Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=1)[N:7]=[C:6]2[C:27]([O:29]C)=[O:28].O1CCCC1.[OH-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([C:15]1[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=1)[N:7]=[C:6]2[C:27]([OH:29])=[O:28]
Reactant: COC(=O)c1nc(-c2cc(OC)c(OC)c(OC)c2)nc2cc(OC)c(OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2nc(-c3cc(OC)c(OC)c(OC)c3)nc(C(=O)O)c2cc1OC

Procedure:
Into a 100-mL round-bottom flask, was placed methyl 6,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)quinazoline-4-carboxylate (2 g, 4.83 mmol, 1.00 equiv) and tetrahydrofuran (30 mL). This was followed by the addition of a solution of sodium hydroxide (1 g, 25.00 mmol, 5.18 equiv) in water (20 mL) dropwise with stirring. The resulting solution was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 100 mL of water. The resulting solution was extracted with 2×50 mL of dichloromethane and the organic layers combined. The pH value of the solution was adjusted to 5 with hydrogen chloride (1 M). The resulting solution was extracted with 3×100 mL of dichloromethane. The solids were filtered out. The mixture was concentrated under vacuum. This resulted in 1 g (52%) of 6,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)quinazoline-4-carboxylic acid as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 3.77 (s, 3H), 3.93-3.95 (d, 9H), 4.04 (d, 3H), 7.49 (s, 1H), 7.78 (s, 1H), 7.89 (s, 2H); MS (ESI) m/z 401 ([M+H]+).
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:31]=[CH:30][C:11]([O:12][C:13]2[CH:14]=[CH:15][C:16]3[S:22](=[O:24])(=[O:23])[CH2:21][CH2:20][C:19]([C:25]([O:27]C)=[O:26])=[CH:18][C:17]=3[CH:29]=2)=[CH:10][CH:9]=1)[CH2:2][CH3:3].[OH-].[Na+]>C1COCC1.CO>[CH2:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13]2[CH:14]=[CH:15][C:16]3[S:22](=[O:24])(=[O:23])[CH2:21][CH2:20][C:19]([C:25]([OH:27])=[O:26])=[CH:18][C:17]=3[CH:29]=2)=[CH:30][CH:31]=1)[CH2:2][CH3:3]
Reactant: CCCOCCOc1ccc(Oc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCOCCOc1ccc(Oc2ccc3c(c2)C=C(C(=O)O)CCS3(=O)=O)cc1
Temperature: 65 °C
Reaction time: 16 h
Yield: 64.5 %

Procedure:
To methyl 7-[4-(2-propoxyethoxy)phenoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.40 g) dissolved in THF (12 ml)/methanol (6.0 ml) was added a 1 N aqueous solution (2.7 ml) of sodium hydroxide, and the resulting mixture was stirred at 65° C. for 16 hours. After cooling to the room temperature, the reaction mixture was concentrated under reduced pressure to remove a half of the solvent. A 1 N aqueous solution of sodium hydroxide (3.0 ml) was added to the resulting mixture, which was washed with ethyl acetate. After being adjusted to pH=about 5, the resulting aqueous layer was extracted with ethyl acetate and the extract was washed with an aqueous saturated solution of sodium chloride and was then dried with magnesium sulfate. After evaporation to remove the solvent, the resulting residue was washed with hexane/ethyl acetate (=8/1) to obtain 7-[4-(2-propoxyethoxy)phenoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (0.25 g).
Reaction SMILES: [C:1](=[O:8])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[NH2:2].[N:9]([CH2:12][CH3:13])=[C:10]=[S:11].[H-].[Na+]>CN(C=O)C>[CH2:12]([NH:9][C:10]([NH:2][C:1](=[O:8])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[S:11])[CH3:13]
Reactant: CCN=C=S
Reactant: CC(C)(C)OC(N)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCNC(=S)NC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 68.8 %

Procedure:
A solution of tert-butyl carbamate (5.0 g, 42.7 mmol) and isothiocyanatoethane (3.7 mL, 42.7 mmol) in dry DMF (30 mL) was added slowly to a stirred solution of sodium hydride (60% suspension, 1.9 g, 47 mmol) in dry DMF (15 mL) under nitrogen, such that the internal temperature was maintained <5° C. After complete addition the reaction was stirred in an ice bath for 1 h. The cooling bath was removed and the reaction was stirred at RT overnight, and then poured on to ice (25 g) and diluted with water (150 mL). The aqueous mixture was extracted with Et2O (3×100 mL). The combined extracts were washed with brine (1×50 mL), dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (normal phase, 100 g, Biotage SNAP cartridge KP-Sil, 50 mL per min, gradient 4% to 8% EtOAc in n-hexane) to give the title compound (6.0 g, colourless solid). 1H NMR (400 MHz, CDCl3) δ ppm 1.29 (t, J=7.33 Hz, 3H) 1.50 (s, 9H) 3.54-3.78 (m, 2H) 7.82 (br. s., 1H) 9.63 (br. s., 1H).
Reaction SMILES: [I:1][C:2]1[C:10]2[CH:9]=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1.[H-].[Na+].[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[C:13]1([S:19]([N:4]2[C:5]3[N:6]=[CH:7][N:8]=[CH:9][C:10]=3[C:2]([I:1])=[CH:3]2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Ic1c[nH]c2ncncc12
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)n1cc(I)c2cncnc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
5-Iodo-7H-pyrrolo[2,3-d]pyrimidine (39, 0.569 g, 2.32 mmol) was added to 10.0 mL of N,N-dimethylformamide in a round bottom flask. Sodium hydride (0.102 g, 2.55 mmol) was added and the reaction stirred at room temperature for 10 minutes, then benzenesulfonyl chloride (40, 326 μL, 2.55 mmol) was added. The reaction was stirred at room temperature overnight, then poured into aqueous saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate adsorbed onto silica. The desired compound was isolated by silica gel column chromatography, eluting with 0.5-6% methanol in dichloromethane. Appropriate fractions were combined and concentrated under vacuum. Toluene was added to the residue, then concentrated under vacuum and the resulting solid was washed with hexane and collected by filtration to provide the desired compound (41, 439 mg). 1H NMR consistent with the compound structure.
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[N:8]=[CH:9][N:10]2[C:16]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=3[C:14](=[O:22])[N:13]([CH3:23])[CH2:12][C:11]=12)=[O:6])[C:2]#[CH:3].I[N:25]1C(=O)[CH2:28][CH2:27][C:26]1=O.C(N)CC>C(O)(=O)C>[F:21][C:19]1[CH:18]=[CH:17][C:16]2[N:10]3[CH:9]=[N:8][C:7]([C:5]4[O:6][C:2]([CH2:3][NH:25][CH2:26][CH2:27][CH3:28])=[CH:1][N:4]=4)=[C:11]3[CH2:12][N:13]([CH3:23])[C:14](=[O:22])[C:15]=2[CH:20]=1
Reactant: O=C1CCC(=O)N1I
Reactant: C#CCNC(=O)c1ncn2c1CN(C)C(=O)c1cc(F)ccc1-2
Solvent: CCCN
Solvent: CC(=O)O
Product: CCCNCc1cnc(-c2ncn3c2CN(C)C(=O)c2cc(F)ccc2-3)o1
Temperature: 25 °C
Reaction time: 90 h
Yield: 9.9 %

Procedure:
A solution of 10 g (0.032 mol) of 8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid prop-2-ynylamide in 200 ml of acetic acid was treated with 10.8 g (0.048 mol) of N-iodosuccinimide while gassing with argon. After stirring at room temperature for 90 hrs. the dark suspension obtained was completely freed from the solvents and dried azeotropically several times with toluene. The dark residue was dissolved in 200 ml of THF, treated with 23 ml (0.278 mol) of propylamine and stirred at room temperature for 5 hrs. The suspension obtained was completely freed from the solvents, the residue was partitioned between ethyl acetate and 1N aqueous hydrochloric acid and extracted. The aqueous-acidic phase was made basic and extracted with ethyl acetate. The organic phase was concentrated and the orange crystalline product was chromatographed twice; firstly over basic Alox (grade III) with ethyl acetate/methanol 4:1 as the eluent, then over silica gel with dichloromethane/methanol 9:1 as the eluent. There were obtained 1.17 g (10%) of 8-fluoro-5-methyl-3-(5-propylaminomethyl-oxazol-2-yl)-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as yellowish crystals; m.p. 134-136°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:49]=[CH:48][C:20]([C:21]([N:23]([CH3:47])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][N:36]4C(=O)C5=CC=CC=C5C4=O)=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.O.NN>C(O)C.C(OCC)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([N:23]([CH3:47])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][NH2:36])=[O:22])=[CH:48][CH:49]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3OCCCCCN3C(=O)c4ccccc4C3=O)cc2)cc1
Agent: NN
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3OCCCCCN)cc2)cc1

Procedure:
A suspension of 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-[2-(5-phthalimidopentyloxy)phenyl]benzamide (1.1 g) in ethanol (20 ml) was stirred rapidly and treated with hydrazine hydrate (844 mg). The mixture was stirred at 60° C. for 3 hours. After cooling, the reaction mixture was diluted with diethyl ether and filtered through Celite. The Celite was washed with diethyl ether, and the filtrate was concentrated. The residual milky oil was again dissolved in diethyl ether, filtered through Celite, washed with diethyl ether, and concentrated to give 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-[2-(5-aminopentyloxy)phenyl]benzamide
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7](C=O)[CH:8]=2)[CH:3]=[CH:2]1.C(O)(=O)C.NC[C@@H](O)[C@@H](NC(=O)OC(C)(C)C)CC1C=C(F)C=C(F)C=1.[BH4-].[Na+]>CC(O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=Cc1ccc2cc[nH]c2c1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CC(=O)O
Product: c1ccc2[nH]ccc2c1
Reaction time: 12 h
Yield: 62.8 %

Procedure:
To a stirred solution of 1H-indole-6-carbaldehyde (99 mg, 0.68 mmol) and tert-butyl (1S,2R)-3-amino-1-(3,5-difluorobenzyl)-2-hydroxypropylcarbamate acetate 3 (256 mg, 0.68 mmol) in 2-propanol (3 mL) was added sodium borohydride (30 mg, 0.82 mmol). The reaction mixture was stirred for 12 h., quenched with methanol, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 1:1 ethyl acetate/hexanes) provided indole (50 mg): 1H NMR (300 MHz, CDCl3) δ 8.41 (br s, 1H), 7.60 (d, J=8 Hz, 1H), 7.38 (s, 1H), 7.21 (t, J=3 Hz, 1H), 7.04 (dd, J=8, 1 Hz, 1H), 6.71–6.73 (m, 3H), 6.61–6.68 (m, 1H), 6.53 (s, 1H), 5.38 (br s, 2H), 4.66 (d, J=9 Hz, 1H), 3.89 (s, 2H), 3.49–3.54 (m, 1H), 2.91–2.98 (m, 1H), 2.62–2.73 (m, 3H), 1.35 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:9][C:10](Cl)=[O:11])=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:9][C:10]([NH:20][C:21]2[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=2[C:23]([O:25][CH3:26])=[O:24])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: COC(=O)c1ccccc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccccc1NC(=O)C=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1

Procedure:
A solution of 20.0 g. of bis(4-chlorophenyl)acryloyl chloride in 150 m. of dichloromethane is added to a stirred solution of 10.3 g. of methyl 2-aminobenzoate and 12.2 ml. of triethylamine in 150 ml. of dichloromethane. This solution is stirred under reflux for 3 hours, then overnight at room temperature, and evaporated. The residue is stirred with 300 ml. of boiliing acetone, filtered white hot, and chilled. The resulting solid is collected and dried in vacuo, giving 15.6 g. of the desired product as a white solid, m.p. 141°-143° C.
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[NH:10][CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[F:22][C:23]1[CH:24]=[CH:25][C:26]([CH3:32])=[C:27]([CH:31]=1)[C:28](Cl)=[O:29]>CN(C)C=O.O.ClCCl>[F:22][C:23]1[CH:24]=[CH:25][C:26]([CH3:32])=[C:27]([C:28]([N:10]2[C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[NH:7][C:6]3[N:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH2:11]2)=[O:29])[CH:31]=1
Reactant: c1cnc2c(c1)CNc1ccccc1N2
Reactant: Cc1ccc(F)cc1C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(F)cc1C(=O)N1Cc2cccnc2Nc2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55.8 %

Procedure:
To a solution of 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine of Example 1, Step B (2.0 g, 10.1 mmol) in dimethylformamide (15 mL) under nitrogen was added potassium carbonate (4.1 g, 29.7 mmol). The mixture was treated dropwise with a solution of crude 5-fluoro-2-methyl benzoyl chloride of Step A (15.0 mmol) in dimethylformamide (10 mL). After stirring at room temperature for 15 minutes, the mixture was diluted with water and stirred to give a solid mass which was collected by filtration. The solid was dissolved in chloroform and washed with 1 N sodium hydroxide and brine. The organic layer was dried over sodium sulfate and evaporated to dryness to give a purple oil. The crude material was dissolved in dichloromethane and absorbed onto a silica Merck-60 flash column. Elution with 20% ethyl acetate in hexane provided 1.88 g of the title product as a foam which was crystallized by sonication from ethanol-hexane, m.p. 138-140° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH2:6])=[O:5].[Cl:7][C:8]1[C:9]([CH3:17])=[C:10]([N:14]=[C:15]=[S:16])[CH:11]=[CH:12][CH:13]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:7][C:8]1[C:9]([CH3:17])=[C:10]([NH:14][C:15](=[S:16])[NH:2][CH2:3][C:4]([NH2:6])=[O:5])[CH:11]=[CH:12][CH:13]=1
Reactant: Cc1c(Cl)cccc1N=C=S
Reactant: NCC(N)=O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1c(Cl)cccc1NC(=S)NCC(N)=O
Temperature: 25 °C
Yield: 88.2 %

Procedure:
A mixture of glycinamide hydrochloride (6.1 g), 3-chloro-2-methylphenyl-isothiocyanate (10.1 g), triethyl amine (5.6 g), and chloroform (200 mL) was heated at reflux for 3 hours then cooled to ambient temperature. The precipitate was collected by filtration, washed with chloroform and air dried to give 2-[3-(3-chloro-2-methylphenyl)-thioureido]-acetamide (12.5 g), m.p. 162°-164° C. (dec.). This compound was used without further purification for the preparation of the title compound of step 2.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:14][O:13][C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].C[C:24]([N:26](C)C)=O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[C-]#N.[Zn+2].[C-]#N.[Zn]>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:14][O:13][C:9]2=[C:10]([C:24]#[N:26])[N:11]=1)=[O:5])[CH3:2]
Reactant: CC(=O)N(C)C
Reactant: CCOC(=O)c1nc(Br)c2onc(-c3ccccc3)c2c1O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCOC(=O)c1nc(C#N)c2onc(-c3ccccc3)c2c1O
Temperature: 120 °C
Reaction time: 2 h

Procedure:
A mixture of 7-bromo-4-hydroxy-3-phenyl-isoxazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester (57.3 mg, 0.16 mmol), tris(dibenzylideneacetone)dipalladium(0) (29 mg, 0.03 mmol), 1,1′-bis(diphenylphosphino)ferrocene (35 mg, 0.06 mmol), zinc cyanide (10 mg, 0.09 mmol), zinc (1 mg, 0.02 mmol), and dimethylacetamide (0.32 ml) was stirred at 120° C. for two hours before it was cooled to room temperature, quenched with water, and filtered. The filtrate was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and dichloromethane to give the title compound as a brown solid (19 mg); MS (m/z): 310.31 (M+H+); 308.31 (M−H+).
Reaction SMILES: [CH3:1][C:2]([CH3:19])([O:4][C:5]([NH:7][C@H:8]([C:16]([OH:18])=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6])[CH3:3].[C:20](=O)(O)[O-].[Na+].IC>CN(C)C=O>[CH3:3][C:2]([CH3:19])([O:4][C:5]([NH:7][C@H:8]([C:16]([O:18][CH3:20])=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6])[CH3:1]
Reactant: O=C([O-])O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Yield: 99.7 %

Procedure:
To a solution containing N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanine (10 g, 37.7 mmole) in dimethylformamide (40 ml) is added solid sodium bicarbonate (4.75 g, 56.6 mmole) and iodomethane (16 g, 113 mmole). The mixture is heated at 40° under argon for 12 hours, the cooled and the reaction mixture partitioned between water (150 ml) and ether (250 ml). The organic layer is rinsed with 2% aqueous sodium bicarbonate (2×100 ml), 2% aqueous sodium bisulfite (100 ml), water (2 ×100 ml), and brine, dried over magnesium sulfate, and concentrated in vacuo to give 10.5 g of N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanine, methyl ester as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])[C:12]2[CH:17]=[CH:16][C:15]([CH2:18]O)=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N-:28]=[N+:29]=[N-:30].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C(Cl)(Cl)(Cl)Cl.CN(C)C=O.CCCCCC>[N:28]([CH2:18][C:15]1[CH:16]=[CH:17][C:12]([CH:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])=[N:13][CH:14]=1)=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=[N-]
Reactant: O=S(=O)(c1ccc(Cl)cc1)C(c1ccc(CO)cn1)c1cc(F)ccc1F
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: ClC(Cl)(Cl)Cl
Product: [N-]=[N+]=NCc1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 48.8 %

Procedure:
The 2-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-5-(hydroxymethyl)pyridine (471 mg, 1.15 mmol) obtained in Example 43 was dissolved in a mixture of carbon tetrachloride (4 ml) and N,N-dimethylformamide (16 ml). To the resulting solution were added sodium azide (112 mg, 1.72 mmol) and triphenylphosphine (451 mg, 1.72 mmol). The resulting mixture was stirred at 90° C. for 3 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed sequentially with water and brine. The resulting organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=3:1 eluate was concentrated under reduced pressure to give the title compound (244 mg, 0.561 mmol, 49%) as a colorless amorphous substance.
Reaction SMILES: [Si]([O:8][CH:9]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24]Cl)=[CH:20][CH:19]=1)[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])(C(C)(C)C)(C)C.[SH:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30].C(N(CC)CC)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>C(Cl)(Cl)Cl.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>[OH:8][CH:9]([C:18]1[CH:19]=[CH:20][C:21]([CH2:24][S:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:22][CH:23]=1)[CH2:10][C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12]
Reactant: COC(=O)CCS
Reactant: CC(C)(C)OC(=O)CC(O[Si](C)(C)C(C)(C)C)c1ccc(CCl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [I-]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)CCSCc1ccc(C(O)CC(=O)OC(C)(C)C)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 23.8 %

Procedure:
To a solution (40 ml) of tert-butyl 3-(tert-butyldimethylsilyl)oxy-3-(4-chloromethylphenyl)propionate (3.25 g, 8.44 mmol) in chloroform were added methyl 3-mercaptopropionate (1.12 g, 9.32 mmol), triethylamine (2.4 ml, 17.29 mmol), and tetrabutylammonium iodide (156 mg, 0.42 mmol), and the mixture was stirred overnight at 50° C. The solvent was evaporated under reduced pressure 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 again. The obtained crude product was dissolved in THF (35 ml), 1M tetrabutylammonium fluoride-THF solution (8.5 ml, 8.50 mmol) was added, and the mixture was stirred at room temperature for 4 hours. The solvent was evaporated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained crude product was purified by silica gel chromatography (hexane:ethyl acetate=3:1) to give the title compound (711 mg, 24%).
Reaction SMILES: [CH3:1][N:2]([CH3:35])[C:3]1[CH:4]=[CH:5][C:6]([N+:32]([O-])=O)=[C:7]([CH:31]=1)[C:8]([NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][CH2:13]1)=[O:9].[H][H]>CO.[Ni]>[NH2:32][C:6]1[CH:5]=[CH:4][C:3]([N:2]([CH3:35])[CH3:1])=[CH:31][C:7]=1[C:8]([NH:10][CH2:11][CH:12]1[CH2:13][CH2:14][N:15]([CH:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:16][CH2:17]1)=[O:9]
Reactant: [H][H]
Reactant: CN(C)c1ccc([N+](=O)[O-])c(C(=O)NCC2CCN(C(c3ccccc3)c3ccccc3)CC2)c1
Agent: [Ni]
Solvent: CO
Product: CN(C)c1ccc(N)c(C(=O)NCC2CCN(C(c3ccccc3)c3ccccc3)CC2)c1
Yield: 99.4 %

Procedure:
Step 2): A mixture of 5-dimethylamino-2-nitro-N-[(1-diphenylmethylpiperidin-4-yl)-methyl]benzamide (2.4 g, 5 mmol) and Raney Ni in methanol (50 ml) was hydrogenated at room temperature under stirring under 50 psi hydrogen pressure for 2 hours and then filtered. The filtrate was concentrated to give 2-amino-5-dimethylamino-N-[(1-diphenylmethylpiperidin-4-yl)-methyl]benzamide (2.2 g, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)([O:14][CH3:15])[C:10](=[O:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][Mg]Br>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:16]2[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=2)([O:14][CH3:15])[C:10]([OH:23])([CH3:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Mg]Br
Reactant: COC1(c2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC1=O
Solvent: C1CCOC1
Product: COC1(c2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC1(C)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.8 %

Procedure:
To a solution of 4-(4-chloro-phenyl)-4-methoxy-3-oxo-piperidine-1-carboxylic acid tert-butyl ester (470 mg, 1.38 mmol) in anhydrous tetrahydrofuran (10 mL) at 0° C. was added methylmagnesium bromide (1.4 M in diethyl ether, 2.96 mL, 4.15 mmol) and the resulting mixture was stirred at that temperature for 3 h. Excess organomagnesium was quenched by the addition of saturated aqueous ammonium chloride and the reaction was allowed to warm to rt. To the biphasic mixture was added water and ethyl acetate. The phases were separated and the organic phase washed with brine, dried over magnesium sulfate, filtered, dried and concentrated to afford a crude residue which was purified by silica gel chromatography (100% methylene chloride −97.5% methylene chloride/2.5% methanol gradient) to afford pure 4-(4-chloro-phenyl)-3-hydroxy-4-methoxy-3-methyl-piperidine-1-carboxylic acid tert-butyl ester (269 mg, 58%).