Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]2[CH:11]=[C:10]([CH2:12][CH3:13])[C:9](B(O)O)=[CH:8][CH:7]=2)=[CH:4][CH:3]=1.[C:19]([O-:22])(=[O:21])[CH3:20].[C:23]([O-:26])(=[O:25])[CH3:24].[C:27]([O-:30])(=[O:29])[CH3:28].C([O-])(=O)C.[Pb+4:35].CCCCCC.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[C:19]([O-:22])(=[O:21])[CH3:20].[C:23]([O-:26])(=[O:25])[CH3:24].[C:27]([O-:30])(=[O:29])[CH3:28].[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]2[CH:11]=[C:10]([CH2:12][CH3:13])[C:9]([Pb+3:35])=[CH:8][CH:7]=2)=[CH:4][CH:3]=1
Reactant: [Pb+4]
Reactant: CCc1cc(-c2ccc(Cl)cc2)ccc1B(O)O
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: CCc1cc(-c2ccc(Cl)cc2)ccc1[Pb+3]
Temperature: 25 °C
Yield: 58.3 %

Procedure:
4′-Chloro-3-ethylbiphen-4-ylboronic acid (4.2 g, 0.016 mol) is added in one portion to a mixture of lead tetraacetate (7.86 g, 0.017 mol) and mercuric acetate (0.25 g, 5 mol %) in chloroform (23 ml) under an atmosphere of nitrogen. The reaction mixture is stirred at ambient temperature until dissolution is complete, and then heated at 40° C. for 4 hours. The reaction mixture is cooled to ambient temperature, filtered through a plug of diatomaceous earth and the filtrate is concentrated under reduced pressure to give an orange solid. Trituration with hexane (50 ml) affords a yellow solid which is dried under high vacuum. This solid is then dissolved in chloroform (100 ml), anhydrous potassium carbonate (26.7 g, 0.19 mol) is added and the suspension is stirred rapidly for 10 minutes. The mixture is filtered through a plug of diatomaceous earth, and the filtrate is concentrated under reduced pressure to give 4′-chloro-3-ethylbiphen-4-yllead triacetate (5.6 g) as a cream solid.
Reaction SMILES: [CH:1]1[C:6]([C:7]2[C:16](=[O:17])[C:15]3[C:14](O)=[CH:13][C:12](O)=[CH:11][C:10]=3[O:9][CH:8]=2)=[CH:5][CH:4]=[C:3](O)[CH:2]=1.C([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[O:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16](=[O:17])[C:7]([C:6]2[CH:1]=[CH:2][CH:3]=[CH:4][CH:5]=2)=[CH:8]1
Reactant: O=c1c(-c2ccc(O)cc2)coc2cc(O)cc(O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: O=c1c(-c2ccccc2)coc2ccccc12
Yield: 65.7 %

Procedure:
Prepared according to the general procedure using genistein (500 mg, 1.85 mmol), K2CO3 (1.02 g, 7.4 mmol), acetone (15 mL) and MeI (0.277 mL). Purified by flash column chromatography (SiO2, 10% EtOAc/Hex) to afford 16 (270 mg, 49%) as an off-white solid. Analytical data for isoflavone 16: 1H NMR (500 MHz, CDCl3) δ 12.88 (s, 1H), 7.88 (s, 1H), 7.48 (d, J=8.5 Hz, 2H), 7.00 (d, J=9 Hz, 2H), 6.41 (d, J=8.5 Hz, 2H), 3.89 (s, 3H), 3.86 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 181.1, 165.8, 163.0, 160.0, 158.2, 152.9, 130.4, 123.9, 123.2, 114.3, 106.5, 98.4, 92.7, 56.1, 55.6; LCMS: Mass calculated for C17H14O5, [M+H]+, 299. Found 299.
Reaction SMILES: C([O:8][C:9]([C@H:11]1[CH2:14][C@@H:13]([CH:15]([O:18][CH3:19])[O:16][CH3:17])[N:12]1CC1C=CC=CC=1)=[O:10])C1C=CC=CC=1.O.[H][H]>CO.[OH-].[OH-].[Pd+2]>[NH3:12].[CH3:17][O:16][CH:15]([O:18][CH3:19])[C@H:13]1[NH:12][C@@H:11]([C:9]([OH:10])=[O:8])[CH2:14]1
Reactant: [H][H]
Reactant: COC(OC)[C@@H]1C[C@H](C(=O)OCc2ccccc2)N1Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(OC)[C@@H]1C[C@H](C(=O)O)N1
Product: N
Yield: 97.9 %

Procedure:
12.5 mg (35 μmol) of cis-N-benzyl-4-(dimethoxymethyl)azetidine-2-carboxylic acid benzyl ester in 10 ml of methanol is hydrogenated in a Parr shaker over 53 mg of 20% Pd(OH)2 /C (containing 31% water) under 4 atm of hydrogen for 3 h. Filtration through a double paper filter, repeated washing with methanol and evaporation gives a crude product which is filtered over silica gel with isopropanol/water/conc. ammonia (17:2:1) to yield 3.0 mg (49%) of cis-4-(dimethoxymethyl)azetidine-2-carboxylic acid as a colorless glass. 1H NMR (D20): δ4.73 (d, 1H, overlapping), 4.72 (t, 1H, overlapping), 3.53 (s, 3H), 3.50 (s, 3H), 2.80 (dt, 1H, J=12 (d), 9.5(t)), 2.50 (dt, 1H, J=12(d), 8(t)).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C@H:6]([N:13]1[C:17]([CH2:18]O)=[CH:16][NH:15][C:14]1=[S:20])[CH2:7]2.CN(C=O)C.S(Cl)(Cl)=O.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>C1COCC1>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C@H:6]([N:13]1[C:17]([CH2:18][N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:16][NH:15][C:14]1=[S:20])[CH2:7]2
Reactant: OCc1c[nH]c(=S)n1[C@H]1CCc2c(F)cc(F)cc2C1
Reactant: C1CCNC1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Fc1cc(F)c2c(c1)C[C@@H](n1c(CN3CCCC3)c[nH]c1=S)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.7 %

Procedure:
A solution of (S)-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-5-hydroxymethyl-1,3-dihydroimidazole-2-thione (140 mg, 0.47 mmol), prepared as in Example 18, in 20 mL of THF and I drop of DMF was cooled to between 0° and 5° C. and thionyl chloride (13.7 M, 109 μL, 1.49 mmol) was added drop-wise under a nitrogen atmosphere. The mixture was stirred at room temperature for 0.5 hours, under reflux for 0.5 hours and again at room temperature for 0.5 hours. The mixture then was cooled to between 0° and 5° C. and pyrrolidine (12.0 M, 818 μL, 9.8 mmol) was added drop-wise. The mixture was stirred under reflux for 1.5 hours. The solvents were removed by evaporation and the residue was diluted with water. Ethyl acetate was added to the dilution and the mixture was adjusted to pH 7. The ethyl acetate layer was dried and concentrated by evaporation. Purification of the residue by column chromatography gave (S)-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydro-5-(pyrrolidin-1-ylmethyl)-imidazole-2-thione (100 mg, 0.29 mmol). [α]D =-10.96° (C=1.3, DMSO).
Reaction SMILES: [Si:1]([O:8][NH2:9])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][N:32]([S:35]([N:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH:39]3[C:44](O)=[O:45])(=[O:37])=[O:36])[CH2:31][CH2:30]2)=[CH:25][CH:24]=1>C(Cl)Cl>[O:8]([NH:9][C:44]([CH:39]1[CH2:40][CH2:41][CH2:42][CH2:43][N:38]1[S:35]([N:32]1[CH2:33][CH2:34][N:29]([C:26]2[CH:25]=[CH:24][C:23]([Cl:22])=[CH:28][CH:27]=2)[CH2:30][CH2:31]1)(=[O:37])=[O:36])=[O:45])[Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C(O)C1CCCCN1S(=O)(=O)N1CCN(c2ccc(Cl)cc2)CC1
Reactant: CC(C)(C)[Si](C)(C)ON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)ONC(=O)C1CCCCN1S(=O)(=O)N1CCN(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
O-(tert-butyldimethylsilyl)hydroxylamine (57 mg, 0.39 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (59 mg, 0.31 mmol) were added to a solution of 1-[4-(4-chlorophenyl)piperazine-1-sulfonyl]piperidine-2-(RS)-carboxylic acid (100 mg, 0.26 mmol), [prepared as described above] in methylene chloride (4 ml). The reaction mixture was stirred overnight at RT and then diluted with methylene chloride. The solution was washed with water, 10% citric acid, and brine, and dried over MgSO4. After the organics were removed the residue was chromatographed (SiO2, 20-30% ethyl acetate/hexane) to give N-tert-butyldimethylsiloxy-1-[4-(4-chlorophenyl)piperazine-1-sulfonyl]piperidine-2-(RS)-carboxamide as a colorless foam (56%).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:14]1([P:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[PH4+]>C1C=CC=CC=1>[Br-:1].[CH2:8]([O:7][C:5]([C:4]1[CH:10]=[CH:11][CH:12]=[CH:13][C:3]=1[CH2:2][P+:20]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:6])[CH3:9]
Reactant: CCOC(=O)c1ccccc1CBr
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [PH4+]
Solvent: c1ccccc1
Product: CCOC(=O)c1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Reaction time: 290 h

Procedure:
20 g of the ester described under (1) above are mixed with a solution of 28 g of triphenyl phosphine in 250 ml of benzene, and the mixture is heated to boiling for about 290 hours. The precipitated phosphonium salt is sucked off and dried.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][Br:12])[CH3:2].[C:14]1([P:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[Br-:12].[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][P+:20]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:13])[CH3:2]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)c1ccccc1CBr
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Temperature: 25 °C

Procedure:
A mixture of 2-bromomethylbenzoic acid ethyl ester (25 g, 102.8 mmol) and triphenylphosphine (32.4 g, 123.5 mmol) in toluene is refluxed for 1 h. The solution is cooled to RT and filtered to afford the title compound as a brown solid: (M+1)+=243, 245.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][N:11]3[CH:17]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:25]([OH:29])[CH2:26][C:27]#[CH:28]>C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:29][CH2:25][CH2:26][C:27]#[C:28][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][N:11]3[CH:17]=2)=[CH:4][CH:3]=1
Reactant: C#CCCO
Reactant: Cc1ccn2cc(-c3ccc(Br)cc3)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccn2cc(-c3ccc(C#CCCO)cc3)nc2c1
Temperature: 60 °C
Yield: 71.7 %

Procedure:
The product of Step A (1.8 g) in dry acetonitrile (40 mL) was treated sequentially with tetrakis(triphenylphosphine)palladium(0) (0.1 g), triethylamine (1.27 g), and Cul (10 mg) then heated at 60° C. for 30 minutes. The mixture was cooled to ambient temperature, treated with 3-butyn-1-ol (0.361 g) and heated at reflux temperature for 18 hours. The mixture was cooled to ambient temperature and evaporated to dryness. The residue was crystallized, twice, from acetone to afford the title compound (1.02 g).
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].O1[C:7]23[C@:23]([CH3:28])([CH2:24][CH2:25][C:26](=[O:27])[CH:6]12)[C@@H:22]1[C@H:10]([C@H:11]2[C@:19]([CH3:29])([CH2:20][CH2:21]1)[C@@H:14]([C@H:15]([CH3:18])[CH2:16][OH:17])[CH2:13][CH2:12]2)[CH2:9][CH2:8]3.[N-:30]=[N+]=[N-].[Na+].S(=O)(=O)(O)O.O>CS(C)=O>[C:1]([OH:4])(=[O:3])[CH3:2].[NH2:30][C:6]1[C:26](=[O:27])[CH2:25][CH2:24][C@@:23]2([CH3:28])[C:7]=1[CH:8]=[CH:9][C@@H:10]1[C@@H:22]2[CH2:21][CH2:20][C@@:19]2([CH3:29])[C@H:11]1[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:18])[CH2:16][OH:17]
Reactant: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC45OC4C(=O)CC[C@]5(C)[C@H]3CC[C@]12C
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CS(C)=O
Product: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3C=CC4=C(N)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a vigorously stirred solution of the (20S)-4,5-epoxy-21-hydroxy-20-methylpregnan-3-one acetate (2.0 g, 5.15 mmole) obtained in Example 7, in dimethyl sulfoxide (70 mL) and heated to 60° C., there was added sodium azide (5.4 g) and then concentrated sulfuric acid (0.37 mL). The mixture was quickly brought to a temperature of 100° C. and held at that temperature for 1 hour. The cooled mixture was then poured into cold water (450 mL). The solids were collected by filtration, washed with water, and dried by suction to give a yellow solid which was purified by flash chromatography to give (20S)-4-amino-21-hydroxy-20-methylpregna-4,6-dien-3-one acetate (1.04 g, 52.5%). IR 3488, 3446, 3360, 1740, 1668, 1612 (m), 1592 (m), 1562 (m), 1252 cm-1 ; MS (CI) 386 (20%, M +1), 326 (100%, M+1 - AcOH); 1H NMR (CDCl3)δ0.78 (3H, s, C18 -Me), 1.03 (d, C22 -Me), 1.06 (s, C19 -Me), 2.07 (S, Ac-Me), 3.69+3.78 (3H, v br+dd, NH2 +1/2C21 -CH2), 4.09 (1H, dd, 1/2C21 -CH2), 5.97 (1H, dd), 6.30 (1H, dd). This compound has the following structure: ##STR5##
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH2:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1.C(OCC)(=O)C.CCCCCC>CO>[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:21][C:16]2[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]3[O:12][C:11]([CH3:24])([CH3:23])[CH:10]([C:7]4[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=4)[C:14]=3[C:15]=2[CH3:22])=[O:31])=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1NC(=O)c1ccc(F)cc1)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Yield: 91 %

Procedure:
By using (+)-3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine and 4-fluorobenzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 91%. Melting point: 251-253° C. (Ethyl acetate-hexane) [α]D=+74.4° (c=0.501, methanol)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=1.[OH-].[Li+].Cl>C(O)(C)C.O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[C:10]1[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1
Reactant: COC(=O)c1ccc(-c2c(C)cc(C)cc2C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: Cc1cc(C)c(-c2ccc(C(=O)O)cc2)c(C)c1

Procedure:
The compound from Example 9 part (a) (1.3 g) was dissolved in a mixture of isopropanol (15 mL) and water (8 mL). Lithium hydroxide (1.3 g) was added and the reaction mixture was refluxed. After 2 hours the solution was poured into 2N HCl and the product was extracted into ether. After drying the organic phase with MgSO4 and evaporation a white solid was obtained (1.15 g, 91%).
Reaction SMILES: C[O:2][B:3]([O:6]C)OC.[Cl-].[Mg+2].[Cl:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1.[Cl-]>C(OCC)(=O)C>[Cl:10][C:11]1[CH:16]=[C:15]([B:3]([OH:6])[OH:2])[CH:14]=[CH:13][CH:12]=1
Reactant: COB(OC)OC
Reactant: Clc1ccccc1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Product: OB(O)c1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of trimethylborate in 200 mL of ethyl acetate was cooled to -65° C. 3-Chlorobenzene magnesium chloride (0.8M, 60 mL), i.e., a grignard reagent, was added to the solution in a dropwise manner over 20 minutes. The mixture was kept in the temperature range of -60° C. to -70° C. and stirred. After 30 minutes, the mixture was allowed to warm to 0° C. and stirred for 1 hour. The mixture was quenched with H2O (25 mL) and stirred at room temperature for 1 hour. The solvent was removed and the remaining mass was extracted ethyl ether (3×100 mL). The organic layers were combined and washed with H2O (2×50 mL), dilute HCl (2×100 mL), H2O (2×50 mL) and brine (1×50 mL). The organic layer was dried with MgSO4, concentrated and allowed to stand. 100 mL of hexanes was added and the solution was stirred for 1 hour. The solution was filtered and allowed to air dry yielding 4.6 g of 3-chlorobenzene boronic acid as a white solid.
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[C:11]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[C:6]2=[N:5][CH:4]=1)#[CH:2].I[C:24]1[CH:25]=[C:26]([CH:40]=[CH:41][C:42]=1[CH3:43])[C:27]([NH:29][C:30]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][N:31]=1)=[O:28].C(N(C(C)C)CC)(C)C>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:43][C:42]1[CH:24]=[CH:25][C:26]([C:27]([NH:29][C:30]2[CH:35]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:33]=[CH:32][N:31]=2)=[O:28])=[CH:40][C:41]=1[C:2]#[C:1][C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[C:11]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[C:6]2=[N:5][CH:4]=1
Reactant: Cc1ccc(C(=O)Nc2cc(C(F)(F)F)ccn2)cc1I
Reactant: C#Cc1cnc2c(Nc3ccc(S(C)(=O)=O)cc3)cccn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)Nc2cc(C(F)(F)F)ccn2)cc1C#Cc1cnc2c(Nc3ccc(S(C)(=O)=O)cc3)cccn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.8 %

Procedure:
A mixture of 3-ethynyl-N-(4-(methylsulfonyl) phenyl)imidazo[1,2-a]pyridin-8-amine 5 (0.048 g, 0.154 mmol), 0.069 g (0.170 mmol) of 3-iodo-4-methyl-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide, 0.009 g (0.008 mmol) of Pd(PPh3)4, 0.002 g (0.012 mmol) of Cul, and 0.04 mL (0.23 mmol) of diisopropylethylamine in 0.8 mL of DMF was stirred at ambient temperature overnight under an atmosphere of N2. The reaction mixture was concentrated and the crude product was purified by silica gel flash chromatography (triethylamine-treated silica gel; eluted with 10% EtOAc/hexanes to 100% EtOAc) to provide 0.047 g of product as a solid: 590 m/z (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)(O)[O-].[Na+].C(#N)C.[Cl:17][CH2:18][C:19](Cl)=[O:20]>CO.O>[Cl:17][CH2:18][C:19]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8])=[O:20]
Reactant: Nc1ccccc1O
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CO
Product: O=C(CCl)Nc1ccccc1O
Temperature: 10 °C
Reaction time: 3 h

Procedure:
109.1 g (1 mol) of 2-aminophenol, 84.1 g (1 mol) of sodium bicarbonate, 900 mL of acetonitrile and 100 mL of water were added under room temperature into a 2 L flask with four inlets and attached with a stirrer and a thermometer. The internal temperature was cool down to 10° C. and 112.9 g (1 mol) of chloroacetyl chloride was added to the solution over a period of 3 hours and stirred for 3 hours at room temperature. Following to the completion of the reaction, 10 mL of methanol was added, and then acetonitrile was distilled out under reduced pressure and the resultant residue was subjected to recrystallization with toluene. Then, salt was taken out in a cleaning process using water to obtain 2-chloroacetyl-2-hydroxyaniline.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:17]([CH3:22])[C:18]([O:20][CH3:21])=[O:19].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[CH3:21][O:20][C:18](=[O:19])[CH:17]([O:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)[CH3:22]
Reactant: COC(=O)C(C)Br
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)C(C)Oc1ccc(OCc2ccccc2)cc1

Procedure:
In analogy to the procedure described in Example 1b), the alkylation of 4-benzyloxy-phenol [Example 2a)] with methyl (RS)-2-bromopropionate in acetone using cesium carbonate as the base yielded the (RS)-2-(4-Benzyloxy-phenoxy)-propionic acid methyl ester as light yellow oil; MS: m/e=304 (M+NH4)+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=[O:7])[N:3]=[CH:2]1.[CH3:9]O>>[NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH3:9])=[O:7])[N:3]=[CH:2]1
Reactant: O=C(O)c1c[nH]cn1
Reactant: CO
Product: COC(=O)c1c[nH]cn1
Temperature: 25 °C

Procedure:
112.09 g (1 mol) (1H-imidazol-4-yl)carboxylic acid are added to 1.3 l methanol. Dry HCl-gas is bubbled through the mixture which is heated under reflux for 4 hours. Cooling to room temperature and evaporation to 300 ml afford 98 g of the title compound as white crystals. Repeated evaporation leads to 46.5 g additional material (total: 144.5 g, 88.9%). An analytical sample is recrystallized from methanol, melting point: 173°-174° C. (ref.1) mp: 156° C.).
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH3:10])[C:5]([CH2:11][S:12]([C:14]2[N-:18][C:17]3[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:16]=3[N:15]=2)=[O:13])=[N:4][CH:3]=1.[CH3:25][C:26]1[C:31]([O:32][CH3:33])=[C:30]([CH3:34])[C:29]([CH2:35][S:36]([C:38]2[N-:42][C:41]3[CH:43]=[CH:44][C:45]([O:47][CH3:48])=[CH:46][C:40]=3[N:39]=2)=[O:37])=[N:28][CH:27]=1.O.O.O.[Mg+2:52]>ClCCl.CO>[CH3:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][S+:12]([O-:13])[C:14]2[N-:18][C:17]3[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:16]=3[N:15]=2)=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].[CH3:25][C:26]1[CH:27]=[N:28][C:29]([CH2:35][S+:36]([O-:37])[C:38]2[N-:42][C:41]3[CH:43]=[CH:44][C:45]([O:47][CH3:48])=[CH:46][C:40]=3[N:39]=2)=[C:30]([CH3:34])[C:31]=1[O:32][CH3:33].[Mg+2:52]
Reactant: COc1ccc2[n-]c(S(=O)Cc3ncc(C)c(OC)c3C)nc2c1
Agent: [Mg+2]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: COc1ccc2[n-]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Yield: 64.5 %

Procedure:
Esomeprazole magnesium trihydrate (200 g) was dissolved in a mixture of dichloromethane (1200 ml) and methanol (1200 ml) at 25-30° C., Any undissolved material was filtered off and triethylamine (2 ml) was added to the filtrate. The clear solution thus obtained was spray dried in a mini spray dryer (Model Buchi—190) with an inlet temperature of 65-68° C. and an outlet temperature of 22-42° C. in 2 to 3 hours. The solid was further dried under vacuum at 60-65° C. for 14 to 15 hours to yield 120 g of esomeprazole magnesium of amorphous form. X-ray powder diffraction pattern showed a plain halo, which demonstrates the amorphous nature of the product. The following physical characteristics were obtained: Purity 99.77% by HPLC, Chiral purity 99.90% by HPLC, SOR 145.9°, Mg content 3.4.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]([O:7][CH3:8])[O:5][CH3:6].C(N(CC)CC)C.[Cl-].[Ca+2].[Cl-].[Cl:19][CH2:20][C:21](Cl)=[O:22]>C(Cl)Cl.C(OCC)C>[CH3:1][N:2]([CH2:3][CH:4]([O:7][CH3:8])[O:5][CH3:6])[C:21](=[O:22])[CH2:20][Cl:19]
Reactant: CNCC(OC)OC
Reactant: O=C(Cl)CCl
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(CN(C)C(=O)CCl)OC
Temperature: -20 °C
Reaction time: 1 h

Procedure:
N-Methyl-2,2-dimethoxyethanamine (50.0 grams; 0.42 mole), methylene chloride (200 ml) and triethylamine (46.6 grams; 0.462 mole) were charged into a glass reaction vessel fitted with a mechanical stirrer, and thermometer. A calcium chloride filled drying tube was attached and the solution was cooled to about -20° C. Chloroacetyl chloride (49.7 grams; 0.44 moles) dissolved in methylene chloride (25 ml) was then added dropwise, with stirring, while holding the temperature at about -20° C. to -10° C. At the end of the addition, stirring was continued at -20° C. to 10° C. for a period of about 1 hour. The solution was allowed to warm to room temperature, then was stirred at this temperature for a period of about 16 hours. Diethyl ether (125 ml) was then added and the resulting solution filtered. The filtrate was washed with water (30 ml). The washed filtrate was dried and filtered. The solvent was distilled off under mild heat and reduced pressure to yield a residue which was fractionally distilled under reduced pressure to yield the desired product N-methyl-N-(2,2-dimethoxyethyl)-2-chloroacetamide as a fraction boiling at 112° C.-119° C. at 0.30 mm. Hg.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[C-:11]#[N:12].[K+].CCOC(C)=O>CN(C=O)C.O>[C:11]([CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7])#[N:12]
Reactant: N#Cc1cccc(CBr)c1
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: N#CCc1cccc(C#N)c1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
3-Bromomethyl-benzonitrile (150 mg, 0.76 mmol) was dissolved in DMF (2 ml). KCN (55 mg, 0.84 mmol) was dissolved in the minimum amount of water and was added to the reaction. The resulting solution was stirred at 85° C. overnight. The reaction mixture was allowed to cool to room temperature, EtOAc (5 ml) was added, and the solution was washed with saturated NaHCO3 (4×10 ml). The organic layer was dried (MgSO4), filtered and the solvent removed in vacuo to give the title compound.