Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1.C(O)(=O)[CH2:17][C:18]([OH:20])=[O:19].N1CCCCC1.C(=O)=O.Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[CH:17][C:18]([OH:20])=[O:19])=[CH:10][CH:9]=1
Reactant: O=Cc1ccc(-c2ccccc2Cl)cc1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Agent: O=C=O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1ccc(-c2ccccc2Cl)cc1
Temperature: 0 °C

Procedure:
A mixture of 21.6 g. (0.1 mole) of 4-(2'-chlorophenyl)benzaldehyde is heated on a steam bath with 13.2 g. of malonic acid and 95 ml. of pyridine containing 5 drops of piperidine. The mixture is heated for four hours until the liberation of carbon dioxide ceases. The cooled mixture is poured into a mixture of 110 ml. concentrated hydrochloric acid and 500 ml. of ice water. The solid which separates is filtered, washed and 15 ml. portions of cold water and then resuspended in 200 ml. of cold water, filtered, washed with cold water and dried at 40°C. The residue is then recrystallized from ethanol to obtain 4-(2'-chlorophenyl)cinnamic acid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]#[N:13])=[CH:7][CH:6]=1)[CH3:3]>N.[H][H].[Ni]>[CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH2:13])=[CH:7][CH:6]=1)[CH3:3]
Reactant: CN(C)Cc1ccc(CC#N)cc1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Product: CN(C)Cc1ccc(CCN)cc1

Procedure:
3.60 g (20.7 mmol) of (4-dimethylaminomethylphenyl)acetonitrile (IX.1.a) is dissolved in 50 mL of methanolic ammonia and hydrogenated for 5 hours at 50° C. at a pressure of 3 bar with hydrogen and 0.45 g of Raney nickel as catalyst. Then the catalyst is filtered off and the solvent is eliminated. Yield: 3.60 g (98% of theory); Rf value: 0.20 (silica gel, methylene chloride/methanol=9:1); C11H18N2; EII mass spectrum: m/z=179 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[N+:10]([O-])([OH:12])=[O:11]>ClC1C=CC=CC=1>[N+:10]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])O
Reactant: Brc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Clc1ccccc1
Product: O=[N+]([O-])c1ccc(Br)cc1

Procedure:
The bromobenzene may then be converted to phenols by a reaction with a sodium hydroxide solution, similar to the hydrolysis of chlorobenzene, with NaOH under pressure. In addition, bromobenzene may be reacted with nitric acid to form p-nitro-bromobenzene, which can then be converted after several other chemical processing steps to p-methoxyphenol. Other chemicals may be produced using bromobenzene as a raw starting material.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[N:14]1([CH2:13][CH2:12][NH:11][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: NCCN1CCCCC1
Product: O=[N+]([O-])c1ccc(NCCN2CCCCC2)cc1

Procedure:
Using an analogous procedure to that described in Method 23, but starting from 4-fluoronitrobenzene and 1-(2-aminoethyl)piperidine, the product was obtained. NMR: 1.3 (m, 2H), 1.5 (m, 4H), 2.3 (m, 4H), 2.4 (t, 2H), 3.2 (m, 2H), 6.6 (d, 2H), 7.1 (m, 1H), 8.0 (d, 2H); MS (MH+): 250.
Reaction SMILES: [CH2:1]([O:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19]C3C=CC(CC(OC)=O)=CC=3)=[CH:14][C:13]=2[CH3:31])[CH2:11][CH2:10]1)[C:2]1C=CC=CC=1.[C:32](=O)([O-])[O-].[K+].[K+]>CO>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([C:9]2([O:8][CH:1]([CH3:2])[CH3:32])[CH2:10][CH2:11]2)=[C:13]([CH3:31])[CH:14]=1)#[CH:19]
Reactant: COC(=O)Cc1ccc(C#Cc2ccc(C3(OCc4ccccc4)CC3)c(C)c2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(C2(OC(C)C)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using General Procedure E; [4-(1-isopropoxycyclopropyl)-3-methyl-phenylethynyl]-trimethylsilane (Intermediate 80, 250.0 mg, 0.87 mmol) in 8 methanol (10 mL) was treated with potassium carbonate (100.0 mg, 0.72 mmol) and stirred overnight at ambient temperature. The crude alkyne (180 mg, 98%) was used directly in the next reaction.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[NH2:20][CH2:21][CH2:22][CH:23]1[CH2:26][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:24]1>CN(C=O)C.CCOC(C)=O>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:20][CH2:21][CH2:22][CH:23]2[CH2:26][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:24]2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(CCN)C1
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(CCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)C1
Temperature: 120 °C
Yield: 28.6 %

Procedure:
2-tert-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (74 mg, 0.249 mmol) was dissolved in dry DMF (1 mL) nitrogen atmosphere. tert-Butyl 3-(2-aminoethyl)azetidine-1-carboxylate (50 mg, 0.249 mmol) was added followed by TEA (25 mg, 0.247 mmol) and the reaction mixture was heated in a microwave reactor for at 120° C. for 20 mins. The reaction mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3-solution, dried over Na2SO4, filtered and evaporated. The crude product was purified by preparative HPLC affording the title compound (33 mg, 28.8%). 1H NMR (500 MHz, CDCl3): δ 1.43 (s, 9H), 1.62 (q, 2H), 1.73 (s, 9H), 2.19-2.27 (m, 1H), 2.83 (q, 2H), 3.23-3.26 (m, 2H), 3.84 (t, 2H), 5.25 (t, 1H), 7.42-7.51 (m, 5H); 13C NMR (125 MHz, CDCl3): δ 26.24, 27.82, 28.61, 34.35, 41.72, 54.06, 61.82, 79.63, 107.55, 125.15, 128.93, 130.09, 131.79, 135.04, 156.38, 159.81; Mass Spectrum: M−H+ 462.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].[C:10](Cl)(=[O:12])[CH3:11]>C(O)(=O)C>[CH3:11][C:10]([NH:4][C:3]1[C:2]([Cl:1])=[CH:8][CH:7]=[CH:6][C:5]=1[Cl:9])=[O:12]
Reactant: CC(=O)Cl
Reactant: Nc1c(Cl)cccc1Cl
Solvent: CC(=O)O
Product: CC(=O)Nc1c(Cl)cccc1Cl
Temperature: 90 °C

Procedure:
To a mechanically stirred solution of 2,6-dichloroaniline (76 g, 0.047 mol) in 60 mL of glacial acetic acid is added dropwise acetyl chloride (36 mL, 0.5 mol). After the addition is complete, the reaction mixture is heated at 90° C. for 20 minutes. The solution is poured into ice water (500 mL), forming a white precipitate. The solids are filtered, washed with water and dried to give the product (91.8 g, 96%, white solid, m.p. 179°-180° C., lit. m.p. 180°-181° C. form glacial acetic acid).
Reaction SMILES: F.N1C=CC=CC=1.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH:16]1[CH2:26][CH2:25][CH:24]([O:27][Si](C(C)C)(C(C)C)C(C)C)[C:19]2=[N:20][CH:21]=[CH:22][CH:23]=[C:18]2[CH:17]1[F:38]>O1CCCC1>[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH:16]1[CH2:26][CH2:25][CH:24]([OH:27])[C:19]2=[N:20][CH:21]=[CH:22][CH:23]=[C:18]2[CH:17]1[F:38]
Reactant: CC(C)[Si](OC1CCC(c2cccc(F)c2F)C(F)c2cccnc21)(C(C)C)C(C)C
Agent: F
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: OC1CCC(c2cccc(F)c2F)C(F)c2cccnc21
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Pyridine hydrofluoride (0.037 g, 0.38 mmol) was added dropwise to a solution of (5R,6S,9R and 5S,6R,9S)-6-(2,3-difluorophenyl)-5-fluoro-9-((triisopropylsilyl)oxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine (0.155 g, 0.345 mmol) in tetrahydrofuran (3 mL) cooled to 0° C., and the mixture was stirred for 3 h. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate (3×). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash chromatography on silica gel, eluting with 55% dichloromethane in petroleum ether to give the title compound as a racemic mixture. MS: m/z=294.2 (M+1).
Reaction SMILES: [BrH:1].[NH:2]([C:4]1[NH:5][CH2:6][CH2:7][N:8]=1)[NH2:3].[CH:9]([C@@H:11]1[C@:19]2([CH3:20])[C@@:14]([OH:27])([CH2:15][C@@H:16]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17][CH2:18]2)[CH2:13][CH2:12]1)=O>O.O1CCOCC1>[BrH:1].[NH:8]1[CH2:7][CH2:6][N:5]=[C:4]1[NH:2]/[N:3]=[CH:9]/[C@@H:11]1[C@:19]2([CH3:20])[C@@:14]([OH:27])([CH2:15][C@@H:16]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:17][CH2:18]2)[CH2:13][CH2:12]1
Reactant: NNC1=NCCN1
Reactant: C[C@]12CC[C@H](c3ccccc3)C[C@@]1(O)CC[C@@H]2C=O
Agent: Br
Solvent: C1COCCO1
Solvent: O
Product: C[C@]12CC[C@H](c3ccccc3)C[C@@]1(O)CC[C@@H]2/C=N/NC1=NCCN1
Reaction time: 2 h
Yield: 53.7 %

Procedure:
To a solution of 0.93 g of 2-hydrazino-2-imidazoline hydrobromide in 45 ml of water and 30 ml of dioxane a solution of 0.89 g of (1S,3aS,5S,7aR)-1-formyl-5-phenyl-7a-methylperhydroinden-3a-ol in 30 ml of dioxane was added dropwise at room temperature and the mixture was stirred for 2 hrs. The solution was evaporated to dryness under reduced pressure and the residue was ground with ethanol/water then with ethanol to give 0.78 g of the title compound (I-al) as a white solid.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].ClC1C=[CH:20][C:16]([C:17](N)=[O:18])=[C:15](OCCC)N=1.[H-].[Na+]>C(#N)C>[Cl:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([NH2:6])=[O:5])=[C:2]([O:18][CH2:17][CH:16]([CH3:20])[CH3:15])[N:10]=1
Reactant: CCCOc1nc(Cl)ccc1C(N)=O
Reactant: NC(=O)c1ccc(Cl)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)COc1nc(Cl)ccc1C(N)=O
Yield: 66.6 %

Procedure:
To a solution of 2,6-dichloro-nicotinamide (1) (3 g, 15.7 mmol) in acetonitrile (anhydrous, 30 mL) were added 2-methyl-propan-1-ol (2) (1.22 g, 16.5 mmol) and NaH (0.42 g, 16.5 mmol). The reaction was kept at r.t. O/N. The suspension was filtered and the filtrate was concentrated in vacuo. The residue was purified by Biotage silica gel chromatography with 10%-80% EtOAc/hexanes gradient elution to afford 2.39 g (66% yield) of the title compound.
Reaction SMILES: CO.[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]3[CH:45]=[CH:44][C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[N:37]=3)=[CH:30][CH:29]=2)([CH3:27])[CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:17][CH:16]=1.[OH-].[Na+:47]>O1CCOCC1>[Na+:47].[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]3[CH:45]=[CH:44][C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[N:37]=3)=[CH:30][CH:29]=2)([CH3:27])[CH2:22][CH2:23][C:24]([O-:26])=[O:25])=[CH:17][CH:16]=1
Reactant: CC(CCC(=O)O)(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CC(CCC(=O)[O-])(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1

Procedure:
To a solution in dioxane (10 mL) and methanol (10 mL) of 4,4-bis (4-(2-quinolylmethoxy)phenyl)pentanoic acid (320 mg, 0.56 mmol), prepared as in step 1, was added aqueous 1N sodium hydroxide (0.55 ml, 0.55 mmol). The mixture was then concentrated in vacuo. The product was crystallized by dissolving in CH2Cl2 and precipitation by dropwise addition of a mixture of ethyl acetate-ethyl ether (1:2): 1H NMR (300 MHz, DMSO--d6) d 1.47 (s, 3H), 1.63 (m, 2H), 2.18 (m, 2H), 5.31 (s, 4H), 6.95 (d, 4H, J=9 Hz), 7.08 (d, 4H, J=9 Hz), 7.64 (m, 4H), 7.78 (m, 2H), 8.00 (m, 4H), 8.40 (d, 2H, J=8 Hz); MS (FAB+) m/e 591 (M+H)+ ; (FAB-) 589 (M-H)-. Anal. Calc'd. for C37H31N2 O4Na.0.25 H2O:C, 74.67; H, 5.34; N, 4.71; Found: C, 74.57; H, 5.32; N, 4.52.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C(O[CH2:10][C:11]1[CH:16]([C:17]([OH:19])=[O:18])[N:15]2[C:20](=[O:32])[CH:21]([NH:22][C:23](=[O:31])[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:14]2[S:13][CH:12]=1)(=O)C.C1(C)C=CC=CC=1>FC(F)(F)C(O)=O>[C:25]1([CH2:24][C:23]([NH:22][CH:21]2[C:20](=[O:32])[N:15]3[CH:16]([C:17]([OH:19])=[O:18])[C:11]([CH2:10][C:5]4[S:1][CH:2]=[CH:3][CH:4]=4)=[CH:12][S:13][C@H:14]23)=[O:31])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: c1ccsc1
Reactant: CC(=O)OCC1=CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)O
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)O)C(Cc3cccs3)=CS[C@H]12
Reaction time: 0.25 h

Procedure:
A solution of 3.4 g of thiophene in 200 ml of trifluoroacetic acid is mixed with 4 g of 3-acetoxymethyl-7-(N-phenylacetyl-amino)-ceph-2-em-4ξ-carboxylic acid and the solution is left to stand for 15 minutes at room temperature and then mixed with an equal quantity of toluene, and the mixture is evaporated under reduced pressure. The residue is triturated with acetic acid ethyl ester and the solid material is twice crystallised from a mixture of methanol and acetic acid ethyl ester. 7-(N-Phenylacetyl-amino)-3-(2-thenyl)-ceph-2-em-4ξ-carboxylic acid is thus obtained as colourless crystals, melting point 189°C; thin layer chromatogram (silica gel): Rf = 0.72 (system n-butanol/acetic acid/water, 75:7.5:21), Rf = 0.81 (system n-butanol/acetic acid/water, 67:10:23) and Rf = 0.50 (system n-butanol/ethanol/water, 40:10:50); ultraviolet absorption spectrum (in methanol):λmax = 233 mμ (ε = 15400); infrared absorption spectrum (in mineral oil): characteristic bands at 3.01μ, 5.73μ, 5.82μ and 6.05μ. A further quantity of the desired product can be obtained by concentrating the mother liquor and recrystallising the crystalline material.
Reaction SMILES: C([O:3][C:4](=[O:34])[C@@H:5]([O:32][CH3:33])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:21][CH:20]=2)=[CH:9][CH:8]=1)C.[Li+].[OH-]>>[CH3:33][O:32][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:23][CH:24]=2)=[CH:11][CH:12]=1)[C:4]([OH:34])=[O:3]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCCOc2ccc(Oc3ccccc3)cc2)cc1)OC
Agent: [Li+]
Agent: [OH-]
Product: CO[C@@H](Cc1ccc(OCCCCOc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-2-Methoxy-3-{4-[4-(4-phenoxy-phenoxy)-butoxy]-phenyl}-propionic acid ethyl ester, from Step A under the Standard hydrolysis procedure C. (LiOH). 1H-NMR (200.15 MHz, CDCl3): 7.4–7.2 (m, 2H), 7.15 (d, 2H, J=8.6), 7.1–6.7 (m, 9H), 4.0–3.9 (m, 5H), 3.34 (s, 3H), 3.08 (dd, 1H, J=14.0, 4.0), 2.93 (dd, 1H, J=14.0, 7.8), 2.1–1.9 (m, 4H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH:4]=[C:5]([C:10]([CH3:12])=O)[C:6]([O:8][CH3:9])=[O:7].[NH2:17]/[C:18](/[CH2:25][O:26][CH2:27][CH2:28][N:29]1[C:33](=[O:34])[C:32]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]2[C:30]1=[O:39])=[CH:19]\[C:20]([O:22][CH2:23][CH3:24])=[O:21].CO>CC(O)C>[CH3:24][CH2:23][O:22][C:20]([C:19]1[CH:4]([C:3]2[C:2]([Cl:1])=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:10]([CH3:12])[NH:17][C:18]=1[CH2:25][O:26][CH2:27][CH2:28][N:29]1[C:30](=[O:39])[C:31]2[C:32](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]1=[O:34])=[O:21]
Reactant: COC(=O)C(=Cc1ccccc1Cl)C(C)=O
Reactant: CCOC(=O)/C=C(\N)COCCN1C(=O)c2ccccc2C1=O
Solvent: CC(C)O
Solvent: CO
Product: CCOC(=O)C1=C(COCCN2C(=O)c3ccccc3C2=O)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Temperature: 0 °C
Yield: 69.6 %

Procedure:
Methyl 2-(2-chlorobenzyliden)acetoacetate (40.6 g; 169.9 mmol) was condensed with ethyl 3-amino-4-[2-(phthalimido)ethoxy]crotonate (51.5 g; 161.8 mmol) in 2-propanol (160 ml) under reflux for 11 hours. Methanol (103 ml) was added and mixture was cooled to 5/0° C. The solid was filtered off and dried at 40° C. Phthaloyl Amlodipine (60.7 g, purity: 98.6%; 0.86% of impurity HA) was obtained.
Reaction SMILES: Cl[CH2:2][C:3]([CH3:6])([OH:5])[CH3:4].[NH2:7][CH2:8][CH2:9][OH:10]>>[OH:10][CH2:9][CH2:8][NH:7][CH2:2][C:3]([CH3:6])([OH:5])[CH3:4]
Reactant: NCCO
Reactant: CC(C)(O)CCl
Product: CC(C)(O)CNCCO
Reaction time: 48 h

Procedure:
1-Chloro-2-methyl-2-propanol (135 ml) was added dropwise over 10 min to stirred 2-aminoethanol (400 ml) at 10° C. under nitrogen. The cooling bath was then removed and stirring was continued at room temperature for 48 h. A solution of sodium hydroxide (48.8 g) in methanol (440 ml) was added and the resulting white suspension was stirred for 10 min. The mixture was filtered through a pad of kieselguhr and the filtrate was concentrated under reduced pressure. The residual oil was distilled in vacuo to give 1-[(2-hydroxyethyl)amino]-2-methyl-2-propanol (133 g). b.p. 100°-108° C. (1.5 mm Hg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:20]=[CH:19][C:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[C:10]([F:21])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C1C(=O)N([Br:29])C(=O)C1.C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>C(#N)C.C(OCC)(=O)C>[NH2:1][C:2]1[C:7]([C:8]2[CH:20]=[CH:19][C:11]([C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])=[C:10]([F:21])[CH:9]=2)=[CH:6][C:5]([Br:29])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cccnc2N)cc1F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)c1ccc(-c2cc(Br)cnc2N)cc1F
Reaction time: 0.17 h
Yield: 90 %

Procedure:
A solution of tert-butyl 4-(2-aminopyridin-3-yl)-2-fluorobenzoate (700 mg, 2.43 mmol) in acetonitrile (10 mL) was treated with NBS (453 mg, 2.55 mmol). After 10 min, the reaction was completed. The reaction was treated with 1:1 sat. aq. NaHCO3: sat.aq. Na2S2O3 (10 mL). The mixture was stirred vigorously for 10 min. The mixture was diluted with ethyl acetate (30 mL) and the layers were separated. The organics were washed with brine, dried over magnesium sulfate, filtered and concentrated to provide tert-butyl 4-(2-amino-5-bromopyridin-3-yl)-2-fluorobenzoate (803 mg, 90% yield). LCMS (m/z): 367.2, 369.2 (MH+), 0.75 min.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[C:5]([CH3:8])=[N:4][CH:3]=1.C([Li])CCC.CON(C)[C:17]([C:19]1[N:23]([CH3:24])[N:22]=[N:21][CH:20]=1)=[O:18].[Cl-].[NH4+]>O1CCCC1>[CH3:7][N:6]1[C:2]([C:17]([C:19]2[N:23]([CH3:24])[N:22]=[N:21][CH:20]=2)=[O:18])=[CH:3][N:4]=[C:5]1[CH3:8]
Reactant: CON(C)C(=O)c1cnnn1C
Reactant: Cc1ncc(Br)n1C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ncc(C(=O)c2cnnn2C)n1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 5-bromo-1,2-dimethyl-1H-imidazole (1.5 g, 7.54 mmol) in tetrahydrofuran (25 mL) was cooled to −66° C. Maintaining a temperature of <−50° C., n-butyllithium (3.2 mL, 2.5 M in hexanes, 8.3 mmol) was added over 5 minutes. The reaction mixture was stirred for 15 minutes and then a solution of N-methoxy-N,1-dimethyl-1H-1,2,3-triazole-5-carboxamide (1.3 g, 7.54 mmol, Intermediate 77: step a) in tetrahydrofuran (3 mL) was added over 3 minutes. The mixture was allowed to warm to room temperature while stirring over 30 minutes. Half-saturated aqueous ammonium chloride solution (40 mL) was added and the layers were mixed and separated. The aqueous layer was extracted twice with tetrahydrofuran (50 mL) and then with dichloromethane (50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to dryness. The material was triturated with isopropyl alcohol (29 mL), filtered, and rinsed twice with hexanes (25 mL) providing the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:21]([F:24])([F:23])[F:22])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Br:25]N1C(=O)CCC1=O>ClC(Cl)C>[Br:25][CH2:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]2[CH2:10][C:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)([C:21]([F:22])([F:24])[F:23])[O:13][N:12]=2)=[CH:19][CH:18]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1
Solvent: CC(Cl)Cl
Product: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CC(c2ccc(CBr)cc2)=NO1
Yield: 39 %

Procedure:
A solution of 5-(3,5-dichlorophenyl)-3-(4-methylphenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (5.3 g), N-bromosuccinimide (3.7 g) and 2,2′-azobisisobutylonitrile (0.1 g) in dichloroethane (40 mL) was heated to reflux for 3 hours. After the solvent was distilled off under reduced pressure, the residue was diluted with t-butylmethylether, and the solution was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was then purified by silica gel chromatography to obtain 3-[4-(bromomethyl)phenyl]-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (2.5 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:17])[C:5]2[S:16][CH2:15][CH2:14][C:9]3([S:13][CH2:12][CH2:11][S:10]3)[C:6]=2[C:7]=1[CH3:8].C([Li])CCC.[C:23](=[O:25])=[O:24]>O1CCCC1.CCCCCC>[CH3:8][C:7]1[C:6]2[C:9]3([CH2:14][CH2:15][S:16][C:5]=2[C:4]([CH3:17])=[CH:3][C:2]=1[C:23]([OH:25])=[O:24])[S:13][CH2:12][CH2:11][S:10]3
Reactant: O=C=O
Reactant: Cc1cc(Br)c(C)c2c1SCCC21SCCS1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)c(C)c2c1SCCC21SCCS1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the title compound of Step A (2.7 g, 7.7 mmol) in tetrahydrofuran (20 mL) under a nitrogen atmosphere cooled to -78° C. was added n-butyllithium (Aldrich, 4.6 mL, 11.5 mmol of a 2.5 M solution in hexane) dropwise while maintaining the temperature below -60° C. After stirring for 2 h, excess carbon dioxide (dry ice) was added. The resulting mixture was allowed to warm to room temperature and was left at room temperature overnight. To this reaction mixture was added hexanes (30 mL), and the mixture was filtered. The solid was added to a mixture of water:methylene chloride (20 mL:20 mL), cooled to about 0° C., and acidified to pH 1 with concentrated hydrochloric acid. The organic layer was separated, and aqueous layer was extracted with diethyl ether (3×25 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure to about 10 mL. A white solid precipitated and this solid was isolated by filtration to afford the title compound of Step B (1.62 g) as a solid melting at 236-238° C. 1H NMR (Me2SO-d6): δ2.17 (s,3H), 2.68 (m,2H), 2.81 (s,3H), 3.11 (m,2H), 3.50-3.70 (4H), 7.33 (s,1H), 12.78 (s,1H).
Reaction SMILES: [CH3:1][C:2]([OH:33])([CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[C:41]1([CH3:51])[CH:46]=[CH:45][C:44]([S:47](Cl)(=[O:49])=[O:48])=[CH:43][CH:42]=1>ClCCl>[OH:33][C:2]([CH3:1])([CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:15][CH2:16][CH:17]([CH2:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([O:28][C:29]([F:32])([F:30])[F:31])=[CH:26][CH:27]=3)[CH2:18][CH2:19]2)=[CH:12][CH:13]=1)[CH2:3][CH2:4][O:5][S:47]([C:44]1[CH:45]=[CH:46][C:41]([CH3:51])=[CH:42][CH:43]=1)(=[O:49])=[O:48]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(O)(CCO)COc1ccc(N2CCC(CCc3ccc(OC(F)(F)F)cc3)CC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCC(C)(O)COc2ccc(N3CCC(CCc4ccc(OC(F)(F)F)cc4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
3-Methyl-4-(4-{4-[2-(4-trifluoromethoxyphenyl)ethyl]piperidin-1-yl}phenoxy)butane-1,3-diol (1.68 g, 3.6 mmol), dichloromethane (17 ml), triethylamine (1.00 ml, 7.2 mmol) and p-toluenesulfonyl chloride (0.82 g, 4.3 mmol) were mixed and ice-cooled. 1,1,3,3,-Tetramethylpropanediamine (0.12 ml, 0.7 mmol) was added thereto and stirred at room temperature for 1 hour. The reaction mixture was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. The organic layer was concentrated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0, 50:50) to afford the title compound as a colorless powder (2.03 g, 91%).