Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8](C(Cl)(Cl)Cl)[N:7]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[N:15]=3)[C:6]=2[CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:28][O:29][CH2:30][CH2:31][NH2:32]>>[NH2:20][C:16]1[N:15]=[C:14]([N:7]2[C:6]3[CH:21]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=3[N:9]=[C:8]2[NH:32][CH2:31][CH2:30][O:29][CH3:28])[CH:19]=[CH:18][N:17]=1
Reactant: Nc1nccc(-n2c(C(Cl)(Cl)Cl)nc3ccc(Br)cc32)n1
Reactant: COCCN
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COCCNc1nc2ccc(Br)cc2n1-c1ccnc(N)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 39 %

Procedure:
A mixture of 4-[6-bromo-2-(trichloromethyl)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine (1.5 g, 3.68 mmol) and cesium carbonate (2.5 g, 7.67 mmol) in 2-methoxyethan-1-amine (15 mL) was stirred under nitrogen for 3 days at room temperature. The reaction mixture was concentrated under vacuum and the residue was purified on a C18 column (acetonitrile/water, 5:95-80:20) to give 0.55 g (39%) of 1-(2-aminopyrimidin-4-yl)-6-bromo-N-(2-methoxyethyl)-1H-1,3-benzodiazol-2-amine as a yellow solid. LC-MS: m/z=+363 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]2[CH:6]=[C:7]([C:9]3[C:18]([N:19]([CH3:23])[CH:20]([CH3:22])[CH3:21])=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:24]([O:26]C)=[O:25])[CH:15]=4)[N:10]=3)[O:8][C:4]=2[CH:3]=1.[OH-].[Na+].Cl>CO.O>[F:1][C:2]1[CH:29]=[CH:28][C:5]2[CH:6]=[C:7]([C:9]3[C:18]([N:19]([CH3:23])[CH:20]([CH3:22])[CH3:21])=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:24]([OH:26])=[O:25])[CH:15]=4)[N:10]=3)[O:8][C:4]=2[CH:3]=1
Reactant: COC(=O)c1ccc2nc(-c3cc4ccc(F)cc4o3)c(N(C)C(C)C)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1cc2ccc(F)cc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.2 %

Procedure:
To a solution of methyl 2-(6-fluoro-1-benzofuran-2-yl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate (55 mg, 0.14 mmol) in methanol (20 mL) and water (1 mL) was added sodium hydroxide (12 mg, 0.30 mmol). After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure to afford a residue, which was dissolved in water (10 mL), adjusted the pH value to 5 with 3N HCl and filtered to give 2-(6-fluoro-1-benzofuran-2-yl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylic acid as a light yellow solid (28.8 mg, 54%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH3:10])[CH:5]=[C:4]([O:18][CH2:19][CH:20]2[CH2:22][CH2:21]2)[CH:3]=1.[NH2:23][C:24]1[CH:29]=[N:28][CH:27]=[CH:26][N:25]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C(OCC)(=O)C.O1CCOCC1>[CH:20]1([CH2:19][O:18][C:4]2[CH:3]=[C:2]([NH:23][C:24]3[CH:29]=[N:28][CH:27]=[CH:26][N:25]=3)[N:7]=[C:6]([NH:8][C@H:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[CH3:10])[CH:5]=2)[CH2:22][CH2:21]1
Reactant: Nc1cnccn1
Reactant: C[C@H](Nc1cc(OCC2CC2)cc(Cl)n1)c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@H](Nc1cc(OCC2CC2)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 77.8 %

Procedure:
112 mg of (S)-6-chloro-4-(cyclopropylmethoxy)-N-[1-(4-fluorophenyl)ethyl]pyridine-2-amine, 43 mg of 2-aminopyrazine, 67 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 51 mg of sodium t-butoxide and 36 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn to 2 ml of degassed 1,4-dioxane, and the mixture was stirred at 100° C. for 1.5 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 103 mg of the objective compound as brown powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]2[CH2:32][CH2:33][N:34]([CH3:37])[C:35](=[O:36])[C:10]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:38]1(CN(CCO)C(C2C(OCC3C=CC=CC=3)=C(O)N=C(CC3(C4C5C(=CC=CC=5)C=CC=4)CCCC3)N=2)=O)[CH2:40][CH2:39]1>>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]2[CH2:32][CH2:33][N:34]([CH2:37][CH:38]3[CH2:40][CH2:39]3)[C:35](=[O:36])[C:10]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCn2c(CC3(c4cccc5ccccc45)CCCC3)nc(=O)c(OCc3ccccc3)c2C1=O
Reactant: O=C(c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1)N(CCO)CC1CC1
Product: O=C1c2c(OCc3ccccc3)c(=O)nc(CC3(c4cccc5ccccc45)CCCC3)n2CCN1CC1CC1

Procedure:
This compound was prepared following the same method as described for 9-benzyloxy-2-methyl-6-(1-naphthalen-1-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (352) from 5-benzyloxy-6-hydroxy-2-(1-naphthalen-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid cyclopropylmethyl-(2-hydroxyethyl)-amide (359) (150 mg, 0.27 mmol). The yield was 94 mg of a semi pure, white sticky solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)[NH2:5].[C:13](OC(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:13](=[O:15])[CH3:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(Br)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 109.8 %

Procedure:
To a solution of 3-bromo-5-(trifluoromethyl)aniline (10 g) in pyridine (50 mL) was added acetic anhydride (5.6 g) at 0° C., and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated, 1M hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1M hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution, and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated to give the title compound (12.9 g, yield quant.) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[N+:16]([O-])=O)[N:9]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:8]=2[CH3:25])=[CH:4][CH:3]=1.C(N(CC)CC)C>CCOC(C)=O.[Pt]>[NH2:16][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[C:7]([O:6][C:5]1[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][CH:4]=1)=[C:8]([CH3:25])[N:9]2[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)Cn1c(C)c(Oc2ccc(Cl)cc2)c2c([N+](=O)[O-])cccc21
Agent: [Pt]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)Cn1c(C)c(Oc2ccc(Cl)cc2)c2c(N)cccc21

Procedure:
The product from step (iii) (1.0 g) was dissolved in EtOAc (20 ml), triethylamine (1.1 ml) added, followed by 5% Pt/C (50 mg) and hydrogenated at 1 atm and RT for 6 h. The catalyst was filtered off and the filtrate evaporated to give a light brown solid. Yield 800 mg.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].[CH:10](O)=[O:11]>C1C=CC=CC=1>[F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH:4][CH:10]=[O:11]
Reactant: O=CO
Reactant: Nc1cc(F)ccc1F
Solvent: c1ccccc1
Product: O=CNc1cc(F)ccc1F
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 25.8 g of 2A, 18.5 g of formic acid and 100 ml of benzene was refluxed (80° C.) for 2 hours. The mixture was allowed to stand overnight. The solid that formed was separated and taken up in ether. Hexane was added. The solid that formed was separated and washed with cold hexane to give N-(2,5-difluorophenyl)formamide (2B), m.p.: 112°-114° C.
Reaction SMILES: Cl.Cl.Cl.[N:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[S:11][C:12]([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][NH2:23])[CH2:18][CH2:17]2)=[CH:13][N:14]=1.Cl.C(N=C=NCCCN(C)C)C.[NH2:36][C:37]1[CH:42]=[CH:41][N:40]=[C:39]([C:43](O)=[O:44])[CH:38]=1.O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CC(N(C)C)=O.C(OCC)(=O)C>[NH2:36][C:37]1[CH:42]=[CH:41][N:40]=[C:39]([C:43]([NH:23][CH2:22][CH:19]2[CH2:18][CH2:17][N:16]([CH2:15][C:12]3[S:11][C:10]([C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][N:4]=4)=[N:14][CH:13]=3)[CH2:21][CH2:20]2)=[O:44])[CH:38]=1
Reactant: Nc1ccnc(C(=O)O)c1
Reactant: NCC1CCN(Cc2cnc(-c3ccccn3)s2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: O
Product: Nc1ccnc(C(=O)NCC2CCN(Cc3cnc(-c4ccccn4)s3)CC2)c1
Reaction time: 48 h
Yield: 11.1 %

Procedure:
The compound prepared in Example 214 (0.44 g), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (0.25 g), 4-aminopicolinic acid (0.18 g), 1-hyroxybenzotriazole hydrate (0.20 g) and N-ethyl-N-isopropylpropan-2-amine (1.2 ml) were combined in dimethylacetamide (8 mL) and the reaction was allowed to stir 2 days. The reaction was diluted with ethyl acetate and washed with aqueous sodium bicarbonate and brine. The organic phase was dried over magnesium sulfate, filtered, concentrated and purified by column chromatography using an eluant (2 to 6% methanol/dichloromethane) to provide the title compound (0.05 g) with the following physical data.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:17]=3[CH:18]=2)=[C:10]([F:25])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:29]I>CN(C=O)C>[C:1]([O:5][C:6](=[O:26])[N:7]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:17]=3[CH:18]=2)=[C:10]([F:25])[N:9]=1)[CH3:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc2oc(-c3ccc(NC(=O)OC(C)(C)C)nc3F)cc2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2oc(-c3ccc(N(C)C(=O)OC(C)(C)C)nc3F)cc2c1
Reaction time: 0.17 h
Yield: 81.3 %

Procedure:
To a stirred solution of [6-fluoro-5-(5-methoxy-benzofuran-2-yl)-pyridin-2-yl]-carbamic acid tert-butyl ester (78 mg, 0.218 mmol) in DMF (5 mL) at 0° C., NaH (11 mg, 0.26 mmol, 57% dispersion in oil) was added and the resulting mixture was stirred for 10 minutes. Methyl iodide (15 μL, 0.24 mmol) was then added and the stirring was continued for 30 minutes at room temperature. Additional portions of NaH (11 mg, 0.26 mmol, 57% dispersion in oil) and methyl iodide (15 μL, 0.24 mmol) were added and the solution was stirred for 1 hour. The reaction mixture was quenched with water (5 mL) and the product was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. Purification of the crude product by flash column chromatography using 10% ethyl acetate in hexane afforded title compound (66 mg) as an off-white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ: 8.25-8.33 (m, 1 H) 7.87 (m 1H) 7.41 (d, J=9.37 Hz, 1 H) 7.14 (s, 1 H) 7.06 (d, J=2.34 Hz, 1 H) 6.92 (d, J=8.98 Hz, 1 H) 3.86 (s, 3 H) 3.43 (s, 3 H) 1.56 (s, 9 H)
Reaction SMILES: N1(C([O-])=O)CCC=CC1.[Si:10]([O:17][CH2:18][C@@H:19]1[CH:24]=[C:23]([CH2:25][OH:26])[C:22](=[O:27])[CH2:21][N:20]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].ClC(Cl)(Cl)C(=N)O[CH2:39][C:40]1[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=1.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[La+3]>C1(C)C=CC=CC=1>[Si:10]([O:17][CH2:18][C@@H:19]1[CH:24]=[C:23]([CH2:25][O:26][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[C:22](=[O:27])[CH2:21][N:20]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: COc1ccc(COC(=N)C(Cl)(Cl)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C(CO)=C[C@H]1CO[Si](C)(C)C(C)(C)C
Agent: O=C([O-])N1CC=CCC1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [La+3]
Solvent: Cc1ccccc1
Product: COc1ccc(COCC2=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)CC2=O)cc1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a solution of (2S)-tert-butyl 5-hydroxy-4-(hydroxymethyl)-2-(isopropyldimethylsilyl)oxy)methyl)-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 117, 13.0 g, 34.99 mmol) in toluene (150 mL) was added 4-methoxybenzyl 2,2,2-trichloroacetimidate (7.65 mL, 10.42 g, 36.74 mmol) and La(OTf)3 (205 mg, 0.35 mmol). The mixture was stirred at 50° C. for 4 h. Aqueous work-up with ethyl acetate and the organic layer was dried over MgSO4 to afford the crude product.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.C([Li])CCC.C([Li])(CC)C.[O:22]1CCC[CH2:23]1>CN(C)C=O>[O:9]=[C:7]1[NH:6][C:5]2[CH:10]=[CH:11][C:2]([CH:23]=[O:22])=[CH:3][C:4]=2[O:8]1
Reactant: C1CCOC1
Reactant: O=c1[nH]c2ccc(Br)cc2o1
Agent: [Li]C(C)CC
Agent: [Li]CCCC
Solvent: CN(C)C=O
Product: O=Cc1ccc2[nH]c(=O)oc2c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of 6-bromo-3H-benzooxazol-2-one (0.9236 g, 4.31 micromoles) in anhydrous tetrahydrofuran (25 mL) and dimethylformamide (3 mL) under nitrogen was cooled to −78° C. before addition of n-butyllithium (2.5M in hexane) (3.8 mL, 2.2 equiv). After stirring for 10 min at −78° C., 24 mL of sec-butyllithium (1.4 M in cyclohexane, 8 equiv) was added. The reaction was stirred while slowly warming to −40° C. When this temperature was reached, the reaction was quenched by addition of methanol. The reaction mixture was concentrated in vacuo and water was added. The aqueous layer was acidified with 1N HCl (ca. pH 5) and extracted with ethyl acetate (3×50 mL), dried over sodium sulfate, filtered and concentrated to give the product, 0.6402 g (91%). MS (ESI) 164 (MH)+. 1H NMR (400 MHz, DMSO-d6) δ 9.90 (1H, s), 7.79 (1H, d, J=8.0 Hz), 7.74 (1H, s), 7.28 (1H, d, J=8.0 Hz).
Reaction SMILES: [CH2:1]([C@:3]1([OH:11])[CH2:7][CH2:6][NH:5][C@H:4]1[CH:8]([CH3:10])[CH3:9])[CH3:2].[Cl:12][C:13]1[CH:20]=[C:19](F)[CH:18]=[CH:17][C:14]=1[C:15]#[N:16].C(=O)([O-])[O-].[Li+].[Li+]>>[Cl:12][C:13]1[CH:20]=[C:19]([N:5]2[CH2:6][CH2:7][C@:3]([CH2:1][CH3:2])([OH:11])[C@@H:4]2[CH:8]([CH3:10])[CH3:9])[CH:18]=[CH:17][C:14]=1[C:15]#[N:16]
Reactant: CC[C@]1(O)CCN[C@H]1C(C)C
Reactant: N#Cc1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CC[C@]1(O)CCN(c2ccc(C#N)c(Cl)c2)[C@H]1C(C)C

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-3-ethyl-2-isopropylpyrrolidin-3-ol 0.5 oxalate (162 mg), 2-chloro-4-fluorobenzonitrile (125 mg) and lithium carbonate (126 mg), the title compound was obtained as pale-brown oil (yield: 151 mg, yield: 65%).
Reaction SMILES: [CH:1]1([S:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.[OH:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[N:16][CH:17]=1.C1(S)C=CC=CC=1.C(O)(=O)C>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[CH3:18][C:15]1[CH:14]=[CH:13][C:12]([O:11][C:1]2([S:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:3][CH2:2]2)=[CH:17][N:16]=1
Reactant: Cc1ccc(O)cn1
Reactant: c1ccc(SC2CC2)cc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: Cc1ccc(OC2(Sc3ccccc3)CC2)cn1
Reaction time: 0.17 h
Yield: 43.7 %

Procedure:
Cyclopropylphenyl thioether (5.0 g, 33.3 mmol) was dissolved in tetrahydrofuran (50 mL), and n-butyllithium (25.1 mL, 39.9 mmol) was dropwisely added at 0° C. for 5 minutes under an argon atmosphere. Then, a solution of N-iodosuccinimide (8.99 g, 39.9 mmol) in tetrahydrofuran (100 mL) was dropwisely added at −78° C. The resultant mixture was stirred overnight, and gradually warmed to room temperature. The reaction solution was added with a saturated aqueous solution of sodium hydrogen carbonate, and extracted with hexane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified using silica-gel column chromatography (hexane), to obtain a crude product ((1-iodocyclopropyl)(phenyl)sulfane:cyclopropylphenylthioether (=2.4:1) (5.64 g). Next, 5-hydroxy-2-methylpyridine (1.82 g, 16.7 mmol) was dissolved in toluene (150 mL). The resultant mixture was added with silver carbonate (9.19 g, 33.3 mmol) and 1-iodocyclopropyl)(phenypsulfane:cyclopropylphenylthioether (=2.4:1) mixture (5.64 g, 16.7 mmol (*converted in terms of 1-iodocyclopropyl)(phenyl)sulfane), and stirred overnight at room temperature. Then, acetic acid (200 mL) was added thereto, and stirred for 10 minutes. The reaction solution was filtered using celite and concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane/ethyl acetate), and 2-methyl-5-(1-(phenylthio)cyclopropoxy)pyridine (1.88 g, yield 44%) was obtained as a yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]2[O:13][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH2:21])=[O:20])=[CH:17][CH:16]=1>C(OCC)(=O)C>[OH:13][C@@H:10]1[CH2:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:12][C@H:11]1[O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH2:21])=[O:20])=[CH:17][CH:16]=1
Reactant: c1ccc(CN2CC3OC3C2)cc1
Reactant: NC(=O)c1ccc(O)cc1
Solvent: CCOC(C)=O
Product: NC(=O)c1ccc(O[C@@H]2CN(Cc3ccccc3)C[C@H]2O)cc1
Yield: 19 %

Procedure:
A mixture of 28 g. of 1-benzyl-3,4-epoxypyrrolidine and 20.6 g. of 4-hydroxybenzamide was heated at 130° C. for 8 hrs. The cooled mixture was columned on silica gel using 5% methanol in ethyl acetate to elute the product, which was then crystallized from chloroform-benzene-methanol. The yield was 19% of product melting at 133.0°-6.0° C.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].C(N(CC)CC)C.[C:29](Cl)(=[O:32])[O:30][CH3:31]>C(Cl)Cl>[CH3:31][O:30][C:29]([NH:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]2)[CH2:9]1)=[O:6])=[O:32]
Reactant: COC(=O)Cl
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 40.5 %

Procedure:
To a suspension of (R)-quinuclidin-3-yl 2-amino-2-phenylacetate dihydrochloride (I25) (150 mg, 0.45 mmol) in DCM (5 ml), were added triethylamine (188 μl, 1.35 mmol) and methyl carbonochloridate (41.7 μl, 0.54 mmol). The reaction was stirred at RT for 4 hours, and then the solvent was evaporated. The residue was taken up with EtOAc and washed with water and brine. The organic phase was dried over Na2SO4 and evaporated to obtain (R)-quinuclidin-3-yl 2-(methoxycarbonylamino)-2-phenylacetate (58.0 mg; 40% yield). The compound was used in the next step without any further purification.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:32]([O:36][CH2:37][CH2:38][OH:39])([CH3:35])([CH3:34])[CH3:33].O[C:41]1[CH:42]=[C:43]2[C:47](=[CH:48][CH:49]=1)[NH:46][CH:45]=[CH:44]2>C(Cl)Cl.O>[C:32]([O:36][CH2:37][CH2:38][O:39][C:41]1[CH:42]=[C:43]2[C:47](=[CH:48][CH:49]=1)[NH:46][CH:45]=[CH:44]2)([CH3:35])([CH3:34])[CH3:33]
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OCCOc1ccc2[nH]ccc2c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 36.3 %

Procedure:
Add triphenylphosphine (600 mg, 2.29 mmol) to a solution of diethyl azodicarboxylate (0.36 mL, 2.29 mmol) in methylene chloride (10 ml) at 0° C. followed by ethylene glycol mono-t-butyl ether (0.30 mL, 2.29 mmol), and stir the mixture for 20 minutes at 0° C. Add 5-hydroxyindole (200 mg, 1.5 mmol), remove the cold bath, and stir for 5 hours. Add water (2 mL), transfer the resultant mixture to a separatory funnel, and separate the layers. Wash the organic layer with 0.1 N aqueous HCl and brine, then dry over sodium sulfate, filter, and concentrate. Purification by flash chromatography and eluting with hexane:ethyl acetate gives 127 mg (36%) of the title compound as a light yellow solid. Mass spectrum: electrospray (m/z) 232 (M−−1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([CH:20]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[OH:21])[C:16]([O:18]C)=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([CH:20]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[OH:21])[C:16]([OH:18])=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(c1ccccc1OCc1ccccc1)C(O)C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C(c1ccccc1OCc1ccccc1)C(O)C1CCCCC1
Reaction time: 24 h
Yield: 66.7 %

Procedure:
To a solution of methyl (2RS,3SR)-2-(2-benzyloxyphenyl)-3-cyclohexyl-3-hydroxypropionate (500 mg) in ethanol (10 ml) was added a 1N aqueous solution of sodium hydroxide (5 ml). After being stirred for 24 hours the mixture was concentrated under reduced pressure. The residue was washed with diethyl ether and acidified by 1N aqueous hydrochloric acid solution. The separated oily product was extracted by ethyl acetate. The organic layer was washed with brine, dried and evaporated under reduced pressure to afford (2RS,3SR)-2-(2-benzyloxyphenyl)-3-cyclohexyl-3-hydroxypropionic acid (321 mg).
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH:14]1[O:18][CH2:17][CH2:16][O:15]1.[C:19](Cl)(=[O:23])[C:20]([CH3:22])=[CH2:21]>C(Cl)Cl>[C:19]([O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH:14]1[O:15][CH2:16][CH2:17][O:18]1)(=[O:23])[C:20]([CH3:22])=[CH2:21]
Reactant: C=C(C)C(=O)Cl
Reactant: OCCOCCC1OCCO1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)OCCOCCC1OCCO1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 500 ml four-neck round bottom flask equipped with a mechanical stirrer, condenser, thermometer and addition funnel were added 22.0 g triethylamine, 32.4g.2-[2-(2-hydroxyethoxy)ethyl-1,3-dioxolane, and 180 ml methylene chloride. The temperature was reduced to about 0° C. to -5° C. A total of 23.22 g. methacryloyl chloride was added dropwise through an addition funnel. While maintaining the temperature at about 0 to -5°, the mixture was then allowed to warm to room temperature and stirred for 30 min. and added to an equal volume (180 ml) of ice-water. The methylene chloride layer was separated from the aqueous layer, a small amount of anhydrous magnesium sulfate (3 g) was added, the solution was filtered, and methylene chloride was stripped off to isolate the product. Purification was done by distillation at 106° C. under 0.2 Hg pressure.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:17][CH:18]3OCCC[O:19]3)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].C(O)=O>C1(C)C=CC=CC=1>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:17][CH:18]=[O:19])[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCC3OCCCO3)CC2)CC1
Solvent: Cc1ccccc1
Solvent: O=CO
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCC=O)CC2)CC1

Procedure:
In 3.0 l of toluene was dissolved 300 g (930 mmol) of the 2-(2-(trans-4-(trans-4-propylcyclohexyl)cyclohexyl)ethyl)-1,3-dioxane obtained by the procedures described above, 428 g (9300 mmol) of formic acid was added thereto, and they were heated to reflux for 4 hours. The reaction mixture was washed with 600 ml of saturated aqueous sodium bicarbonate solution twice and with 1.0 l of water five times, and the solvent was distilled off under a reduced pressure to obtain 240 g of a crude 3-(trans-4-(trans-4-propylcyclohexyl)-cyclohexyl)propanal.