Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:40])[CH:15]([N:26]3[CH2:30][C:29]([O:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[Cl:38])=[CH:28][C:27]3=[O:39])[CH2:16][CH:17]([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[N:9]2)[CH2:4][O:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:6][C@@H:5]([CH2:4][OH:3])[CH2:7][N:8]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:40])[CH:15]([N:26]2[CH2:30][C:29]([O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[Cl:38])=[CH:28][C:27]2=[O:39])[CH2:16][CH:17]([C:22]([F:23])([F:25])[F:24])[C:18]([F:20])([F:19])[F:21])=[N:9]1
Reactant: CC1(C)OC[C@@H](Cn2ccc(NC(=O)C(CC(C(F)(F)F)C(F)(F)F)N3CC(Oc4ccccc4Cl)=CC3=O)n2)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: O=C(Nc1ccn(C[C@@H](O)CO)n1)C(CC(C(F)(F)F)C(F)(F)F)N1CC(Oc2ccccc2Cl)=CC1=O
Yield: 87.6 %

Procedure:
In a round bottom flask was placed 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-5,5,5-trifluoro-4-trifluoromethyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (32 mg, 0.05 mmol), methanol (2 mL) and p-toluenesulfonic acid hydrate (5 mg, 0.15 mmol) and stirred at 25° C. for 48 h. The mixture was concentrated in vacuo and then taken up in ethyl acetate/methanol and concentrated in vacuo with silica gel (1.5 g). Purification by Biotage flash chromatography (AnaLogix SF15-12 g column, 100% ethyl acetate to 10% methanol/ethyl acetate) afforded 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-5,5,5-trifluoro-4-trifluoromethyl-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide (25 mg, 84%) as a colorless gum: HR-ES-MS m/z calculated for C22H21N4O5ClF6 [M+H]+ 571.1178, observed 571.1177; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.20-2.37 (m, 1H), 2.38-2.48 (m, 1H), 3.21-3.32 (m, 2H), 3.71-3.82 (m, 1H), 3.82-3.98 (m, 2H), 4.10 (dd, J=13.6, 4.0 Hz, 1H), 4.29 (d, J=17.9 Hz, 1H), 4.45 (d, J=17.9 Hz, 1H), 4.71 (t, J=5.5 Hz, 1H), 4.89 (s, 1H), 4.89-4.98 (m, 2H), 6.43 (d, J=2.1 Hz, 1H), 7.31-7.42 (m, 1H), 7.43-7.53 (m, 3H), 7.56 (d, J=2.1 Hz, 1H), 7.66 (d, J=7.7 Hz, 1H), 10.91 (s, 1H).
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].[CH2:20](O)[CH3:21]>>[ClH:3].[NH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: O=S(Cl)Cl
Reactant: NCCCCCCCCCCCC(=O)O
Reactant: CCO
Product: CCOC(=O)CCCCCCCCCCCN
Product: Cl
Temperature: 0 °C

Procedure:
Ethanol (150 mL) was cooled to 0° C., and thionyl chloride (16.57 mL, 139.3 mmol) was added over a period of ten minutes. The reaction was stirred for ten minutes at 0° C., and 12-aminododecanoic acid (25.0 g, 116 mol) was then added. The reaction was allowed to warm to ambient temperature, stirred at a slightly elevated temperature for one hour, and stirred at ambient temperature for two hours. The Ethanol was removed under reduced pressure, and the solid residue was recrystallized from ethyl acetate. The crystals were isolated by filtration, washed with diethyl ether, and dried under vacuum to provide 37.4 g of ethyl 12-aminododecanoate hydrochloride as a white solid.
Reaction SMILES: CS(O[CH:6]1[CH2:12][C@@H:11]2[N:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@@H:8]([CH2:9][CH2:10]2)[CH:7]1[C:21]([O:23][CH3:24])=[O:22])(=O)=O.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[C@H:8]12[N:13]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[C@H:11]([CH2:10][CH2:9]1)[CH2:12][CH:6]=[C:7]2[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)C1C(OS(C)(=O)=O)C[C@H]2CC[C@@H]1N2C(=O)OC(C)(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COC(=O)C1=CC[C@H]2CC[C@@H]1N2C(=O)OC(C)(C)C
Yield: 52.1 %

Procedure:
(1S,5R)-8-tert-butyl 2-methyl 3-(methylsulfonyloxy)-8-azabicyclo[3.2.1]octane-2,8-dicarboxylate (14.22 g, 39.15 mmol) and DBU (58.55 mL, 391.15 mmol) in DMF (73.87 mL) were heated at 100° C. for 10 hours. The reaction was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic fractions were combined, dried with sodium sulfate and concentrated to give crude product. The crude was purified using flash chromatography (0-100% Ethyl Acetate in Hexane) to give 5.45 g of (1S,5R)-8-tert-butyl 2-methyl 8-azabicyclo[3.2.1]oct-2-ene-2,8-dicarboxylate.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Li]CCCC.[CH3:11][CH:12]([CH3:15])[CH2:13]I.O>C1COCC1>[CH2:11]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH:12]([CH3:15])[CH3:13]
Reactant: CC(C)CI
Reactant: c1ccsc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Cc1cccs1
Temperature: -40 °C
Reaction time: 2 h
Yield: 29.8 %

Procedure:
A solution of thiophene (6.00 g, 0.0714 mol) in 80 mL of THF (80 mL) was treated with n-BuLi (1.6 M in hexane, 54 mL, 0.0864 mol) at −78° C. The mixture was stirred at −40° C. for about 2 hours. The solution was then cooled to −78° C. again and treated with 2-methylpropyliodide (16.04 g, 0.0871 mol). The solution was stirred at 0° C. for 2 hours, and then overnight at room temperature for about 16 hours. The solution was treated with water (25 mL) and extracted with petroleum ether (3×25 mL). The organic layer was dried over magnesium sulfate and filtered. The crude product was purified by distillation (54-55° C. at 12 mmHg) to give the sub-title compound (3.0 g, 0.0213 mol) in 30% yield.
Reaction SMILES: C(OC(=O)[CH2:5][N:6]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:7](=[O:28])[CH:8]([NH:20][C:21](OC(C)(C)C)=[O:22])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)C>C(Cl)Cl.Cl.O1CCOCC1.ClC(Cl)C>[CH2:29]([N:6]1[CH2:5][C:21](=[O:22])[NH:20][C@H:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[C:7]1=[O:28])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CCOC(=O)CN(Cc1ccccc1)C(=O)C(Cc1ccc(C(F)(F)F)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: O=C1CN(Cc2ccccc2)C(=O)[C@@H](Cc2ccc(C(F)(F)F)cc2)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.4 %

Procedure:
To a stirred solution of [benzyl-[2-tert-butoxycarbonylamino-3-(4-trifluoromethyl-phenyl)-propionyl]-amino]-acetic acid ethyl ester (1.5 g, 2.95 mmol) in dry CH2Cl2 (50 mL), 4N HCl in dioxane (25 mL, Aldrich) was added and stirred at room temperature for 2 h and then conc in vacuo. The r×n product was partitioned between CH2Cl2 (100 mL) and saturated NaHCO3 (20 mL). The organic layer was separated, dried over MgSO4 and conc in vacuo to give a clear oil. The oil was diluted in dichloroethane (50 mL) and stirred in 60° C. bath for 2 h to yield 1.02 g (95%) of the product as a off white solid. MS (ESI) 363 (M+H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].F[C:8]1[CH:20]=[CH:19][C:11]2[C:12](=[O:18])[N:13]([CH3:17])[CH2:14][CH2:15][O:16][C:10]=2[C:9]=1[F:21].[Si]([O:29][CH2:30][C@H:31]([CH3:49])[O:32][C:33]1[CH:34]=[C:35]([CH:45]=[C:46]([OH:48])[CH:47]=1)[C:36]([NH:38][C:39]1[CH:43]=[CH:42][N:41]([CH3:44])[N:40]=1)=[O:37])(C(C)(C)C)(C)C>CN1CCCC1=O>[F:21][C:9]1[C:10]2[O:16][CH:15]([CH3:14])[N:13]([CH3:17])[C:12](=[O:18])[C:11]=2[CH:19]=[CH:20][C:8]=1[O:48][C:46]1[CH:45]=[C:35]([CH:34]=[C:33]([O:32][C@@H:31]([CH3:49])[CH2:30][OH:29])[CH:47]=1)[C:36]([NH:38][C:39]1[CH:43]=[CH:42][N:41]([CH3:44])[N:40]=1)=[O:37]
Reactant: CN1CCOc2c(ccc(F)c2F)C1=O
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CC1Oc2c(ccc(Oc3cc(O[C@@H](C)CO)cc(C(=O)Nc4ccn(C)n4)c3)c2F)C(=O)N1C
Temperature: 140 °C
Yield: 40.9 %

Procedure:
Potassium carbonate (152 mg, 1.1 mmol) was added to a solution of 8,9-difluoro-4-methyl-3,4-dihydro-1,4-benzoxazepin-5(2H)-one (117 mg, 0.55 mmol) and 3-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyloxy)-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide (223 mg, 0.55 mmol) in 1-methyl-2-pyrrolidinone (10 mL) and the mixture heated at 140° C. for 3 days. The mixture was concentrated in vacuo and the residue suspended in ethyl acetate (20 mL). The suspension was filtered through Celite® and evaporated. The residue was purified by column chromatography (eluting with 0-20% methanol in DCM) to afford a colourless gum which solidified on evaporation from 30% methanol in DCM to afford the title compound as a colourless solid (109 mg, 33%).
Reaction SMILES: [C:1]([C:4]1[C:31](O)=[CH:30][CH:29]=[CH:28][C:5]=1[O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([C:23]([O:25]CC)=[O:24])[CH:17]=[CH:16]2)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:39](Br)[CH:40]=C.CN(C)[CH:45]=[O:46]>O>[C:1]([C:4]1[C:31]([O:46][CH2:45][CH:39]=[CH2:40])=[CH:30][CH:29]=[CH:28][C:5]=1[O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([C:23]([OH:25])=[O:24])[CH:17]=[CH:16]2)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1ccc2cc(OCCCCCOc3cccc(O)c3C(C)=O)ccc2c1
Reactant: CN(C)C=O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C=CCOc1cccc(OCCCCCOc2ccc3cc(C(=O)O)ccc3c2)c1C(C)=O

Procedure:
Ethyl 6-[5-(2-acetyl-3-hydroxyphenoxy)pentyloxy]naphthalene-2-carboxylate (1.85 g), potassium carbonate (0.59 g) and allyl bromide (0.74 ml) were stirred in dry dimethyl formamide (40 ml) for 20 hr. The mixture was diluted with water and extracted with ethyl acetate, which was washed with water, dried and evaporated to yield the ethyl ester of the sub-title compound (2.2 g) as a pale yellow solid. The ester (0.65 g) was hydrolysed by the method of Example 2f to give the title acid (0.36 g), mp 157°-157.5°.
Reaction SMILES: [F:1][C:2]1[C:3]([O:29][CH3:30])=[C:4]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([C:18]4[CH:19]=[N:20][N:21]([CH:23]5[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]5)[CH:22]=4)[CH:16]=3)[NH:11][CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[F:1][C:2]1[C:3]([O:29][CH3:30])=[C:4]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([C:18]4[CH:19]=[N:20][N:21]([CH:23]5[CH2:24][CH2:25][N:26]([S:39]([CH3:38])(=[O:41])=[O:40])[CH2:27][CH2:28]5)[CH:22]=4)[CH:16]=3)[NH:11][CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1c(F)cc(F)cc1-c1c[nH]c2ncc(-c3cnn(C4CCNCC4)c3)cc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(F)cc(F)cc1-c1c[nH]c2ncc(-c3cnn(C4CCN(S(C)(=O)=O)CC4)c3)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 282 (100 mg, 0.244 mmol) in DCM was added triethylamine (49 mg, 0.4887 mmol). Methanesulfonyl chloride 335 (41 mg, 0.3665 mmol) was added to the reaction and stirred for 2 h at rt. The reaction mixture was diluted with dichloromethane and washed with water twice. The organic layer was dried over sodium sulphate and concentrated to get the crude, which was purified by flash column using 100-200 mesh silica gel. The compound was eluted at 2% methanol in chloroform as off white coloured solid 3-(3,5-difluoro-2-methoxyphenyl)-5-(1-(1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-1H pyrrolo[2,3-b]pyridine 336. 1H NMR (400 MHz, DMSO) δ: 12.05 (s, 1H), 8.55 (d, 1H), 8.30 (s, 1H), 8.19 (d, 1H), 7.97 (s, 1H), 7.82 (d, 1H), 7.24 (m, 2H), 4.33 (m, 1H), 3.65 (d, 2H), 3.60 (s, 3H), 2.94, (m, 2H), 2.92 (s, 3H), 2.03 (m, 2H), 1.98 (m, 2H) and MS ES+488.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([O:16]C)=[O:15])=[C:12]([CH3:18])[N:11]=[CH:10][CH:9]=2)=[C:4]([F:19])[CH:3]=1.[OH-].[Na+]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([OH:16])=[O:15])=[C:12]([CH3:18])[N:11]=[CH:10][CH:9]=2)=[C:4]([F:19])[CH:3]=1
Reactant: COC(=O)c1c(-c2ccc(Cl)cc2F)ccnc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1nccc(-c2ccc(Cl)cc2F)c1C(=O)O
Temperature: 25 °C
Reaction time: 14 h
Yield: 79 %

Procedure:
To a solution of methyl 4-(4-chloro-2-fluorophenyl)-2-methylnicotinate (40 mg, 0.143 mmol) in MeOH (2 mL) and water (3 mL) was added NaOH (11.44 mg, 0.286 mmol) and the reaction mixture was stirred at RT for 14 h. The reaction mixture was concentrated under reduced pressure and acidified with 1.5N HCl the extracted with ethyl acetate (5 mL). The organic layer was washed with saturated NaHCO3 (2×10 mL) and water (10 mL); dried over Na2SO4 and concentrated under reduced pressure to afford crude 4-(4-chloro-2-fluorophenyl)-2-methylnicotinic acid (30 mg, 0.113 mmol, 79% yield) as brown solid. This was taken into the next step without further purification. LC/MS, (ESI) m/z 266.1 [(M+H)+, calcd for C13H10ClFNO2. 266.0]; LC/MS retention time (method D): tR=0.64 min.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([O:21][CH3:22])[C:14](Br)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:32]1COC[CH2:33]1>O>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([O:21][CH3:22])[C:14]([CH2:32][CH3:33])=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CCOC1
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1OC
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCc1ccc(CS(=O)(=O)c2ccccc2)c(C(=O)OC)c1OC
Temperature: 140 °C

Procedure:
A mixture of methyl 6-(benzenesulphonylmethyl)-3-bromo-2-methoxybenzoate (Intermediate 65, 1.31 g) and potassium phosphate (2.02 g) in THF (9 ml) and water (4.5 ml) was degassed and palladium chloride dppf adduct with DCM (0.134 g) and triethyl borane (1M solution in THF, 4.6 ml) were added. The mixture was stirred and heated in the microwave at 140° C. for 18 minutes. The mixture was partitioned between ethyl acetate and water and the organic layer was separated, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 5-40% to give methyl 6-(benzenesulphonylmethyl)-3-ethyl-2-methoxybenzoate (0.754 g) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[C:5]([F:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:5]([F:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: C1CCNCC1
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1Cl
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc(F)c(N2CCCCC2)cc1Cl
Reaction time: 1 h
Yield: 82 %

Procedure:
A solution of 4.8 (25 mmol) of 2-chloro-4,5-difluoronitrobenzene in 14.4 g of toluene is introduced into a 100 ml three-necked flask fitted with dropping funnel, precision-ground glass stirrer and reflux condenser. 4.3 g (50 mmol) of piperidine are added dropwise to this solution at room temperature and with stirring over the course of 1 hour. The mixture is then stirred at room temperature for a further 2 hours. The reaction solution formed in the reaction is washed three times with 35 ml of water in each case and dried. Removal of the solvent gives 5.3 g (21 mmol) of 2-chloro-5-fluoro-4-piperidinonitrobenzene. This corresponds to a yield of 82.0%, based on 2-chloro-4,5-difluoronitrobenzene used.
Reaction SMILES: ClC1C=CC(OCC(O)=O)=C([C:8]2[CH:13]=[CH:12][C:11]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])=[C:10]([F:21])[CH:9]=2)C=1.B([C:30]1[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[CH:38][C:31]=1[O:32][C@@H:33]([CH3:37])[C:34]([OH:36])=[O:35])(O)O>>[F:21][C:10]1[CH:9]=[C:8]([C:30]2[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[CH:38][C:31]=2[O:32][C@@H:33]([CH3:37])[C:34]([OH:36])=[O:35])[CH:13]=[CH:12][C:11]=1[C:14]([N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:15]
Reactant: C[C@H](Oc1ccc(C(F)(F)F)cc1B(O)O)C(=O)O
Reactant: O=C(O)COc1ccc(Cl)cc1-c1ccc(C(=O)N2CCCC2)c(F)c1
Product: C[C@H](Oc1ccc(C(F)(F)F)cc1-c1ccc(C(=O)N2CCCC2)c(F)c1)C(=O)O

Procedure:
The title compound was prepared using the product of example 24 part a) and (2S)-2-[2-borono-4-(trifluoromethyl)phenoxy]-propanoic acid [WO2004089885] by the method of example 32 step b).
Reaction SMILES: S([O-])([O-])(=O)=O.[Mg+2].[CH3:7][C:8]([N:10](C)C)=O.[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[S:19]1[CH2:24][CH2:23]C(=O)[CH2:21][CH2:20]1.CC(C)(O)C#N>>[N:13]1([C:7]2([C:8]#[N:10])[CH2:23][CH2:24][S:19][CH2:20][CH2:21]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C1CCNCC1
Reactant: CC(=O)N(C)C
Reactant: O=C1CCSCC1
Agent: CC(C)(O)C#N
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Product: N#CC1(N2CCCCC2)CCSCC1
Temperature: 45 °C
Reaction time: 48 h

Procedure:
Magnesium sulphate (9.3 g, 77.4 mmoles), DMA (2.25 g, 25.8 mmoles), piperidine (4.4 g, 51.6 mmoles), tetrahydro-4H-thiopyran-4-one (3 g, 25.8 mmoles) and acetone cyanhydrin (2.2 g, 25.8 mmoles) are introduced in succession into a 250 ml two-necked flask. The reaction medium is agitated for 48 hours at 45° C.
Reaction SMILES: CO[C:3]([C:5]1[CH:6]=[N:7][C:8]2[N:9]([N:21]=[C:22]([CH3:24])[CH:23]=2)[C:10]=1[NH:11][C:12](=[O:20])[CH2:13]C1C=CC=CC=1)=[O:4].C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C(Cl)Cl>O>[CH3:24][C:22]1[CH:23]=[C:8]2[N:7]=[CH:6][C:5]3[C:3]([OH:4])=[CH:13][C:12]([OH:20])=[N:11][C:10]=3[N:9]2[N:21]=1
Reactant: COC(=O)c1cnc2cc(C)nn2c1NC(=O)Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc2ncc3c(O)cc(O)nc3n2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 250 mL round bottom flask containing Compound (20-1) (1.62 g, 5.0 mmol, 1 eq.), THF (30 mL), and NaHMDS (7.5 mL, 7.5 mmol, 1.5 eq.) was stirred at room temperature for 2 h. The reaction was treated with CH2Cl2 (30 mL) and water (40 mL). The aqueous phase was extracted with CH2Cl2 (2×15 mL). The water layer was acidified with concentrated HCl (˜10 mL). The precipitated solid was filtered and washed with CH2Cl2 (4 mL) to furnish Compound (20-2) as a yellowish solid. The acidified water layer was extracted with 5% MeOH in CH2Cl2 (3×25 mL). The combined organic phases were dried over Na2SO4. After filtration and concentration, the residue was purified by silica gel chromatography using MeOH and CH2Cl2 as the mobile phases to furnish Compound (20-2) as a yellowish solid.
Reaction SMILES: [C:1]([C:3]1[C:4]([F:14])=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O)#[N:2].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1.C(N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[C:1]([C:3]1[C:4]([F:14])=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([NH:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1)=[O:8])#[N:2]
Reactant: COc1ccc(C(=O)O)c(F)c1C#N
Reactant: COc1ccc(N)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ccc(NC(=O)c2ccc(OC)c(C#N)c2F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
A mixture of the above benzoic acid derivative (360 mg, 1.85 mmol), p-anisidine (315 mg, 2.56 mmol), N,N-diisopropylethylamine (1.34 mL, 7.68 mmol) and PyBop (1.6 g, 3.1 mmol) in dry DMF (7 mL) was stirred at room temperature overnight and then diluted with water (40 mL). The precipitates were filtered, washed with water three times, and dried in vacuo to give 3-cyano-2-fluoro-4-methoxy-N-(4-methoxy-phenyl)-benzamide (540 mg, 98%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([Cl:19])=[CH:11][C:10]=1[CH2:20][CH:21]([OH:24])[CH2:22][OH:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>N1C=CC=CC=1>[CH3:35][C:25]1[CH:30]=[CH:29][C:28]([S:31]([O:23][CH2:22][CH:21]([OH:24])[CH2:20][C:10]2[CH:11]=[C:12]([Cl:19])[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)(=[O:33])=[O:32])=[CH:27][CH:26]=1
Reactant: OCC(O)Cc1cc(Cl)c2ccccc2c1OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC(O)Cc2cc(Cl)c3ccccc3c2OCc2ccccc2)cc1
Yield: 80.2 %

Procedure:
Treatment of (±)-3-[1-(benzyloxy)-4-chloro-2-naphthyl]propane-1,2-diol (24 g, 0.07 mol) with p-toluenesulfonyl chloride (14 g, 0.074 mol) in pyridine (600 mL) generally according to the procedure described for Intermediate 18 gave 27.9 g (80%) of (±)-3-[1-(benzyloxy)-4-chloro-2-naphthyl]-2-hydroxypropyl 4-methylbenzenesulfonate as a white solid. mp 85-87° C.; Anal. calcd. for C27H25ClO5S: C, 65.25; H, 5.07. Found: C, 65.37; H, 4.97.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1)=O.[F:13][C:14]1[CH:25]=[CH:24][C:17]([CH2:18][C:19]2[CH2:23][CH2:22][CH2:21][N:20]=2)=[CH:16][CH:15]=1.C([O-])(O)=O.[Na+].O>C(OCC)C.C(O)C>[F:13][C:14]1[CH:25]=[CH:24][C:17]([C:18]2[C:3]([C:5]3[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=3)=[CH:2][N:20]3[C:19]=2[CH2:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=1
Reactant: Fc1ccc(CC2=NCCC2)cc1
Reactant: CSc1ccc(C(=O)CBr)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: CSc1ccc(-c2cn3c(c2-c2ccc(F)cc2)CCC3)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.9 %

Procedure:
2-Bromo-1-(4-methylsulphanylphenyl)-1-ethanone (0.83 g, 3.4 mmol), dissolved in diethyl ether (10 ml), is treated with a solution of 2-(4-fluorobenzyl)-1-pyrroline (0.6 g, 3.3 mmol) in ethanol (10 ml) and NaHCO3 (0.6 g, 7 mmol). The mixture is stirred in the dark at RT for 18 h. The reaction is checked by TLC: SiO2/hexane-ether 9:1. The mixture is treated with H2O (10 ml), extracted 2 times with diethyl ether (100 ml) and the combined ether phase is then rewashed with water (30 ml). The organic phase dried over Na2SO4 Sicc. is concentrated in vacuo. The residue which remains is purified by CC on Al2O3/hexane/diethyl ether 1:1. Fractions 1-3 afford 330 mg of orange-red oil.
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH2:4][C@@H:5]3[CH2:14][NH:13][CH2:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1.[C:15](=[O:18])([O-])[O-].[K+].[K+].[C:21](#N)C>>[Br:1][C:2]1[C:3]2[CH2:4][C@@H:5]3[CH2:14][N:13]([CH2:21][CH2:15][OH:18])[CH2:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CC#N
Reactant: O=C([O-])[O-]
Reactant: Brc1cccc2c1C[C@@H]1CNCCN21
Agent: [K+]
Product: OCCN1CCN2c3cccc(Br)c3C[C@@H]2C1
Reaction time: 48 h

Procedure:
(10aR)-9-Bromo-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole (0.10 g, 0.39 mmol) and 2-(bromoethoxy)-tert-butyl-dimethylsilane (88 mg, 0.39 mmol) were dissolved in acetonitrile (2 mL). Potassium carbonate (63 mg, 0.46 mmol) was added and the solution was boiled with stirring for 2 d. The solvent was removed and the residue was partitioned between dichloromethane and brine. The organic phases were pooled, dried with MgSO4 and the solvent was evaporated. Chromatography on silica gel (dichloromethane/methanol 98:2) yielded the intermediate silyl-protected alcohol (124 mg, 76%), MS: m/e=413.3 (M+H+).