Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:11]1[CH2:16][C@@H:15]([C:17]([O:19][CH3:20])=[O:18])[CH2:14][C@H:13]([NH:21][CH2:22][C:23]2[CH:28]=[C:27]([O:29][C:30]([F:33])([F:32])[F:31])[CH:26]=[CH:25][C:24]=2[O:34][CH3:35])[C@@H:12]1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=O)C1C=CC=CC=1.C1COCC1>[OH-].[OH-].[Pd+2].CO>[CH3:20][O:19][C:17]([C@@H:15]1[CH2:16][NH:11][C@@H:12]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C@@H:13]([NH:21][CH2:22][C:23]2[CH:28]=[C:27]([O:29][C:30]([F:33])([F:31])[F:32])[CH:26]=[CH:25][C:24]=2[O:34][CH3:35])[CH2:14]1)=[O:18]
Reactant: COC(=O)[C@H]1C[C@H](NCc2cc(OC(F)(F)F)ccc2OC)[C@H](c2ccccc2)N(C(=O)OCc2ccccc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1CN[C@@H](c2ccccc2)[C@@H](NCc2cc(OC(F)(F)F)ccc2OC)C1
Temperature: 25 °C

Procedure:
A mixture of (2S*,3S*,5S*)-1-benzyloxycarbonyl-5-methoxycarbonyl-3-[N-(2-methoxy-5-trifluoromethoxybenzyl)amino]-2-phenylpiperidine (1.007 g, 1.758 mmol) and 20% Pd(OH)2 /C (0.258 g), THF (5.0 ml), and MeOH (30.0 ml) was stirred under an atmosphere of H2 (baloon) at room temperature for an hour. The catalyst was filtered off by the aid of Celite, and washed with THF. The combined filtrate and THF washings were concentrated in vacuo to give title compound (0.789 g, quantitatively) as a pale yellow oil. IRmax (film): 3340(s), 1735(s), 1718(s), 1608(m), 1250(br., s), 1150(br., s), 1033(s), 810(m), 750(m), 700(m) cm-1 ; 1H-NMR δ: 7.36-7.18(m, 5H), 7.00(dd, J=9.2, 2.2 Hz, 1H), 6.84(d, J=2.2 Hz, 1H), 6.62(d, J=9.2 Hz, 1H), 3.89(d, J=2.2 Hz, 1H), 3.71(s, 3H), 3.68(d, J=14.3 Hz, 1H), 3.51(ddd, J=11.9, 3.7, 1.8 Hz, 1H), 3.47(s, 3H), 3.40(d, J=14.3 Hz, 1H), 3.05(dddd, J=12.3, 11.9, 3.7, 3.7 Hz, 1H), 2.92-2.82(m, 1H), 2.88(dd, J=11.9, 11.9 Hz, 1H), 2.37(dm, J=13.6 Hz, 1H), 1.78(ddd, J=13.6, 12.3, 2.9 Hz, 1H), 1.68(br.s, 2H, NH×2) ppm.
Reaction SMILES: Cl.[CH3:2][C:3]1[O:4][C:5]2[C:14]3[CH:13]([CH2:15][CH2:16][NH2:17])[CH2:12][CH2:11][C:10]=3[CH:9]=[CH:8][C:6]=2[N:7]=1.C(N(CC)CC)C.[CH:25]1([C:28](Cl)=[O:29])[CH2:27][CH2:26]1.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:2][C:3]1[O:4][C:5]2[C:14]3[CH:13]([CH2:15][CH2:16][NH:17][C:28]([CH:25]4[CH2:27][CH2:26]4)=[O:29])[CH2:12][CH2:11][C:10]=3[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1nc2ccc3c(c2o1)C(CCN)CC3
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nc2ccc3c(c2o1)C(CCNC(=O)C1CC1)CC3
Reaction time: 0.25 h
Yield: 42.3 %

Procedure:
2-(2-Methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethanamine hydrochloride (100 mg, 0.396 mmol) and triethylamine (111 μL, 0.792 mmol) were dissolved in tetrahydrofuran (4 mL), cyclopropanecarbonyl chloride (43.1 μL, 0.475 mmol) was added under ice-cooling, and the mixture was stirred for 15 min. To the reaction solution was added saturated aqueous sodium hydrogencarbonate solution, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=40/60→80/20) to give the title compound (47.6 mg, yield 42%).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:10]=[CH:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=2)[CH:13]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C>[CH2:3]([NH:10][CH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=2)[CH:13]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COc1ccc2cc(C=NCc3ccccc3)ccc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc2cc(CNCc3ccccc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
Sodium borohydride (0.19 g, 5 mmol) was added in portions under nitrogen to a solution of benzyl-(6-methoxy-naphthalen-2-ylmethylene)-amine (1.38 g, 5 mmol), prepared in the previous step, in 150 mL of absolute ethanol at room temperature. After the addition the reaction was stirred at room temperature for 20 h (overnight). The reaction was quenched with 30 mL of 1N HCl (pH 2 by litmus paper). The solvent was removed under reduced pressure to give a solid. The solid was partitioned between methylene chloride and water. The aqueous layer was made basic with 1N NaOH. The aqueous layer was separated and extracted two times with methylene chloride. The organic extracts were combined, dried (MgSO4) and the solvent removed under reduced pressure to give benzyl-(6-methoxy-naphthalen-2-ylmethyl)-amine (1.38 g, 100%) as an off-white solid, mp 45-53° C.
Reaction SMILES: [C:1]([C:3]1[C:4]([I:16])=[C:5]([CH2:14][OH:15])[C:6]([I:13])=[C:7]([C:11]=1[I:12])[C:8]([OH:10])=[O:9])#[N:2].[OH-:17].[Na+]>O>[C:1]([C:3]1[C:4]([I:16])=[C:5]([CH2:14][OH:15])[C:6]([I:13])=[C:7]([C:11]=1[I:12])[C:8]([OH:10])=[O:9])(=[O:17])[NH2:2]
Reactant: [OH-]
Reactant: N#Cc1c(I)c(CO)c(I)c(C(=O)O)c1I
Agent: [Na+]
Solvent: O
Product: NC(=O)c1c(I)c(CO)c(I)c(C(=O)O)c1I
Reaction time: 3 h
Yield: 87.1 %

Procedure:
27.8 g of 5-cyano-3-hydroxymethyl-2,4,6-triiodobenzoic acid is suspended in 120 ml of water and dissolved by adding 10 g of sodium hydroxide. The batch is held at 60° C. for 3 hours and then precipitated into 50 ml of semiconcentrated sulfuric acid. After several hours of agitation in an ice bath, the precipitate is vacuum-filtered, washed with water, and dried at 50° C., thus obtaining 25 g of 5-carbamoyl-3-hydroxymethyl-2,4,6-triiodobenzoic acid as a white powder with a decomposition point above 280° C. Yield: 88% of theory.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[O:9]1CCC[CH2:10]1>C(OCC)C>[F:8][C:5]1[CH:6]=[CH:7][C:2]([CH:10]=[O:9])=[N:3][CH:4]=1
Reactant: C1CCOC1
Reactant: Fc1ccc(Br)nc1
Solvent: CCOCC
Product: O=Cc1ccc(F)cn1

Procedure:
The title compound was prepared according to the methods of preparations 1 and 2, starting from 2-bromo-5-fluoropyridine. This gave crude material containing tetrahydrofuran and diethyl ether which was used without further purification. 1H NMR (CDCl3, 400 MHz) δ 7.57 (1H, dt), 8.03 (1H, dd), 8.62 (1H, d), 10.04 (1H, s); LRMS (APCI+) 126 [MH+].
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1)(=[O:14])[CH3:13].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([S:22][C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:12](=[O:14])[CH3:13])=[CH:21][CH:20]=2)[CH:7]=1
Reactant: CC(=O)Nc1ccc(S)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(Sc2cc(Cl)ccc2[N+](=O)[O-])cc1
Temperature: 100 °C

Procedure:
A mixture of 2,4-Dichloro nitro benzene (0.25 g, 1.3 mmol), 4-Acetamido thiophenol (0.26 g, 1.43 mmol) and cesium carbonate (0.466 g, 1.43 mmol) in DMF (3 mL) was heated 2.5 hr at 100° C. The mixture was cooled, diluted with ethyl acetate (100 mL) and the organic layer was washed with water and aqueous 10% sodium chloride solution, then, dried over anhydrous sodium sulfate. The drying agent was filtered and the solvent removed under vacuum. The residue is purified by silica gel column chromatography eluting with CH2Cl2/methanol leaving the title compound as a yellow solid (0.25 g, 63%).
Reaction SMILES: [F:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:9]=[C:10]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)[CH:11]=[CH:12][C:13]=2[N+:14]([O-])=O)[CH2:3]1.CCO.O>CC(O)=O.CCOC(C)=O.[Fe]>[F:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:9]=[C:10]([N:17]3[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]3)[CH:11]=[CH:12][C:13]=2[NH2:14])[CH2:3]1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(N3CCCC(F)C3)c2)CC1
Agent: [Fe]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN1CCN(c2ccc(N)c(N3CCCC(F)C3)c2)CC1
Temperature: 80 °C
Yield: 84 %

Procedure:
A solution of 1-[3-(3-fluoro-piperidin-1-yl)-4-nitro-phenyl]4-methyl-piperazine (as prepared in the previous step, 60 mg, 0.19 mmol) in 2:1 EtOH:water (6 mL), was treated with glacial AcOH (1 drop) and iron powder (10 mg, 0.93 mmol). The mixture was heated to 80° C. for 30 min. The reaction cooled to room temperature, diluted with EtOAc and washed with saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4 and concentrated in vacuo to afford the title compound (46 mg, 84%), which was used directly in the next reaction. LC-MS (ESI, m/z): Calcd. for C16H25FN4 293.2 (M+H), found 293.2.
Reaction SMILES: [CH2:1]([CH2:11][C:12](=[O:14])[CH3:13])/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].[NH4+].[Cl-].[Na+].[Cl-].[CH3:19][O:20][C:21](=O)[O:22]C>>[O:14]=[C:12]([CH2:11][CH2:1][CH:2]=[C:3]([CH3:4])[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])[CH2:13][C:21]([O:20][CH3:19])=[O:22]
Reactant: COC(=O)OC
Reactant: CC(=O)CC/C=C(\C)CCC=C(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: COC(=O)CC(=O)CCC=C(C)CCC=C(C)C
Reaction time: 1 h

Procedure:
The obtained mixture was heated to reflux (bath temperature 100°) then, during 1 h, there was added a solution of 0.5M of geranylacetone in 135 g (1.5M) of dimethylcarbonate, where upon the resulting reaction mixture was kept refluxing during 10 min. It was finally poured into a 10% aqueous solution of NH4Cl saturated with NaCl. An ether extraction, followed by the usual work up of the combined organic extracts and fractional distillation gave methyl 3-oxo-7,11-dimethyl-dodeca-6,10-dienoate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]2[CH:13]=NN(C)C=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[NH:18]1[C:22](B(O)O)=CC=[N:19]1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]2[NH:19][N:18]=[CH:22][CH:13]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: OB(O)c1ccn[nH]1
Reactant: COC(=O)c1cc(C)ccc1-c1cnn(C)c1
Product: COC(=O)c1cc(C)ccc1-c1ccn[nH]1

Procedure:
The title compound was synthesized following the same general protocol as described for methyl 5-methyl-2-(1-methyl-1H-pyrazol-4-yl)benzoate in Example A1, using (1H-pyrazol-5-yl)boronic acid. ESI-MS (m/z): 217 [M+1]+.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:8]1[CH2:10][C@@H:9]1[C:11]([O:13][CH3:14])=[O:12]>C1COCC1>[CH:1]1([CH2:10][C@@H:9]([OH:8])[C:11]([O:13][CH3:14])=[O:12])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)[C@H]1CO1
Reactant: Br[Mg]C1CCCC1
Solvent: C1CCOC1
Product: COC(=O)[C@H](O)CC1CCCC1
Temperature: -10 °C
Reaction time: 0.33 h

Procedure:
A solution of Li2CuCl4 (0.2 M in THF, 125 mL, 25.0 mmol) was added slowly to a suspension of cyclopentylmagnesium bromide (2 M in diethyl ether, 135 mL, 270 mmol; Aldrich Chemical Company, Inc., Milwaukee, Wis.) and THF (500 mL) at −50° C. over 2-3 mins. The pale grey/brown suspension was then allowed to warm slowly to −10° C. over 30 mins, by which time the color had developed to a dark grey. The mixture was re-cooled to −78° C. and (R)-methyl oxirane-2-carboxylate (25.0 g, 245 mmol; Aldrich Chemical Company, Inc., Milwaukee, Wis.) was added neat via syringe over 90 seconds. The reaction was then stirred at −78° C. for 20 mins, before removing the ice-bath and allowing to warm to approximately −50° C. over 30 mins. Saturated NH4Cl (aq, 700 mL) was then added and the mixture stirred for 30 mins. The organic layer was collected and the aqueous layer extracted with diethyl ether (2×250 mL). The combined organics were washed with saturated NH4Cl (aq, 350 mL), dried over MgSO4, and evaporated. Distillation of the crude residue (68-70° C. at 0.8 mbar) yielded 65-70% of (I-1b) as a pale yellow oil. A small amount of less volatile material remained in the still pot. 1H NMR (400 MHz; CDCl3): δ 4.17 (1 H), 3.76 (3 H), 2.67 (1 H), 2.01 (1 H), 1.48-1.88 (8 H), 1.11 (2 H).
Reaction SMILES: N[C@@H](CC1CCCCC1)[C@@H](O)C(O)CO.[CH:16]1([CH2:22][C@H:23]2[C@H:27]([C:28]([CH:30]3[CH2:32][CH2:31]3)=[O:29])[O:26]C(C)(C)[N:24]2C(OC(C)(C)C)=O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[NH2:24][C@@H:23]([CH2:22][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C@@H:27]([OH:26])[C:28]([CH:30]1[CH2:32][CH2:31]1)=[O:29]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CC2CCCCC2)[C@H](C(=O)C2CC2)OC1(C)C
Agent: N[C@@H](CC1CCCCC1)[C@@H](O)C(O)CO
Product: N[C@@H](CC1CCCCC1)[C@@H](O)C(=O)C1CC1

Procedure:
In a manner analogous to the procedure described in Example 24 for the preparation of (2RS,3R,4S)-4-amino-5-cyclohexyl-1,2,3-pentanetriol, starting from tert-butyl (4S,5R)-4-(cyclohexylmethyl)-5-(cyclopropylcarbonyl)-2,2-dimethyl-3-oxazolidinecarboxylate there is obtained (2R,3S)-3-amino-4-cyclohexyl-1-cyclopropyl-2-hydroxy-1-butanone, MS: 226 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:25]2[C:26]([CH3:39])=[CH:27][C:28]([O:31][CH2:32][C:33]([CH3:38])([CH3:37])[C:34]([OH:36])=[O:35])=[N:29][CH:30]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[N:9](COCC[Si](C)(C)C)[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=1.[OH-].[Na+]>FC(F)(F)C(O)=O.O>[F:1][C:2]1[CH:3]=[C:4]([C:25]2[C:26]([CH3:39])=[CH:27][C:28]([O:31][CH2:32][C:33]([CH3:37])([CH3:38])[C:34]([OH:36])=[O:35])=[N:29][CH:30]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[NH:12][C:11]([C:13]([F:14])([F:16])[F:15])=[CH:10][N:9]=1
Reactant: Cc1cc(OCC(C)(C)C(=O)O)ncc1-c1ccc(-c2nc(C(F)(F)F)cn2COCC[Si](C)(C)C)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(OCC(C)(C)C(=O)O)ncc1-c1ccc(-c2ncc(C(F)(F)F)[nH]2)c(F)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 87.6 %

Procedure:
In trifluoroacetic acid (2.0 mL) and water (0.1 mL) was dissolved 3-[(5-{3-fluoro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]-2,2-dimethylpropanoic acid (640 mg), and the solution was stirred at room temperature for 10 hours. The solution was neutralized by adding 2N aqueous sodium hydroxide solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with a saturated brine, the organic layer was separated and concentrated under reduced pressure. Ether was added to the obtained residue, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain 3-[(5-{3-fluoro-4-[5-(trifluoromethyl)-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]-2,2-dimethylpropanoic acid (432 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][Si:14]([CH3:18])([CH3:17])[CH2:13][CH2:12]1.C([O-])(O)=O.[Na+].[C:24](Cl)([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25].O>C1COCC1.[Pd]>[CH3:17][Si:14]1([CH3:18])[CH2:15][CH2:16][N:11]([C:3]2[CH:4]=[CH:5][C:6]([NH:8][C:24](=[O:25])[O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:7][C:2]=2[F:1])[CH2:12][CH2:13]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[Si]1(C)CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[Si]1(C)CCN(c2ccc(NC(=O)OCc3ccccc3)cc2F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
To a solution of compound 9 (610 mg, 2.28 mmol) in THF (25 mL), Pd/C (30 mg) is added and hydrogenated under a pressure of 35 psi in a par hydrogenator for 8 h. The reaction mixture is filtered through celite. Celite pad is washed with THF (2×20 mL). To the filtrate, saturated NaHCO3 (420 mg, 5.01 mmol) and CBzCl (427 mg, 2.5 mmol) are added at 0° C. and stirred at 25° C. for 5 h. 10 mL water is added to reaction mixture and the aqueous layer is extracted with EtOAc (2×20 mL). The crude mixture is then subjected to column chromatography on silica gel using hexane-EtOAc mixtures to afford the product as a viscous liquid 10 (690 mg) in 82% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:16]2[C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([NH2:25])[C:19]=3[CH:18]=[N:17]2)([CH2:14][CH3:15])[CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:4][CH:3]=1.CN1CCOCC1.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:16]2[C:24]3[C:19](=[C:20]([NH:25][S:34]([CH3:33])(=[O:36])=[O:35])[CH:21]=[CH:22][CH:23]=3)[CH:18]=[N:17]2)([CH2:14][CH3:15])[CH2:9][C:10]([F:13])([F:11])[F:12])=[CH:4][CH:3]=1
Reactant: CCC(CC(F)(F)F)(c1ccc(Cl)cc1)n1ncc2c(N)cccc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCC(CC(F)(F)F)(c1ccc(Cl)cc1)n1ncc2c(NS(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of the product of Step F (50 mg, 0.13 mmol) and NMM (31 mg, 0.3 mmol) in DCM (3 mL) was added methanesulfonyl chloride (20 mg, 0.21 mmol). The mixture was stirred at room temperature for 3 h, then quenched with saturated ammonium chloride solution (10 mL), and extracted with ethyl acetate. The organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated. The residue was purified by Pre-HPLC (Mobile phase: acetonitrile/water (0.03% TFA)) to afford the title compound. LC/MS m/z=446.1[M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:14])=[C:6]([CH:13]=1)[C:7](N(OC)C)=[O:8].[CH:15]1([Mg]Br)[CH2:17][CH2:16]1>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:14])=[C:6]([C:7]([CH:15]2[CH2:17][CH2:16]2)=[O:8])[CH:13]=1
Reactant: CON(C)C(=O)c1cc(Br)ccc1F
Reactant: Br[Mg]C1CC1
Solvent: C1CCOC1
Product: O=C(c1cc(Br)ccc1F)C1CC1

Procedure:
In an analogous manner to that described for the preparation of Building block C [a)], the reaction of 5-bromo-2-fluoro-N-methoxy-N-methyl-benzamide with cyclopropylmagnesium bromide in tetrahydrofuran yielded the title compound as a light yellow liquid; (HPLC 2.783 min 100%). Mass (calculated) C10H8BrFO [243.074]; (found) [M+H]+=243, [M+2-H]+=245.
Reaction SMILES: [O:1]1[CH2:27][CH:2]1[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=3)[CH2:10][C:11]([CH3:16])([CH3:15])[O:12]2)=[CH:7][CH:6]=1.[CH3:28][NH2:29]>>[OH:1][CH:2]([CH2:27][NH:29][CH3:28])[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=3)[CH2:10][C:11]([CH3:16])([CH3:15])[O:12]2)=[CH:7][CH:6]=1
Reactant: CN
Reactant: CC1(C)CC(c2ccc3ccccc3c2)c2ccc(OCC3CO3)cc2O1
Product: CNCC(O)COc1ccc2c(c1)OC(C)(C)CC2c1ccc2ccccc2c1

Procedure:
Reaction of 7-(2,3-epoxypropoxy)-2,2-dimethyl-4-(2-naphthyl)chroman with methylamine, by an analogous method to that described in Example 2 gave 7-(2hydroxy-3-methylaminopropoxy)-2,2-dimethyl-4-(2-naphthyl)chroman isolated as its hydrochloride salt m.p. 183-188°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1.[F:25][C:26]([F:30])([F:29])[CH2:27][NH2:28]>>[F:25][C:26]([F:30])([F:29])[CH2:27][NH:28][C:21]([C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)=[N:9][O:10][C:11]=2[CH3:24])=[CH:20][N:19]=1)=[O:23]
Reactant: Cc1onc(-c2ccc(F)cn2)c1COc1ccc(C(=O)O)nc1
Reactant: NCC(F)(F)F
Product: Cc1onc(-c2ccc(F)cn2)c1COc1ccc(C(=O)NCC(F)(F)F)nc1
Yield: 73 %

Procedure:
As described for example 23f, 5-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-pyridine-2-carboxylic acid (75 mg, 0.23 mmol) was converted, using 2,2,2-trifluorethylamine instead of isopropylamine, to the title compound (68 mg, 73%), which was obtained as a white solid. MS: m/e=411.2 [M+H]+.
Reaction SMILES: [C:1]1([C@H:7]([N:9]2[CH2:14][CH2:13][O:12][C@@H:11]([C:15]3[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=3)[CH2:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[Na+].Cl.[NH2:29]O>C(O)C>[C:1]1([C@H:7]([N:9]2[CH2:14][CH2:13][O:12][C@@H:11]([C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:29])=[CH:17][CH:16]=3)[CH2:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(C=O)cc2)C1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(C#N)cc2)C1
Yield: 83.8 %

Procedure:
To a solution of crude 4-((2S)-4-((1R)-1-phenylethyl)morpholin-2-yl) benzaldehyde (intermediate 8, 55.1 g) in ethanol (280 ml) was added sodium acetate (30.0 g, 365 mmol) and hydroxylamine hydrochloride (25.4 g, 365 mmol) at room temperature. After a reflux for 2 hours, the mixture was partitioned between water and dichloromethane, and the organic layer was washed with water and brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was then added with acetic acid (140 ml) and acetic anhydride (140 ml). After the mixture was refluxed for 2 hours, the solvent was removed under reduced pressure. The residue was partitioned between water and chloroform. The organic layer was washed with aqueous sodium hydrogen carbonate, dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (eluent; hexane/ethyl acetate=9/1) to afford 4-((2S)-4-((1R)-1-phenylethyl)morpholin-2-yl)benzonitrile (intermediate 9, 45.7 g, 86% from intermediate 7)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)=[N:11][C:12]([CH3:18])=[C:13]([CH:17]=1)[C:14](O)=[O:15].B.CO>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:17]=[C:13]([CH2:14][OH:15])[C:12]([CH3:18])=[N:11][C:10]=1[C:19]1[CH:20]=[CH:21][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:23][CH:24]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)c(-c2ccc(Cl)cc2Cl)cc1C(=O)O
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)c(-c2ccc(Cl)cc2Cl)cc1CO
Temperature: 25 °C

Procedure:
To a solution of 3 g of 5-(2,4-Dichloro-phenyl)-2-methyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid in 60 ml of THF, were added dropwise 21 ml of a 1M solution of borane in THF at room temperature. Then the reaction mixture was heated to reflux for 10 h. The reaction mixture was cooled to room temperature and 20 ml of methanol were carefully added. The solvents were removed under reduced pressure and the residue was dissolved in ethyl acetate. The organic layer was washed with 1 M hydrochloric acid, saturated sodium chloride solution and saturated sodium hydrogen carbonate solution. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The product was obtained as a white solid and used without further purification. Yield: 2.2 g.
Reaction SMILES: ClC1C=C(N2C(C)=NC(S)=N2)C=CC=1Cl.C(=O)([O-])[O-].[K+].[K+].Cl.ClCC[N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34]>CO.O.CCOCC.CCOC(C)=O>[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: ClCCN1CCOCC1
Agent: Cc1nc(S)nn1-c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: C1COCCN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-thiol (0.4 mmol) was dissolved in methanol (100 mL) at room temperature. A solution of potassium carbonate in water was added dropwise until pH 9. After 15 min. under stirring a solution of 4-(2-chloroethyl)morpholine hydrochloride (0.4 mmol) in water (20 mL) was added. The reaction was left under stirring at room temperature overnight. The methanol was evaporated and after extraction with CH2Cl2 the organic layer was dried over magnesium sulphate then evaporated and finally purified by chromatographic column to give a dark orange oil. The purified product was dissolved in ether (20 mL) and mixed with a solution of oxalic acid (0.31 mmol) in EtOAc (5 mL) to give 4-(2-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio)ethyl)morpholine oxalate (0.147 g, yield=84%) as a white precipitate which was filtered off and dried in vacuo. H1NMR (300 MHz, DMSO, 25° C.) δ: 7.93 (d, J=2.4 Hz, 1H); 7.82 (d, J=8.7 Hz, 1H); 7.61 (dd, J=2.4 Hz, J=8.6 Hz, 1H); 3.66 (t, J=4.6 Hz, 4H); 3.32 (t, J=6.8 Hz, 2H); 2.983 (t, J=7.0 Hz, 2H); 2.78 (brs, 4H); 2.47 (s, 3H) ppm. EM (ES+) m/z=373 (100%) [M+H]+. C17H20Cl2N4O5S (463.0) calc. C, 44.07%; H, 4.35%; N, 12.09%; S=6.92%. found C, 43.79%; H, 4.60%; N, 11.87%; S,=6.75%.