Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:4][C@H:5]1[CH2:10][CH2:9][CH2:8][O:7][CH2:6]1.C(N(CC)CC)C.[S:29](Cl)([CH3:32])(=[O:31])=[O:30]>C(Cl)Cl>[CH3:32][S:29]([O:1][CH2:2][C@@H:3]([NH:11][C:12]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:21])[CH2:4][C@H:5]1[CH2:10][CH2:9][CH2:8][O:7][CH2:6]1)(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(N[C@H](CO)C[C@H]1CCCOC1)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@H](C[C@H]1CCCOC1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 138.5 %

Procedure:
To a solution of benzyl (5)-1-hydroxy-3-((R)-tetrahydro-2H-pyran-3-yl)propan-2-ylcarbamate (26 g, 69.99 mmol) and triethylamine (21.21 g, 210 mmol) in CH2Cl2 at 0° C. was added mesyl chloride (16.1 g, 140 mmol) dropwise. The reaction mixture was stirred at room temperature until the staring material disappeared. The reaction was quenched with ice-cold water, extracted with CH2Cl2 (3×100 ml), washed with water (3×50 ml), dried over Na2SO4, and concentrated in vacuo to give the product (36 g), which was used for the next step without purification.
Reaction SMILES: C([NH:9][CH:10]([C:14]1[CH:15]=[CH:16][C:17]2[O:21][CH2:20][CH2:19][C:18]=2[CH:22]=1)[C:11]([OH:13])=[O:12])(=O)C1C=CC=CC=1.[H][H]>CO.O.[Pd]>[NH2:9][CH:10]([C:14]1[CH:15]=[CH:16][C:17]2[O:21][CH2:20][CH2:19][C:18]=2[CH:22]=1)[C:11]([OH:13])=[O:12]
Reactant: [H][H]
Reactant: O=C(NC(C(=O)O)c1ccc2c(c1)CCO2)c1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: NC(C(=O)O)c1ccc2c(c1)CCO2
Yield: 60 %

Procedure:
The α-benzamido(2,3-dihydro-5-benzofuranyl)acetic acid (100 mg) is dissolved in 20 ml of methanol and 40 ml of water. Then 20 mg of a palladium on carbon catalyst is added and the mixture subjected to hydrogen pressure of 10 to 40 pounds/in2 for 4 hours. The mixture is filtered to remove the solid and the methanol is evaporated to give the title compound in about 60% yield. NMR(DMSO-D6)ppm(δ)7.95(s,1);6.7(m,3); 4.8(s,1);4.42(t,2);2.95(t,2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1/[C:11](=[C:16](\O)/[CH3:17])/[C:12]([O:14][CH3:15])=[O:13]>C(O)(=O)C.O.C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:16]([CH3:17])[NH:8]2
Reactant: COC(=O)/C(=C(\C)O)c1c(Cl)cccc1[N+](=O)[O-]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1c(C)[nH]c2cccc(Cl)c12
Temperature: 90 °C
Yield: 91 %

Procedure:
(E)-Methyl 2-(2-chloro-6-nitrophenyl)-3-hydroxybut-2-enoate (14.76 mmol, 1.0 equiv.) was dissolved in acetic acid (96 ml), and a solution of TiCl3 (20%-w/w in 2 N HCl, 71.6 ml) was added, with stirring. The mixture was then heated for 5-10 min at 90° C. The reaction mixture was cooled with an ice bath and diluted with water and DCM/methanol (9:1, 100 ml). The phases were separated and the organic phase was washed with water and sat. NaCl solution. Drying over Na2SO4 was then carried out, followed by concentration under reduced pressure. The product was crystallized from hexane. Yield: 91%
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]=[C:7]([C:16]#[N:17])[N:6]=1.Cl[CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH3:32])[CH2:26][CH2:25]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:21][CH2:22][CH2:23][N:24]3[CH2:25][CH2:26][N:27]([CH2:30][CH2:31][CH3:32])[CH2:28][CH2:29]3)[CH:13]=2)[N:8]=[C:7]([C:16]#[N:17])[N:6]=1
Reactant: CCCN1CCN(CCCCl)CC1
Reactant: CC(C)(C)CNc1nc(C#N)nc2ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCN1CCN(CCCOc2ccc3nc(C#N)nc(NCC(C)(C)C)c3c2)CC1

Procedure:
4-(2,2-Dimethyl-propylamino)-6-hydroxy-quinazoline-2-carbonitrile (0.31 mmol), 1-(3-chloro-propyl)4-propyl-piperazine (0.62 mmol) and cesium carbonate (3.1 mmol) are stirred in DMF (3 ml) at RT for 20 hours. Water is added until a clear solution is formed. Then more water is added until the solution gets turbide. The precipitate formed is filtered off, washed with water and dried (vacuum). A powder with mp. 102-104° C., Rf=4 (CH2Cl2/MeOH=9:2) is obtained.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].[C:21](Cl)(=O)C>CO>[NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20]2)[CH:8]=1)[CH2:3][C:4]([O:6][CH3:21])=[O:5]
Reactant: COc1ccc(C(N)CC(=O)O)cc1OC1CCCC1
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)CC(N)c1ccc(OC)c(OC2CCCC2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 45.7 %

Procedure:
To a stirred suspension of 3-amino-3-(3'-cyclopentyloxy-4'-methoxyphenyl)propionic acid (30 grams, 279 mmol) in methanol (150 mL) at 0° C., was added acetyl chloride (15.2 mL, 212 mmol) dropwise. After 15 minutes, the ice-water bath was removed. The resulting clear solution was stirred at room temperature for 2 h. The system was opened and the solvent was blown off with N2 overnight. To the solid was added methanol (50 mL) and ether (300 mL). The resulting suspension was stirred at room temperature for 1 h. The suspension was filtered and the solid was washed with ether (100 mL). The solid was dissolved in a mixture of aqueous sodium carbonate (200 mL, sat), water (200 mL), and methylene chloride (250 mL). The organic layer was separated. The aqueous layer was extracted with methylene chloride (3×250 mL). The combined organic layers were dried over magnesium sulfate. Removal of solvent gave methyl 3-amino-3-(3'-cyclopentoxy-4'-methoxyphenyl)propionate as an oil (28.41 grams, 90% yield): 1H NMR (CDCl3)δ1.56-1.97 (m, 10H, NH2, C5H8), 2.62 (d, J=7 Hz, 2H, CH2), 3.67 (s, 3H, CH3), 3.81 (s, 3H, CH3), 4.34 (t, J=6.8 Hz, 1H, CH), 4.74-4.79 (dd, J=5, 8.5 Hz, 1H, NCH), 6.78-6.90 (m, 3H, Ar); 13C NMR (CDCl3)δ23.97, 32.76, 44.17, 51.58, 52.25, 56.07, 80.37, 111.96, 113.08, 119.08, 137.25, 147.72, 149.27, 172.49.
Reaction SMILES: [CH3:1][Li].[CH3:3][C:4]1[C:9]([CH:10]=[O:11])=[CH:8][C:7]2[O:12][CH2:13][O:14][C:6]=2[CH:5]=1.O>C(OCC)C.O1CCCC1>[CH3:3][C:4]1[C:9]([CH:10]([OH:11])[CH3:1])=[CH:8][C:7]2[O:12][CH2:13][O:14][C:6]=2[CH:5]=1
Reactant: [Li]C
Reactant: Cc1cc2c(cc1C=O)OCO2
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc2c(cc1C(C)O)OCO2
Temperature: -40 °C

Procedure:
32 ml of a 1.4 M solution of methyllithium in diethyl ether was dissolved in 50 ml of anhydrous tetrahydrofuran. The obtained solution was cooled to -40° C. in a nitrogen atmosphere, followed by the addition of 5.0 g of solid (6-methyl-1,3-benzodioxol-5-yl)carboxaldehyde. The mixture was heated to a room temperature over a period of one hour, followed by the addition of water. The obtained mixture was extracted with ether and the obtained organic layer was washed with an aqueous solution of common salt, dried over magnesium sulfate and distilled to remove the solvent. The obtained white solid was recrystallized from diisopropyl ether/n-hexane to obtain 2.8 g of the title compound as a colorless crystal.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=3[CH3:19])[C:6]=2[CH:5]=[C:4]([N+:20]([O-])=O)[CH:3]=1.O.O.[Sn](Cl)Cl.Cl>CO>[Br:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=3[CH3:19])[C:6]=2[CH:5]=[C:4]([NH2:20])[CH:3]=1
Reactant: Cc1c(Cl)cccc1Cn1cnc2c(Br)cc([N+](=O)[O-])cc21
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: Cc1c(Cl)cccc1Cn1cnc2c(Br)cc(N)cc21
Temperature: 80 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
To a solution of 4-bromo-1-(3-chloro-2-methylbenzyl)-6-nitro-1H-benzo[d]imidazole (3.05 g, 8.01 mmol) in Methanol (35 mL) in a 250 ml round bottomed flask was added Tin(II)chloride dihydrate (10.85 g, 48.1 mmol) and HCl (2.19 mL, 72.1 mmol). The reaction mixture was left to stir at 80° C. for 1 h. The solvent was removed and diluted with water (100 mL) and this solution was decanted into a 250 mL Erlenmeyer flask. The brown residue in the round bottomed flask was dissolved in 100 mL of EtOAc and washed with 1N NaOH, brine, dried and evaporated to yield a brown solid. The water layer was extracted with EtOAc, washed with 1N NaOH, brine, dried (MgSO4) and evaporated to a brown solid. The solids found to be identical by 1 cms and were combined to yield a brown solid 4-bromo-1-(3-chloro-2-methylbenzyl)-1H-benzo[d]imidazol-6-amine (2.33 g, 6.64 mmol, 83% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.40 (s, 3H) 5.45 (s, 2H) 6.47 (d, J=1.52 Hz, 1H) 6.56 (d, J=7.58 Hz, 1H) 6.86 (d, J=1.52 Hz, 1H) 7.14 (s, 1H) 7.39 (d, J=7.83 Hz, 1H) 8.11 (s, 1H); LC/MS: MS (ES+) m/e 351 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Al](C)C.[Si:12]([O:29][C@@H:30]1[CH2:34][CH2:33][O:32][C:31]1=[O:35])([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O)(=O)C(C(C(O)=O)O)O.[K].[Na]>C(Cl)Cl>[Si:12]([O:29][C@H:30]([CH2:34][CH2:33][OH:32])[C:31]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:35])([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nc1ccccc1
Reactant: CC(C)(C)[Si](O[C@@H]1CCOC1=O)(c1ccccc1)c1ccccc1
Agent: C[Al](C)C
Agent: O=C(O)C(O)C(O)C(=O)O
Agent: [K]
Solvent: ClCCl
Product: CC(C)(C)[Si](O[C@H](CCO)C(=O)Nc1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 78.4 %

Procedure:
To a solution of aniline (356 mg, 348 μL, 3.82 mmol) in DCM (17 mL) was added trimethylaluminum (2.0M, 2.1 mL, 4.2 mmol) dropwise and the reaction mixture was stirred at RT for 40 min. A solution of (R)-3-(tert-butyldiphenylsilyloxy)-dihydrofuran-2(3H)-one (1.00 g, 2.94 mmol) in DCM (12 mL) was added dropwise and the reaction mixture was stirred at RT for 16 hours. The reaction mixture was poured into a saturated solution of sodium potassium tartaric acid and stirred for 15 min. The layers were separated, and the aqueous layer was washed with DCM (4×). The combined organics were washed with 0.1M HCl (2×), brine, dried over Na2SO4 and evaporated to dryness. Purification by silica gel chromatography (10-30% EtOAc in hexane) afforded the (R)-2-(tert-butyldiphenylsilyloxy)-4-hydroxy-N-phenylbutanamide (1.00 g, 78%). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=434.7; tR=2.16 min.
Reaction SMILES: Cl[C:2]([C:4]1[N:8]([CH3:9])[C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][C:5]=1[CH3:16])=[O:3].N1C=CC=CC=1.[CH2:23]([OH:25])[CH3:24]>C(Cl)Cl.CCOCC.CCOCC>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][C:7]1[N:8]([CH3:9])[C:4]([C:2]([O:25][CH2:23][CH3:24])=[O:3])=[C:5]([CH3:16])[CH:6]=1)[CH3:15]
Reactant: CCO
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)Cl)n1C
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)Cc1cc(C)c(C(=O)OCC)n1C
Reaction time: 3 h
Yield: 87 %

Procedure:
Ethyl 5-chlorocarbonyl-1,4 dimethylpyrrole-2-acetate (29.3 g, 0.12 mol, prepared acc. to U.S. Pat. No. 3,950,355) is dissolved in 150 ml of 1:1 methylene chloride/ether and added over 10 minutes to a solution of pyridine (15 ml) and absolute ethanol (20 ml) in ether (100 ml) with stirring. After addition is complete, 4-N,N-dimethylaminopyridine (300 mg) is added. Stirring is continued for three hours. Ether (250 ml) is then added and deposited solids are removed by filtration. The organic solution is washed with aqueous 1 N HCl (2×100 ml), then brine (100 ml), and the ether layer is dried with magnesium sulfate. The solvent is then removed to give 26.3 g (87%) of ethyl-1,4 dimethyl-5-ethoxycarbonylpyrrole-2-acetate as a low melting red solid.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@H:10]1[C:40]1[C:48]2[C:43](=[C:44]([Cl:49])[CH:45]=[CH:46][CH:47]=2)[N:42]([CH2:50][C:51]2[CH:56]=[CH:55][C:54]([CH2:57][CH2:58][OH:59])=[CH:53][CH:52]=2)[CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:62]I.O>CN(C)C=O.O1CCCC1>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@H:10]1[C:40]1[C:48]2[C:43](=[C:44]([Cl:49])[CH:45]=[CH:46][CH:47]=2)[N:42]([CH2:50][C:51]2[CH:56]=[CH:55][C:54]([CH2:57][CH2:58][O:59][CH3:62])=[CH:53][CH:52]=2)[CH:41]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: OCCc1ccc(Cn2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3cccc(Cl)c32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: COCCc1ccc(Cn2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3cccc(Cl)c32)cc1
Reaction time: 0.25 h

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-7-chloro-1-[4-(2-hydroxyethyl)benzyl]-1H-indole (0.13 g) in N,N-dimethylformamide (3 mL) was added 55% sodium hydride (9 mg) under ice-cooling, and the mixture was stirred at the same temperature for 15 minutes. To this mixture was added a solution of methyl iodide (0.020 mL) in tetra hydrofuran (1 mL) at the same temperature, and the mixture was stirred at the same temperature for 15 minutes, and stirred at room temperature for 1 hour. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1) to give 3-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-7-chloro-1-[4-(2-methoxy-ethyl)benzyl]-1H-indole (0.13 g). This material was dissolved in a mixed solvent of methanol (1 mL) and ethyl acetate (4 mL). To the solution was added 10% palladium-carbon powder (60 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 30 minutes. To the reaction mixture was added sodium hydrogen carbonate (200 mg), and the mixture was stirred at room temperature for 10 minutes. The insoluble material was removed by filtration, and the solvent was removed under reduced pressure. The residue was purified by preparative reverse phase column chromatography (Shiseido CAPCELL PAK C18 ODS, UG80, 5 μm, 20×50 mm, linear gradient water/methanol=90/10-10/90, flow rate 30 mL/min) to give the title compound (39 mg).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].Cl[C:9]1[CH:14]=[C:13]([O:15][CH:16]([CH2:21][CH3:22])[C:17]([CH3:20])([CH3:19])[CH3:18])[N:12]=[CH:11][N:10]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:7][C:9]1[CH:14]=[C:13]([O:15][CH:16]([CH2:21][CH3:22])[C:17]([CH3:19])([CH3:18])[CH3:20])[N:12]=[CH:11][N:10]=1)[C:4]#[C:5][CH3:6]
Reactant: CC#CCO
Reactant: CCC(Oc1cc(Cl)ncn1)C(C)(C)C
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(OC(CC)C(C)(C)C)ncn1
Reaction time: 0.17 h
Yield: 54.8 %

Procedure:
In 3 ml of tetrahydrofuran was suspended 0.08 g of sodium hydride (60% in oil), to which 0.3 ml of a solution containing 0.12 g of 2-butyn-1-ol in tetrahydrofuran was added dropwise at room temperature, followed by stirring for 10 minutes. To this was added dropwise 0.3 ml of a solution containing 0.35 g of 4-chloro-6-(1-ethyl-2,2-dimethylpropyloxy)pyrimidine in tetrahydrofuran at room temperature, followed by stirring for 6 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, which was extracted three times with t-butyl methyl ether. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.22 g of 4-(2-butynyloxy)-6-(1-ethyl-2,2-dimethylpropyloxy)pyrimidine (the present compound (4)).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[K+].[CH:38](=O)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C1COCC1.O.C1(C)C=CC=CC=1>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[CH:12][C:3]([CH:2]=[CH:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:4][CH:5]=1
Reactant: O=Cc1ccccc1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C=Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methyl 4-(bromomethyl)benzoate (458 mg, 2 mmol) was added to dry toluene (8 mL) along with triphenylphosphine (609 mg, 2.2 mmol). Under nitrogen, reflux conditions were applied for three hours and the mixture was then permitted to cool to room temperature. The fine white solid was filtered off, washed thoroughly with EtOAc, and dried under vacuum (967 mg). This solid was stirred in dry THF (4 mL) under nitrogen, and potassium t-butoxide (246 mg, 2.18 mmol) was added. The bright orange mixture was heated under reflux for one hour. Upon cooling, benzaldehyde (202 μL, 212 mg, 1.2 mmol) in dry THF (2 mL) was added. Further heating under reflux was applied for thirty minutes. The reaction mixture was diluted with water and extracted with EtOAc. The organic layers were combined, washed with water and then brine, dried over MgSO4 and concentrated. The product was purified by flash chromatography on SiO2 using EtOAc/hexanes 10:90. A white solid was obtained (97 mg, 20%).
Reaction SMILES: P([O-])(O)(O)=O.[K+].P(=O)(O)(O)O.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](OP(O)(O)=O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.[O:72]=[C:73]1[CH2:78][CH2:77][O:76][CH2:75][C@@H:74]1[NH:79][C:80](=[O:89])[O:81][CH2:82][C:83]1[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=1.[OH-].[Na+]>O>[OH:72][C@H:73]1[CH2:78][CH2:77][O:76][CH2:75][C@@H:74]1[NH:79][C:80](=[O:89])[O:81][CH2:82][C:83]1[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=1
Reactant: O=C(N[C@H]1COCCC1=O)OCc1ccccc1
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=P(O)(O)O
Solvent: O
Product: O=C(N[C@H]1COCC[C@@H]1O)OCc1ccccc1
Temperature: 105 °C
Reaction time: 17 h

Procedure:
To a solution of potassium dihydrogen phosphate (62.7 g, 0.461 mol) in 3.6 L of water was added phosphoric acid to pH=7.0. To this solution was added glucose (112 g, 0.622 mol), NADP (3.6 g), GDH-103 (1.8 g), KRED 119 (3.6 g), and crude benzyl [(3S)-4-oxotetrahydro-2H-pyran-3-yl]carbamate (103.4 g, 0.4148 mol). After 17 h, the reaction was adjusted to pH=6.5 with 5 N NaOH. A white solid was collected via filtration and washed 2× with water (200 mL). The solid was suspended in 600 mL of toluene and stirred with an overhead stirrer at 105° C. for 1 h, then cooled to rt. A white solid was collected via filtration and washed with toluene (200 mL) to provide benzyl [(3S,4S)-4-hydroxytetrahydro-2H-pyran-3-yl]carbamate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]2[C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1.[CH3:29][N:30]([CH3:36])[CH:31]1[CH2:35][CH2:34][NH:33][CH2:32]1>C(OCC)(=O)C.CO>[CH3:29][N:30]([CH3:36])[CH:31]1[CH2:35][CH2:34][N:33]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]3[C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[CH2:32]1
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccc(S(C)(=O)=O)cc2)c1C(=O)C(F)(F)F
Reactant: CN(C)C1CCNC1
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1nc2ccc(N3CCC(N(C)C)C3)cc2c(-c2ccc(S(C)(=O)=O)cc2)c1C(=O)C(F)(F)F
Reaction time: 16 h
Yield: 47 %

Procedure:
The title compound was prepared from 1-[6-Bromo-4-(4-methanesulfonyl-phenyl)-2-methyl-quinolin-3-yl]-2,2,2-trifluoro-ethanone [example 23] and 3-(dimethylamino)pyrrolidine according to the procedure of example 25, except that the reaction time was of 16 h and that ethyl acetate/methanol (9:1) was used. Yield: 47%; MS: m/z=506 (M+H).
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].[CH2:8]([S:10]([C:13]1[CH:14]=[CH:15][C:16](F)=[C:17]([C:19]2[C:20]3[CH:29]=[N:28][N:27]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:21]=3[C:22](=[O:26])[N:23]([CH3:25])[CH:24]=2)[CH:18]=1)(=[O:12])=[O:11])[CH3:9]>O1CCOCC1>[CH:1]1([CH2:4][O:5][C:16]2[CH:15]=[CH:14][C:13]([S:10]([CH2:8][CH3:9])(=[O:11])=[O:12])=[CH:18][C:17]=2[C:19]2[C:20]3[CH:29]=[N:28][N:27]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:36])([CH3:35])[CH3:37])[C:21]=3[C:22](=[O:26])[N:23]([CH3:25])[CH:24]=2)[CH2:3][CH2:2]1
Reactant: OCC1CC1
Reactant: CCS(=O)(=O)c1ccc(F)c(-c2cn(C)c(=O)c3c2cnn3COCC[Si](C)(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCS(=O)(=O)c1ccc(OCC2CC2)c(-c2cn(C)c(=O)c3c2cnn3COCC[Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90 %

Procedure:
Cyclopropylmethanol (0.018 g, 0.25 mmol) in dioxane (0.75 mL) was treated with sodium hydride (60% oil dispersion) (0.023 g, 0.587 mmol) and stirred at ambient temperature for 10 minutes. A solution of Example 322e (0.0683 g, 0.147 mmol) in dioxane (0.75 mL) was added and the mixture was stirred at 60° C. for 8 hours and then at ambient temperature for 16 hours. Additional cyclopropylmethanol (0.018 g, 0.249 mmol) and sodium hydride (60% oil dispersion) (0.023 g, 0.587 mmol) were added and the mixture was heated at 70° C. for 9 hours. The reaction mixture was cooled to ambient temperature and then partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 0 to 30% ethyl acetate in dichloromethane) to provide the title compound (0.0685 g, 90%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:28])[C:15]([C:18]2[CH:27]=[CH:26][C:25]3[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=3[CH:19]=2)=[CH:16][OH:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[K+].Cl[CH:32]([F:34])[F:33]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.COCCOC>[F:33][CH:32]([F:34])[O:17][CH:16]=[C:15]([C:18]1[CH:27]=[CH:26][C:25]2[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=2[CH:19]=1)[C:14]([NH:13][CH2:12][CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:28]
Reactant: COc1ccc(CCNC(=O)C(=CO)c2ccc3c(c2)CCCC3)cc1OC
Reactant: FC(F)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: COCCOC
Product: COc1ccc(CCNC(=O)C(=COC(F)F)c2ccc3c(c2)CCCC3)cc1OC

Procedure:
Five hundred milligrams (500 mg) of N-[2-(3,4-dimethoxyphenyl)ethyl]-3-hydroxy-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acrylamide (1.31 mmol), 1.80 g (3.28 mmol) of 10% aqueous potassium hydroxide solution, 87 mg (0.262 mmol) of tetrabutylammonium bromide and 10 ml of ethylene glycol dimethyl ether were mixed and chlorodifluoromethane gas was blown thereto at room temperature. A sample was taken out from the reaction mixture and the disappearance of the starting material was confirmed by thin layer chromatograph analysis. Then, 5% hydrochrolic acid was added to the reaction mixture, which was followed by extracted with ethyl acetate, washed with 5% hydrochrolic acid, saturated aqueous sodium bicarbonate solution and saturated brine subsequently, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (eluent, hexane:ethyl acetate=2:1) and the obtained residue was washed with hexane to give 350 mg of 3-difluoromethoxy-N-[2-(3,4-dimethoxyphenyl)ethyl]-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acrylamide (the present compound 1104).