Cl)(Cl)Cl.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH3:1][O:2][C:3](=[O:17])[C@@H:4]([O:14][CH2:15][CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[O:23][C:24]=2[CH3:25])=[CH:8][C:7]=1[CH3:13]
Reactant: Cc1oc(-c2ccccc2F)nc1CCl
Reactant: CCO[C@@H](Cc1ccc(O)cc1C)C(=O)OC
Agent: O=C([O-])[O-]
Agent: O=Cc1ccccc1F
Agent: [Cs+]
Solvent: O=P(Cl)(Cl)Cl
Product: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccccc3F)oc2C)cc1C)C(=O)OC

Procedure:
In analogy to the procedure described in example 1 f], (2S)-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester (example 1 d]) was reacted with 4-chloromethyl-2-(2-fluoro-phenyl)-5-methyl-oxazole (prepared from 2-fluoro-benzaldehyde and diacetyl monoxyme followed by treatment with POCl3 in analogy to the procedures described in examples 5 a] and 2 b]) in the presence of cesium carbonate and potassium iodide to yield (S)-2-ethoxy-3-{4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionic acid methyl ester as colorless liquid.
Reaction SMILES: C(=[NH:14])(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:15][O:16][C:17](=[O:39])[CH2:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([C:25]2[CH:30]=[CH:29][C:28](OS(C(F)(F)F)(=O)=O)=[CH:27][CH:26]=2)[CH2:21][CH2:20]1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH3:15][O:16][C:17](=[O:39])[CH2:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([C:25]2[CH:30]=[CH:29][C:28]([NH2:14])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(OS(=O)(=O)C(F)(F)F)cc2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)C[C@H]1CC[C@H](c2ccc(N)cc2)CC1
Temperature: 180 °C
Reaction time: 10 h

Procedure:
Benzophenone imine (5.8 mL, 34.7 mmol) was added to a mixed solution of trans [4-(4-trifluoromethanesulfonyloxyphenyl)cyclohexyl]acetic acid methyl ester (12 g, 31.54 mmol), cesium carbonate (11.3 g, 34.7 mmol), palladium acetate (708 mg, 3.15 mmol), X-phos (3 g, 6.31 mmol) and toluene (78 mL) in a sealed tube. The mixture was purified 5 times with nitrogen and stirred at 180° C. for 10 hours. The prepared solution was cooled to remove the solvent under reduced pressure, the residue was sectioned with ether (600 mL) and water (600 mL) to separate each layer. The aqueous solution layer was extracted with ether (3×180 mL), a mixed organic layer was dried with anhydrous Na2SO4 and concentrated under vacuum to obtain yellow oil. The obtained oil was used without further purification (crude 21 g). The oil was dissolved in methanol (252 mL) and the solution was cooled to be 4° C. Hydrochloric acid (84 mL) 1M was slowly added thereto while maintaining the temperature less than 7° C. The solution was warmed up for 16 hours to ensure the temperature was ambient temperature. Then, methanol was removed in a vacuum state and the reaction mixture was diluted with water (210 mL). The liquid-phase mixture was washed with ether (2×180 mL) and the mixed organic layer was washed with 1M hydrochloric acid (2×90 mL). The mixed aqueous solution layer was basified with a 10% sodium carbonate solution up to pH of 9 to thereby obtain a filtrate. Ethyl acetate (3200 mL) was added thereto to thereby separate each layer. The organic layer was dried with MgSO4 and concentrated in a vacuum state until a filtrate was formed. The mixture was cooled, filtered, and washed with heptane (24 mL) to obtain trans[4-(4-aminophenyl)cyclohexyl]acetic acid methyl ester (4.247% was obtained by two steps) as a white solid.
Reaction SMILES: C([Mg]Cl)(C)C.[CH2:6]([O:10]C1CCCCO1)[CH2:7][C:8]#[CH:9].[CH2:17]([N:24]=[N+:25]=[N-:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1>[CH2:17]([N:24]1[C:8]([CH2:7][CH2:6][OH:10])=[CH:9][N:26]=[N:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: [N-]=[N+]=NCc1ccccc1
Reactant: C#CCCOC1CCCCO1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: OCCc1cnnn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 49.6 %

Procedure:
Add isopropylmagnesium chloride (368 mL, 736.00 mmol) drop-wise to a solution of 2-but-3-ynoxytetrahydropyran (113.50 g, 736.00 mmol) in tetrahydrofuran (1.4 L) at 15° C., maintaining the internal temperature less than 20° C. Remove the ice-water bath, allow the temperature to warm to 25° C., and hold at that temperature for 20 min to ensure gas evolution is complete. Heat the reaction mixture to 30-35° C., and add benzyl azide (70 g, 525.71 mmol) drop-wise to the mixture over 2 h while ensuring benzyl azide concentration in the reaction mixture does not rise to appreciable levels by a method such as LCMS. After a 4 h stir, cool the reaction mixture to 25° C., and quench with saturated aqueous ammonium chloride (400 mL) via drop-wise addition. After a 16 h stir, dilute with methyltert-butyl ether (200 mL), separate the layers, and stir the organic layer with 3M hydrochloric acid (600 mL) for 4 h. When greater than 98% conversion is achieved by a method such as LCMS, raise the pH of the reaction mixture to pH>10 via dropwise addition of 6 M sodium hydroxide (ca. 350 mL). Extract the resulting mixture with methyltert-butyl ether (3×300 mL) and dichloromethane (3×300 mL). Concentrate the combined organic layers in vacuo, and purify the resulting crude product by silica gel column chromatography, eluting with ethyl acetate, to afford the title compound (53 g, 50%) as an off-white solid. MS (m/z): 204.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[O-:12][CH2:13][CH3:14].[Na+]>C(O)C.O1CCOCC1>[Cl:1][C:2]1[N:6]2[N:7]=[C:8]([O:12][CH2:13][CH3:14])[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: CC[O-]
Reactant: Clc1ccc2nnc(Cl)n2n1
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCO
Product: CCOc1ccc2nnc(Cl)n2n1

Procedure:
The 3-chloro-6-ethoxy[1,2,4]triazolo[4,3-b]pyridazine was prepared according to the method described in Example 16b, but using 1 g of commercial 3,6-dichloro[1,2,4]triazolo[4,3-b]pyridazine, 1.71 g of a solution at 21% of sodium ethoxide in ethanol and 30 cm3 of dioxane, after reaction at reflux for 5.5 h. 874 mg of 3-chloro-6-ethoxy[1,2,4]triazolo[4,3-b]pyridazine are thus obtained in the form of a whitish powder, the characteristics are as follows:
Reaction SMILES: O1CCCC1.[C:6]([C:8]1[CH:18]=[CH:17][C:11]2[S:12][C:13]([CH:15]=O)=[CH:14][C:10]=2[CH:9]=1)#[N:7].[Cl-].[CH2:20]([O:22][C:23]1[C:24]([O:56][CH3:57])=[CH:25][C:26]([CH2:49][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])=[C:27]([CH2:29][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:28]=1)[CH3:21].C1CCN2C(=NCCC2)CC1>C(O)C>[C:6]([C:8]1[CH:18]=[CH:17][C:11]2[S:12][C:13]([CH2:15][CH2:29][C:27]3[CH:28]=[C:23]([O:22][CH2:20][CH3:21])[C:24]([O:56][CH3:57])=[CH:25][C:26]=3[CH2:49][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])=[CH:14][C:10]=2[CH:9]=1)#[N:7]
Reactant: CCOC(=O)CCc1cc(OC)c(OCC)cc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#Cc1ccc2sc(C=O)cc2c1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: CCOC(=O)CCc1cc(OC)c(OCC)cc1CCc1cc2cc(C#N)ccc2s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.2 %

Procedure:
To a mixture solution of 50 ml of tetrahydrofuran and 50 ml of ethanol were dissolved 1.5 g of 5-cyanobenzo[b]thiophene-2-carbaldehyde and 6.34 g of crude [5-ethoxy-2-(2-ethoxycarbonylethyl)-4-methoxyphenyl]methyltriphenylphosphonium chloride obtained in the above step d). 1.83 g of 1,8-diazabicyclo[5.4.0]-7-undecene was added thereto, followed by stirring at room temperature for 18 hours. The resulting reaction solution was concentrated under a reduced pressure, and the residue was dissolved in a mixture solution of 20 ml of tetrahydrofuran and 20 ml of ethanol. The thus prepared solution was mixed with 1.70 g of 10% palladium carbon catalyst (50% wet type) and subjected to catalytic hydrogenation under normal pressure until hydrogen absorption was completed. After removing the catalyst by filtration, the solvent was distilled off. By subjecting the resulting residue to silica gel column chromatography, 1.2 g of oily ethyl 3-[2-[2-(5-cyanobenzo[b]thien-2-yl)ethyl]-4-ethoxy-5-methoxyphenyl]propionate was obtained.