Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Mg]Cl)(C)C.[CH2:6]([N:13]1[C:17]([C:18]2[CH:19]=[CH:20][C:21]3[O:26][CH2:25][CH2:24][CH2:23][C:22]=3[CH:27]=2)=[C:16](Br)[C:15]([C:29]([F:32])([F:31])[F:30])=[N:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl[C:34](=[O:40])[C:35]([O:37][CH2:38][CH3:39])=[O:36]>O1CCCC1.O>[CH2:6]([N:13]1[C:17]([C:18]2[CH:19]=[CH:20][C:21]3[O:26][CH2:25][CH2:24][CH2:23][C:22]=3[CH:27]=2)=[C:16]([C:34](=[O:40])[C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:15]([C:29]([F:32])([F:31])[F:30])=[N:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)C(=O)Cl
Reactant: FC(F)(F)c1nn(Cc2ccccc2)c(-c2ccc3c(c2)CCCO3)c1Br
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(=O)c1c(C(F)(F)F)nn(Cc2ccccc2)c1-c1ccc2c(c1)CCCO2
Temperature: -20 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
Under nitrogen, isopropyl magnesium chloride 2M in tetrahydrofuran (0.30 mL, 0.59 mmol) was added dropwise to a solution of 1-benzyl-4-bromo-5-(3,4-dihydro-2H-1-benzopyran-6-yl)-3-(trifluoromethyl)-1H-pyrazole (49d) (200 mg, 0.46 mmol) in anhydrous tetrahydrofuran (1.0 mL), previously cooled to −20° C. After 2 hour stirring at the same temperature, ethyl chlorooxoacetate (87 μL, 0.78 mmol) was dropwise added. The mixture was stirred at −20° C. for 60 minutes before being poured in water (2 mL). The mixture was extracted with ethyl acetate (2×3 mL) and the organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC (cyclohexane/ethyl acetate 75/25) to provide the desired keto-ester (49e) (80 mg, 0.17 mmol, 38%)
Reaction SMILES: [CH:1](/[C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=O)CC)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[CH:2]\[CH2:3][CH2:4][CH3:5].C(C([C@H]1CC[C@H](C2C=CC(C#[N:38])=CC=2)CC1)CC)=C.[BH4-].[Na+].C(C1C=CC=CC=1)(=O)CC>CO>[CH:1](/[C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:38])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[CH:2]\[CH2:3][CH2:4][CH3:5]
Reactant: C=CC(CC)[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Reactant: CCC/C=C/[C@H]1CC[C@H](c2ccc(C(=O)CC)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCC(=O)c1ccccc1
Solvent: CO
Product: CCC/C=C/[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1

Procedure:
A solution of 7 1 mmol of ethylmagnesium bromide (prepared from 172 mg of magnesium and 530 μl of ethyl bromide) in 20 ml of absolute tetrahydrofuran was placed at -78° C. while gassing with argon in a sulphonation flask provided with a thermometer, a dropping funnel and a serum cap and treated successively with 3 6 ml of a 0.48 M solution of dilithium tetrachlorocuprate in absolute tetrahydrofuran and with a solution of 500 mg of p-[trans-4-(3-acetoxy-trans-1-propenyl)cyclohexyl]benzonitrile in 10 ml of absolute tetrahydrofuran. After completion of the addition, the reaction mixture was warmed to -15° C., stirred at this temperature for 1.5 hours, subsequently treated with 20 ml of saturated ammonium chloride solution and stirred ar room temperature for a further 1 hour. The aqueous phase which was now deep blue, was separated and extracted twice with 50 ml of diethyl ether each time. The organic phases were washed twice with 50 ml of water each time, dried over magnesium sulphate and concentrated. Low-pressure chromatography (0.5 bar) of the residue (0.4 g) on silica gel with ethyl acetate/petroleum ether (vol. 3.97) gave 375 mg of crude p-[trans-4-(trans-1-pentenyl)-cyclohexyl]benzonitrile which, according to analysis by gas chromatography, was contaminated to 8.5% with p-[trans-4-(trans-1-pentenyl)cyclohexyl]propiophenone and to 4.0% with p-[trans-4-(1-vinylpropyl)cyclohexyl]benzonitrile. Treatment of this crude product with an excess of sodium borohydride in methanol at 0° C. (in order to reduce the propiophenone) working-up, low-pressure chromatography (0.5 bar) on silica gel with ethyl acetate/petroleum ether (vol. 1:9) and finally recrystallization from methanol at -78° C. gave p-[trans-4-(trans-1-pentenyl)-cyclohexyl]benzonitrile in a purity of 98.6%; m.p. (C-N) 15.5° C., cl.p (N-I) 57.0° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=1.CO>C1COCC1>[CH3:21][C:19]1[CH:18]=[CH:17][N:16]=[C:15]([NH:14][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([NH2:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=2)[CH:20]=1
Reactant: Nc1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Reactant: Cc1ccnc(N)c1
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccnc(NC(=O)c2ccc(N)c([N+](=O)[O-])c2)c1
Temperature: 25 °C

Procedure:
The product obtained in 116a (550 mg, 2.74 mmol) in 5 mL THF was added to a mixture of 2-amino-4-methyl-pyridine (750 mg, 6.94 mmol) in 10 mL THF under stirring at ambient temperature. The mixture was stirred for 20 min at ambient temperature, then 1 mL methanol was added and the mixture was concentrated i.vac. The residue was purified by HPLC (C18 symmetry, eluent-gradient: (water+0.15% HCOOH)/acetonitrile=90:10->0:100). Conc. ammonia (aq) was added to the product containing fractions until alkaline, and acetonitrile was removed by evaporation. The aqueous mixture was extracted with dichloromethane/methanol 9:1, the combined organic layers dried over MgSO4 and concentrated to dryness i. vac. and the residue triturated with methanol. After filtration, the solid was washed with methanol and dried at 55° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:20][O:21][CH2:22][C@H:23](O)[CH2:24][CH3:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1>C1COCC1>[CH3:20][O:21][CH2:22][C@@H:23]([O:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[CH2:24][CH3:25]
Reactant: COC(=O)c1cc(O)cc(OCc2ccccc2)c1
Reactant: CC[C@@H](O)COC
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC[C@@H](COC)Oc1cc(OCc2ccccc2)cc(C(=O)OC)c1
Temperature: 10 °C
Reaction time: 16 h
Yield: 68.6 %

Procedure:
A stirred solution of methyl 3-hydroxy-5-{[phenylmethyl]oxy}benzoate (7.5 g, 29 mmol), (R)-1-methoxy-butan-2-ol (3.76 g, 36.25 mmol) and triphenylphosphine (9.5 g, 36.25 mmol) in dry THF (75 mL) was cooled in an ice-bath and a solution of 40% DEAD in toluene (15.8 mL, 36.25 mmol) was added dropwise over 30 minutes. The reaction mixture was allowed to warm slowly to 10° C. and stirred for 16 hours. The THF was evaporated and the residue was dissolved in 30% ethyl acetate in isohexane and cooled in ice. The resultant precipitate was removed by filtration and washed with 10% ethyl acetate in isohexane. The filtrate was evaporated and purified by column chromatography, eluting with 10% ethyl acetate in isohexane, to give the title compound as a colourless oil (6.85 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:8][C:9]1[CH:37]=[CH:36][C:12]([C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([NH:23][C:24]3[N:29]=[C:28]([C:30]4[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=4)[CH:27]=[CH:26][N:25]=3)[CH:17]=2)=[O:14])=[CH:11][CH:10]=1>C(O)C.O>[CH3:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:13](=[O:14])[C:12]2[CH:11]=[CH:10][C:9]([CH2:8][N:1]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)=[CH:37][CH:36]=2)=[CH:17][C:18]=1[NH:23][C:24]1[N:29]=[C:28]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[CH:27]=[CH:26][N:25]=1
Reactant: Cc1ccc(NC(=O)c2ccc(CCl)cc2)cc1Nc1nccc(-c2cccnc2)n1
Reactant: C1CNCCN1
Solvent: O
Solvent: CCO
Product: Cc1ccc(NC(=O)c2ccc(CN3CCNCC3)cc2)cc1Nc1nccc(-c2cccnc2)n1
Temperature: 25 °C

Procedure:
25.8 g (300 mmol) of piperazine are suspended in a mixture of 25 ml of ethanol and 25 ml of water. After almost a clear solution has formed, 12.9 g (30 mmol) of 4-chloromethyl-N-[4-methyl-3-(4-pyridine-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide are added step by step. The yellow solution is boiled under reflux for 14 hours, cooled to room temperature and filtered over Celite. 100 ml of water is added to the solution, the ethanol is evaporated under vacuum and 30 ml of 1N NaOH is added, leading to crystallization of the product. Drying at 50 mbar and 60° C. yields N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-4-piperazin-1-ylmethyl-benzamide; Rf=0.15 (methylene chloride:ethyl acetate:methanol:conc. aqueous ammonium hydroxide solution=60:10:30:2); tR(HPLC)2) 14.6 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10](I)=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[C:23]([O:28][CH3:29])(=[O:27])[C:24]([CH3:26])=[CH2:25].ClCCl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:29][O:28][C:23](=[O:27])[C:24]([CH3:26])=[CH:25][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]2[CH:14]=[CH:15][CH:16]=[C:2]([F:1])[CH:3]=2)=[CH:8][CH:9]=1
Reactant: Fc1cccc(COc2ccc(I)cc2)c1
Reactant: C=C(C)C(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)C(C)=Cc1ccc(OCc2cccc(F)c2)cc1
Temperature: 90 °C
Yield: 41.5 %

Procedure:
A mixture of 1.2 g (3.7 mmol) of 1-(3-fluorobenzyloxy)-4-iodo-benzene, 2.06 g (14.9 mmol) of potassium carbonate and 1.70 g (52.8 mmol) of tetrabutyl ammonium bromide in 10 ml of dimethylformamide is treated under Ar with 48 mg (0.21 mmol) of palladium-(II)-acetate. 1.49 g (14.9 mmol) of methyl methacrylate is added and the mixture heated at 90° C. for about 40 min. The reaction mixture is poured into 150 ml dichloromethane, filtered and washed successively with 0.1 molar hydrochloric acid, saturated aqueous sodium hydrogencarbonate and water. The solution is dried over magnesium sulfate. Flash chromatography (silica gel, hexane/ethyl acetate 95:5) yields 461 mg (42%) of a colorless solid. MS: m/e=301.3 (M++H).
Reaction SMILES: [C:1]1([C@@H:13]2[CH2:18][CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]2)[N:5]2[C:6]3[CH:12]=[CH:11][NH:10][C:7]=3[N:8]=[CH:9][C:4]2=[N:3][N:2]=1.C(OC(N1CCC[C@@H](C(O)=O)C1)=O)(C)(C)C.O=S(Cl)[Cl:44].C([O-])([O-])=O.[Na+].[Na+].Cl>O1CCOCC1.C(Cl)CCl>[ClH:44].[NH:15]1[CH2:16][CH2:17][CH2:18][C@@H:13]([C:1]2[N:5]3[C:6]4[CH:12]=[CH:11][NH:10][C:7]=4[N:8]=[CH:9][C:4]3=[N:3][N:2]=2)[CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](c2nnc3cnc4[nH]ccc4n23)C1
Reactant: O=S(Cl)Cl
Agent: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)O)C1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCCl
Solvent: C1COCCO1
Product: c1cc2c(ncc3nnc([C@@H]4CCCNC4)n32)[nH]1
Temperature: 60 °C
Yield: 82 %

Procedure:
A round bottom flask was charged with (R)-tert-butyl 3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)piperidine-1-carboxylate (0.92 g, 2.68 mmol; prepared using A from Preparation #9, (R)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid [CNH Technologies], EDC and TEA, and E using SOCl2, TEA, and saturated aqueous Na2CO3), HCl (4 N in 1,4-dioxane, 2.9 mL, 11.5 mmol), and 1,4-dioxane (20 mL). The reaction mixture was heated at about 60° C. for about 3 h. The reaction mixture was cooled to ambient temperature then filtered under vacuum and washed with Et2O (35 mL). The solid was then dried for about 16 h in a heated vacuum oven (at about 70° C.) to give (R)-1-(piperidin-3-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine hydrochloride as a brown solid (0.69 g, 82%): LC/MS (Table 2, Method a) Rt=0.45 min; MS m/z 243 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH2:14](O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O>[C:15]1([CH2:14][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: OCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CCc1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Yield: 58.8 %

Procedure:
To an ice-cooled solution of methyl 4-hydroxybenzenepropanoate (0.70 g, 3.9 mmol), benzyl alcohol (0.48 mL, 4.7 mmol) and triphenylphosphine (1.2 g, 4.7 mmol) in tetrahydrofuran (5 mL) was added dropwise diethyl azodicarboxylate (0.73 mL, 4.7 mmol), and the mixture was stirred under ice-cooling for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=17:3) to give the title compound (0.62 g, yield 59%) as a powder.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]1([S:19][CH2:20][CH2:21][CH2:22]O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:43]1(=[O:53])[NH:47][C:46](=[O:48])[C:45]2=[CH:49][CH:50]=[CH:51][CH:52]=[C:44]12>O1CCCC1>[C:13]1([S:19][CH2:20][CH2:21][CH2:22][N:47]2[C:43](=[O:53])[C:44]3[C:45](=[CH:49][CH:50]=[CH:51][CH:52]=3)[C:46]2=[O:48])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: OCCCSc1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCCSc1ccccc1
Reaction time: 15 h
Yield: 85 %

Procedure:
Diethyl azodicarboxylate (14 ml, 89 mmol) was added over 3 minutes to a stirred solution of 3-phenylthiopropanol (14.91 g, 89 mmol), triphenylphosphine (23.25 g, 89 mmol) and phthalimide (13.05 g, 89 mmol) in tetrahydrofuran (350 ml) at room temperature. After 15 hours, the mixture was concentrated in vacuo. Flash chromatography of the residue, eluting with 1:1 ether/hexane, gave the title compound as a white solid (22.5 g 85%). NMR (200 MHz, CDCl3): δ 2.0 (q, 2H), 2.95 (t, 2H), 3.85 (t, 2H), 7.25 (m, 5H), 7.8 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](F)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[F:12].[CH3:13][O-:14].[Na+]>CO>[CH3:13][O:14][C:6]1[CH:7]=[C:2]([Br:1])[C:3]([F:12])=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cc(F)c(Br)cc1F
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(Br)c(F)cc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 95 %

Procedure:
1-Bromo-2,5-difluoro-4-nitrobenzene (15.0 g, 63.0 mmol) was added to a solution of sodium methoxide in methanol (164 mL, 0.5 M, Aldrich). The reaction was heated to 60° C. for 1 h. After cooling to room temperature, the solution was concentrated, and the residue was diluted with water (100 mL) followed by extraction with Ethyl acetate (2×80 mL). The organic phase was dried (Na2SO4) and concentrated to afford 5-bromo-4-fluoro-2-nitrophenyl methyl ether as an orange solid (15.2 g, 95% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.93 (s, 3 H), 7.76 (d, J=5.5 Hz, 1 H), 8.08 (d, J=8.4 Hz, 1 H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:10][CH3:11].[Li]CCCC.C[O:18]B(OC)OC.OO>C1COCC1.O.C(O)(=O)C>[CH2:10]([O:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[OH:18])[CH3:11]
Reactant: COB(OC)OC
Reactant: CCOc1ccc(F)cc1Br
Agent: OO
Agent: [Li]CCCC
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOc1ccc(F)cc1O
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 80.1 %

Procedure:
The 2-bromo-1-ethoxy-4-fluoro-benzene (3.1 g) described in example 1.1 was dissolved in THF (25 ml). The solution was cooled to −75° C. and a solution of n-BuLi (9.73 ml, 1.6 M in hexane) was added slowly. The mixture was stirred for 30 min at −75° C. Trimethylborate (1.62 g) was added within 5 min. Acetic acid (1.27 g) and a 30% solution of H2O2 (1.51 g) were added sequentially. The mixture was stirred for 30 min at 0° C. and for 3 h at room temperature. Water was added and the mixture was extracted with ethyl acetate. The crude product was purified by column chromatography (n-hexane/ethyl acetate) to yield 1.77 g of 2-ethoxy-5-fluoro-phenol as a colorless oil. MS: 156 ([M]+).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]12([CH2:17][CH2:18][C:19]3[NH:23][C:22]([CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)=[N:21][C:20]=3[C:30](O)=[O:31])[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH2:8]1)[CH2:14]2.[CH:33]1[CH:38]=[C:37]([S:39]([OH:42])(=[O:41])=[O:40])[CH:36]=[C:35]([NH2:43])[CH:34]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C=O)C.CN(C)C1C=CN=CC=1.CO.C(OCC)(=O)C.O>[C:7]12([CH2:17][CH2:18][C:19]3[NH:23][C:22]([CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)=[N:21][C:20]=3[C:30]([NH:43][C:35]3[CH:36]=[C:37]([S:39]([OH:42])(=[O:40])=[O:41])[CH:38]=[CH:33][CH:34]=3)=[O:31])[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH2:8]1)[CH2:14]2
Reactant: Nc1cccc(S(=O)(=O)O)c1
Reactant: O=C(O)c1nc(C2CCCCC2)[nH]c1CCC12CC3CC(CC(C3)C1)C2
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(S(=O)(=O)O)c1)c1nc(C2CCCCC2)[nH]c1CCC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
Oxalyl chloride (147 μl, 1.69 mmol) was added to an ice cooled suspension of 5-(2-adamantan-1-yl-ethyl)-2-cyclohexyl-1H-imidazole-4-carboxylic acid (Example 252) (500 mg, 1.40 mmol) in DCM (8 ml), followed by two drops of DMF. The mixture was stirred at room temperature for 1 h, then the solvent was evaporated. The residue was susupended in THF (8 ml), and tretaed sequentially with metanilic acid (346 mg, 2.00 mmol), N,N-diisopropylethylamine (348 μl, 2.00 mmol) and 4-dimethylaminopyridine (DMAP) (cat). The suspension was stirred at room temperature for 120 h. Water (30 ml), ethyl acetate (30 ml) and methanol (2 ml) were added and the mixture was stirred for 1 h. The solid was filtered and dried to afford the title compound (294 mg, 41%). 1H NMR (300 MHz, d6-DMSO) 10.10 (1H, br s), 7.92 (1H, br s), 7.67 (1H, m), 7.34 (2H, m), 2.98-2.86 (3H, m), 2.02-1.34 (27H, m). The acid was converted to the N-methyl-D-glucamine salt and lyophilised from water/dioxan. Found: C, 57.87; H, 7.73; N, 7.74%. C35H54N5O9S.1.0 mol H2O requires: C, 57.99; H, 7.79; N, 7.73%.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1.N1C=CN=C1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>ClCCl>[C:17]([Si:14]([CH3:16])([CH3:15])[O:8][C@H:5]1[CH2:6][CH2:7][C@H:2]([NH2:1])[CH2:3][CH2:4]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](N)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of trans-4-aminocyclohexanol (5.0 g, 43.4 mmol) (TCl US) in dichloromethane (100 mL) was added imidazole (14.78 g, 0.22 mol) (Aldrich) and tert-butyidimethylsilyl chloride (19.63 g, 0.13 mol) (Avocardo Research Chemicals). The reaction mixture was stirred at room temperature for 1 day. It was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (100 mL) and water (100 mL). The organic layer was washed with 1 N sodium hydroxide solution, water and brine, dried (MgSO4), filtered and concentrated to give crude trans-4-(tert-butyl-dimethyl-silanyloxy)-cyclohexylamine which was used in the next step without further purification. (Yield 7.62 g, 76.5%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][C@@H:14]3[CH2:18][CH2:17][N:16]([C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:24])=[C:4]([F:25])[CH:3]=1.[F:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][C:32]=1[CH3:33].O.Cl>O1CCOCC1.C(=O)([O-])[O-].[K+].[K+].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].ClCCl>[CH:21]1([C:19]([N:16]2[CH2:17][CH2:18][C@@H:14]([CH2:13][C:12]3[N:8]([C:5]4[CH:6]=[CH:7][C:2]([C:29]5[CH:30]=[CH:31][C:32]([CH3:33])=[C:27]([F:26])[CH:28]=5)=[CH:3][C:4]=4[F:25])[C:9](=[O:24])[NH:10][N:11]=3)[CH2:15]2)=[O:20])[CH2:23][CH2:22]1
Reactant: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2F)C1
Reactant: Cc1ccc(B(O)O)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1ccc(-c2ccc(-n3c(C[C@@H]4CCN(C(=O)C5CC5)C4)n[nH]c3=O)c(F)c2)cc1F
Yield: 58 %

Procedure:
A mixture of 4-(4-bromo-2-fluorophenyl)-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (0.244 mmol), (3-fluoro-4-methylphenyl)boronic acid (0.370 mmol), and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane adduct (0.012 mmol) in dioxane (2.0 mL) and 2M aq potassium carbonate (0.5 mL) was irradiated in the microwave at 150° C. for 15 min. The reaction mixture was poured into water (50 mL) and the pH was adjusted to 5 with addition of 1N aq HCl. The aqueous layer was extracted with ethyl acetate (3×50 mL) and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification of the residue by flash chromatography (100% ethyl acetate) and then reverse phase HPLC (30-65% acetonitrile/water with 0.1% NH4OH) provided the title compound as a tan solid (58%). MS(ES)+ m/e 439.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C:9]1[CH:35]=[CH:34][C:12]([O:13][C@H:14]2[C:22]3[C:17](=[C:18]([O:24][C:25]4[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=4)[CH:19]=[CH:20][C:21]=3[F:23])[CH2:16][CH2:15]2)=[CH:11][CH:10]=1)=[O:5])[CH3:2].Cl.CN.[CH:39]([N:42](CC)C(C)C)(C)C.[B-](F)(F)(F)F.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C>O1CCCC1>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C:9]1[CH:35]=[CH:34][C:12]([O:13][C@H:14]2[C:22]3[C:17](=[C:18]([O:24][C:25]4[CH:33]=[CH:32][C:28]([C:29](=[O:30])[NH:42][CH3:39])=[CH:27][CH:26]=4)[CH:19]=[CH:20][C:21]=3[F:23])[CH2:16][CH2:15]2)=[CH:11][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)[C@H]1C[C@@H]1c1ccc(O[C@@H]2CCc3c(Oc4ccc(C(=O)O)cc4)ccc(F)c32)cc1
Agent: CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1C[C@@H]1c1ccc(O[C@@H]2CCc3c(Oc4ccc(C(=O)NC)cc4)ccc(F)c32)cc1
Reaction time: 8 h
Yield: 95.3 %

Procedure:
4-{(R)-1-[4-((1S,2S)-2-Ethoxycarbonyl-cyclopropyl)-phenoxy]-7-fluoro-indan-4-yloxy}-benzoic acid (Intermediate 23, 100 mg, 0.21 mmol), methylamine hydrochloride (16 mg, 0.23 mmol), N,N-diisopropylethylamine (0.11 mL, 0.63 mmol) and 0-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU, 74 mg, 0.23 mmol) are combined in dry tetrahydrofuran (7 mL) and stirred overnight. The mixture is concentrated under vacuum, diluted with ethyl acetate, washed with 1 M aqueous HCl solution, saturated sodium bicarbonate solution and water, dried over sodium sulfate, filtered and the solvent removed. The residue is purified by flash chromatography (50% ethyl acetate in cyclohexane) to give the title compound (Yield 98 mg). LC (METHOD 5): tR=1.36 min; Mass spectrum (ES+): m/z=490 [M+H]+.
Reaction SMILES: [O:1]([C:8]1[N:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17](OCC)(=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19].C[O-].[Na+].CO>C(OCC)C>[O:23]=[C:17]([CH2:15][C:14](=[O:16])[C:11]1[CH:12]=[N:13][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:9][CH:10]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CC(=O)c1cnc(Oc2ccccc2)nc1
Reactant: CCOC(=O)C(=O)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: CCOC(=O)C(=O)CC(=O)c1cnc(Oc2ccccc2)nc1

Procedure:
A mixture consisting of 1-(2-phenoxypyrimidin-5-yl)ethanone (Example 38, Step B, 214 mg, 1.00 mmol) and diethyl oxalate (0.14 mL, 150 mg, 1.0 mmol) in diethyl ether (10 mL) under a nitrogen atmosphere at room temperature was stirred for ten minutes. Sodium methoxide (65 mg, 1.2 mmol) was subsequently added followed by methanol (1.0 mL). The solution was stirred overnight at room temperature. The off-white precipitate which had formed was collected by filtration and washed with diethyl ether. The solid was dissolved in water and the pH adjusted to 3 using acetic acid. The solid precipitate which formed was filtered and washed with water. The solid was air dried to afford a mixture comprising both the ethyl and methyl esters.