Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][C:16]2=[O:20])[N:11](CC2C=CC=CC=2)[CH2:10][C@H:9]1[CH3:28])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)(=O)C.C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][C:16]2=[O:20])[NH:11][CH2:10][C@H:9]1[CH3:28])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1CN(Cc2ccccc2)[C@@H](CN2CCCC2=O)CN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: C[C@@H]1CN[C@@H](CN2CCCC2=O)CN1C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 86 %

Procedure:
(2R,5S)-4-Benzyl-2-methyl-5-(2-oxo-pyrrolidin-1-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (5.9 g, 15.25 mmol) and 10% Pd/C (2.13 g, 1.5 mmol) were dissolved in glacial acetic acid/ethanol (27.2 mL/72.6 mL) and stirred under hydrogen at 1 bar for 1 h. The mixture was filtered and the filtrate concentrated. Saturated aqueous sodium hydrogen carbonate and EtOAc were added. The EtOAc layer was separated and the aqueous phase extracted with DCM (3×). The combined DCM layers were dried with sodium sulfate, filtered and concentrated. The residue was azeotroped with toluene, to give the title compound (3.9 g), 1H NMR (CDCl3): 4.23-4.08 (1H, m), 3.95-3.77 (1H, m), 3.69 (1H, d), 3.59-3.46 (1H, m), 3.46-3.34 (1H, m), 3.34-3.07 (3H, m), 3.07-2.89 (1H, m), 2.55-2.39 (3H, m), 2.15-1.92 (2H, m), 1.48 (9H, s), 1.23 (3H, d).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.Cl[C:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17].N1C=CC=CC=1>CCCCCC>[C:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][CH:2]([NH:1][C:16]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])[CH2:7][CH2:6]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: c1ccncc1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)Oc2ccccc2)CC1
Yield: 37.6 %

Procedure:
A reaction similar to Production example 2-1 using t-Butyl 4-aminopiperidin-1-ylcarboxylate (328 mg, 1.64 mmol), phenyl chloroformate (0.226 ml, 1.80 mmol) and pyridine (0.146 ml, 1.80 mmol); and the obtained crystals were suspended in hexane:ethyl acetate=4:1, filtered off, and the filtrate was purified by silica gel column chromatography (Fuji Silysia BW-300, hexane:ethyl acetate=4:1 to 1:1). The purified crystals were then suspended in hexane:ethyl acetate=4:1 and filtered off. The title compound (215 mg, 0.617 mmol, 40.9%) was obtained as colorless crystals, together with the previously obtained crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5](B(O)O)=[C:4]([CH3:12])[CH:3]=1.[F-].[K+].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>CCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:4]([CH3:12])[CH:3]=1
Reactant: Cc1cc(Cl)cc(C)c1B(O)O
Reactant: CCOC(=O)CBr
Agent: [F-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1c(C)cc(Cl)cc1C

Procedure:
Ethyl 4-chloro-2,6-dimethylphenylacetate was prepared by the general experimental method from 4-chloro-2,6-dimethylphenylboronic acid (186 mg, 1.00 mmol). This involved using 290 mg [5 mmol] of KF and 418 mg [2.5 mmol] of ethyl bromoacetate. After workup by column chromatography (hexane/ethyl acetate, 5:1), ethyl 4-chloro-2,6-dimethylphenylacetate is obtained as a colourless liquid in a yield of 68% of theory. 1H NMR (400 MHz, CDCl3): δ=7.02 (s, 2H), 4.13 (q, J=0.7 Hz, 2H), 3.62 (s, 2H), 2.29 (s, 6H), 1.23 (t, J=7.2 HZ, 3H) ppm; 13C NMR (101 MHz, CDCl3): δ=170.8, 139.0, 132.2, 131.6, 130.3, 127.9, 113.6, 60.8, 35.0, 20.1, 14.2 ppm; MS (70 eV), m/z (%): 226 (22) [M+], 180 (9), 153 (100), 115 (17), 91 (11); IR (NaCl): ν=2980 (m), 1733 (s), 1328 (w), 1155 (m), 1030 (m) cm−1; elemental analysis: (theor): C=63.58, H=6.67, (exp): C=63.30, H=6.78.
Reaction SMILES: N[C:2]1[N:7]=[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:4][CH:3]=1.[CH2:14]=O.[BH3-][C:17]#[N:18].[Na+]>CO.CC(O)=O>[CH3:14][N:18]([CH3:17])[C:2]1[N:7]=[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: [BH3-]C#N
Reactant: C=O
Reactant: CCOC(=O)Cc1cccc(N)n1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)Cc1cccc(N(C)C)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 57.9 %

Procedure:
To the solution of ethyl 2-(6-aminopyridin-2-yl)acetate (150 mg, 0.83 mmol) and paraformaldehyde (54.8 mg, 1.83 mmol) in methanol (6 mL) was added NaBH3CN (130.3 mg, 2.08 mmol) and AcOH (1 drop, cat.). The mixture was stirred at room temperature for 12 h. Then, the reaction was quenched with aqueous ammonium chloride and extracted with DCM. The organic layer was with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by a standard method to get desired product (100 mg).
Reaction SMILES: [F:1][C:2]([F:23])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][NH:4][C:5]1[C:6]([F:16])=[C:7]([CH2:12][C:13]([OH:15])=O)[C:8]([Cl:11])=[CH:9][CH:10]=1.[NH2:24][CH2:25][C:26]1[CH:27]=[CH:28][C:29]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[N:30][C:31]=1[CH3:32].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:23][C:2]([F:1])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][NH:4][C:5]1[C:6]([F:16])=[C:7]([CH2:12][C:13]([NH:24][CH2:25][C:26]2[C:31]([CH3:32])=[N:30][C:29]([NH:33][C:34]([O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[O:35])=[CH:28][CH:27]=2)=[O:15])[C:8]([Cl:11])=[CH:9][CH:10]=1
Reactant: O=C(O)Cc1c(Cl)ccc(NCC(F)(F)c2ccccc2)c1F
Reactant: Cc1nc(NC(=O)OC(C)(C)C)ccc1CN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(NC(=O)OC(C)(C)C)ccc1CNC(=O)Cc1c(Cl)ccc(NCC(F)(F)c2ccccc2)c1F
Reaction time: 18 h
Yield: 91.2 %

Procedure:
To a solution of 2-{3-[(2,2-difluoro-2-phenylethyl)amino]-6-chloro-2-fluorophenyl}acetic acid (516 mg, 1.5 mmol), as prepared in step 15 of Example 1, in DMF (8.0 mL) was added N-[5-(aminomethyl)-6-methyl (2-pyridyl)](tert-butoxy) carboxamide (498 mg, 2.1 mmol) (Sanderson, P. E., et al., WO 97/01338 (1997)), BOP (1.06 g, 2.4 mmol), and DIEA (0.78 mL, 4.5 mmol). After stirring for 18 hours, additional amine (107 mg, 450 μmol) was added, and the mixture continued to stir for 18 hours. The solvents were evaporated, and the reaction mixture was partitioned between DCM and saturated NaHCO3. The organic layer was separated, and the aqueous layer extracted with DCM. The organic layers were combined, washed with 10% KHSO4 (2 times), H2O, and brine, dried over Na2SO4, concentrated, and flash chromatographed on silica gel eluting with MeOH/DCM (0, 1.5, and 2.5%) to give the title compound (770 mg, 91% yield) as a pale brown foam. 1H-NMR (400 MHz, CDCl3) δ 7.66 (d, J=8.4 Hz, 1H), 7.51-7.41 (m, 6H), 7.23 (bs, 1H), 7.01 (dd, J=8.8, 1.5 Hz, 1H), 6.57 (t, J=9.0 Hz, 1H), 5.64 (br s, 1H), 4.37 (d, J=5.6 Hz, 2H), 4.26-4.22 (m, 1H), 3.79-3.70 (m, 4H), 2.35 (s, 3), 1.50 (s, 9H). Mass spectrum (LCMS, ESI) calc'd for C28H31ClF3N4O3 (M+H): 563.2. Found: 562.9.
Reaction SMILES: [I:1][C:2]1[NH:6][N:5]=[C:4]([C:7](OCC)=[O:8])[C:3]=1[CH3:12].[OH-].[NH4+:14]>CO>[I:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([NH2:14])=[O:8])[C:3]=1[CH3:12]
Reactant: [NH4+]
Reactant: CCOC(=O)c1n[nH]c(I)c1C
Agent: [OH-]
Solvent: CO
Product: Cc1c(C(N)=O)n[nH]c1I
Temperature: 60 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of ethyl 5-iodo-4-methyl-1H-pyrazole-3-carboxylate (compound 258.1, 500 mg, 1.79 mmol) in methanol (5 mL). Then ammonium hydroxide (15 mL, 25% aq.) was added and the resulting solution was stirred overnight at 60° C. The mixture was concentrated under reduced pressure to obtain the title compound as a white solid (400 mg, 89%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7](Cl)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[CH2:23]([C:37]1[CH:38]=[C:39]([CH:46]=[CH:47][CH:48]=1)[O:40][CH2:41][CH:42]([OH:45])[CH2:43][OH:44])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>O1CCCC1.N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:44][CH2:43][CH:42]([OH:45])[CH2:41][O:40][C:39]2[CH:46]=[CH:47][CH:48]=[C:37]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:38]=2)=[CH:5][CH:4]=1
Reactant: CCCCCCCCCCCCCCc1cccc(OCC(O)CO)c1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCc1cccc(OCC(O)COC(c2ccccc2)(c2ccccc2)c2ccc(OC)cc2)c1
Reaction time: 8 h
Yield: 89.9 %

Procedure:
A solution of 25.94 g of 4-methoxytrityl chloride in 15 ml of dry tetrahydrofuran was added to a stirred solution of 21.84 g of 3-(3-tetradecylphenoxy)-1,2-propanediol in 40 ml of pyridine under argon. This mixture was stirred overnight, the solvents removed under reduced pressure and the residue dissolved in chloroform. This solution was washed with saturated aqueous sodium bicarbonate, then water, dried and evaporated, giving 34.3 g of the desired compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][C:6](=[O:8])[CH:7]=1)[CH3:2]>[Pd].CCOC(C)=O>[CH2:1]([CH:3]1[CH2:7][C:6](=[O:8])[CH2:5][CH:4]1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2]
Reactant: CCOC(=O)C1CC(=O)C=C1CC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CC(=O)CC1CC
Temperature: 0 °C
Reaction time: 48 h
Yield: 99.1 %

Procedure:
A round-bottom flask was charged with 10% palladium on carbon (10 g, 9.4 mmol). The flask was cooled to about 0° C. and EtOAc (400 mL) was added under a nitrogen atmosphere. The cooling bath was removed and ethyl 2-ethyl-4-oxocyclopent-2-enecarboxylate (47.8 g, 263 mmol) was added. Hydrogen gas was bubbled through the mixture for about 5 min and the mixture was then stirred under a hydrogen atmosphere for about 48 h at ambient temperature. The hydrogen source was removed, the mixture was bubbled with nitrogen for about 5 min and was filtered through a pad of Celite®. The filter cake was rinsed with EtOAc (400 mL). The filtrate was concentrated under reduced pressure to give ethyl 2-ethyl-4-oxocyclopentanecarboxylate (about 9:1 mixture cis:trans) (48.0 g, 99%) as a yellow liquid: 1H NMR (CDCl3) δ 4.23-4.10 (m, 2H), 3.22 (m, 1H), 2.59-2.50 (m, 1H), 2.44-2.28 (m, 3H), 2.26-2.16 (m, 1H), 1.58-1.46 (m, 1H), 1.41-1.30 (m, 1H), 1.30-1.23 (m, 3H), 1.02-0.91 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1Br.[Mg].[C:11]([CH:13]1[CH2:15][CH:14]1[C:16](N(OC)C)=[O:17])#[N:12]>C(OCC)C.BrC(Br)C.C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:16]([CH:14]1[CH2:15][CH:13]1[C:11]#[N:12])=[O:17]
Reactant: Fc1ccc(Br)c(Cl)c1
Reactant: CON(C)C(=O)C1CC1C#N
Agent: CC(Br)Br
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: N#CC1CC1C(=O)c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 24.0 g (115 mmol) of 2-chloro-4-fluorobromobenzene in 20 ml of diethyl ether was added dropwise to 2.92 g (120 mmol) of magnesium turnings in 780 ml of diethyl ether, activated by adding a few drops of dibromoethane, and the reaction mixture was heated under reflux overnight. The reaction solution was added dropwise under argon to a solution of 17.7 g (68.8 mmol) of the compound from Example 73A in 300 ml of THF, and the reaction mixture was stirred initially at RT overnight and then under reflux for 8 h. It was concentrated and taken up in ethyl acetate and saturated aqueous ammonium chloride solution, the phases were separated, and the organic phase was washed with water and saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate gradient) to result in 2.20 g (14% of theory) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[CH:15]=[C:14]([CH2:16]O)[NH:13][C:10]2=[N:11][CH:12]=1)=[O:5].P(Br)(Br)[Br:23]>O1CCCC1>[Br:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[CH:15]=[C:14]([CH2:16][Br:23])[NH:13][C:10]2=[N:11][CH:12]=1)=[O:5]
Reactant: O=C(Nc1cnc2[nH]c(CO)cc2c1)c1ccccc1Br
Reactant: BrP(Br)Br
Solvent: C1CCOC1
Product: O=C(Nc1cnc2[nH]c(CBr)cc2c1)c1ccccc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.9 %

Procedure:
A flask is charged successively with 1 g (2.89 mmol) of 2-bromo-N-(2-(hydroxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide (Example 16), 100 mL of tetrahydrofuran and 408 μL (4.34 mmol) of phosphorus bromide (PBr3) under argon atmosphere. It is stirred at room temperature for 18 hours. The solvent is then evaporated under reduced pressure, and the residue is taken up in 150 mL of ethyl acetate. The organic phase is washed with 3×50 mL of water, dried over sodium sulphate and evaporated under reduced pressure. The precipitate obtained is dried under vacuum for 1 h, finally obtaining 957 mg of a brown solid (raw yield 81%).
Reaction SMILES: C(O[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:24])[C@H:18]([OH:23])[CH2:19][C:20](=[O:22])[CH3:21])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.ClC1[C:35]2[C:30](=[CH:31][C:32]([CH3:36])=[CH:33][CH:34]=2)[N:29]=[C:28]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[OH:43])[N:27]=1.C(N(CC)CC)C>[Pd].CO>[OH:23][C@H:18]([CH2:19][C:20](=[O:22])[CH3:21])[C:17]([N:14]1[CH2:13][CH2:12][N:11]([C:9]2[C:35]3[C:30](=[CH:31][C:32]([CH3:36])=[CH:33][CH:34]=3)[N:29]=[C:28]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[OH:43])[N:27]=2)[CH2:16][CH2:15]1)=[O:24]
Reactant: Cc1ccc2c(Cl)nc(-c3ccccc3O)nc2c1
Reactant: CC(=O)C[C@@H](O)C(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(=O)C[C@@H](O)C(=O)N1CCN(c2nc(-c3ccccc3O)nc3cc(C)ccc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.7 %

Procedure:
A mixture of 4-((R)-2-hydroxy-4-oxo-pentanoyl)-piperazine-1-carboxylic acid benzyl ester (0.13 g, 0.39 mmol) and MeOH (4 mL) was stirred with 10 mg of Pd/C (10% wt Pd on carbon) under H2 atmosphere at ambient pressure overnight. After filtration and evaporation of the solvent, the residue was taken up in CH2Cl2, and 2-(4-chloro-7-methylquinazolin-2-yl)phenol (0.11 g, 0.39 mmol) and triethylamine (0.11 mL, 0.78 mmol) were added. The reaction mixture was stirred at room temperature overnight, washed with water, dried over Na2SO4, and concentrated. Purification via silica gel chromatography using 0-10% MeOH/CH2Cl2 provided (R)-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)pentane-1,4-dione as a yellow solid (91 mg, 54%). LC/MS: m/z 435.5 (M+H)+ at 2.13 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:33])=[C:5]([C:21]([O:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].C([O-])([O-])=O.[K+].[K+].C1(=O)O[CH2:43][CH2:42][O:41]1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[NH:3][C:4]([CH3:33])=[C:5]([C:21]([O:23][CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:43][CH2:42][OH:41])=[CH:30][CH:31]=2)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCc2ccc(O)cc2)C1c1cccc([N+](=O)[O-])c1
Reactant: O=C1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCc2ccc(OCCO)cc2)C1c1cccc([N+](=O)[O-])c1
Yield: 91.1 %

Procedure:
A mixture of 1.0 g of 2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-5-[2-(4-hydroxyphenyl)ethoxycarbonyl]-1,4-dihydropyridine (11), 0.5 g of K2CO3, and 0.5 g of ethylene carbonate in 20 mL of toluene was heated at reflux for 18 h. The mixture was filtered and the filtrate evaporated to yield 1.0 g of 2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-5-(2-[4-(2-hydroxyethoxy)phenyl]ethoxycarbonyl)-1,4-dihydropyridine (1, R1 =A1, m=2, p=0) as an amorphous solid.
Reaction SMILES: [CH2:1]([N:4]([CH3:29])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=2)=[O:19])=[C:14]([O:27]C)[CH:13]=1)[CH:2]=[CH2:3].[C:30]([O-:37])(=[O:36])/[CH:31]=[CH:32]/[C:33]([O-:35])=[O:34]>C(Cl)Cl>[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34].[CH2:1]([N:4]([CH3:29])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=2)=[O:19])=[C:14]([OH:27])[CH:13]=1)[CH:2]=[CH2:3]
Reactant: O=C([O-])/C=C/C(=O)[O-]
Reactant: C=CCN(C)CCCCCCOc1ccc(C(=O)c2ccc(Br)cc2)c(OC)c1
Solvent: ClCCl
Product: C=CCN(C)CCCCCCOc1ccc(C(=O)c2ccc(Br)cc2)c(O)c1
Product: O=C(O)/C=C/C(=O)O
Reaction time: 2 h

Procedure:
The fumarate obtained is taken up in methylene chloride/saturated sodium bicarbonate solution and the organic phase is dried and concentrated. 3.09 g of the thus-obtained [4-[6-(allyl-methyl-amino)-hexyloxy]-2-methoxy-phenyl]-(4-bromo-phenyl)-methanone are boiled in 13 ml of acetic acid/7.7 ml of 62% HBr solution at 90° C. for 2 hrs. The reaction mixture is concentrated and the residue is converted into the free base with methylene chloride/saturated sodium bicarbonate solution. The residue is treated with 0.74 g of fumaric acid and processed using ethanol/ether. There are obtained 2.05 g of [4-[6-(allyl-methyl-amino)-hexyloxy]-2-hydroxy-phenyl]-(4-bromo-phenyl)-methanone fumarate, MS: m/e 446 (M+H+, 1Br).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5](NCC)=[CH:4][CH:3]=1.[C:11]([NH:18][CH2:19][C:20]([OH:22])=O)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].Cl.[CH2:24]([N:26]=C=NCCCN(C)C)[CH3:25].C(=O)([O-])O.[Na+]>N1C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:19]([NH:18][C:11](=[O:12])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17])[C:20]([NH:26][CH2:24][CH3:25])=[O:22])=[CH:9][CH:10]=1
Reactant: CCNc1ccc(Br)cc1
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCNC(=O)C(NC(=O)OC(C)(C)C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.6 %

Procedure:
To a solution of 4-bromo-N-ethylaniline (1.28 g, 6.4 mmol), N-Boc-glycine (1.57 g, 9.0 mmol) in pyridine (10 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.47 g, 7.7 mmol) at 0° C. The reaction mixture was stirred at room temperature for 4 hrs. The reaction mixture was poured into a mixture of diluted aqueous sodium hydrogen carbonate solution and ethyl acetate. The mixture was stirred, stood still and partitioned. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give tert-butyl [(4-bromophenyl)(ethyl)aminocarbonylmethyl]carbamate (2.255 g, yield 99%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([Cl:11])[CH:5]=[CH:4][N:3]=1.Cl.N>[Fe].CO>[Cl:11][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[C:7]=1[NH2:8]
Reactant: Nc1nccc(Cl)c1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Agent: N
Solvent: CO
Product: Nc1nccc(Cl)c1N

Procedure:
3.6 g of 2-amino-4-chloro-3-nitropyridine was added to 21 ml of methanol and 24 ml of concentrated hydrochloric acid, and the mixture was vigorously stirred. Powdery iron was added in small portions to the mixture. 10 min after the completion of the addition, the mixture was poured into an iced concentrated aqueous ammonia and extracted with ethyl acetate. The extract was dried over magnesium sulfate, and the solvent was distilled off in vacuo. The residue was purified by silica gel chromatography (CH2Cl2 :MeOH=20:1→10:1) to prepare 2.6 g of 4-chloro-2,3-diaminopyridine as a purplish white crystal.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH:11]1[NH:14][C:13](=[O:15])[CH:12]1[CH2:16][CH3:17])C1C=CC=CC=1>[Pd].C(O)(=O)C>[CH2:16]([CH:12]1[CH:11]([CH2:10][CH2:9][OH:8])[NH:14][C:13]1=[O:15])[CH3:17]
Reactant: CCC1C(=O)NC1CCOCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCC1C(=O)NC1CCO
Reaction time: 3 h
Yield: 81.1 %

Procedure:
A 1-l flask connected to a hydrogenation apparatus and placed on on air driven magnetic stirrer is charged with 4-(2-benzyloxyethyl)-3-ethyl-azetidin-2-one (19.5 g), glacial acetic acid (200 ml) trifluoroacetic acid (9.47 ml) and 10% Palladium on carbon (2.9 g). The mixture is hydrogenated at room temperature and pressure for about 3 hours, then the catalyst is removed by filtration under vacuum, washing with acetic acid. The solvent is evaporated under reduced pressure by heating to 40°-50° C. and the obtained residue is dissolved in methanol (150 ml). Anhydrous potassium carbonate (17.27 g) is added to the resulting solution and the obtained mixture is stirred for 30 minutes. The inorganic salts are removed by filtration and the filtrate is brought to pH 6 by the addition of dilute acetic acid. The residue which is obtained by evaporating the solvent is taken up with water (100 ml) and extracted with toluene (three 50-ml portions). The toluene extracts are washed with a small amount of water and then discarded while the mother liquors plus the aqueous washes are combined, saturated with (NH4)2SO4 (100 g) and extracted with ethyl acetate (five 50-ml portions). The organic extracts are dried over Na2SO4 and evaporated to dryness under vacuum yielding 9.7 g of 3-ethyl-4-(2-hydroxyethyl)-azetidin-2-one as a 6:4 cis/trans mixture.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[NH:10][C:11]2[S:12][CH:13]=[C:14](/[CH:16]=[CH:17]/[CH2:18][OH:19])[N:15]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:20])[NH:10][C:11]2[S:12][CH:13]=[C:14](/[CH:16]=[CH:17]/[CH:18]=[O:19])[N:15]=2)=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc(Br)cc1)Nc1nc(/C=C/CO)cs1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C/C=C/c1csc(NC(=O)Nc2ccc(Br)cc2)n1

Procedure:
Following a procedure similar to that described in Preparation 49, the desired compound was prepared from 0.84 g of (E)-3-[2-(3-p-bromophenylureido)thiazol-4-yl]allyl alcohol, 1.13 g of a sulfur trioxide pyridine complex, 0.72 g of triethylamine and 20 ml of dimethyl sulfoxide. The resulting product was a pale brown powder having the following physical properties.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH3:14])[S:10]([CH3:13])(=[O:12])=[O:11].C(Br)(Br)(Br)[Br:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Br:16][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH3:14])[S:10]([CH3:13])(=[O:12])=[O:11]
Reactant: BrC(Br)(Br)Br
Reactant: CN(c1ccccc1CO)S(C)(=O)=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(c1ccccc1CBr)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
196 d) To a stirred mixture of N-(2-hydroxymethyl-phenyl)-N-methyl-methanesulfonamide (0.90 g, 4.2 mmol) and carbon tetrabromide (2.40 g, 7.24 mmol) in dry tetrahydrofuran (50 mL) was added triphenylphosphine (1.90 g, 7.23 mmol). The mixture was stirred at room temperature for 18 hours. The volatiles were evaporated under reduced pressure. The residue was triturated with ethyl acetate (30 mL) then filtered and evaporated under reduced pressure. The residue was purified via chromatography (silica gel column 40 g 5%→100% ethyl acetate:hexane). N-(2-Bromomethyl-phenyl)-N-methyl-methanesulfonamide was isolated as pale yellow solid (0.86 g, 74%), 1H NMR (400 MHz, CDCl3, δ, ppm): 7.57-7.52 (m, 1H), 7.41-7.34 (m, 2H), 7.30-7.25 (m, 1H), 5.29-4.30 (br m, 2H), 3.34 (s, 3H), 2.98 (s, 3H).