Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][C:10](=O)[C:9]2[C:15]([F:19])=[CH:16][CH:17]=[CH:18][C:8]1=2)=[O:6])([CH3:3])[CH3:2].[F:20][C:21]([F:35])([F:34])[C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:25][NH2:26]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH:11]=[C:10]([NH:26][CH2:25][C:24]2[CH:27]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:29]=[C:22]([C:21]([F:20])([F:34])[F:35])[CH:23]=2)[C:9]2[C:15]([F:19])=[CH:16][CH:17]=[CH:18][C:8]1=2)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCCC(=O)c2c(F)cccc21
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Product: CC(C)OC(=O)N1CCC=C(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2c(F)cccc21
Reaction time: 14 h
Yield: 77.4 %

Procedure:
Inject titanium isopropoxide (1.3 mL, 4.32 mmol) to a mixture of 6-fluor-5-oxo-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid isopropyl ester (572 mg, 2.16 mmol) and 3,5-bis(trifluoromethyl)benzylamine (972 mg, 3.2 mmol) at room temperature under an atmosphere of nitrogen and stir the solution for 14 h. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford 5-(3,5-Bis-trifluoromethyl-benzylamino)-6-fluoro-2,3-dihydro-benzo[b]azepine-1-carboxylic isopropyl ester (820 mg, 77%). Add methanol (9.3 mL) and platinum oxide (37 mg, 0.16 mmol) to 5-(3,5-Bis-trifluoromethyl-benzylamino)-6-fluoro-2,3-dihydro-benzo[b]azepine-1-carboxylic isopropyl ester (742 mg, 1.5 mmol) and hydrogenate the mixture at 1 atmosphere and room temperature for 2 h. Filter through celite and remove the solvent under reduced pressure to afford 5-(3,5-Bis-trifluoromethyl-benzylamino)-6-fluoro-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid isopropyl ester (730 mg, quantitative). Add acetic anhydride (0.5 mL, 5.78 mmol) dropwise to a suspension of the amine (190 mg, 0.385 mmol) and pyridine (0.5 mL, 5.78 mmol) in dichloromethane (1.5 mL), stir under nitrogen at room temperature for 14 h. Add 1 M hydrochloric acid and extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford the title compound (141 mg, 68%); MS (ES+): 535 (M+H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][CH3:12])=[C:7]([CH:10]=1)[C:8]#[N:9].C(=O)([O-])[O-].[K+].[K+].[CH2:19]([OH:21])[CH3:20]>>[CH2:19]([O:21][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][CH3:12])=[C:7]([CH:10]=1)[C:8]#[N:9])[CH3:20]
Reactant: COc1ccc(CCl)cc1C#N
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOCc1ccc(OC)c(C#N)c1
Temperature: 25 °C
Yield: 68 %

Procedure:
To a solution of 5-chloromethyl-2-methoxy-benzonitrile (254 mg, 1.399 mmol) in ethanol (10 mL) was added potassium carbonate (387 mg, 2.798 mmol). The mixture was heated at reflux for 12 h. Upon cooling to room temperature, the solvent was removed. Water (2-5 mL) was added and the product was extracted with diethyl ether (2×20 mL). The organic layers were washed with brine (1×5 mL) and dried over anhydrous sodium sulfate. The solid was then filtered off, and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 20% ethyl acetate in hexanes yielded 5-ethoxymethyl-2-methoxy-benzonitrile (182 mg, 68%).
Reaction SMILES: [Cl-].Cl[CH2:3][CH2:4][NH2+:5][CH:6]([CH2:9][CH3:10])[CH2:7][CH3:8].[CH3:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[N:21]=[C:22]=[S:23]>>[CH3:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[N:21]=[C:22]1[N:5]([CH:6]([CH2:9][CH3:10])[CH2:7][CH3:8])[CH2:4][CH2:3][S:23]1
Reactant: CCC(CC)[NH2+]CCCl
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Agent: [Cl-]
Product: CCC(CC)N1CCSC1=Nc1ccc([N+](=O)[O-])cc1C

Procedure:
3-Pentylamine was converted to N-(2-hydroxyethyl)-N-(3-pentyl)amine according to Method B5a. The amine was reacted with SOCl2 according to Method B7a to give N-(2-chloroethyl)-N-(3-pentyl)ammonium chloride. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1a to give to give 2-(2-methyl-4-nitrophenylimino)-3-(3-pentyl)-1,3-thiazolidine.
Reaction SMILES: [CH:1]12[O:6][CH:5]1[CH2:4][N:3]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH2:2]2.[OH-].[Na+].[OH-].[NH4+:20]>>[NH2:20][C@H:1]1[C@H:5]([OH:6])[CH2:4][N:3]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:2]1
Reactant: O=C(OCc1ccccc1)N1CC2OC2C1
Reactant: [NH4+]
Agent: [Na+]
Agent: [OH-]
Product: N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1O
Yield: 95 %

Procedure:
benzyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (10.5 g) was stirred in 200 ml of saturated ammonium hydroxide at 35° C. for 40 h. The reaction mixture was poured into 100 ml of 2 N NaOH, extracted methylene chloride (4×200 ml), dried MgSO4, filtered and concentrated to provide the title compound as an oil (10.15 g, 95%): 1H NMR (300 MHz, CDCl3) δ) 7.34, 5.14, 3.99, 3.78, 3.37, 3.19, 1.77; HRMS (FAB) calcd for C12H16N2O3+H 237.1239, found 237.1244.
Reaction SMILES: [ClH:1].Br[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[CH:17]3[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]3)[CH2:13]2)=[O:11])=[CH:5][CH:4]=1.[OH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC>[ClH:1].[OH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:3]2[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]3[CH:17]4[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]4)[CH2:13]3)=[O:11])=[CH:5][CH:4]=2)=[CH:24][CH:23]=1
Reactant: O=C(Nc1ccc(Br)cc1)C1CN2CCC1CC2
Reactant: OCc1ccc(B(O)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: O=C(Nc1ccc(-c2ccc(CO)cc2)cc1)C1CN2CCC1CC2

Procedure:
90 mg (0.26 mmol) of N-(4-bromophenyl)-1-azabicyclo[2.2.2]octane-3-carboxamide hydrochloride, 50 mg (0.31 mmol) of 4-(hydroxymethyl)phenylboronic acid, 190 mg (0.57 mmol) of cesium carbonate and 20 mg (0.03 mmol) of bis(diphenylphosphino)ferrocenepalladium(II) chloride are reacted in 1 ml of 1,2-dimethoxyethane by the general method. 5.9 mg (6% of theory) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH2:9][CH:10]2[O:12][CH2:11]2)=[CH:6][CH:5]=[C:4]([CH3:13])[N:3]=1.[NH:14]1[CH2:19][CH2:18][CH:17]([N:20]2[CH2:24][CH2:23][NH:22][C:21]2=[O:25])[CH2:16][CH2:15]1>C(O)(C)C>[OH:12][CH:10]([CH2:9][O:8][C:7]1[C:2]([Cl:1])=[N:3][C:4]([CH3:13])=[CH:5][CH:6]=1)[CH2:11][N:14]1[CH2:15][CH2:16][CH:17]([N:20]2[CH2:24][CH2:23][NH:22][C:21]2=[O:25])[CH2:18][CH2:19]1
Reactant: O=C1NCCN1C1CCNCC1
Reactant: Cc1ccc(OCC2CO2)c(Cl)n1
Solvent: CC(C)O
Product: Cc1ccc(OCC(O)CN2CCC(N3CCNC3=O)CC2)c(Cl)n1

Procedure:
1.1 g of 2-chloro-3-(2,3-epoxy-propoxy)-6-methylpyridine and 0.76 g of 1-(4-piperidyl)-imidazolidin-2-one are refluxed in 40 ml of isopropanol for 1 hour. Evaporating off the solvent and recrystallising the residue from the isopropanol/ether yields 1-{1-[2-hydroxy-3-(2-chloro-6-methyl-3-pyridyloxy)-propyl]-4-piperidyl}-imidazolidin-2-one with a melting point of 175°-180°.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[C:4]#[C:5][CH2:6][OH:7].[C:9]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:22][C:23]2[C:28]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36][CH3:37])=[C:27](Cl)[N:26]=[C:25]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)[N:24]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.CN1C(=O)N(C)CCC1>[C:9]([C:13]1[CH:14]=[CH:15][C:16]([S:19]([NH:22][C:23]2[C:28]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36][CH3:37])=[C:27]([O:7][CH2:6][C:5]#[C:4][CH2:3][OH:8])[N:26]=[C:25]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)[N:24]=2)(=[O:21])=[O:20])=[CH:17][CH:18]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: OCC#CCO
Reactant: COc1ccccc1Oc1c(Cl)nc(N2CCOCC2)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Solvent: CN(C)C=O
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCOCC2)nc1OCC#CCO
Temperature: 25 °C
Yield: 16.2 %

Procedure:
To a suspension of 675 mg of NaH in 45 ml of DMF and 5 ml of DMPU was added 4.85 g of 2-butyne-1,4-diol. The mixture was stirred at room temperature until evolution of gas had ceased. Then 1.5 g of 4-tert.-butyl-N-[6-chloro-5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yl]-benzene sulfonamide was added and the resulting mixture was heated to 95° C. and stirred for 5 days. Eventually, the mixture was pourred into 150 ml of 10% aqueous citric acid and extracted three times with 150 ml of ethyl acetate. The organic layers were washed with water and brine, dried over MgSO4 and evaporated. The resulting residue was purified by column chromatography on silicagel eluting with hexane:ethyl acetate 1:1 to give 265 mg of 4-tert.-butyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yl]-benzene sulfonamide as a beige foam along with 1.13 g of the starting material 4-tert.-butyl-N-[6-chloro-5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yl]-benzene sulfonamide. LC-MS: tR=5.39 min, [M+1]+=583.41, [M−1]−=581.35.
Reaction SMILES: Cl[C:2]1[C:12]([I:13])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.[F:14][C:15]([F:20])([F:19])[CH:16]([OH:18])[CH3:17].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[I:13][C:12]1[C:2]([O:18][CH:16]([CH3:17])[C:15]([F:20])([F:19])[F:14])=[N:3][CH:4]=[C:5]([CH:11]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CC(O)C(F)(F)F
Reactant: CCOC(=O)c1cnc(Cl)c(I)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(OC(C)C(F)(F)F)c(I)c1
Yield: 48.1 %

Procedure:
To a solution of 120 mg (0.39 mmol) of ethyl 6-chloro-5-iodonicotinate (from Step A) and 52 μL (0.58 mmol) of 1,1,1-trifluoro-2-propanol in 5 mL of THF at rt was added 578 μL (0.58 mmol) of sodium bis(trimethylsilyl)amide (1.0 M in THF). After refluxing overnight, the reaction mixture was concentrated. Chromatography on a Biotage 40S cartridge using 1:49 v/v Et2O/hexanes as the eluant gave 73 mg of the title compound: 1H NMR (500 MHz, CDCl3) δ 1.39 (t, J=7.1, 3H), 1.55 (d, J=6.6, 3H), 4.38 (q, J=7.1, 2H), 5.79 (m, 1H), 8.66 (d, J=2.1, 1H), 8.73 (d, J=2.0, 1H).
Reaction SMILES: [C:1]([Si:5]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](I)=[CH:12][CH:11]=1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[Br:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][C:19]=1[F:27]>>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([C:13]2[CH:14]=[CH:15][C:10]([CH2:9][O:8][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6])=[CH:11][CH:12]=2)=[CH:20][C:19]=1[F:27]
Reactant: OB(O)c1ccc(Br)c(F)c1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(I)cc1
Product: CC(C)(C)[Si](C)(C)OCc1ccc(-c2ccc(Br)c(F)c2)cc1
Yield: 73 %

Procedure:
In accordance with Example 4-(2), but using tert-butyl[(4-iodobenzyl)oxy]dimethylsilane instead of tert-butyl[2-(4-iodophenyl)ethoxy]dimethylsilane, and (4-bromo-3-fluorophenyl)boronic acid instead of (4-bromophenyl)boronic acid, the title compound (yield 73%) was afforded as a white solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:25][CH2:26][CH:27]1[O:31][CH2:30][CH2:29][O:28]1.O>CN(C)C=O>[CH2:3]([N:10]1[CH2:11][CH2:12][N:13]([C:16](=[O:23])[CH:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:25][CH2:26][CH:27]2[O:31][CH2:30][CH2:29][O:28]2)[CH2:14][CH2:15]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrCCC1OCCO1
Reactant: CCOC(=O)CC(=O)N1CCN(Cc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(CCC1OCCO1)C(=O)N1CCN(Cc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
To a stirred suspension of sodium hydride (60% dispersion in oil, 1.4 g) in anhydrous dimethylformamide (50 ml) was added dropwise, under nitrogen, a solution of 4-benzyl-1-[(ethoxycarbonyl)acetyl]-piperazine (8.5 g, 29.3 mmol) in anhydrous dimethylformamide (50 ml) over 25 minutes at room temperature. After a further 30 minutes at room temperature, 2-(2-bromoethyl)-1,3-dioxolane (3.6 ml, 30.7 mmol) was added dropwise over 3 minutes and the resulting yellow solution was stirred for 24 hours. Water (400 ml) was added and products were extracted with diethyl ether (3×300 ml). The combined ethereal phases were washed with brine (1×150 ml), dried (MgSO4) and concentrated. Flash chromatography of the residue (silica gel, diethyl ether--ethanol, 95:5) afforded 8 g of the title compound (70%) as a colourless oil, δ (360 MHz, CDCl3), 1.25 (3H, t, J=7.1Hz), 1.56-1.78 (2H, m), 2.06 (2H, q, J=7.4Hz), 2.44 (4H, br s), 3.46-3.96 (11H, m), 4.16 (2H, q, J=7.1Hz), 4.86 (1H, t, J=4.6Hz), 7.24-7.36 (5H, m); m/e (ES) 391 (M+1)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([Cl:12])=[N:7][CH:6]=[CH:5]2.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C.[C:64]1([CH2:70][SH:71])[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:70]([S:71][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([Cl:12])=[N:7][CH:6]=[CH:5]2)[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1
Reactant: SCc1ccccc1
Reactant: Clc1nccc2cc(Br)ccc12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Clc1nccc2cc(SCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A three-neck 2 L flask equipped with an overhead stirrer, a thermocouple and a nitrogen inlet was charged with 6-bromo-1-chloroisoquinoline (60.0 g, 247 mmol), xantphos (7.16 g, 12.4 mmol) and Pd2(dba)3 (5.66 g, 6.19 mmol) in that order. The flask was evacuated. To the reaction flask was charged sparged dioxane (540 mL) and DIPEA (64.8 mL, 371 mmol). The flask was purged with N2 and warmed to 63° C. upon which a solution of phenylmethanethiol (30.5 mL, 260 mmol) in 180 mL of sparged dioxane was charged to the reaction mixture dropwise over 1 hr. The reaction was completed according to LC/MS. The solids were filtered off. The filtrate was concentrated down to a low volume. 500 mL of isopropanol was added into a separate flask. The concentrated product solution was charged slowly to the flask containing isopropanol. The product crystallized out of the solution. The resulting slurry was stirred at RT for 2 hours. The slurry was cooled to 0° C., filtered, washed with 50% IPA/heptanes, and dried under a vacuum with nitrogen sweep. The product was obtained as yellow solids (44.3 g; 63% isolated yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm=8.26-8.10 (m, 2H), 7.63-7.51 (m, 2H), 7.46-7.39 (m, 3H), 7.37-7.28 (m, 3H), 4.31 (s, 2H); m/z (ESI) 286.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:14])[CH2:6][CH2:7][C:8]([O:10][CH2:11][CH:12]=[CH2:13])=[O:9])[CH:2]=[CH2:3].[CH3:15][O:16][SiH:17]([O:20][CH3:21])[O:18][CH3:19]>[Pt]>[CH3:15][O:16][Si:17]([CH2:3][CH2:2][CH2:1][O:4][C:5](=[O:14])[CH2:6][CH2:7][C:8]([O:10][CH2:11][CH2:12][CH2:13][Si:17]([O:20][CH3:21])([O:18][CH3:19])[O:16][CH3:15])=[O:9])([O:20][CH3:21])[O:18][CH3:19]
Reactant: C=CCOC(=O)CCC(=O)OCC=C
Reactant: CO[SiH](OC)OC
Agent: [Pt]
Product: CO[Si](CCCOC(=O)CCC(=O)OCCC[Si](OC)(OC)OC)(OC)OC
Yield: 84 %

Procedure:
A 250 milliliter round-bottom flask was equipped with a reflux condenser, a stir bar, a nitrogen inlet, and charged with 100 grams diallylsuccinate (0.504 moles) and 30 parts per million Platinum (64.1 microliters (μl) of a 5% Karstedt's solution). The mixture was heated and stirred at 70° C. for 5 minutes after which time trimethoxysilane was slowly added (145 milliliters; 135 grams; 1.11 mol). The mixture was allowed to react for 24 hours after which time the excess trimethoxysilane was stripped in vacuo. A yield of 184 grams of bis(trimethoxysilylpropyl)succinate (84% yield) was obtained. The purity and identity of the product were determined by proton nuclear magnetic resonance spectroscopy (4.1 ppm 4H triplet, 3.5 ppm 18H singlet, 2.6 ppm 4H singlet, 1.8 ppm 4H multiplet, 0.6 ppm 4H triplet).
Reaction SMILES: [CH2:1]([S:3]([CH2:6][CH2:7][CH2:8][C:9]12[CH2:16][CH2:15][C:12]([C:17]([NH:19][CH3:20])=O)([CH2:13][CH2:14]1)[CH2:11][CH2:10]2)(=[O:5])=[O:4])[CH3:2].C(Cl)(=O)C(Cl)=O.[F:27][C:28]([F:41])([F:40])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]1NN=[N:37][N:36]=1>C(Cl)Cl.CN(C=O)C>[CH2:1]([S:3]([CH2:6][CH2:7][CH2:8][C:9]12[CH2:16][CH2:15][C:12]([C:17]3[N:19]([CH3:20])[C:35]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[C:28]([F:27])([F:41])[F:40])=[N:36][N:37]=3)([CH2:13][CH2:14]1)[CH2:11][CH2:10]2)(=[O:5])=[O:4])[CH3:2]
Reactant: FC(F)(F)c1ccccc1-c1nnn[nH]1
Reactant: CCS(=O)(=O)CCCC12CCC(C(=O)NC)(CC1)CC2
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCS(=O)(=O)CCCC12CCC(c3nnc(-c4ccccc4C(F)(F)F)n3C)(CC1)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl amide 11-9 (0.470 g, 1.56 mmol) was dissolved in anhydrous methylene chloride (5 mL) and treated with oxalyl chloride (2M in methylene chloride, 1.56 mL, 3.12 mmol) and DMF (2 drops). The solution was stirred at room temperature for 1 h, then solvent removed by evaporation under reduced pressure. The residue was redissolved in anhydrous toluene (7 mL) and treated with 5[2-(trifluoromethyl)phenyl]1H-tetrazole (368 mg, 1.72 mmol). The mixture was refluxed for 18 h. The reaction was cooled to room temperature and the precipitate was filtered and washed to give 300 mg of crude product as the HCl salt. The salt was taken up in methylene chloride/1N HCl and the aqueous layer was washed with two additional portions of methylene chloride. The organic layers were combined and evaporated and the residue was chromatographed by flash silica gel chromatography. Elution was carried out with a gradient ranging from 0 to 5% methanol/methylene chloride. The appropriate fractions were combined and evaporated to give 3-{4-[3-(ethylsulfonyl)propyl]bicyclo[2.2.2]oct-1-yl}-4methyl-5-[2-(trifluoromethyl)phenyl]-4H -1,2,4-triazole (11-10) as a white powder.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:43]([NH2:45])=[O:44])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][CH2:36][C@@H]5CCCO5)[CH:31]=[C:30]([F:42])[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].[O:46]1[CH2:50][CH2:49][CH2:48][C@H:47]1[CH2:51]N>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:14][CH2:15][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:43]([NH2:45])=[O:44])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][CH2:36][CH:48]5[CH2:49][CH2:50][O:46][CH2:51][CH2:47]5)[CH:31]=[C:30]([F:42])[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:17][CH2:18]1)(=[O:11])=[O:12])[CH3:9]
Reactant: NC[C@@H]1CCCO1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(F)cc(CNC[C@@H]5CCCO5)c4)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(F)cc(CNCC5CCOCC5)c4)cc23)CC1
Yield: 68.7 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-furanylmethyl]amino}methyl)phenyl]-1H-indole-7-carboxamide trifluoroacetate, substituting 1-(tetrahydro-2H-pyran-4-yl)methanamine (60 mg, 0.525 mmol) for 1-[(2S)-tetrahydro-2-furanyl]methanamine to afford 40.1 mg of the title compound (68.7%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=2)=[CH:4][CH:3]=1.[C:23](O)(=[O:25])[CH3:24].C(OC(=O)C)(=O)C>O>[C:23]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([CH3:15])([CH3:16])[CH3:17])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=2)=[CH:4][CH:3]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)O
Reactant: CC(C)(C)c1cc(-c2ccc(N)cc2)cc(C(C)(C)C)c1O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)Nc1ccc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc1

Procedure:
A solution of 15 g. (0.050 mole) of 4-(4'-aminophenyl)-2,6-di(t-butyl)phenol in 100 ml. of glacial acetic acid is treated with 5.2 g. (0.050 mole) of acetic anhydride. The resulting solution is heated gently for 10 minutes, diluted with water, cooled, and the solid product is separated by filtration. Recrystallization from a benzene-hexane mixture provides 4-(4'-acetamidophenyl)-2,6-di(t-butyl)phenol, m.p. 173°-174.5° C.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][CH:15]3[CH2:17][CH2:16]3)=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[CH3:18][C:19]([CH3:28])([CH3:27])[CH:20]([NH2:26])[C:21]1[S:22][CH:23]=[CH:24][N:25]=1>>[CH3:18][C:19]([CH3:28])([CH3:27])[CH:20]([NH:26][C:10]([C:7]1[CH:6]=[C:5]([O:13][CH2:14][CH:15]2[CH2:17][CH2:16]2)[C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:9][N:8]=1)=[O:12])[C:21]1[S:22][CH:23]=[CH:24][N:25]=1
Reactant: CC(C)(C)C(N)c1nccs1
Reactant: O=C(O)c1cc(OCC2CC2)c(C2CC2)cn1
Product: CC(C)(C)C(NC(=O)c1cc(OCC2CC2)c(C2CC2)cn1)c1nccs1

Procedure:
The title compound was synthesized in analogy to Example 24d, using 5-Cyclopropyl-4-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42c) and 2,2-Dimethyl-1-thiazol-2-yl-propylamine (CAN 1247122-26-4) as starting materials and isolated (15 mg, 26%) as white solid; MS (ESI, m/z): 386.4 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:18])[CH2:15][CH:16]=[CH2:17])=[CH:4][CH:3]=1.I[C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:22][CH:21]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:18])[CH2:15]/[CH:16]=[CH:17]/[C:30]2[CH:31]=[CH:32][C:27]([O:26][C:23]3[CH:24]=[CH:25][CH:20]=[CH:21][CH:22]=3)=[CH:28][CH:29]=2)=[CH:6][CH:7]=1
Reactant: C=CCC(O)c1c(C)noc1-c1ccc(Br)cc1
Reactant: Ic1ccc(Oc2ccccc2)cc1
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)C/C=C/c1ccc(Oc2ccccc2)cc1

Procedure:
Prepared according to the procedure described in Example 32, Step 2, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-but-3-en-1-ol and 1-iodo-4-phenoxy-benzene.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[N:16]=[C:15]([CH3:17])[CH:14]=[CH:13][N:12]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[O:26][C:25]([NH:27][CH2:28][C@@H:29]3[C@H:34]([CH3:35])[CH2:33][CH2:32][CH2:31][NH:30]3)=[N:24][C:23]=2[CH:36]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[O:26][C:25]([NH:27][CH2:28][C@@H:29]3[C@H:34]([CH3:35])[CH2:33][CH2:32][CH2:31][N:30]3[C:7]([C:6]3[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=3[C:11]3[N:16]=[C:15]([CH3:17])[CH:14]=[CH:13][N:12]=3)=[O:9])=[N:24][C:23]=2[CH:36]=1
Reactant: Cc1ccc(-c2nccc(C)n2)c(C(=O)O)c1
Reactant: C[C@@H]1CCCN[C@@H]1CNc1nc2cc(Cl)ccc2o1
Product: Cc1ccc(-c2nccc(C)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2nc3cc(Cl)ccc3o2)c1

Procedure:
The title compound was prepared following the same general protocol as described in Example A1, using 5-methyl-2-(4-methylpyrimidin-2-yl)benzoic acid and 5-chloro-N-(((2S,3R)-3-methylpiperidin-2-yl)methyl)benzo[d]oxazol-2-amine. ESI-MS (m/z): 490 [M+1]+.
Reaction SMILES: Br[O-:2].[Na+].BrBr.[OH-].[Na+].[CH3:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](C)=[O:18])=[CH:13][CH:12]=1>O.O1CCOCC1>[CH2:10]([C:11]1[CH:12]=[CH:13][C:14]([C:17]([OH:18])=[O:2])=[CH:15][CH:16]=1)[CH2:9][CH3:8]
Reactant: CCCc1ccc(C(C)=O)cc1
Reactant: [O-]Br
Agent: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCCc1ccc(C(=O)O)cc1

Procedure:
A solution of sodium hypobromite prepared by dissolving bromine (1.0 mole) in a solution of sodium hydroxide (3.5 mole) in water (700 ml) at 0° C. was added to a well stirred solution of 4-n-propylacetophenone (0.2 mole), prepared in step A1, in dioxan (500 ml). Throughout the addition and for 0.25 hours afterwards the temperature was maintained at 35°-45° C. The excess of sodium hypobromite wad destroyed by adding a solution of sodium metabisulphite. Water (3.5 L) was added and bromoform distilled from the reation mixture. On cooling, the solution was acidified with concentrated hydrochloric acid and the precipitated product filtered off and washed with water. The product was crystallised from ethanol/water to yield white crystals mpt 141.2° C.