Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:4]1[N:7]([Si](C(C)(C)C)(C)C)[C:6](=[O:15])[CH:5]1[CH3:16])[CH:2]=[CH2:3].[F-].[K+].C1OCCOCCOCCOCCOCCOC1>O1CCCC1>[CH2:1]([CH:4]1[NH:7][C:6](=[O:15])[CH:5]1[CH3:16])[CH:2]=[CH2:3]
Reactant: C=CCC1C(C)C(=O)N1[Si](C)(C)C(C)(C)C
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCC1NC(=O)C1C

Procedure:
Part of the isomeric mixture from (ii) (1.20 g) in dry tetrahydrofuran (50 ml) was treated with potassium fluoride (0.45 g) and 18-crown-6 ether (0.07 g). After one hour the solution was partitioned between brine and ethylacetate. The organic phase was separated, dried (Na2SO4), evaporated and chromatographed on silica gel 60 (<230 mesh) eluting with ethylacetate:hexane 6:4. This separated the trans and cis isomers of 4-allyl-3-methyl azetidin-2-one.
Reaction SMILES: [N:1]([O-:3])=[O:2].[Na+].[Br:5][C:6]1[S:10][C:9](N)=[N:8][N:7]=1>O.Cl.[Cu]>[Br:5][C:6]1[S:10][C:9]([N+:1]([O-:3])=[O:2])=[N:8][N:7]=1
Reactant: O=N[O-]
Reactant: Nc1nnc(Br)s1
Agent: [Cu]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1nnc(Br)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.5 %

Procedure:
To a stirred solution of NaNO2 (116 g, 1.68 mol) in water (1200 mL) was added copper metal powder (72 g, 1.12 mol) and 1.2 mL conc. HCl. Thereafter, 5-bromo-1,3,4-thiadiazol-2-amine (100 g, 0.56 mol) was warmed to dissolve in 4 M aq. HCl (120 mL) and added potionwise. The mixture was stirred at r.t. for 3 hrs. The precipitated yellow solid was filtered and washed with water. The solid was dissolved in ether, filtered and the filtrate concentrated in vacuo to give 2-bromo-5-nitro-[1,3,4]thiadiazole (57 g, 88% purity in HPLC, 48% yield).
Reaction SMILES: [Br:1][C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][C:9](Br)=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.[C:19]1([NH:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.CC(O)=O.CC(O)=O.[Pd]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:16]3=[C:17]4[C:12](=[CH:11][CH:10]=[C:9]([N:25]([C:26]5[CH:35]=[CH:34][C:33]6[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=6)[CH:27]=5)[C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)[C:8]4=[CH:7][CH:6]=2)[CH:13]=[CH:14][C:15]=13
Reactant: Brc1ccc2ccc3c(Br)ccc4ccc1c2c43
Reactant: c1ccc(Nc2ccc3ccccc3c2)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: Brc1ccc2ccc3c(N(c4ccccc4)c4ccc5ccccc5c4)ccc4ccc1c2c43
Temperature: 100 °C
Yield: 36.9 %

Procedure:
A mixture of 18 g (50 mmol) of 1,6-dibromopyrene, 11 g (50 mmol) of N-phenylnaphthalen-2-amine, 0.16 g (0.7 mmol) of Pd(OAC)2, 0.5 g (1.4 mmole) of tri-tert-butylphosine, 6 g (75 mmol) sodium tert-butoxide was stirred in 200 ml dry toluene, the reaction mixture was then heat to 100° C. for about overnight under nitrogen. The solution was filtered. The toluene solution was removed under reduced pressure from the filtrate. The residue was extracted three times with dichloromethane and water, dried with MgSO4 and filtered, and the dichloromethane was removed under reduced pressure. The product was purified by column chromatography to get 9.2 g of product (yield 37%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([NH2:12])=[O:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[F:28])[CH2:23]Br>CC(CC)=O.O>[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[F:28])[CH2:23][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([NH2:12])=[O:11])=[CH:6][CH:7]=1
Reactant: NC(=O)CCc1ccc(O)cc1
Reactant: Fc1ccc(CBr)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: NC(=O)CCc1ccc(OCc2ccc(F)c(F)c2)cc1
Reaction time: 24 h
Yield: 41.3 %

Procedure:
A mixture of 106 mg (0.64 mmol) 3-(4-hydroxy-phenyl)-propionamide, 178 mg (1.29 mmol) potassium carbonate and 140 mg (0.68 mmol) 3,4-difluorobenzyl bromide in 5 ml ethyl methyl ketone is hold at 50° C. for 24 hours. The reaction mixture is cooled, diluted with water and extracted with diethyl ether. Crystallization from n-hexane yields 77 mg (41%) of a colorless solid. MS: m/e=291.3 (M+).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]=[C:5]=[O:6].[CH2:7]([NH2:10])[C:8]#[CH:9]>C1COCC1>[CH2:7]([N:10]1[CH2:2][CH2:3][NH:4][C:5]1=[O:6])[C:8]#[CH:9]
Reactant: O=C=NCCCl
Reactant: C#CCN
Solvent: C1CCOC1
Product: C#CCN1CCNC1=O
Temperature: 25 °C
Yield: 81.3 %

Procedure:
Chloroethyl isocyanate (12.2 g, 0.11 mol) was added at 0° C. to a stirred solution of propargylamine (6.6 g, 0.12 mol) in THF (200 mL). The solution was allowed to warm to room temperature and sodium hydride (5.5 g of 50% in oil, washed with ether to remove the oil) was added. The reaction was quenched with acetic acid (6.0 mL), the THF was removed under reduced pressure, and the residue was partitioned between ethyl acetate and water. The ethyl acetate was evaporated and the residual solid was crystallized from ethyl acetate; Skellysolve B to give 11.1 g of 1-(2-propynyl)-2-imidazolidinone, m.p. 110°-115° C.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH2:12][C@H:11]([NH:16][S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])[CH2:10]2.S(Cl)([Cl:32])=O>C(Cl)Cl>[Cl:32][CH2:2][C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH2:12][C@H:11]([NH:16][S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])[CH2:10]2
Reactant: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(Cc3cc(CO)cc(C(F)(F)F)c3)cc2C1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(Cc3cc(CCl)cc(C(F)(F)F)c3)cc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-N-(5-(3-(hydroxymethyl)-5-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-2-yl)propane-2-sulfonamide (1.053 mmol, 450 mg) in CH2Cl2 (8 mL) was added Thionyl chloride (2.316 mmol, 0.169 mL, 276 mg) and the whole was stirred for 2 h at RT before the reaction mixture was concentrated under reduced pressure and re-dissovled in DCM. The process was repeated ×4 to drive off the excess thionyl chloride. The material was used immediately in the next reaction.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[CH:10]=[C:9]1[C:19](O)([CH3:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CCOCC>CCOC(C)=O.CCO.[Pd]>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[CH:10]=[C:9]1[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2cc(C(C)(C)O)n(Cc3ccccc3)c2c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COc1ccc2cc(C(C)C)n(Cc3ccccc3)c2c1
Reaction time: 1 h

Procedure:
To a solution of 2-(1-benzyl-6-methoxy-1H-indol-2-yl)propan-2-ol (Compound 3, 1.05 g, 3.57 mmol) in EtOAc (35 ml) and EtOH (15 ml) was added 10% Pd—C (190 mg, 0.18 mmol) and HCl-Et2O (1.0 M, 1.25 ml, 1.25 mmol). The mixture was stirred under hydrogen gas (atmospheric pressure) for 1 h and was filtered. To the filtrate was added NaHCO3 (0.5 g) and H2O (0.5 ml), followed by Na2SO4 and MgSO4. This was then filtered and concentrated in vacuo to yield the crude title compound as a yellow solid.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[F:5][C:6]([F:44])([F:43])[C:7]1[CH:8]=[C:9]([CH:17]([NH:20][CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=2[C:32]2[CH:37]=[C:36]([CH:38]([CH3:40])[CH3:39])[CH:35]=[CH:34][C:33]=2[O:41][CH3:42])[CH2:18][OH:19])[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1.CCN(C(C)C)C(C)C.O>C1(C)C=CC=CC=1.C(Cl)Cl>[F:5][C:6]([F:43])([F:44])[C:7]1[CH:8]=[C:9]([CH:17]2[CH2:18][O:19][C:1](=[O:2])[N:20]2[CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:25]=[CH:24][C:23]=2[C:32]2[CH:37]=[C:36]([CH:38]([CH3:39])[CH3:40])[CH:35]=[CH:34][C:33]=2[O:41][CH3:42])[CH:10]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:12]=1
Reactant: O=C(Cl)Cl
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CNC(CO)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)OCC1c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 0.08 h

Procedure:
To a solution of phosgene (21 μL of a 20% solution in toluene, ˜0.0535 mmol) in CH2Cl2 (0.5 mL) was added 2-[3,5-bis(trifluoromethyl)phenyl]-2-({[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)ethanol (3.1 mg, 0.00535 mmol) in CH2Cl2 (0.5 mL), followed by DIPEA (19 μL, 0.107 mmol). After stirring for 5 minutes, the reaction was poured into water (1 mL) and the mixture was extracted with EtOAc (20 mL). The organic extract was washed with H2O, saturated NaHCO3, and brine (5 mL each). The organic layer was then dried over Na2SO4, filtered, and concentrated. The residue was purified by PTLC to afford 4-[3,5-bis(trifluoromethyl)phenyl]-3-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1,3-oxazolidin-2-one. Rf=0.27 (25% EtOAc/hexanes). LCMS=606.3 (M+1)+. 1H NMR (CD2Cl2, 500 MHz) (Doubling of some peaks observed; atropisomers present in 1:1 ratio) δ 7.84 (s, 1H), 7.19-7.60 (m, 6H), 6.80-6.87 (m, 2H), 3.84-4.68 (m, 5H), 3.68 & 3.64 (2 singlets, 3H), 2.82 (m, 1H), 1.17-1.21 (m, 6H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][C:23]=1[N+:31]([O-:33])=[O:32].O>C1COCC1>[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:8][CH:7]=2)=[O:27])=[CH:24][C:23]=1[N+:31]([O-:33])=[O:32]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: O=C(Cl)c1ccc(F)c([N+](=O)[O-])c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccc(C(F)(F)F)cc1)c1ccc(F)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The title compound was prepared by dissolving 4-Trifluoromethyl-phenylamine (475 mg, 2.95 mmol) in THF (20 ml) at room temperature. To this solution was added Hunig's base (762 mg, 5.86 mmol) and then a solution of the product from Example 172a (600 mg, 2.95 mmol) in THF (10 mL) was added drop wise over 5 minutes. After complete addition the reaction mixture was allowed to stir at room temperature for 1 hr and was poured into water and the title compound collected by filtration (900 mg, 93%).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:13]2[C:8](=[C:9]([CH3:17])[C:10]([CH3:16])=[C:11]([OH:15])[C:12]=2[CH3:14])[S:7][C:6]2([CH2:20][CH2:19][CH2:18]2)[CH2:5]1.C1COCC1.[BH3-]C#N.[Na+]>C(O)(=O)C>[CH3:1][O:2][NH:3][CH:4]1[C:13]2[C:8](=[C:9]([CH3:17])[C:10]([CH3:16])=[C:11]([OH:15])[C:12]=2[CH3:14])[S:7][C:6]2([CH2:20][CH2:19][CH2:18]2)[CH2:5]1
Reactant: CON=C1CC2(CCC2)Sc2c(C)c(C)c(O)c(C)c21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CONC1CC2(CCC2)Sc2c(C)c(C)c(O)c(C)c21
Reaction time: 120 h

Procedure:
To a solution of 6′-hydroxy-5′,7′,8′-trimethylspiro[cyclobutane-1 ,2′-thiochromen]-4′(3′H)-one O-methyloxime, prepared as described above (50 mg) in 2 mL of BH3 1.0 M THF solution was added large excess of NaCNBH3 and 0.5 mL of acetic acid. The reaction mixture was allowed to stir for 5 days. The mixture was washed with water and extracted with ethyl acetate. After concentration in vacuo, the residue was purified by flash chromatography eluted with 20% ethyl acetate in hexane to give 5.4 mg of 4′-(methoxyamino)-5′,7′,8′-trimethyl-3′,4′-dihydrospiro[cyclobutane-1,2′-thiochromen]-6′-ol as a white paste.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)#[CH:12].N>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[CH:12]=2)=[CH:14][CH:15]=1
Reactant: C#Cc1ccc(F)cc1
Reactant: ON=C(Cl)c1cccnc1
Agent: N
Product: Fc1ccc(-c2cc(-c3cccnc3)no2)cc1

Procedure:
The titled compound was prepared as the hydrochloride salt according to Method CB using the product of Example 1A (78 mg, 0.5 mmol) and 1-ethynyl-4-fluorobenzene (Aldrich, 60 mg, 0.5 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.40-7.52 (m, 2H), 7.70-7.81 (m, 2H), 7.92-8.08 (m, 2H), 8.44 (dt, J=8.0, 1.9 Hz, 1H), 8.80 (d, J=4.4 Hz, 1H), 9.18 (s, 1H) ppm; MS (DCI/NH3) m/z 241 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH:11]=[N:10][C:9]([OH:12])=[N:8]1.C(=O)([O-])[O-].[K+].[K+].[P:19](=[S:25])(Cl)([O:22][CH3:23])[O:20][CH3:21]>C(#N)C.CN(C)C1C=CN=CC=1>[P:19](=[S:25])([O:12][C:9]1[N:10]=[CH:11][N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[N:8]=1)([O:22][CH3:23])[O:20][CH3:21]
Reactant: Oc1ncn(-c2ccccn2)n1
Reactant: COP(=S)(Cl)OC
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COP(=S)(OC)Oc1ncn(-c2ccccn2)n1
Reaction time: 2 h

Procedure:
A mixture of 8.10 g (0.05 m) of 1-(2-pyridinyl)-1H-1,2,4-triazol-3-ol and 8.29 g (0.06 m) of powdered potassium carbonate in 150 ml of acetonitrile was vigorously stirred together for 21/2 hours at 40°-50° C. To this mixture was successively added a solution of 0.29 g (0.0024 m (5 mole percent)) of 4-dimethylaminopyridine in 25 ml of acetonitrile followed by a solution of 7.94 g (0.048 m) of O,O-dimethyl phosphorochloridothioate in 25 ml of acetonitrile. After a 2 hour period, the reaction was complete and the reaction mixture was filtered and evaporated to dryness. The oil which remained as a residue was triturated with hexane and solidification occurred. The solid, crude O,O-dimethyl O-(1-(2-pyridinyl)-1H-1,2,4-triazol-3-yl) phosphorothioate product was recovered in a yield of 11.3 g (82 percent of theoretical) and melted at 88°-91° C. The product after recrystallization from methyl cyclohexane melted at 95°-96° C. Upon analysis, the product was found to have carbon, hydrogen and nitrogen contents of 37.68, 3.91 and 19.51 percent, respectively, as compared with the theoretical contents of 37.76, 3.87 and 19.58 percent, respectively, as calculated for the named compound. (Compound 6).
Reaction SMILES: C[O:2][C:3](=[O:14])[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[N:8]=1.[OH-].[Li+]>CO>[Br:13][C:9]1[N:8]=[C:7]([CH2:6][O:5][CH2:4][C:3]([OH:14])=[O:2])[CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)COCc1cccc(Br)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)COCc1cccc(Br)n1
Temperature: 25 °C

Procedure:
To a solution of methyl[(6-bromopyridin-2-yl)methoxy]acetate (2.5 g, 19.2 mmol) in methanol (50 mL) was added aqueous lithium hydroxide (1M) dropwise over 15 min at 0° C. The reaction mixture was allowed to warm to room temperature overnight. The organic solvent was removed in vacuum and the residual aqueous solution was extracted with Et2O, and the aqueous phase was acidified to pH 2 with 1 N HCl. The aqueous phase was extracted with CH2Cl2 (3×100 mL). The combined organic extracts were dried and concentrated to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:13](O)(=[O:33])[CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].CCN=C=NCCCN(C)C.Cl.CN(C1C=CC=CN=1)C>ClCCl>[OH:12][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:13](=[O:33])[CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)O
Reactant: COC(=O)c1cc(N)ccc1O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Product: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)Nc1ccc(O)c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.7 %

Procedure:
To a solution of methyl 5-amino-2-hydroxybenzoate (0.27 g, 1.6 mmol) in dichloromethane (10 mL) was added arachidonic acid (0.5 g, 1.6 mmol), EDCl (0.32 g, 1.7 mmol) and dimethylaminopyridine (0.020 g, 0.2 mmol). The reaction was stirred (RT, 2 h), and then partitioned between CH2Cl2 and brine. The aqueous layer was extracted with CH2Cl2, and the combined organic layers were washed with 1 N HCl, water, saturated aqueous NaHCO3 and water, and then dried over MgSO4. The crude product was purified by silica chromatography (0-5% MeOH/CH2Cl2) to afford 0.6 g of methyl 2-hydroxy-5-(5Z,8Z,11Z,14Z)-icosa-5,8,11,14-tetraenamidobenzoate as a brown oil. Mass calculated for C28H39NO4=453.61; found: [M+H]+=454.3.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11].[H][H]>[Pd].C(O)(=O)C>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: [H][H]
Reactant: COc1cc(C#N)ccc1F
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1cc(CN)ccc1F
Reaction time: 8 h
Yield: 134 %

Procedure:
Add 4-fluoro-3-methoxy-benzonitrile (2 g, 0.01 mol), 10% palladium on carbon (0.400 g) and glacial acetic acid (120 ml) to a pressure vessel. Purge the reaction vessel with nitrogen, purge the reaction vessel with hydrogen, pressurize the reaction mixture with hydrogen (415 Kpa), seal the vessel, and agitate the reaction. After 8 hours stop the agitation, vent the excess hydrogen from the vessel and purge the vessel with nitrogen. Filter the reaction mixture to remove the 5% palladium on carbon and return the filtrate for product isolation. Concentrate the crude solution, re-dissolve in CH2Cl2 (80 mL) and washe with 5N NaOH (35 mL). Separate the organic and aqueous phases and extract the aqueous with additional CH2Cl2 (20 mL). Combine the organic solutions, dry, filter and concentrate to give the crude material 2.08 g (100%). The title compound as the major product (Rf=0.12, 10% MeOH/CH2Cl2) is used without further purification. MS (ES+) 156.1 (M+1)+. 1H NMR (400 MHz, CDCl3): δ 7.01 (dd, 1H, J=8.2, 11.4), 6.95 (dd, 1H, J=2.1, 8.4), 6.80 (m, 1H), 3.89 (s, 3H), 3.82 (s, 2H), 1.54 (br s, 2H).
Reaction SMILES: CO[C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([NH:24][CH:25]([CH3:27])[CH3:26])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1.[NH2:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH:25]([NH:24][C:23]1[C:18]([N:15]2[CH2:16][CH2:17][N:12]([C:10]([C:7]3[CH:6]=[CH:5][C:4]([C:3](=[O:28])[NH:29][CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:9][CH:8]=3)=[O:11])[CH2:13][CH2:14]2)=[N:19][CH:20]=[CH:21][CH:22]=1)([CH3:26])[CH3:27]
Reactant: NCCN1CCCCC1
Reactant: COC(=O)c1ccc(C(=O)N2CCN(c3ncccc3NC(C)C)CC2)cc1
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)NCCN3CCCCC3)cc2)CC1
Yield: 70 %

Procedure:
By the same procedure as described in the example 56, synthesis was carried out starting with 4-[1-[3-(isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]benzoic acid methyl ester and using 1-(2-aminoethyl)piperidine. Then, the product was recrystallized using acetonitrile and hexane to give the desired compound.
Reaction SMILES: COC1C=CC2NC(S(CC3C(C)=C(OC)C(C)=CN=3)=O)=NC=2C=1.N1C=CC=CC=1CS(C1NC2C=CC=CC=2N=1)=O.N1C=CC=CC=1CSC1NC2C=CC=CC=2N=1.[Cl:60][C:61]1[CH:62]=[C:63]([CH:68]=[CH:69][CH:70]=1)[C:64]([O:66]O)=[O:65]>C(Cl)(Cl)Cl>[Cl:60][C:61]1[CH:62]=[C:63]([CH:68]=[CH:69][CH:70]=1)[C:64]([OH:66])=[O:65]
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: COc1ccc2[nH]c(S(=O)Cc3ncc(C)c(OC)c3C)nc2c1
Agent: O=S(Cc1ccccn1)c1nc2ccccc2[nH]1
Agent: c1ccc(CSc2nc3ccccc3[nH]2)nc1
Solvent: ClC(Cl)Cl
Product: O=C(O)c1cccc(Cl)c1
Temperature: 5 °C

Procedure:
5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl- 1H-benzimidazole (omeprazole) was disclosed for the first time in U.S. Pat. No. 4,255,431. In the process of preparing 2-(2-pyridylmethylsulfinyl)benzimidazole compounds there is mentioned an oxidation of corresponding 2-(2-pyridylmethylthio)benzimidazole compounds with 3-chloroperoxybenzoic acid in a chloroform solution under stirring and cooling at a temperature under 5° C. 3-chlorobenzoic acid formed is then filtered off, the filtrate is diluted with methylene chloride, washed with Na2CO3, dried with Na2SO4, evaporated in vacuo and the residue is crystallized under addition of CH3CN. Since omeprazole is unstable in an acidic medium, the cooling of the reaction mixture to 5° C. is necessary to prevent a decomposition of the omeprazole formed.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[CH2:18][CH2:17][CH:7]2[N:8]([CH3:16])[C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][C:14]=3[CH:6]2[CH2:5]1.S(Cl)([Cl:21])=O>>[Cl:21][CH2:2][CH2:3][N:4]1[CH2:18][CH2:17][CH:7]2[N:8]([CH3:16])[C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][C:14]=3[CH:6]2[CH2:5]1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc2c(c1)C1CN(CCO)CCC1N2C
Product: Cc1ccc2c(c1)C1CN(CCCl)CCC1N2C
Yield: 77.1 %

Procedure:
In the same manner as described in Example 7, 2-(β-hydroxyethyl)-5,8-dimethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido-[4,3-b]indole (3.5 g) is reacted with thionyl chloride (5.0 g) to give 2-(β-chloroethyl)-5,8-dimethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (2.9 g) as an oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[CH:20]=[CH2:21]>CN(C)C=O.O>[CH2:21]([O:12][C:3]1[CH:4]=[C:5]([C:8]([F:10])([F:11])[F:9])[CH:6]=[CH:7][C:2]=1[Cl:1])[CH:20]=[CH2:19]
Reactant: C=CCBr
Reactant: Oc1cc(C(F)(F)F)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1cc(C(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 2-chloro-5-trifluoromethyl-phenol (10.00 g, 0.05 mol) in N,N-dimethylformamide (500 mL) was added potassium carbonate (28.12 g, 0.209 mol) followed by allyl bromide (7.38 g, 0.061 mol) and the reaction was allowed to stir at room temperature for 12 h. The reaction mixture was diluted with water (500 mL) to dissolve any solids and extracted with ethyl acetate (3×250 mL). The combined organic layers were washed with water (4×500 mL), saturated aqueous sodium chloride (400 mL), dried (magnesium sulfate) and the solvent removed in vacuo to give 2-(allyloxy)-1-chloro-4-(trifluoromethyl)benzene as a colorless oil. The oil was re-dissolved in mesitylene (35 mL) and heated at reflux for 12 h. Removal of the solvent in vacuo provided a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 2:8) provided 9.6 g (96%) of 2-allyl-6-chloro-3-(trifluoromethyl)phenol as a amber oil. Rf=0.66 (silica, ethyl acetate:hexanes 1:4); 1H NMR (DMSO-d6) δH 9.84 (s, 1H); 7.43 (d, 2H); 7.16 (d, 1H); 5.84 (m, 1H); 4.95 (d, 1H); 4.89 (d, 1H); 3.46 (d, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([Cl:20])=[CH:16][C:17]=2[Cl:19])[N:12]=[C:11]([C:21]([OH:23])=[O:22])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][N:25]([CH3:30])[CH2:26][CH2:27][CH2:28]O>S(Cl)(Cl)=O>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([Cl:20])=[CH:16][C:17]=2[Cl:19])[N:12]=[C:11]([C:21]([O:23][CH2:28][CH2:27][CH2:26][N:25]([CH3:30])[CH3:24])=[O:22])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)CCCO
Reactant: O=C(O)c1cc(OCc2ccccc2)c2c(Cl)cc(Cl)cc2n1
Solvent: O=S(Cl)Cl
Product: CN(C)CCCOC(=O)c1cc(OCc2ccccc2)c2c(Cl)cc(Cl)cc2n1

Procedure:
Treatment of 4-benzyloxy-5,7-dichloroquinoline-2-carboxylic acid (1 g, Example 33b) with thionyl chloride (10 ml) followed by 3-dimethylamino- 1-propanol (1.1 ml) as described in Example 33c gave 3-dimethylaminopropyl 4-benzyloxy-5,7-dichloroquinoline-2-carboxylate (0.52 g). δ (360 MHz, DMSO-d6) 1.93 (2H, m, CO2CH2CH2), 2.20 (6H, s, (CH3)2), 2.44 (2H, t, CH2N), 4.40 (2H, t, CO2CH2), 5.50 (2H s, OCH2), 7.34 (3H, m, m,p-ArH), 7.58 (2H, d, 2 ArH), 7.72 (1H, s, 3-H), 7.88 (1H, d, 6-H) and 8.14 (1H, d, 8-H).