Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[C:20]([C:27]([F:30])([F:29])[F:28])[CH:19]=1>>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:25]([NH:24][C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][C:20]=2[C:27]([F:29])([F:28])[F:30])=[O:26])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: O=C=Nc1ccc(Cl)cc1C(F)(F)F
Reactant: COc1ccc(N)cc1-c1c(Cl)cnn1C
Product: COc1ccc(NC(=O)Nc2ccc(Cl)cc2C(F)(F)F)cc1-c1c(Cl)cnn1C
Yield: 8 %

Procedure:
3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 4-chloro-2-trifluoromethylphenyl isocyanate in a similar manner as described in Example 1.53, providing 4.4 mg (8%) of Compound 79 (Note: Compound 79 did not precipitate out. Therefore, the CH2Cl2 was removed under reduced pressure, the residue was dissolved in 5 mL DMSO, and purified by preparative HPLC): LCMS m/z (%)=461 (M+H37Cl, 60), 459 (M+H35Cl, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.99 (s, 1H), 8.30 (s, 1H), 8.16 (dd, J1=8 Hz, J2=2 Hz, 1H), 8.01 (d, J=8 Hz, 1H), 7.66 (s, 1H), 7.64 (d, J=4 Hz, 1H), 7.45 (d, J=4 Hz, 1H), 7.43 (s, 1H), 7.12 (d, J=8 Hz, 1H), 3.79 (s, 3H), 3.63 (s, 3H).
Reaction SMILES: Br[C:2]1C=CC(C(OC)=O)=C(C)C=1.[F:13][C:14]1[C:22]([I:23])=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[C:16]([CH3:24])[CH:15]=1>>[F:13][C:14]1[C:22]([I:23])=[CH:21][C:17]([C:18]([O:20][CH3:2])=[O:19])=[C:16]([CH3:24])[CH:15]=1
Reactant: Cc1cc(F)c(I)cc1C(=O)O
Reactant: COC(=O)c1ccc(Br)cc1C
Product: COC(=O)c1cc(I)c(F)cc1C

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 6.1, except 4-fluoro-5-iodo-2-methylbenzoic acid (compound 101.1) was used in place of 4-bromo-2-methylbenzoic acid.
Reaction SMILES: [O:1]=[C:2]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][S:13][C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[CH2:7][C@@H:6]1[C:19]([O:21]C)=[O:20].[OH-].[Na+]>Cl>[O:1]=[C:2]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][S:13][C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[CH2:7][C@@H:6]1[C:19]([OH:21])=[O:20]
Reactant: COC(=O)[C@H]1CN(CCSc2cccs2)CC[C@H]1CCC(=O)c1ccnc2ccc(OC)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc2nccc(C(=O)CC[C@@H]3CCN(CCSc4cccs4)C[C@@H]3C(=O)O)c2c1
Temperature: 20 °C
Reaction time: 5 h
Yield: 95.7 %

Procedure:
A mixture of 0.43 g of methyl (3R,4R)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylsulfanyl)-ethyl]piperidine-3-carboxylate in 5 cm3 of 5N hydrochloric acid is brought to a temperature in the region of 80° C. with stirring and under an inert atmosphere for 5 hours. After cooling to around 20° C., the reaction medium is neutralized with 4.7 cm3 of 5N sodium hydroxide until a pH of 6 is obtained, and is then extracted with 30 cm3 of dichloromethane. The organic phase is dried over magnesium sulfate, filtered, and then evaporated to dryness under reduced pressure (2 kPa) at a temperature in the region of 30° C. The residue obtained is purified by chromatography on a column of silica gel (particle size 70–200 μm; diameter 2 cm), eluting with a mixture of chloroformmethanol-aqueous ammonia (28%) (12/3/0.5 by volume) and collecting fractions of 10 cm3. The fractions containing the expected product are pooled and then evaporated according to the conditions described above. 0.4 g of (3R,4R)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylsulfanyl)ethyl]piperidine-3-carboxylic acid, in the form of a yellow-colored oil, is obtained.
Reaction SMILES: [C:1]([N:5]([CH2:10][CH2:11][C:12]([OH:22])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:13][CH:14]=[CH2:15])[C:6](=[O:9])OC)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+]>C1COCC1>[CH2:13]([C:12]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[O:22][C:6](=[O:9])[N:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][CH2:11]1)[CH:14]=[CH2:15]
Reactant: C=CCC(O)(CCN(C(=O)OC)C(C)(C)C)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCC1(c2ccccc2)CCN(C(C)(C)C)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.3 %

Procedure:
To a solution of methyl tert-butyl(3-hydroxy-3-phenylhex-5-enyl)carbamate (600 mg, 1.97 mmol) in dry THF (10 mL) was added NaH (236 mg, 5.91 mmol) at 0° C. under N2, and the mixture was stirred at rt overnight. The reaction was quenched with water, and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to afford the crude product, which was purified by preparative TLC to give 6-allyl-3-tert-butyl-6-phenyl-1,3-oxazinan-2-one (325 mg, 61%). 1H NMR (CDCl3): 1.23 (s, 9H), 2.01-2.21 (m, 1H), 2.28-2.34 (m, 1H), 2.45-2.59 (m, 2H), 2.71-2.81 (m, 1H), 3.13-3.21 (m, 1H), 4.92-5.02 (m, 2H), 5.53-5.63 (m, 1H), 7.21-7.34 (m, 5H).
Reaction SMILES: [CH3:1][C@@H:2]([NH:12][CH2:13][C@H:14]([OH:25])[C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([NH:22][CH:23]=[O:24])[CH:16]=1)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.[C@H:26]([OH:35])([C:32]([OH:34])=[O:33])[C@@H:27]([OH:31])[C:28]([OH:30])=[O:29].CO>C(#N)C>[CH3:1][C@@H:2]([NH:12][CH2:13][C@H:14]([OH:25])[C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([NH:22][CH:23]=[O:24])[CH:16]=1)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.[C:28]([C@@H:27]([C@H:26]([C:32]([O-:34])=[O:33])[OH:35])[OH:31])([O-:30])=[O:29]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: COc1ccc(C[C@@H](C)NC[C@H](O)c2ccc(O)c(NC=O)c2)cc1
Solvent: CC#N
Solvent: CO
Product: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A suspension of 1.007 g (2 mmol) of (R,R)-arformoterol tartrate Form A and 65 mL of methanol was heated to the reflux temperature of the solvent for 30 min. Then, the solution obtained was cooled to 50° C. in 30 min, followed by addition of 90 mL of acetonitrile at the same temperature for 10 minutes. Afterwards, the solution was cooled to 30° C. in 30 minutes and stirred at room temperature for 2 hours. The product was collected by filtration, washed with acetonitrile and dried under vacuum (2-3 mbar, equivalent to 1.5-2.25 mm Hg) at 40° C. for 17 hours to provide acetonitrile solvate of (R,R)-Formoterol-L-tartrate, which contained about 2.7% (w/w) of acetonitrile, as determined by TGA analysis.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.C(N(CC)CC)C.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27](Cl)=[O:28]>ClCCl>[NH:5]1[CH2:4][CH2:3][CH:2]([NH:1][C:27]([C:23]2[S:22][CH:26]=[CH:25][CH:24]=2)=[O:28])[CH2:7][CH2:6]1
Reactant: O=C(Cl)c1cccs1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CCNCC1)c1cccs1
Reaction time: 0.08 h

Procedure:
Commercially available tert-butyl 4-aminopiperidine-1-carboxylate (0.50 g, 1.0 eq) was taken up in dichloromethane and treated with triethylamine (0.42 mL, 1.2 eq). After stirring for 5 minutes, thiophene-2-carbonyl chloride (0.29 ml, 1.1 eq) was slowly added. The reaction stiffed for 15 hours at room temperature. To work up, dichloromethane (5 mL) was added. The organics were washed with water (3×-5 mL) then dried over Na2SO4 and concentrated for 0.80 g tan oil (obs M+Na 323, calc M+Na 323). This product was dissolved in dioxane (5 mL) and treated with 4 N HCl in dioxane (1.88 ml). After stiffing for 15 hours at room temperature, the reaction was concentrated to oily residue (0.63 g, 100% over 2 steps, calc M+H 211, obs M+H 211).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11](=[O:17])[NH:12][CH:13]=[N:14]2)=[CH:9][CH:8]=1.[Na].FC1C=C(C=CC=1)CO.FC1C=C2[C:35]([C:36](=[O:42])[NH:37]C=N2)=CC=1.Cl>O>[F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11](=[O:17])[N:12]([CH2:35][C:36]([NH2:37])=[O:42])[CH:13]=[N:14]2)=[CH:9][CH:8]=1
Reactant: O=c1[nH]cnc2cc(F)ccc12
Reactant: O=c1[nH]cnc2cc(OCc3cccc(F)c3)ccc12
Agent: Cl
Agent: OCc1cccc(F)c1
Agent: [Na]
Solvent: O
Product: NC(=O)Cn1cnc2cc(OCc3cccc(F)c3)ccc2c1=O
Temperature: 25 °C
Yield: 61 %

Procedure:
7-(3-Fluoro-benzyloxy)-3H-quinazolin-4-one: Sodium (1.8 g, 78.6 mmol) was added portionwise to 3-fluorobenzyl alcohol and the resulting mixture heated at 80–90° C. for 4 h under Argon. The resulting suspension was cooled to rt and 7-fluoro-3H-quinazolin-4-one (3.2 g, 19.5 mmol) was added and the resulting mixture heated at 130–140° C. for 14 h. The solid formed was then dissolved with water (400 mL) and the mixture acidified to pH 3–4 with HCl (4 N). The resulting precipitate was then filtered off, washed with water (100 mL) and diethylether (100 mL). Recrystallisation from tetrahydrofuran: ethylacetate (1:1) afforded the title compound (3.2 g, 61%) as white crystals. MS: m/e=271.3 (M+H+).
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]([O:8][CH3:9])=[O:7])(=[O:4])=[O:3].I[CH2:11][CH2:12][CH2:13]I.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:1][S:2]([C:5]1([C:6]([O:8][CH3:9])=[O:7])[CH2:13][CH2:12][CH2:11]1)(=[O:4])=[O:3]
Reactant: COC(=O)CS(C)(=O)=O
Reactant: ICCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)C1(S(C)(=O)=O)CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.8 %

Procedure:
To a solution of methyl methylsulfonylacetate (1.0 g, 6.6 mmol) in 20 mL of acetonitrile was added 1,3-diiodopropane (2.3 mL, 20 mmol) and cesium carbonate (6.4 g, 20 mmol). After stirring at room temperature for 2 h, the reaction was partitioned between water (50 mL) and ethyl acetate (100 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness, and the residue was purified by flash chromatography on silica gel eluting with 20 to 50% ethyl acetate in hexane to give methyl 1-methylsulfonylcyclobutanecarboxlate (1.0 g, 79%). δ 3.84 (s, 3H), 3.02 (s, 3H), 2.84-2.65 (m, 4H), 2.25-2.02 (m, 2H).
Reaction SMILES: [CH2:1]([CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12]C)[CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].Cl.N1C=CC=CC=1>O>[CH2:1]([CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCC1CCc2ccc(OC)cc21
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCC1CCc2ccc(O)cc21
Temperature: 210 °C
Yield: 84.8 %

Procedure:
A mixture of 41 g of 3-ethyl-5-methoxy-indane and 111 g of pyridine hydrochloride was heated for 5 hours at 210° C. After it had cooled, 800 ml of water were added. The aqueous phase was extracted by shaking with chloroform. The combined organic phases were washed until neutral, and dried. Molecular distillation gave 32 g of 3-ethyl-5-hydroxy-indane; boiling point : 144° C/10 mm Hg. ##STR29##
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:6][C@H:5]([C:7](Cl)=[O:8])[CH2:4][O:3]1.Cl.[NH:12]1[CH2:17][CH2:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:28][C@H:27]([CH2:29][N:30]4[N:34]=[N:33][CH:32]=[N:31]4)[O:26][C:25]3=[O:35])=[CH:20][C:19]=2[F:36])=[CH:14][CH2:13]1.N1C=CC=CC=1>ClCCl>[CH3:1][C:2]1([CH3:10])[O:6][C@H:5]([C:7]([N:12]2[CH2:17][CH2:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:28][C@H:27]([CH2:29][N:30]5[N:34]=[N:33][CH:32]=[N:31]5)[O:26][C:25]4=[O:35])=[CH:20][C:19]=3[F:36])=[CH:14][CH2:13]2)=[O:8])[CH2:4][O:3]1
Reactant: CC1(C)OC[C@@H](C(=O)Cl)O1
Reactant: O=C1O[C@@H](Cn2ncnn2)CN1c1ccc(C2=CCNCC2)c(F)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)OC[C@@H](C(=O)N2CC=C(c3ccc(N4C[C@H](Cn5ncnn5)OC4=O)cc3F)CC2)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.7 %

Procedure:
(4S)-2,2-Dimethyl-1,3-dioxolane-4-carbonyl chloride (350 mg, 2.10 mM) was added dropwise to a stirred suspension of (5R)-3-(4-(1,2,5,6-tetrahydropyridin-4-yl)-3-fluoro-phenyl)-5-(tetrazol-2-ylmethyl)oxazolidin-2-one hydrochloride (500 mg, 1.31 mM) and pyridine (0.52 g, 6.57 mM) in dichloromethane (20 ml) with ice/water cooling. The reaction was allowed to warm to room temperature and stirred 1 hour. The resulting solution was washed with water and saturated brine, dried (magnesium sulfate) and evaporated to a small volume. Addition of diethyl ether gave the title compound (600 mg) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH:13]=[CH2:14])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH2:15]([Zn]CC)C.FC(F)(F)C(O)=O.C(I)I>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH:13]2[CH2:15][CH2:14]2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CC[Zn]CC
Reactant: C=COc1ccc(Cl)cc1C(=O)OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ICI
Product: COC(=O)c1cc(Cl)ccc1OC1CC1
Reaction time: 0.33 h
Yield: 92 %

Procedure:
To a solution of methyl 5-chloro-2-(vinyloxy)benzoate in 100 mL dichloromethane was added diethylzinc (1 M hexanes solution) (200 mL, 0.2 mol) under N2 atmosphere. The solution was cooled in an ice bath and a solution of trifluoroacetic acid (16 mL) in dichloromethane (100 mL) was dropped very slowly into the mixture. After stirring for 20 minutes, a solution of CH2I2 (16.4 mL, 0.2 mol) in dichloromethane (100 mL) was added dropwise. After stirring an additional 20 minutes, a solution of methyl 5-chloro-2-(vinyloxy)benzoate (21.3 g, 0.1 mol) in dichloromethane (100 mL) was added and the ice bath was removed. 8 hours later, the mixture was quenched with saturated NH4Cl solution and extracted twice with dichloromethane. The combined organics were dried over Na2SO4, filtered and evaporated to dryness to afford 21 g (92%) of methyl 5-chloro-2-cyclopropoxybenzoate. 1H NMR (400 MHz, CDCl3) δ: 7.75 (d, 1H), 7.43 (q, 1H), 3.86 (s, 3H), 3.80 (m, 1H), 0.85 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([N:10]2[N:14]=[C:13]([CH3:15])[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:11]2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.[N:22]1[N:23]=[CH:24][N:25]([CH2:27][C:28](OCC)=[O:29])[CH:26]=1.C(O)(=O)C.N1CCCCC1>C(O)C>[N:22]1[N:23]=[CH:24][N:25]([C:27]2[C:28](=[O:29])[O:1][C:2]3[C:3]([CH:4]=2)=[CH:6][CH:7]=[C:8]([N:10]2[N:14]=[C:13]([CH3:15])[C:12]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:11]2)[CH:9]=3)[CH:26]=1
Reactant: Cc1nn(-c2ccc(C=O)c(O)c2)nc1-c1ccccc1
Reactant: CCOC(=O)Cn1cnnc1
Solvent: CCO
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: Cc1nn(-c2ccc3cc(-n4cnnc4)c(=O)oc3c2)nc1-c1ccccc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
15.0 g (50.0 mmols) of the Na salt of 2-hydroxy-4-(4-methyl-5-phenyl-2H-1,2,3-triazol-2-yl)-benzaldehyde, 7.75 g (50.0 mmols) of ethyl 1,2,4-triazol-4-yl-acetate, 1.50 g (25.0 mmols) of glacial acetic acid and 500 mg (6.00 mmols) of piperidine are refluxed in 70 ml of anhydrous ethanol for 8 hours under an N2 atmosphere. The mixture is rapidly filtered off under suction and the residue is washed with ethanol and water. Finally, the residue is again stirred with 100 ml of ethanol for 2 hours at 60° C., and the mixture is filtered off under suction and the residue is dried: 12.0 g (65%) of a pale yellow crystalline powder. Recrystallisation from dimethylformamide yields 9.64 g (52%) of 3-(1,2,4-triazol-4-yl)-7-(4-methyl-5-phenyl-2H-1,2,3-triazol-2-yl)-coumarin in the form of pale yellow microplatelets of melting point 324°-326° C. (decomposition).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([C:10]([OH:12])=[O:11])[CH2:6][CH2:5]1)[CH2:2][CH3:3].[Br:13][CH2:14][C:15]([CH3:19])([CH3:18])[CH2:16]O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:13][CH2:14][C:15]([CH3:19])([CH3:18])[CH2:16][O:11][C:10]([CH:7]1[CH2:8][CH2:9][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6]1)=[O:12]
Reactant: CCCC1CCC(C(=O)O)CC1
Reactant: CC(C)(CO)CBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCC1CCC(C(=O)OCC(C)(C)CBr)CC1
Temperature: 25 °C

Procedure:
4-Propyl-cyclohexanecarboxylic acid (10.0 g, 58.0 mmol), 3-bromo-2,2-dimethyl-propan-1-ol (10.0 g, 59.9 mmol) and a catalytic amount of para-toluene sulphonic acid are stirred under reflux in toluene (300 ml) in a flask equipped with Dean-Stark apparatus over night. The solution is allowed to cool to room temperature, is washed with aqueous sodium carbonate and water, dried and evaporated to dryness. Purification is achieved by filtration through a silica pad using petrol as eluant. Evaporation of the appropriate fractions gives 4-propyl-cyclohexanecarboxylic acid 3-bromo-2,2-dimethyl-propyl ester as a liquid. The structure is confirmed by GCMS.
Reaction SMILES: [CH2:1]([N:8]([CH:20]1[CH2:26][CH2:25][CH2:24][C:23]2[CH:27]=[CH:28][C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:30][C:22]=2[CH2:21]1)[CH2:9][C@H:10]([OH:19])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[Si:40]([CH2:45][CH3:46])([CH2:43][CH3:44])[CH2:41][CH3:42].N1C=CN=C1.O>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH2:1]([N:8]([CH2:9][C@H:10]([O:19][Si:40]([CH2:45][CH3:46])([CH2:43][CH3:44])[CH2:41][CH3:42])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:20]1[CH2:26][CH2:25][CH2:24][C:23]2[CH:27]=[CH:28][C:29]([O:31][CH2:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[CH:30][C:22]=2[CH2:21]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[Si](Cl)(CC)CC
Reactant: O[C@H](COc1ccccc1)CN(Cc1ccccc1)C1CCCc2ccc(OCc3ccccc3)cc2C1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)O[C@H](COc1ccccc1)CN(Cc1ccccc1)C1CCCc2ccc(OCc3ccccc3)cc2C1

Procedure:
Under nitrogen, a solution of (2S)-1-[N-benzyl-(3-benzyloxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol (20 g), chlorotriethylsilane (7.4 ml), imidazole (3.2 g) and 4-dimethylaminopyridine (0.48 g) in N,N-dimethylformamide (200 ml) was stirred at room temperature for 12 hours. The resulting mixture was poured into water, and extracted with ethyl acetate-hexane (1:1). The organic layer was successively washed with saturated aqueous sodium hydrogencarbonate and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo to give N-benzyl-N-(3-benzyloxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-[(2S)-3-phenoxy-2-(triethylsilyloxy)-propyl]amine (25 g).
Reaction SMILES: C(=[O:4])CC.[CH3:5][CH:6]1[CH2:11][CH:10]([O:12][CH2:13][C:14](Cl)=[O:15])[CH:9]([CH:17]([CH3:19])[CH3:18])[CH2:8][CH2:7]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO>N1C=CC=CC=1.C1COCC1>[CH3:5][CH:6]1[CH2:11][CH:10]([O:12][CH2:13][C:14]([OH:4])=[O:15])[CH:9]([CH:17]([CH3:19])[CH3:18])[CH2:8][CH2:7]1
Reactant: CC1CCC(C(C)C)C(OCC(=O)Cl)C1
Reactant: CCC=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC1CCC(C(C)C)C(OCC(=O)O)C1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
1-Propenyl L-menthoxyacetate is prepared from propionaldehyde, L-menthoxyacetyl chloride, and pyridine catalyst. A 70 mL stainless steel high pressure reactor fitted with a Pyrex glass liner and magnetic stir bar is charged with THF (5 mL), PPh3)2PdCl2 (0.05 mmol), CH3OH (0.5 mmol), and 1-propenyl L-menthoxyacetate (0.5 mmol). The reactor is sealed, pressurized to 1000 psig with CO, and stirred for 24 hours at 100° C. The product mixture, isolated after removal of gas from the reactor vessel, contains a diastereomeric mixture of methyl L-menthoxyacetyl-L-2-hydroxybutyrate and methyl L-menthoxyacetyl-D-2-hydroxybutyrate. The diastereomers are separated by preparative gas chromatography using an SE-30 liquid phase column. Each diastereomer is hydrolyzed separately by treatment with 2N HCl (aq) for 2 hours at 100° C. to give pure L- and D-2-hydroxybutyric acid, methanol, and L-menthoxyacetic acid.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[CH3:6][C:7]1[CH:18]=[CH:17][CH:16]=[C:9]2[C:10]([O:12][C:13](=[O:15])[NH:14][C:8]=12)=[O:11].S(=O)(=O)(O)O>>[CH3:6][C:7]1[CH:18]=[C:17]([N+:1]([O-:4])=[O:2])[CH:16]=[C:9]2[C:10]([O:12][C:13](=[O:15])[NH:14][C:8]=12)=[O:11]
Reactant: Cc1cccc2c(=O)oc(=O)[nH]c12
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1cc([N+](=O)[O-])cc2c(=O)oc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Potassium nitrate (1.43 g, 14.1 mmole) was added in small portions at <30° C. with external water-bath cooling to a solution of 3-methyl isatoic anhydride (2.50 g, 14.1 mmole) and concentrated sulfuric acid (8 mL). The resulting mixture was stirred at 25° C. for 1.5 hours and then was poured into approximately 200 g of ice with stirring. After the ice had melted, the solid product was isolated by filtration and washed with dilute aqueous HCl and then air-dried. The product was suspended in acetonitrile (50 mL) and concentrated in vacuo to give 2.75 of a yellow solid. 1H NMR (DMSO-d6): δ 11.6 (br s, 1H), 8.45 (d, 1H), 8.42 (d, 1H), 2.43 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([OH:11])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18]([Br:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>C(#N)C>[CH2:18]([Br:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[CH2:18]([O:11][C:4]1[CH:3]=[C:2]([Cl:1])[CH:10]=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NC(=O)c1ccc(Cl)cc1O
Agent: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: NC(=O)c1ccc(Cl)cc1OCc1ccccc1
Temperature: 80 °C
Yield: 107.7 %

Procedure:
To a solution of 4-chloro-2-hydroxybenzamide (0.608 g, 3.54 mmol) in acetonitrile (50 ml) was added dried K2CO3 (1.71 g, 12.40 mmol) followed by benzyl bromide (0.63 ml, 5.32 mmol) and the resulting reaction mixture was refluxed at 80° C. for 16 h. After the completion of the reaction (TLC monitoring), water was added followed by extraction with EtOAc (3×100 ml). The combined organics was dried over anhydrous Na2SO4, filtered and concentrated. The residue was washed repeatedly with hexane to get rid of the excess of benzyl bromide resulting the desired product (0.75 g, 81%).
Reaction SMILES: C(O[C:4]([CH:6]1[CH2:11][NH:10][CH2:9][CH2:8][NH:7]1)=O)C.[CH:12](Br)([CH3:14])[CH3:13]>>[CH:12]([N:7]1[CH2:8][CH2:9][N:10]([CH:6]([CH3:11])[CH3:4])[CH2:11][CH:6]1[C:4]1[NH:7][CH2:8][CH2:9][N:10]=1)([CH3:14])[CH3:13]
Reactant: CCOC(=O)C1CNCCN1
Reactant: CC(C)Br
Product: CC(C)N1CCN(C(C)C)C(C2=NCCN2)C1
Yield: 35 %

Procedure:
Reacting 2-ethoxycarbonylpiperazine with 2,2 aquivalents of isopropyl bromide in the same conditions as for example 21, and treating the obtained product in the same conditions as for example 1, step d, the desired product is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH2:7].[CH3:13][O:14][C:15](=[O:36])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[C:24](Cl)[C:25]3[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[S:28][C:26]=3[N:27]=2)=[CH:18][CH:17]=1>>[CH3:13][O:14][C:15](=[O:36])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[C:24]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:25]3[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[S:28][C:26]=3[N:27]=2)=[CH:18][CH:17]=1
Reactant: COc1ccc(CN)cc1OC
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3cc(C(F)(F)F)sc3n2)cc1
Product: COC(=O)c1ccc(-c2nc(NCc3ccc(OC)c(OC)c3)c3cc(C(F)(F)F)sc3n2)cc1

Procedure:
The reaction procedure as above wherein 3,4-dimethoxy-benzylamine is reacted with 4-(4-chloro-6-trifluoromethyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3,4-dimethoxybenzylamino)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@@H:9]2[CH:11]=[CH2:12])=[CH:4][CH:3]=1.CCCCCC.C(OCC)(=[O:21])C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@@H:9]2[CH2:11][CH2:12][OH:21])=[CH:4][CH:3]=1
Reactant: C=C[C@H]1C[C@@H]1c1ccc(Br)cc1
Reactant: CCOC(C)=O
Solvent: CCCCCC
Product: OCC[C@H]1C[C@@H]1c1ccc(Br)cc1

Procedure:
The product from Example 30B was subjected to the conditions outlined in Example 26F, followed by chromatography (7:3 hexane/ethyl acetate) to provide the title compound.