Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=O)=[O:4].CCN=C=NCCCN(C)C.Cl.[NH2:34][C:35]1[CH:55]=[CH:54][C:53]([N:56]2[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]2)=[CH:52][C:36]=1[C:37]([NH:39][C:40]1[CH:41]=[N:42][C:43]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[N:44][CH:45]=1)=[O:38]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][N:2]([CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[C:3](=[O:4])[C:5]1[CH:13]=[CH:12][CH:11]=[C:7]([C:8]([NH:34][C:35]2[CH:55]=[CH:54][C:53]([N:56]3[CH2:57][CH2:58][CH2:59][CH2:60][CH2:61]3)=[CH:52][C:36]=2[C:37](=[O:38])[NH:39][C:40]2[CH:45]=[N:44][C:43]([C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)=[N:42][CH:41]=2)=[O:10])[CH:6]=1
Reactant: Nc1ccc(N2CCCCC2)cc1C(=O)Nc1cnc(-c2ccccc2)nc1
Reactant: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2cnc(-c3ccccc3)nc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 32.6 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of 3-(methyl(2-morpholinoethyl)carbamoyl)benzoic acid (314 mg, 1.08 mmol, 2.00 equiv) in dichloromethane (10 mL), EDC.HCl (155 mg, 0.81 mmol, 1.50 equiv), 4-dimethylaminopyridine (99 mg, 0.81 mmol, 1.50 equiv), and 2-amino-N-(2-phenylpyrimidin-5-yl)-5-(piperidin-1-yl)benzamide (200 mg, 0.54 mmol, 1.00 equiv). The resulting solution was stirred for 4 h at 25° C. The resulting mixture was concentrated under vacuum. The crude product (200 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 114 mg (28%) of a yellow solid. 1H-NMR (300 MHz, DMSO, ppm): δ 10.98 (m, 2H), 9.70 (s, 1H), 9.29 (s, 2H), 8.35 (m, 2H), 8.01 (m, 3H), 7.63 (m, 2H), 7.52 (m, 4H), 7.28 (m, 1H), 4.03 (m, 2H), 3.82 (m, 2H), 3.61 (m, 4H), 3.43 (m, 2H), 3.24 (m, 6H), 2.95 (s, 3H), 1.59 (m, 6H). MS (ES, m/z): 648 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:15][CH:14]2[N:16](C(OC(C)(C)C)=O)[CH:10]1[CH2:11][O:12][CH2:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.C(O)(C(F)(F)F)=O>C(OCC)C>[CH2:1]([O:8][CH:9]1[CH2:15][CH:14]2[NH:16][CH:10]1[CH2:11][O:12][CH2:13]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C2COCC1C(OCc1ccccc1)C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: c1ccc(COC2CC3COCC2N3)cc1
Reaction time: 2 h
Yield: 99.9 %

Procedure:
A 250-mL round-bottomed flask was charged with tert-butyl 6-(benzyloxy)-3-oxa-8-azabicyclo[3.2.1]octane-8-carboxylate (4.40 g, 13.78 mmol J. Org. Chem. 2010, 75, 1643) and 15 mL of CH2Cl2. To this was added TFA (10.61 mL, 138 mmol). After 2 h at room temperature, the mixture was concentrated and diluted with saturated aqueous NaHCO3 and CH2Cl2. The layers were separated, the organics were dried (MgSO4), filtered, and concentrated to give a white solid. This solid was slurried with 50 mL of diethyl ether. The resulting white solid was collected by filtration to give 6-(benzyloxy)-3-oxa-8-azabicyclo[3.2.1]octane (3.02 g)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)C(F)(F)F)=[C:4]([CH3:15])[CH:3]=1.[NH2:16][C:17]1[N:22]=[C:21]([NH2:23])[C:20]([CH2:24][C:25]2[CH:26]=[C:27]([O:40][CH2:41][CH3:42])[C:28](I)=[C:29]([O:31][S:32]([CH2:35][CH:36]([CH3:38])[CH3:37])(=[O:34])=[O:33])[CH:30]=2)=[CH:19][N:18]=1>>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:28]2[C:27]([O:40][CH2:41][CH3:42])=[CH:26][C:25]([CH2:24][C:20]3[C:21]([NH2:23])=[N:22][C:17]([NH2:16])=[N:18][CH:19]=3)=[CH:30][C:29]=2[O:31][S:32]([CH2:35][CH:36]([CH3:37])[CH3:38])(=[O:33])=[O:34])=[CH:3][C:4]=1[CH3:15]
Reactant: Cc1cc(Br)ccc1NC(=O)C(F)(F)F
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(OS(=O)(=O)CC(C)C)c1I
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OS(=O)(=O)CC(C)C)c1-c1ccc(N)c(C)c1
Yield: 66 %

Procedure:
Starting from 191 mg (0.68 mmol) N-(4-bromo-2-methyl-phenyl)-2,2,2-trifluoro-acetamide and 173 mg (0.34 mmol) 2-methyl-propane-1-sulphonic acid 5-(2,4-diamino-pyrimidin-5-ylmethyl)-3-ethoxy-2-iodo-phenyl ester, 109 mg of the title compound are obtained as a brown solid after chromatography and stirring in 5 ml ether.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[N:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.C1COCC1.[Li]CCCC.Br[C:20]1[S:24][C:23]([C:25]2[N:29]3[N:30]=[C:31]([CH3:39])[CH:32]=[C:33]([CH:34]([CH2:37][CH3:38])[CH2:35][CH3:36])[C:28]3=[N:27][C:26]=2[CH3:40])=[C:22]([CH3:41])[CH:21]=1>CCOC(C)=O.[Cl-].[Cl-].[Zn+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:35]([CH:34]([C:33]1[C:28]2[N:29]([C:25]([C:23]3[S:24][C:20]([C:4]4[N:3]([N:2]([CH3:8])[CH3:1])[CH:7]=[CH:6][CH:5]=4)=[CH:21][C:22]=3[CH3:41])=[C:26]([CH3:40])[N:27]=2)[N:30]=[C:31]([CH3:39])[CH:32]=1)[CH2:37][CH3:38])[CH3:36]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)cc3C)c(C)nc12
Reactant: CN(C)n1cccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(CC)c1cc(C)nn2c(-c3sc(-c4cccn4N(C)C)cc3C)c(C)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
To a 0° C. solution 1-(dimethylamino)-pyrrole (0.24 mL, 2.04 mmol) and THF (4 mL) is added 1.24 M n-BuLi (1.73 mL, 2.14 mmol). The solution is warmed to ambient temperature and stirred for two hours. 0.5 M ZnCl2 (4.28 mL, 2.14 mmol) is added and the solution is stirred for one hour. 3-(5-Bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.40 g, 1.02 mmol) and PdCl2(dppf) (0.037 g, 0.051 mmol) is added and the solution is heated at 65° C. overnight. The solution is diluted with EtOAc (30 mL), washed with sat. NH4Cl (30 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO flash chromatography (15%-20% EtOAc gradient) furnish the title compound (0.41 g, 0.97 mmol, 95%). 1H NMR (CDCl3) δ 0.87 (t, J=7.5 Hz, 6H), 1.73-1.91 (m, 4H), 2.11 (s, 3H), 2.51 (s, 6H), 2.83 (s, 6H), 3.29-3.39 (m, 1H), 6.18-6.21 (m, 1H), 6.35 (dd, J=4.0, 1.8 Hz, 1H), 6.65 (s, 1H), 6.98 (dd, J=4.0, 1.8 Hz, 1H), 7.25 (s, 1H). LC/MS (m/z): calcd. for C24H31N5S (M+H)+: 422.2; found: 422.4.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]([CH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H-].[Na+].[C:25]1([CH2:31][CH2:32][CH2:33][CH2:34]Br)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CCOCC>COCCOC>[CH2:9]([O:8][C:6](=[O:7])[C:5]([CH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)([CH2:34][CH2:33][CH2:32][CH2:31][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:22])[CH3:10]
Reactant: CCOC(=O)C(Cc1cccc2ccccc12)C(=O)OCC
Reactant: BrCCCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: COCCOC
Product: CCOC(=O)C(CCCCc1ccccc1)(Cc1cccc2ccccc12)C(=O)OCC
Yield: 73.4 %

Procedure:
To a solution of 2.62 g of 2-(1-naphthylmethyl)malonic acid diethyl ester in 40 ml of dry 1,2-dimethoxyethane was added 0.46 g of a 50% sodium hydride (suspension in oil) while ice-cooling, and then 2.05 g of 4-phenylbutyl bromide was added dropwise to the mixture. The mixture was heated under reflux for 19 hours. After cooling, an aqueous ether was added to the reaction mixture and the mixture was extracted with diethyl ether. The ethereal layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: benzene/hexane=1/1 by volume) to obtain 2.77 g of 2-(1-naphthylmethyl)-2-(4-phenylbutyl)malonic acid diethyl ester as a colorless oil.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=4[F:37])=[O:28])=[C:22]([Cl:38])[CH:21]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:39][CH3:40])C1C=CC=CC=1.[H][H].C(OCC)(=O)C>CN(C)C=O.[C].[Pd]>[Cl:38][C:22]1[CH:21]=[C:20]([O:19][C:13]2[C:12]3[C:17](=[CH:18][C:9]([OH:8])=[C:10]([O:39][CH3:40])[CH:11]=3)[N:16]=[CH:15][CH:14]=2)[CH:25]=[CH:24][C:23]=1[NH:26][C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[F:37])=[O:28]
Reactant: [H][H]
Reactant: COc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(Cl)c3)ccnc2cc1OCc1ccccc1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(Cl)c3)ccnc2cc1O
Yield: 96.4 %

Procedure:
N-(4-{[7-(Benzyloxy)-6-methoxy-4-quinolyl]oxy}-2-chlorophenyl)-N′-(2,4-difluorophenyl)urea (215 mg) was dissolved in dimethylformamide (11 ml). Palladium-carbon (215 mg) was added to the solution, and the mixture was stirred in a hydrogen atmosphere at room temperature overnight. Ethyl acetate (30 ml) was added to the reaction solution, and the mixture was then filtered through Celite. The solvent was removed by distillation under the reduced pressure to give 174 mg (yield 96%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][CH2:4]Cl)[CH3:2].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:18][C:19](=[O:28])[C:20]2[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[CH:21]=2)[CH2:15][CH:16]=[CH2:17])=[CH:9][CH:8]=1.[OH-].[Na+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)C1C=CC=CC=1.ClCCl>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:18]([CH2:4][O:3][CH2:1][CH3:2])[C:19](=[O:28])[C:20]2[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[CH:21]=2)[CH2:15][CH:16]=[CH2:17])=[CH:9][CH:8]=1
Reactant: CCOCCl
Reactant: C=CCC(Cc1ccc(Cl)cc1)NC(=O)c1cc(C)cc(C)c1
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: C=CCC(Cc1ccc(Cl)cc1)N(COCC)C(=O)c1cc(C)cc(C)c1

Procedure:
2.36 ml (25.2 mmol) of chloromethyl ethyl ether are added in small portions over the course of 2 hours to a vigorously stirred solution of 5.5 g (16.8 mmol) of N-{5-(4-chlorophenyl)pent-1-en-4-yl}-3.5-dimethylbenzamide and 100 mg of benzyltributylammonium chloride in 15 ml of 50% strength aqueous sodium hydroxide solution and 15 ml of dichloromethane at 0°-5°. The organic phase is taken up in dichloromethane and water, the organic phase is separated off, dried over sodium sulfate and evaporated to dryness under reduced pressure. The oily residue is purified by chromatography on silica gel with ethyl acetate/hexane (1:4) as mobile phase; TLC (ethyl acetate/hexane; 1:3):Rf =0.50; 1H-NMR (300 MHz, CDCl3):mixture of rotamers, δ=7.31-7.18 (m, 4 H), 7.04-6.85 (m, 2.6 H), 6.42 (hr. s, 0.4 H), 5.92-5.60 (m, 1 H), 5.20-5.02 (m, 2 H), 4.54-4.24 (m, 2 H), 3.96-3.67 (m, 1 H), 3.25-2.40 (m, 6 H), 2.28 (s, ca 5 H), 2.24 (s, ca 1 H), 1.34-1.21(m, ca 0.5 H), 1.08 (t, J=7, ca 2.5 H).
Reaction SMILES: S(=O)(=O)(O)O.[OH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.[CH3:22][CH2:23]CCCC>C(O)C>[CH2:22]([O:18][C:17](=[O:19])[C:16]1[CH:20]=[CH:21][C:13]([C:10]2[CH:9]=[CH:8][C:7]([OH:6])=[CH:12][CH:11]=2)=[CH:14][CH:15]=1)[CH3:23]
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: CCCCCC
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCOC(=O)c1ccc(-c2ccc(O)cc2)cc1

Procedure:
At room temperature, 0.7 ml of concentrated sulfuric acid was added to 5.00 g of 4-(4-hydroxyphenyl)benzoic acid suspended in 50 ml of ethanol. After the mixture was refluxed with heating for 7 hours, the mixture was concentrated under reduced pressure. Water and ethyl acetate were added to the residue, and then the organic layer was washed in order with water, saturated sodium hydrogen carbonate and saturated sodium chloride solution. And it was dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. Obtained crude crystals were purified by silica gel column chromatography with toluene-ethyl acetate eluent. Obtained crystals were dispersed by hexane and collected by filtration and washed with hexane. 4-(4-hydroxyphenyl)benzoate ethylester 5.04 g was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]([C:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16]CC3C=CC=CC=3)=[CH:13][CH:14]=2)[N:9]([CH2:24][CH3:25])[CH:8]=1)=O)[CH3:2]>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:7]1[C:15]2[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=2)[N:9]([CH2:24][CH3:25])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(=O)c1cn(CC)c2cc(OCc3ccccc3)ccc12
Solvent: C1COCCO1
Product: CCOC(=O)Cc1cn(CC)c2cc(O)ccc12
Temperature: 25 °C
Yield: 95 %

Procedure:
(6-Benzyloxy-1-ethyl-1H-indol-3-yl)-oxo-acetic acid ethyl ester (0.843 g, 2.40 mmol) is dissolved in anhydrous dioxane (10 mL) then purged and back filled with nitrogen a few times. Palladium on carbon (10%) (0.200 g, 20% by wt.) is added and the reaction followed by heating to reflux. Slow addition of a saturated solution of sodium hypophosphite is initiated and the reaction is monitored by TLC. After the starting material is completely consumed, the reaction is allowed to cool to room temperature, diluted with dichloromethane and celite added. The mixture is filtered through a plug of celite and the two phases are separated. The organic layer is washed with water and brine, dried over sodium sulfate, then concentrated. The residue is further purified using flash column chromatography. The (1-Ethyl-6-hydroxy-1H-indol-3-yl)-acetic acid ethyl ester (0.564 g, 2.28 mmol) is formed in 95% yield.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]([OH:17])=[O:16])=[C:13]([CH3:18])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:11](=[O:29])[N:10]2[S:30]([CH3:33])(=[O:32])=[O:31])=[C:5]([S:34]([CH3:37])(=[O:36])=[O:35])[CH:4]=1)#[N:2].Br[CH2:39][CH2:40][OH:41].C(N(CC)CC)C>CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]([O:17][CH2:39][CH2:40][OH:41])=[O:16])=[C:13]([CH3:18])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:27])([F:28])[F:26])[CH:20]=3)[C:11](=[O:29])[N:10]2[S:30]([CH3:33])(=[O:31])=[O:32])=[C:5]([S:34]([CH3:37])(=[O:35])=[O:36])[CH:4]=1)#[N:2]
Reactant: OCCBr
Reactant: CC1=C(C(=O)O)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(S(C)(=O)=O)C(=O)N1c1cccc(C(F)(F)F)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1=C(C(=O)OCCO)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(S(C)(=O)=O)C(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
The reaction was carried out under argon. (4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-6-methyl-3-(methylsulfonyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (84 mg, 150 μmol) was initially charged in dry DMF (2 ml), 2-bromoethanol (75 mg, 600 μmol; 4 eq.) and triethylamine (31 mg, 300 μmol; 2 eq.) were added and the mixture was stirred at 70° C. for 8 h. The reaction mixture was then concentrated under reduced pressure, and the residue was taken up in ethyl acetate (50 ml). The organic phase was washed with saturated sodium bicarbonate solution (2×20 ml) and saturated sodium chloride solution (20 ml), dried over solid sodium sulfate, filtered and concentrated under reduced pressure. The crude product was subjected to flash chromatography on silica gel (mobile phase: cyclohexane→cyclohexane/ethyl acetate 1:3). The title compound was obtained as a colorless solid (56 mg, 62% of theory).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:12]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Nc1cc(C(F)(F)F)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A solution of 2-nitro-4-trifluoromethyl-benzoic acid (100 g, 425 mmol) in MeOH (600 mL) was treated with palladium on carbon (10%) and the mixture was stirred at r.t. for 2 h under hydrogen (7 bars). The mixture was then filtered and concentrated in vacuo to give 2-amino-4-trifluoromethyl-benzoic acid (87.2 g, 425 mmol, 100%) as a yellow solid, m.p. 172-173° C., ESI-MS: m/z 206 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:22]([O-])=O)[C:5]([O:8][C:9]2[CH:21]=[CH:20][C:12]([O:13][CH:14]([CH3:19])[C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[H][H]>O1CCOCC1.[Ni]>[NH2:22][C:4]1[C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([O:13][CH:14]([CH3:19])[C:15]([O:17][CH3:18])=[O:16])=[CH:20][CH:21]=2)=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: [H][H]
Reactant: COC(=O)C(C)Oc1ccc(Oc2ncc(Cl)cc2[N+](=O)[O-])cc1
Agent: [Ni]
Solvent: C1COCCO1
Product: COC(=O)C(C)Oc1ccc(Oc2ncc(Cl)cc2N)cc1

Procedure:
190.8 g (0.541 mole) of methyl 2-[4-(5-chloro-3-nitropyridin-2-yloxy)phenoxy]propionate are dissolved in 1.9 l of dioxan. 40 g of Raney nickel catalyst are added and hydrogenation is effected with hydrogen at 20°-25° C. The catalyst is then removed by filtration, the solvent is distilled off and the still warm oily residue is crystallised by stirring it in hexane. The crystalline precipitate is isolated by filtration and dried, affording 167.4 (96% of theory) of methyl 2-[4-(3-amino-5-chloropyridin-2-yloxy)phenoxy]propionate with a melting point of 92°-94° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]=[O:9].[CH3:10][Mg]Br.CCOCC.[NH4+].[Cl-]>C1COCC1>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]([OH:9])[CH3:10]
Reactant: C[Mg]Br
Reactant: O=Cc1ccncc1Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)c1ccncc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a cooled (0° C.) solution of 3-bromo-pyridine-4-carbaldehyde (2.0 g, 10.8 mmol) in dry THF (45 mL) is added methyl magnesium bromide solution in Et2O (3M; 3.9 mL, 11.8 mmol). The mixture is stirred at 0° C. for 1 h then warmed and stirred at room temperature for 1 h. Saturated aqueous NH4Cl solution is added and the mixture is extracted with EtOAc. The organic layers are combined and concentrated to afford 2.1 g of 1-(3-bromo-pyridin-4-yl)-ethanol.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][S+:12]([O-:24])[C:13]2[NH:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH3:23])=[CH:19][C:20]=3[N:21]=2)=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].C1(C(C2C=CC=CC=2)(O)[C@H](C2C=CC=CC=2)O)C=CC=CC=1>C(O)(C)C>[CH3:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH3:10])[C:5]([CH2:11][S@@:12]([C:13]2[NH:21][C:20]3[CH:19]=[C:18]([O:22][CH3:23])[CH:17]=[CH:16][C:15]=3[N:14]=2)=[O:24])=[N:4][CH:3]=1
Reactant: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Agent: O[C@@H](c1ccccc1)C(O)(c1ccccc1)c1ccccc1
Solvent: CC(C)O
Product: COc1ccc2nc([S@@](=O)Cc3ncc(C)c(OC)c3C)[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of omeprazole (250 mg, 0.72 mmol) and (S)-1,1,2-triphenyl-1,2-ethanediol (315 mg, 1.08 mmol) was dissolved in a minimum volume of isopropyl alcohol (10 ml) at reflux temperature. On dissolution, the solution was cooled to ambient temperature slowly with vigorous stirring, and on reaching this temperature was stirred for a further 1 h. The precipitate was filtered, was washed with isopropyl alcohol (2×2 ml) and was dried in vacuo to afford (S)-omeprazole.2[(S)-1,1,2-triphenyl-1,2-ethanediol] inclusion complex (240 mg, 72%, 97% e.e.) as an off-white powder.
Reaction SMILES: [C:1]([O:6][C@@H:7]1[C@@H:15]([CH2:16][CH2:17]I)[C:14](=[O:19])[O:13][CH2:12][C@H:11]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:10](=[O:28])[O:9][C@H:8]1[CH3:29])(=[O:5])[CH:2]([CH3:4])[CH3:3].CCCC[SnH](CCCC)CCCC.CC(N=NC(C#N)(C)C)(C#N)C>C1C=CC=CC=1>[C:1]([O:6][C@@H:7]1[C@@H:15]([CH2:16][CH3:17])[C:14](=[O:19])[O:13][CH2:12][C@H:11]([NH:20][C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[C:10](=[O:28])[O:9][C@H:8]1[CH3:29])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)O[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC(=O)[C@@H]1CCI
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: c1ccccc1
Product: CC[C@H]1C(=O)OC[C@H](NC(=O)OC(C)(C)C)C(=O)O[C@@H](C)[C@@H]1OC(=O)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
To a solution of (3S,6S,7R,8R)-3-(tert-butoxycarbonylamino)-8-(2-iodoethyl)-6-methyl-4,9-dioxo-1,5-dioxonan-7-yl isobutyrate (30 mg, 0.057 mmol) in benzene (1.5 mL) was added Bu3SnH (27 mg, 0.091 mmol) and AIBN (1 mg) at room temperature (about 22° C.), and the reaction solution was heated to reflux. After 1 h, the solution was cooled to room temperature. The solvent was removed under vacuum and the residue was purified via column chromatography (SiO2, hexanes/EtOAc gradient) to afford the title compound (20 mg, 88%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 5.44-5.19 (m, 2H), 5.03 (dd, J=13.0, 6.9 Hz, 1H), 4.91-4.73 (m, 2H), 3.70-3.52 (m, 1H), 2.68-2.52 (m, 1H), 2.45 (ddd, J=19.2, 12.0, 6.2 Hz, 1H), 1.71-1.56 (m, 2H), 1.45 (s, J=9.2 Hz, 9H), 1.26 (d, J=6.2 Hz, 3H), 1.20 (d, J=7.0 Hz, 6H), 0.86 (t, J=7.4 Hz, 3H); ESIMS m/z 424 ([M+Na]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([F:12])[C:3]=1[CH:13]=[O:14].[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([F:12])[C:3]=1[CH2:13][OH:14]
Reactant: CC(=O)Nc1ccc(Cl)c(C=O)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)Nc1ccc(Cl)c(CO)c1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
A 0° C. solution of N-(4-chloro-2-fluoro-3-formylphenyl)acetamide (1.1 g, 5.10 mmol) in MeOH (10 mL) was treated portion-wise with sodium borohydride (0.193 g, 5.10 mmol), stirred at 0° C. for 0.5 h, then warmed to RT and concentrated to dryness. The residue was treated with water, extracted with EtOAc (2×) and the combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness to afford N-(4-chloro-2-fluoro-3-(hydroxymethyl)phenyl)acetamide (1.05 g, 95% yield) as a white solid. MS (ESI) m/z: 218.0 [M+H]+.
Reaction SMILES: C([O:4][CH2:5][C:6]1([CH2:28][O:29]C(=O)C)[S:10][C:9]2[CH:11]=[C:12]3[S:16][C:15]([CH2:22][O:23]C(=O)C)([CH2:17][O:18]C(=O)C)[S:14][C:13]3=[CH:27][C:8]=2[S:7]1)(=O)C.C([O-])([O-])=O.[K+].[K+]>CO>[OH:23][CH2:22][C:15]1([CH2:17][OH:18])[S:14][C:13]2[CH:27]=[C:8]3[S:7][C:6]([CH2:5][OH:4])([CH2:28][OH:29])[S:10][C:9]3=[CH:11][C:12]=2[S:16]1
Reactant: CC(=O)OCC1(COC(C)=O)Sc2cc3c(cc2S1)SC(COC(C)=O)(COC(C)=O)S3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: OCC1(CO)Sc2cc3c(cc2S1)SC(CO)(CO)S3

Procedure:
2,2,6,6-Tetra(acetoxymethyl)benzo[1,2-d:4,5-d']bis(1,3)dithiole (1.8 g, 3.5 mmol) and K2CO3 (1.9 g) were stirred in methanol (100 mL) for 1 h at ambient temperature. The solvent was evaporated and water (100 mL) was added. The mixture was neutralized (2M HCl) and the precipitate was collected.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[N:3]=1.[CH3:9][S:10]([CH3:13])(=[O:12])=[O:11]>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:9][S:10]([CH3:13])(=[O:12])=[O:11])[N:3]=1
Reactant: CS(C)(=O)=O
Reactant: Fc1cccc(Br)n1
Product: CS(=O)(=O)Cc1cccc(Br)n1
Yield: 70 %

Procedure:
The title compound was prepared from 2-bromo-6-fluoro-pyridine and dimethylsulfone following a procedure analogous to that described in Step 1 for Intermediate 14. Yield: ca. 70% of theory (crude); LC (method 3): tR=1.98 min; Mass spectrum (ESI+): m/z=250/252 (Br) [M+H]+.