Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([O:9][CH3:10])[C:2](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O:3][CH3:4].[Li]CCCC.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([CH:31]=[O:32])[CH2:27][CH2:26]2)=[CH:19][CH:18]=1>C1COCC1.CCCCCC>[CH3:4][O:3][C:2]1[C:1]([O:9][CH3:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH:31]([CH:28]1[CH2:29][CH2:30][N:25]([CH2:24][CH2:23][C:20]2[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=2)[CH2:26][CH2:27]1)[OH:32]
Reactant: O=CC1CCN(CCc2ccc(F)cc2)CC1
Reactant: COc1ccccc1OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cccc(C(O)C2CCN(CCc3ccc(F)cc3)CC2)c1OC
Temperature: -78 °C
Reaction time: 2.5 h

Procedure:
To a stirred solution of veratrole (0.93 g, 6.7 mmol) in THF (20 mL) under argon at 0° C. was added n-BuLi (2.7 mL of a 2.5 M solution in hexane, 6.75 mmol). After stirring 2.5 h, the solution was cooled to -78° C. and treated with 1-[2-(4-fluorophenyl)ethyl]4-piperidinecarboxaldehyde (1.30 g, 5.5 mmol) in THF (25 mL) via an addition funnel. The cooling bath was removed and the solution was allowed to stir for 2 hours. Water was added, the layers separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered, and chromatographed on silica gel, eluting with acetone. The appropriate fractions were combined and evaporated to afford a white solid. The solid was recrystallized from hexane to afford racemic alpha(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol as shiny white needles, m.p. 126-127° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:14]=[CH:13][C:12]([C:15]([N:17]([CH3:39])[C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:25]4[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[C@@H:27]([CH3:38])[CH2:26]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:14]=[CH:13][C:12]([C:15]([N:17]([CH3:39])[C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:25]4[CH2:30][CH2:29][NH:28][C@@H:27]([CH3:38])[CH2:26]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(Oc4ccc(F)cc4)nc3)cc2)CCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(Oc4ccc(F)cc4)nc3)cc2)CCN1
Reaction time: 1.5 h
Yield: 89.9 %

Procedure:
1,1-Dimethylethyl (2S)-4-({4-[({6-[(4-fluorophenyl)oxy]-3-pyridinyl}carbonyl)(methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate (D16) (0.518 g, 0.97 mmol) was dissolved in DCM (19.2 mL) and TFA (4.8 mL) added. The solution was stirred for 1.5 h then the solvent was removed in vacuo. The product was taken up in methanol and eluted through an SCX (10 g) column with 2M NH3 in methanol solution. The solvent was removed to give a colourless oil which was purified by column chromatography. Elution with a 0-5% (2M NH3 in methanol)/DCM gradient yielded the title compound as a colourless oil (0.379 g). δH (CDCl3, 400 MHz) 8.07 (1H, dd), 7.65 (1H, dd), 7.22 (2H, d), 7.04 (6H, m), 6.70 (1H, d), 3.48 (3H, s), 3.43 (2H, s), 3.13 (br.s), 2.95 (3H, m), 2.70 (2H, d), 2.04 (1H, m), 1.74 (1H, m), 1.05 (3H, d). MS (ES): MH+ 435.3.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=2[NH:23][CH:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)=O)=[CH:6][CH:5]=1)[CH3:2].P(Cl)(Cl)(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[N:23]([CH:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)[C:15]3[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:14]=3[N:13]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(CC(=O)Nc2cc([N+](=O)[O-])ccc2NC2CCN(C)CC2)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCOc1ccc(Cc2nc3cc([N+](=O)[O-])ccc3n2C2CCN(C)CC2)cc1
Temperature: 25 °C
Yield: 69.8 %

Procedure:
2-(4-Ethoxy-phenyl)-N-[2-(1-methyl-piperidin-4-ylamino)-5-nitro-phenyl]-acetamide 53 (190 mg, 0.461 mmol), Phosphorous pentachloride (100.7 mg, 0.483 mmol) were dissolved in anhydrous chloroform (10 mL) in a small, argon purged flask fitted with an condenser and magnetic stirbar. The solution was heated to reflux in an oil bath for 4 hours and cooled to room temperature overnight. The solid that had precipitated from the reaction mixture was collected on a sintered glass funnel and washed with a small amount of chloroform. The sticky solid was washed off the funnel in methanol and concentrated to residue. The residue was taken up in H2O and chloroform and 2M ammonium hydroxide solution added to adjust pH to 9-10. The mixture was transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with chloroform and the combined organic layers were washed with brine, dried over magnesium sulphate, filtered and concentrated to afford crude. The product was purified using silica gel column chromatography eluting with a solvent system of 5% 2M NH3 in methanol/95% dichloromethane to afford a pale yellow oil 54 2-(4-Ethoxy-benzyl)-1-(1-methyl-piperidin-4-yl)-5-nitro-1H-benzimidazole Yield: 127 mg (70.0%). 1H NMR (DMSO) δ: 1.29 (t, 3H, J=7.0), 1.39 (br d, 2H, J=9.8), 1.89-1.97 (m, 2H), 2.19 (s, 3H), 2.20-2.31 (m, 2H), 2.82 (br d, 2H, J=11.2), 3.96 (q, 2H, J=7.0), 4.29-4.37 (m, 1H), 4.37 (s, 2H), 6.87 (d, 2H, J=8.7), 7.17 (d, 2H, J=8.4), 7.82 (d, 1H, J=9.0), 8.07 (dd, 1H, J=9.0, 2.4), 8.48 (d, 1H, J=2.3); MS (ESI): 395 (MH+, 100%).
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:10])[NH:5][C:6](=[O:9])[NH:7][CH:8]=1)#[N:2].[CH2:11]([N:17]=[C:18]=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].O>N1C=CC=CC=1>[C:1]([C:3]1[C:4](=[O:10])[NH:5][C:6](=[O:9])[N:7]([C:18]([NH:17][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:19])[CH:8]=1)#[N:2]
Reactant: CCCCCCN=C=O
Reactant: N#Cc1c[nH]c(=O)[nH]c1=O
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCNC(=O)n1cc(C#N)c(=O)[nH]c1=O
Temperature: 100 °C
Yield: 15.6 %

Procedure:
5-Cyanouracil (0.10 g, 0.73 mmol) was dissolved in dry pyridine (5.0 mL) and hexyl isocyanate (0.08 mL, 1.10 mmol) was added. The mixture was heated under microwave irradiation to 100° C. for 10 min and then was poured into water (50 mL). The product was extracted with dichloromethane (2×50 mL), the combined organic layers were dried over Na2SO2 and the solvent was concentrated under reduced pressure. The crude was purified by column chromatography using SI (2 g) cartridge (dichloromethane) and subsequently washed with warm heptane to afford the title compound (0.03 g, 16%) as white powder. 1H NMR (400 MHz, DMSO-d6): δ 0.86-0.96 (m, 3H), 1.29-1.41 (m, 6H), 1.57-1.70 (m, 2H), 3.44 (q, J=6.4, 2H), 5.01 (s, 1H), 8.85 (br s, 1H), 9.05 (s, 1H). MS (ESI) m/z: 263 [M-H]−.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C@H:15]2[CH2:17][C@@H:16]2[CH2:18][OH:19])[CH:12]=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br.Br[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.[NH4+].[Cl-]>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([O:8][C:9]1[CH:14]=[N:13][CH:12]=[C:11]([C@H:15]2[CH2:17][C@@H:16]2[CH2:18][O:19][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC[C@H]1C[C@@H]1c1cncc(OCc2ccccc2)c1
Reactant: BrCc1ccccn1
Agent: Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: C1CCOC1
Product: c1ccc(COc2cncc([C@H]3C[C@@H]3COCc3ccccn3)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
To a solution of (1S,2S)-2-[5-(benzyloxy)-3-pyridyl]cyclopropylmethanol (150 mg, 0.59 mmol) in anhydrous THF (5 mL) in a 25 mL round-bottom flask was added sodium hydride (60% dispersion in mineral oil, 57 mg, 1.41 mmol, 2.4 equiv.). The flask was equipped with a condenser, and the atmosphere was exchanged with Ar (3 times). The suspension was stirred at room temperature for 2 h. 2-(Bromomethyl)pyridine hydrobromide (178 mg, 0.70 mmol, 1.2 equiv.) and tetra-n-butylammonium iodide (23 mg, 60 μmol, 0.1 equiv.) in dry THF (2 mL) were added. The resulting mixture was again protected with Ar and was stirred at room temperature overnight. Saturated NH4Cl solution (15 mL) was added to quench excessive sodium hydride, and the product was extracted into EtOAc (3×20 mL). The combined organic phases were washed with brine (15 mL), dried over Na2SO4, and concentrated. The residue was purified by CC on SiO2 (25×1.0 cm, EtOAc) to give the crude product as a colorless oil (181 mg, 88%). MS (EI) m/z 346 (M+, 6.8%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:12]2[NH:16][C:15](=[O:17])[N:14]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[N:13]=2)[C:6]([CH:9]([F:11])[F:10])=[N:7][CH:8]=1.C[O:29][CH2:30][C:31]([CH3:36])([CH3:35])[C:32](O)=[O:33].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[F:10][CH:9]([F:11])[C:6]1[N:7]=[CH:8][C:3]([CH2:2][NH:1][C:30](=[O:29])[C:31]([CH3:36])([CH3:35])[CH2:32][OH:33])=[CH:4][C:5]=1[C:12]1[NH:16][C:15](=[O:17])[N:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:26])([F:25])[F:27])=[CH:20][CH:19]=2)[N:13]=1
Reactant: NCc1cnc(C(F)F)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Reactant: COCC(C)(C)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(CO)C(=O)NCc1cnc(C(F)F)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Yield: 43.7 %

Procedure:
The title compound was prepared by following the procedure as described in Example-107 by using 3-(5-(aminomethyl)-2-(di flu oromethyl)pyridin-3-yl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one (step-1 of Example-186, 0.130 g, 0.33 mmol), DMF (5 mL), 3-methoxy-2,2-dimethylpropanoic acid (0.060 g, 0.50 mmol), BOP (0.224 g, 0.50 mmol), TEA (2.0 mL) to afford 0.070 g of the desired product. MS (m/z): 486.22 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13](O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.Cl[C:24]([O:26][CH2:27]C(C)C)=[O:25].[N+](=C)=[N-]>C1COCC1.CCOCC.C(N(CC)CC)C.C([O-])(=O)C1C=CC=CC=1.[Ag+]>[CH3:27][O:26][C:24](=[O:25])[CH2:13][C@H:9]1[CH2:10][CH2:11][CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: CC(C)COC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Agent: [Ag+]
Agent: C=[N+]=[N-]
Agent: O=C([O-])c1ccccc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CN1CCOCC1
Product: COC(=O)C[C@H]1CCCN1C(=O)OC(C)(C)C
Temperature: -30 °C
Reaction time: 0.33 h
Yield: 45.4 %

Procedure:
(R)-1-(tert-Butyloxycarbonyl)pyrrolidin-2-yl-carboxylic acid (9.7 g, 48 mmol) is dissolved in THF (250 mL) cooled to −30° C. and treated with NMM (5.75 mL, 52 mmol), isobutyl chloroformate (6.79 mL, 52 mmol) and stirred for 20 min. The reaction mixture is filtered and the filtrate is added to a solution of diazomethane (˜71 mmol) in ether (200 mL) at 0° C. The reaction mixture is stirred for 20 min. then quenched with acetic acid dropwise. The solvent is removed under vacuo and the residue is dissolved in methanol (100 mL) and treated with a solution of silver benzoate (2.18 g, 9.5 mmol) in triethylamine (21.4 mL) for 35 min. The reaction mixture is concentrated, diluted with ethyl acetate (600 mL) and washed with saturated sodium bicarbonate (3×150 mL), water (3×150 mL), potasium sulfite (3×150 mL) and brine. The organic layer is dried (MgSO4) and concentrated; flash chromatography gives the title compound as a clear oil (5.3 g, 21.8 mmol). 1H NMR (CDCl3, 300 MHz) □ 4.1(br.s., 1H), 3.66(s, 3H), 3.38-3.28(m, 2H), 2.92-2.80(m, 1H), 2.30(dd, 1H), 2.10-1.98(m, 1H), 1.90-1.65(m, 3H), 1.43(s, 9H).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7](/[C:10](=[N:16]/[OH:17])/[C:11]([O:13]CC)=[O:12])=[CH:6][CH:5]=1.Cl[CH2:19][C:20]1[CH:39]=[CH:38][C:23]([O:24][CH2:25][C:26]2[N:27]=[C:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:29][C:30]=2[CH3:31])=[CH:22][CH:21]=1.Cl.C(=O)(O)[O-].[Na+]>CN(C)C=O>[Br:3][C:4]1[CH:5]=[CH:6][C:7](/[C:10](=[N:16]/[O:17][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:24][CH2:25][C:26]3[N:27]=[C:28]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[O:29][C:30]=3[CH3:31])=[CH:38][CH:39]=2)/[C:11]([OH:13])=[O:12])=[CH:8][CH:9]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Reactant: CCOC(=O)/C(=N\O)c1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\C(=O)O)c2ccc(Br)cc2)cc1
Reaction time: 1 h
Yield: 80.6 %

Procedure:
Sodium hydride (60% in oil, 127 mg) was added under a nitrogen atmosphere to a solution of ethyl Z-2-(4-bromophenyl)-2-hydroxyiminoacetate (868 mg) and 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (100 g) in N,N-dimethylformamide (10 ml) at room temperature and the mixture was stirred for 1 hour. After adding 1N HCl (5 ml), aqueous sodium bicarbonate was added, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residue was subjected to column chromatography on silica gel to obtain an oil from a fraction eluted with ethyl acetate-hexane (1:2, v/v). This oil was dissolved in tetrahydrofuran (5 ml)-methanol (10 ml), and 0.5N aqueous solution of sodium hydroxide (10 ml) was added and the mixture was heated under reflux for 1.5 hours. 1N HCl (5.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residual crystal was recrystallized from ethyl acetate to obtain Z-2-(4-bromophenyl)-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]acetic acid (1.34 g, yield 81%) as colorless crystals. m.p. 189-190° C. (decomposition)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:3][CH:2]=1.C(O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([Li])CCC>O1CCCC1>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([O:10][CH2:11][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:9])=[CH:3][CH:2]=1
Reactant: COC(=O)Cc1ccncc1
Reactant: OCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(Cc1ccncc1)OCc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of methyl 4-pyridylacetate (Step A, 2.5 g, 16 mmol) and benzyl alcohol (3.4 mL, 33 mmol) in anhydrous tetrahydrofuran (10 mL) at −10° C. was added butyllithium (2 M in cyclohexane, 16 mL, 33 mL), and the reaction was allowed to warm to room temperature overnight. The volatile materials were removed on a rotary evaporator, and the residue was diluted with methylene chloride (50 mL), washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness, and the residue was purified by flash column chromatography eluted with 30% ethyl acetate in hexane to give the title compound. 1H NMR (400 MHz, CD3OD): δ 8.43 (d, 2H), 7.38 (d, 2H), 7.32 (m, 5 H), 5.16 (s, 2H), 3.99 (s, 2H).
Reaction SMILES: [C:1]([CH2:9][C:10]([CH3:12])=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH:15](OC)[N:16](C)[CH3:17]>>[CH3:15][N:16]([CH3:17])[C:9]([CH:10]=[CH2:12])=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)CC(=O)c1ccccc1
Reactant: COC(OC)N(C)C
Product: C=CC(=Cc1ccccc1)N(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
A mixture of 1-benzoylacetone (24.00 g, 0.15 mole) and dimethylformamide dimethylacetal were stirred overnight at room temperature under argon. The resulting reddish-colored mixture was concentrated on the rotary evaporator, then dissolved in THF (tetrahydrofuran). The resulting solution was stirred and heated to boiling and slowly diluted with hexane. At the point of turbidity heating was discontinued. An orange gum precipitated and rapidly solidified. The mixture was chilled in an ice bath and filtered yielding 25.25 g (78%) of 2-(dimethyl-amino)-1-phenyl-1,3-butanediene m.pt. 72°-74° C.
Reaction SMILES: [I:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]=[C:9]=[O:10])=O)=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:19]=[C:18]([F:20])[C:17]([CH2:21][NH:22][C:23](=[O:28])[C:24]([F:27])([F:26])[F:25])=[CH:16][C:15]=1[NH:29][NH:30]C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:13][C:14]1[C:15]([N:29]2[C:9](=[O:10])[NH:8][C:6]([C:5]3[CH:11]=[CH:12][C:2]([I:1])=[CH:3][CH:4]=3)=[N:30]2)=[CH:16][C:17]([CH2:21][NH:22][C:23](=[O:28])[C:24]([F:26])([F:27])[F:25])=[C:18]([F:20])[CH:19]=1
Reactant: O=C=NC(=O)c1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)NNc1cc(CNC(=O)C(F)(F)F)c(F)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCc1cc(-n2nc(-c3ccc(I)cc3)[nH]c2=O)c(Cl)cc1F)C(F)(F)F
Yield: 61.7 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using 4-iodobenzoyl isocyanate (Intermediate-67, 0.700 g, 1.8 mmol), tert-butyl 2-(2-chloro-4-fluoro-5-{[(trifluoroacetyl)amino]methyl}phenyl)hydrazine carboxylate (Intermediate-89, 0.992 g, 3.63 mmol), DCM (50 mL), trifluoro acetic acid (5.0 mL) to afford 0.600 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 4.47 (s, 2H), 7.61 (d, J=2.1 Hz, 3H), 7.86-7.90 (br d, 3H), 10.05 (br s, 1H).
Reaction SMILES: O=[O+][O-].CC1(C)OC(=O)C(C[CH:13]([OH:16])[CH2:14][Cl:15])=CO1.CO.CSC.[C:23]([O:26][CH2:27][CH3:28])(=[O:25])[CH3:24]>>[Cl:15][CH2:14][CH:13]([OH:16])[CH2:24][C:23]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(C)=O
Reactant: CC1(C)OC=C(CC(O)CCl)C(=O)O1
Agent: O=[O+][O-]
Solvent: CSC
Solvent: CO
Product: CCOC(=O)CC(O)CCl
Temperature: 80 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
Ozone was introduced into a mixture of 225.5 mg (1 mmol) of (+)-2,2-dimethyl-(3-chloro-2-hydroxypropyl)-1,3-dioxin-4-one (96% ee) obtained in Example 4 and 20 ml of methanol at -78° C. for 5 hours, and 2 ml of dimethyl sulfide were added thereto, followed by stirring at the same temperature for 2 hours. The temperature was gradually returned to room temperature, and the solution was then stirred for 5 hours. Afterward, the solvent was distilled off, and the resultant residue was then dissolved in ethanol. 3 drops of concentrated sulfuric acid were added thereto, and the solution was then heated at 80° C. for 30 minutes. Next, ethanol was distilled off, and the residue was diluted with water. The solution was extracted with dichloromethane and then dried over anhydrous sodium sulfate, and the solvent was distilled off and the residue was then subjected to column chromatography (an eluent of hexane:ethyl acetate=5:1), thereby obtaining 109.4 mg (yield 66%) of (+)-ethyl 4-chloro-3-hydroxybutanoate.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:6]=1[C:15]1[C:16]2[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[O:26])[C:17]=2[N:18]=[CH:19][N:20]=1)[CH3:3].C([O:37][C@@H:38]([CH3:42])[C:39](Cl)=[O:40])(=O)C>>[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:13])([F:12])[F:14])=[CH:7][C:6]=1[C:15]1[C:16]2[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]3[CH2:29][CH2:30][N:31]([C:39](=[O:40])[C@@H:38]([OH:37])[CH3:42])[CH2:32][CH2:33]3)=[O:26])[C:17]=2[N:18]=[CH:19][N:20]=1)[CH3:3]
Reactant: CCOc1ccc(C(F)(F)F)cc1-c1ncnc2c(C(=O)NC3CCNCC3)c(C)[nH]c12
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: CCOc1ccc(C(F)(F)F)cc1-c1ncnc2c(C(=O)NC3CCN(C(=O)[C@H](C)O)CC3)c(C)[nH]c12

Procedure:
Starting from 4-[2-ethoxy-5-(trifluoromethyl)phenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f34) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [SH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.C(N(CC)C(C)C)(C)C.O>CN(C)C=O>[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:4]([C:3]2[C:2]([SH:1])=[N:10][CH:9]=[CH:8][CH:7]=2)=[O:6])=[CH:14][CH:13]=1
Reactant: O=C(O)c1cccnc1S
Reactant: Nc1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(Nc1ccc(Cl)cc1)c1cccnc1S
Reaction time: 20 h
Yield: 59 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetrauroniumhexafluorophosphate (5.4 g, 14 mmol) was added to a suspension of 2-mercaptonicotinic acid (2.0 g, 13 mmol), 4-chloroaniline (1.7 g, 13 mmol) and N,N-diisopropylethylamine (4.5 mL, 26 mmol) in anhydrous N,N-dimethylformamide (20 mL) at room temperature, and the mixture was stirred for 20 hours. Water (20 mL) was added thereto, the precipitated solid was filtered off, and washed with ethyl acetate. The resulting solid was dried at 40° C. under reduced pressure to give 2.0 g of the title Reference Compound as a yellow solid (Yield: 59%)
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:5][C@H:4]1[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:21])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[CH:15]=2)=[CH:8][CH:7]=1.[CH3:22][N:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1.C(=O)([O-])O.[Na+].[BH4-].[Na+]>CO.O>[Br:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[C:13]([NH:12][C:9]1[CH:10]=[CH:11][C:6]([C@@H:4]2[CH2:5][C@H:3]2[NH:2][CH:26]2[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]2)=[CH:7][CH:8]=1)=[O:21]
Reactant: N[C@@H]1C[C@H]1c1ccc(NC(=O)c2cccc(Br)c2)cc1
Reactant: CN1CCC(=O)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Solvent: O
Product: CN1CCC(N[C@@H]2C[C@H]2c2ccc(NC(=O)c3cccc(Br)c3)cc2)CC1
Temperature: 70 °C
Reaction time: 1 h
Yield: 10.7 %

Procedure:
To a solution of N-[4-(trans-2-aminocyclopropyl)phenyl]-3-bromobenzamide hydrochloride (80 mg) in methanol (2 mL) were added 1-methylpiperidin-4-one (24.6 mg) and sodium hydrogen carbonate (27.4 mg). The mixture was stirred at 70° C. for 1 hr, and ice-cooled to 0° C. and sodium borohydride (12.4 mg) was added. The mixture was stirred for 1 hr and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized (ethyl acetate) to give the title compound (10.0 mg).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].O=O.[CH3:11]O>[Fe]>[CH3:11][O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1
Reactant: Oc1ccc(O)cc1
Reactant: CO
Agent: [Fe]
Agent: O=O
Product: COc1ccc(O)cc1
Reaction time: 4.5 h

Procedure:
After being filtered, washed with methanol and dried, the resin contains 1.0 milliequivalent of iron per gram of resin. 2.0 g of the catalyst prepared in this manner are fed into the autoclave together with 5.0 g of hydroquinone and 40 cm3 of methanol. The autoclave is pressurised to 5 kg/cm2 with O2 and kept at 105° for 4.5 hours. 4.1 g of hydroquinone monomethyl ether are obtained (conversion 80%, selectivity 91%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:5][OH:6])[CH3:4].N1C=CN=C1.[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>CN(C)C=O>[C:15]([Si:12]([CH3:14])([CH3:13])[O:6][CH2:5][C@H:3]([NH2:2])[CH3:4])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@@H](N)CO
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C[C@@H](N)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
D-Alaninol hydrochloride (500 mg, 6.66 mmol) (Aldrich) was dissolved in anhydrous dimethylformamide (10 mL) (Aldrich). Imidazole (544 mg, 8 mmol) (Aldrich) and tert-butyldimethylsilyl chloride (1.05 g, 7 mmol) (Aldrich) were successively added at room temperature. This mixture was stirred at room temperature for 2 hours, quenched with a solution of water-saturated aqueous sodium bicarbonate solution (5:1, 15 mL) and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, and concentrated under reduce pressure to yield (R)-2-(tert-butyl-dimethyl-silanyloxy)-1-methyl-ethylamine as a colorless oil. (Yield 852 mg, 68%).