Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])[N:11]([CH:17]2[CH2:19][CH2:18]2)[C:10]=1[C:20]([NH:22][CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:21])C1C=CC=CC=1.[H][H]>C(O)C.CO.[Pd]>[CH:24]1([CH2:23][NH:22][C:20]([C:10]2[N:11]([CH:17]3[CH2:19][CH2:18]3)[C:12]([CH3:16])=[CH:13][C:14](=[O:15])[C:9]=2[OH:8])=[O:21])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: [H][H]
Reactant: Cc1cc(=O)c(OCc2ccccc2)c(C(=O)NCC2CCCCC2)n1C1CC1
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: Cc1cc(=O)c(O)c(C(=O)NCC2CCCCC2)n1C1CC1
Temperature: 25 °C
Yield: 63 %

Procedure:
A mixture of 3-(benzyloxy)-N-(cyclohexylmethyl)-1-cyclopropyl-6-methyl-4-oxo-1,4-dihydropyridine-2-carboxamide (2.0 g, 4.8 mmol), Pd/C (10% wet, 0.45 g) in ethanol (150 mL) was hydrogenated in a Parr apparatus at 50 psi of hydrogen pressure for 16 h. The reaction mixture was filtered over a pad of Celite® and the Celite® was thoroughly washed with EtOH (25 mL). Evaporation of the solvent afforded a pale pink solid. The solid was dissolved in hot methanol, then cooled to RT as solid product precipitated out. The solid was collected by suction filtration. The mother liquor was concentrated in vacuo and the residual solid was again dissolved in hot methanol and cooled to RT to precipitate out the product, which was then collected. This process was repeated one more time. The three combined white solid fractions weighed 0.95 g (63% yield).
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([C:5]1[O:6][C:7]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:8]=2[C:9]=1[CH2:10][C:11](O)=[O:12])=[O:4].C1C=CC2N(O)N=NC=2C=1.[CH2:32]([NH:35][CH2:36][CH2:37][CH3:38])[CH2:33][CH3:34].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[CH3:21][C:2]([CH3:20])([CH3:1])[C:3]([C:5]1[O:6][C:7]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:8]=2[C:9]=1[CH2:10][C:11]([N:35]([CH2:36][CH2:37][CH3:38])[CH2:32][CH2:33][CH3:34])=[O:12])=[O:4]
Reactant: COc1ccc2oc(C(=O)C(C)(C)C)c(CC(=O)O)c2c1
Reactant: CCCNCCC
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCN(CCC)C(=O)Cc1c(C(=O)C(C)(C)C)oc2ccc(OC)cc12
Temperature: 40 °C

Procedure:
Dissolve a mixture of 17 mg [2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]acetic acid from the Step B Example 1 and 18.5 mg HOBt in 1 mL dry DMF. Add 12.1 μL dipropylamine followed by 23.0 mg EDC and 35 μL DIEA. This solution was heated at 40° C. for 2 hours. It was purified directly on RP-HPLC using 60-100% MeCN gradient. The fractions containing pure product were pooled and lyophilized to give the title compound. LC-MS: 4.16 min. (m/Z=290.1, 374.2, 396.1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS([C:27]([F:30])([F:29])[F:28])(=O)=O)[CH:5]=[C:6]([Cl:22])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([N:14]2[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]2)[C:10]1=[O:21].[F:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.[C:41](=O)([O-:43])[O-:42].[Na+].[Na+]>C1COCC1.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:30][C:27]([F:28])([F:29])[C:41]([OH:43])=[O:42].[Cl:22][C:6]1[CH:5]=[C:4]([C:35]2[CH:36]=[CH:37][C:32]([F:31])=[CH:33][CH:34]=2)[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([N:14]2[CH2:15][CH2:16][CH:17]([OH:20])[CH2:18][CH2:19]2)[C:10]1=[O:21]
Reactant: O=C([O-])[O-]
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=C1[C@H](Cc2c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc2Cl)CCN1N1CCC(O)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)C(F)(F)F
Product: O=C1[C@H](Cc2c(Cl)cc(-c3ccc(F)cc3)cc2Cl)CCN1N1CCC(O)CC1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 17.3 %

Procedure:
Bring a mixture of trifluoro-methanesulfonic acid (R)-3,5-dichloro-4-[1-(4-hydroxy-piperidin-1-yl)-2-oxo-pyrrolidin-3-ylmethyl]-phenyl ester (0.102 g, 0.21 mmol), 4-fluorophenylboronic acid (0.035 g, 0.25 mmol), sodium carbonate (0.066 g, 0.62 mmol) in THF (10 mL) and water (3 mL) to 60° C. To the mixture at 60° C., add Pd(PPh3)4 (0.015 g, 0.011 mmol), raise the reaction temperature to 80° C., and stir for 2.5 hours. Cool the reaction, dilute with ethyl acetate, and wash with water and brine. Dry the organic layer (Na2SO4), remove the solvent in vacuo to afford crude product, and purify on silica gel column and HPLC (Reverse Phase) to afford 0.02 g of the titled product.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][NH:3][C:2]1=[O:11].O1CC1C[C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=1[O:23][C:24]1[CH:29]=[CH:28]C(OC)=CC=1CC1OC1.C[OH:38]>C1(C)C=CC=CC=1>[CH3:22][O:21][C:19]1[CH:20]=[CH:15][C:16]([O:23][CH2:24][CH:29]([OH:38])[CH2:28][N:8]2[CH2:7][CH2:6][C:5]3([O:1][C:2](=[O:11])[NH:3][CH2:4]3)[CH2:10][CH2:9]2)=[CH:17][CH:18]=1
Reactant: CO
Reactant: COc1ccc(Oc2ccc(OC)cc2CC2CO2)c(CC2CO2)c1
Reactant: O=C1NCC2(CCNCC2)O1
Solvent: Cc1ccccc1
Product: COc1ccc(OCC(O)CN2CCC3(CC2)CNC(=O)O3)cc1

Procedure:
A mixture of 3.4 g 1-oxa-3,8-diazaspiro[4.5]decan-2-one, 2.26 g 2,3-epoxypropyl-p-methoxyphenyl ether, 5 ml methanol and 15 ml toluene is heated at reflux for 24 hours. Evaporation of solvent and recrystallization from ethyl acetate gives 2.7 g 8-[3-(4-methoxyphenoxy)-2-hydroxypropyl]-1-oxa-3,8-diazaspiro[4.5]decan-2-one, mp 151°-153°. To a solution of 1 g of 8-[3-(4-methoxyphenoxy)-2-hydroxypropyl]-1-oxa-3,8-diazaspiro[4.5]decan-2-one in 5 ml methanol is added 10 ml of 3% hydrochloric acid in methanol. Addition of 200 ml diethyl ether, followed by filtration gives 8-[3-(4-methoxyphenoxy)-2-hydroxypropyl]-1-oxa-3,8-diazaspiro[4.5]decan-2-one hydrochloride, mp 198°-203°.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]([NH:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:27](Br)[CH:28]=[CH2:29].O>CN(C=O)C>[CH2:3]([O:10][C:11]([N:13]([CH:14]1[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]1)[CH2:29][CH:28]=[CH2:27])=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)CC1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCN(C(=O)OCc1ccccc1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 109.9 %

Procedure:
Sodium hydride (47 mg of 60% oil dispersion, 1.2 mmol) was added to a solution of 4-(benzyloxycarbonylamino)-1-(tert-butoxycarbonyl)piperidine (200 mg, 0.598 mmol) from Procedure 4, Step C and allyl bromide (0.251 mL, 351 mg, 2.9 mmol) in 2.0 mL of DMF, and the reaction was stirred overnight at rt. The reaction mixture was poured into 20 mL of water and extracted with 3×20 mL of ethyl ether. The combined organic layers were washed with 30 mL of brine, dried over sodium sulfate, and evaporated. The crude product was purified by FC on silica gel, eluting with 20% ethyl acetate in hexane, to give 246 mg of the title compound as a viscous oil.
Reaction SMILES: C([O:3][C:4](=[O:57])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([NH:13][C:14]1[CH:19]=[C:18]([CH3:20])[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([S:27]([C:30]3[CH:34]=[C:33]([C:35]([NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[NH:36])[S:32][C:31]=3[S:45][CH3:46])(=[O:29])=[O:28])[CH:22]=2)=[C:16]([NH:47][C:48](=[O:56])[CH2:49][CH2:50][CH2:51][S:52]([CH3:55])(=[O:54])=[O:53])[CH:15]=1)=[O:12])C.[Li+].[OH-]>CO.O>[C:41]([O:40][C:38]([NH:37][C:35](=[NH:36])[C:33]1[S:32][C:31]([S:45][CH3:46])=[C:30]([S:27]([C:23]2[CH:22]=[C:21]([C:17]3[C:18]([CH3:20])=[CH:19][C:14]([NH:13][C:11](=[O:12])[NH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:57])=[O:3])=[CH:15][C:16]=3[NH:47][C:48](=[O:56])[CH2:49][CH2:50][CH2:51][S:52]([CH3:55])(=[O:53])=[O:54])[CH:26]=[CH:25][CH:24]=2)(=[O:28])=[O:29])[CH:34]=1)=[O:39])([CH3:44])([CH3:42])[CH3:43]
Reactant: CCOC(=O)CCCCCNC(=O)Nc1cc(C)c(-c2cccc(S(=O)(=O)c3cc(C(=N)NC(=O)OC(C)(C)C)sc3SC)c2)c(NC(=O)CCCS(C)(=O)=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc(NC(=O)NCCCCCC(=O)O)cc2NC(=O)CCCS(C)(=O)=O)c1

Procedure:
The procedure as in Example 278: step e was followed using 6-{3-[3′-[5-(tert-butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-2-(4-methanesulfonyl-butyrylamino)-6-methyl-biphenyl-4-yl]-ureido}-hexanoic acid ethyl ester (48 mg, 54.3 μmol, Example 279: step a) in a MeOH/H2O (2:1) solution and 4N LiOH (54.3 μL, 0.217 mmol). The crude was taken on directly to the next step. ESI-MS (m/z): Calcd. for C36H47N5O10S4: 838.2 (M+1); found: 837.8.
Reaction SMILES: I[C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9]([C:15]([F:18])([F:17])[F:16])[CH:8]=2)=[CH:4][CH:3]=1.[BH:21]([OH:23])[OH:22].O[C:25]([C:28](O)([CH3:30])[CH3:29])([CH3:27])[CH3:26].OC(C(O)(C)C)(C)C.CC([O-])=O.[K+]>O1CCOCC1.O>[CH3:26][C:25]1([CH3:27])[C:28]([CH3:30])([CH3:29])[O:23][B:21]([C:2]2[CH:20]=[CH:19][C:5]([O:6][C:7]3[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9]([C:15]([F:18])([F:17])[F:16])[CH:8]=3)=[CH:4][CH:3]=2)[O:22]1
Reactant: N#Cc1ccc(Oc2ccc(I)cc2)cc1C(F)(F)F
Reactant: OBO
Reactant: CC(C)(O)C(C)(C)O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)OB(c2ccc(Oc3ccc(C#N)c(C(F)(F)F)c3)cc2)OC1(C)C
Yield: 57.2 %

Procedure:
4-(4-Iodophenoxy)-2-trifluoromethyl benzonitrile (20 g, 51.4 mmol) was treated with bis-pinacol boronate (13 g, 51.4 mmol, NetChem), KOAc (10 g, 102.8 mmol), and PdCl2dppf*CH2Cl2 (2.1 g, 2.57 mmol) in 50 mL dioxane at 100° C. for 20 hours. The reaction mixture was diluted with 500 mL water and extracted with 2×300 mL EtOAc. The combined organic layers were washed with 250 mL brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was chromatographed on silica using a gradient of EtOAc (20% max) in hexane as the eluent to give 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-2-(trifluoromethyl)benzonitrile (11.45 g, 57%). 1H NMR (400 MHz, CDCl3): 7.93-7.86 (2 H, m), 7.79-7.71 (1 H, m), 7.36-7.32 (1 H, m), 7.17-7.12 (1 H, m), 7.10-7.04 (2 H, m), 1.38-1.34 (12 H, s).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:28])[N:4]([C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=2[F:27])[C:5]([CH2:18][OH:19])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].CC(C)=[O:31].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[Br:1][C:2]1[C:3](=[O:28])[N:4]([C:20]2[C:21]([F:27])=[CH:22][CH:23]=[CH:24][C:25]=2[F:26])[C:5]([C:18]([OH:31])=[O:19])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: CC(C)=O
Reactant: O=c1c(Br)c(OCc2ccc(F)cc2F)cc(CO)n1-c1c(F)cccc1F
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1c(F)cccc1F
Temperature: 0 °C
Yield: 65 %

Procedure:
In a 100 ml round bottom flask, 3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-(hydroxymethyl)pyridin-2(1H)-one (1.70 g, 3.7 mmol) was dissolved in acetone (10 mL) and cooled to 0° C. in ice bath. To the reaction was added 1M acetone solution of Jones (5 ml, excess amount). Additional Jones reagent was added over time (approximately 6 hours) until the reaction was complete. The reaction was then concentrated down to dryness. The residue was then taken up in ethyl acetate (10 mL) and washed with brine. The dark yellow to brown colored crude product was purified by dissolving in 1N aqueous NaOH. The remaining organic impurities were removed by extracting with diethyl ether. The organic layers were discarded and the aqueous layer was acidified with dilute HCl (til pH app 1) to precipitate the pure acid which was then filtered and triturated with ether to obtain 1.17 g (65%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 7.66 (q, J=9.41 Hz, 1H), 7.57-7.50 (m, 1H), 7.34 (dt, J=10.11, 2.78 Hz, 1H), 7.28-7.23 (m, 3H), 7.18 (dt, 8.90, 2.42 Hz, 1H), 5.47 (s, 2H). ES-HRMS m/z 471.9814 (M+H calcd for C19H11BrF4NO4, requires 471.9808)
Reaction SMILES: [Br:1][C:2]([CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[CH2:3].[OH-].[K+].[CH:14]([Br:17])(Br)[Br:15]>C(Cl)Cl>[Br:15][C:14]1([Br:17])[CH2:3][C:2]1([Br:1])[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: C=C(Br)COCCCCCC
Reactant: BrC(Br)Br
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: CCCCCCOCC1(Br)CC1(Br)Br
Temperature: 25 °C
Reaction time: 48 h
Yield: 12.9 %

Procedure:
A mixture of 5.9 g of 2-bromo-3-hexyloxypropene(26.7 mmol), 2.05 g of N,N′-dibenzyl-ethane-1,2-bis-(diethylammonium bromide), 10.5 g of 45% potassium hydroxide (84 mmol), 23.3 g of bromoform (92 mmol) and 70 g of methylene chloride were rapidly stirred at room temperature for two days. When the reaction stalled, the reaction mixture was transferred to a separatory funnel and washed with water. The methylene chloride phase was transferred to a flask and treated with the same amount of the phase transfer catalyst and 45% potassium hydroxide, then stirred at room temperature for an additional 3 days. The workup-recharge sequence was repeated once more, and the reaction was stirred one more day at room temperature. The reaction mixture was washed with water, the methylene chloride phase was dried with magnesium sulfate, and then stripped. The product was chromatographed on silica gel with 20% ethyl acetate 80% hexane to give 1.35 g of 87% pure 1,1,2-tribromo-2-(hexyloxymethyl)cyclopropane.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([NH2:11])[C:5]=2[O:4][CH2:3][CH2:2]1.[CH2:12]([O:14][C:15](=[O:25])[C@@H:16]([CH3:24])[N:17]([CH2:21][CH2:22]Cl)[CH2:18][CH2:19]Cl)[CH3:13]>ClC1C=CC=CC=1>[CH2:12]([O:14][C:15](=[O:25])[C@@H:16]([CH3:24])[N:17]1[CH2:18][CH2:19][N:11]([C:10]2[C:5]3[O:4][CH2:3][CH2:2][O:1][C:6]=3[CH:7]=[CH:8][CH:9]=2)[CH2:22][CH2:21]1)[CH3:13]
Reactant: Nc1cccc2c1OCCO2
Reactant: CCOC(=O)[C@@H](C)N(CCCl)CCCl
Solvent: Clc1ccccc1
Product: CCOC(=O)[C@@H](C)N1CCN(c2cccc3c2OCCO3)CC1
Temperature: 130 °C

Procedure:
A solution of 2,3-dihydro-1,4-benzodioxin-5-amine (0.327 g; 2.16 mmol) in chlorobenzene (2 mL) is added to a solution of N,N-bis(2-chloroethyl)-(R)-alanine ethyl ester (trifluoromethanesulfonic acid salt; 0.850 g; 2.16 mmol) in the same solvent (2 mL). The stirred reaction mixture is heated at 130° C. for 15 hours, the volatiles are removed on a rotavap, and the semi-solid residue is partitioned between 10% sodium bicarbonate (15 mL) and ether. Organic extracts are washed with brine, dried over magnesium sulfate, and filtered. TLC (chloroform) shows formation of a new product with RF 0.15, (R)-4-(2,3-dihydro-1,4-benzodioxin-5-yl)-α-methyl-1-piperazineacetic acid ethyl ester. Upon addition of 1 N ethereal HCl, (R)-4-(2,3-dihydro-1,4-benzodioxin-5-yl)-α-methyl-1-piperazineacetic acid ethyl ester is converted into its hydrochloride salt that is collected by filtration; 0.615 g (80%), mp 168-171° C. The salt can be recrystallized from ethanol-ether, or acetone-ether. 1H NMR (300 MHz, DMSO-d6) δ 1.25 (t, J=7.1 Hz, 3H), 1.58 (d, J=7.2 Hz, 3H), 3.16 (m, 2H), 3.36 (m, 2H), 4.23 (m, 4H), 4.26-4.38 (m, 3H), 4.48 (b, 4H), 6.52 (d, J=7.9 Hz, 1H), 6.57 (d, J=8 Hz, 1H), 6.76 (t, J=8 Hz, 1H), 11.3 (b, <1H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]2[N:15](C3C=CN=CC=3)[N:14]=[CH:13][O:12]2)=[CH:3]1.C[I:23].[CH3:24][C:25]([CH3:27])=O>>[I-:23].[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[O:12][C:13]([C:25]3[CH:27]=[CH:3][N+:2]([CH3:10])=[CH:1][CH:24]=3)=[N:14][N:15]=2)=[CH:3]1
Reactant: CC(C)=O
Reactant: Cn1cc(C2OC=NN2c2ccncc2)c2ccccc21
Reactant: CI
Product: Cn1cc(-c2nnc(-c3cc[n+](C)cc3)o2)c2ccccc21
Product: [I-]
Temperature: 25 °C

Procedure:
4-[2-(1-methylindol-3-yl)-1,3,4-oxadiazol-3-yl]pyridine (50 mg) was dissolved in dry acetone (10 ml), methyl iodide (127 mg) was then added, and the resulting solution heated at reflux for twenty four hours under a dry nitrogen atmosphere. The solution was allowed to cool to room temperature and the yellow solid isolated by filtration. Recrystallisation from acetone afforded the title compound (70 mg); m.p. 290° C. (dec); Found: C, 47.85; H, 3.56; N, 13.12; C17N16N4O15I requires C, 47.79; H, 3.77; N, 13.11%; δH (360 MHz, DMSO-d6) 3.98 (3H, s, N--CH3), 4.43 (3H, s, +N--CH3), 7.38 (2H, brm, H-5,6), 7.68 (1H, brm, H-4), 8.24 (1H, brm, H-7), 8.49 (1H, s, H-2), 8.70 (2H, d, J=8.4 Hz, CH=CH--N), 9.18 (2H, d, J=8.4 Hz, CH=CH--N); m/z (M+ free base 60%,) 276 (60), 158 (100), 127 (20), 103 (10), 77 (10).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=O.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[Cl:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH2:12][NH:8][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[N:7]=1
Reactant: Nc1cccc(F)n1
Reactant: O=Cc1ccccc1Cl
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Fc1cccc(NCc2ccccc2Cl)n1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To 6-fluoro-pyridin-2-ylamine (43, 2.47 g, 22.0 mmol) in 60.0 mL of acetonitrile, 2-chloro-benzaldehyde (44, 3.09 g, 22.0 mmol), triethylsilane (14.0 mL, 87.6 mmol) and trifluoroacetic acid (7.00 mL, 90.9 mmol) were added. The reaction was stirred at 80° C. for 4 hours, then solvents removed under vacuum, and the residue was combined with aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum to provide the desired compound, which was used in the next step without further purification. MS (ESI) [M+H+]+=272.1.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:3]([Cl:5])=[O:4].[CH3:16]C(CCCCCCCCCC)C(O)=O>>[CH3:1][C:2]([CH3:16])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:3]([Cl:5])=[O:4]
Reactant: CCCCCCCCCCC(C)C(=O)Cl
Reactant: CCCCCCCCCCC(C)C(=O)O
Product: CCCCCCCCCCC(C)(C)C(=O)Cl

Procedure:
In a similar manner to that described in Example 25 except for the use of 2-methyldodecanoyl chloride [synthesized by chlorinating 2-methyldodecanoic acid which was synthesized by the process described in Organic Synthesis, 4, 616, by the method as described in B. D. Roth, et al., Journal of Medicinal Chemistry, 35, 1609-1617 (1992)] instead of 2,2-dimethyldodecanoyl chloride, 82.5 mg of the desired compound was obtained as a white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[C:11]([CH3:13])[O:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[CH:23]([N:26]([CH:39]([CH3:41])[CH3:40])[CH2:27][CH2:28][O:29][C:30]1[CH:31]=[C:32]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[NH2:33])([CH3:25])[CH3:24]>>[CH:39]([N:26]([CH:23]([CH3:24])[CH3:25])[CH2:27][CH2:28][O:29][C:30]1[CH:31]=[C:32]([NH:33][C:20]([C:17]2[CH:16]=[CH:15][C:14]([C:3]3[CH:4]=[CH:5][C:6]([C:8]4[N:12]=[C:11]([CH3:13])[O:10][N:9]=4)=[CH:7][C:2]=3[CH3:1])=[CH:19][CH:18]=2)=[O:21])[CH:34]=[CH:35][C:36]=1[O:37][CH3:38])([CH3:41])[CH3:40]
Reactant: COc1ccc(N)cc1OCCN(C(C)C)C(C)C
Reactant: Cc1nc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)no1
Product: COc1ccc(NC(=O)c2ccc(-c3ccc(-c4noc(C)n4)cc3C)cc2)cc1OCCN(C(C)C)C(C)C

Procedure:
The title compound was prepared from 2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-carboxylic acid (EP 0533268 A1) and 3-(2-diisopropylaminoethoxy)-4-methoxyaniline (D4) following a procedure similar to that described in Example 1 (27%) mp 130°-131° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:6][CH:7]=1.C([Li])CCC.CN([CH:23]=[O:24])C.O>C1COCC1.CCCCCC>[CH:10]1([CH2:9][O:8][C:5]2[CH:4]=[CH:3][C:2]([CH:23]=[O:24])=[CH:7][N:6]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CN(C)C=O
Reactant: Brc1ccc(OCC2CCCC2)nc1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1ccc(OCC2CCCC2)nc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A solution of Intermediate 28 (895 mg) in anhydrous THF (10 ml) was added dropwise with a 1.6 M solution of n-butyllithium in hexane (2.70 ml, Ald) over 5 minutes with cooling at −78° C. under argon gas atmosphere, and stirred for 20 minutes. This reaction mixture was added with dehydrated DMF (330 μl, WAKO) over 3 minutes, stirred for 30 minutes, then warmed to room temperature, and further stirred for 1 hour. The reaction mixture was added with water (10 ml), and extracted with ethyl acetate (30 ml×3). The organic layer was washed with saturated brine and dried, and then the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (Quad, hexane:ethyl acetate=10:1) to obtain the title compound (Intermediate 29, 1.04 g).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[CH2:1]([NH:8][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(NCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of benzylamine (0.125 mmol) in 5 mL of THF is added diisopropylethyl amine (0.15 mmol) and benzoylchloride (0.10 mmol). The reaction mixture is stirred at room temperature for 1 hour or until TLC analysis shows consumption of the benzoyl chloride. To this mixture is added perfluorsulfonic acid resin prepared in example 8 (3 g, 0.3 mmol/g loading) and the slurry is gently agitated for 1 hour. The slurry is filtered and the resin washed with dichloromethane. The combined filtrates are combined and the solvent removed under reduced pressure to afford N-benzylbenzamide as a solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Si:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][N:3]=1.[Br-].[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[Zn+].N.O1CCC[CH2:37]1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:37][C:7]1[CH:6]=[C:5]([Si:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:4]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][N:28]=2)=[N:3][CH:2]=1
Reactant: Brc1ccc([Si](c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: C1CCOC1
Reactant: [Zn+]c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N
Agent: [Br-]
Product: Cc1cnc(-c2ccccn2)c([Si](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C

Procedure:
To a reaction container equipped with a cooling apparatus, 2.50 g of tetrakis(triphenylphosphine)palladium, 9 g of 2-bromo-5-triphenylsilylpyridine obtained in the above-mentioned Example 6-2 and 125 mL of tetrahydrofuran were added. To the obtained mixture, 43.23 mL of 2-pyridyl zinc bromide (0.5 M/tetrahydrofuran solution) was added with stirring at room temperature. The obtained mixture was stirred at 50° C. for 7 hours and 40 minutes to effect reaction. The reaction mixture was cooled until room temperature and then, 170 mL of 28% aqueous ammonia solution was added thereto. The obtained mixture was extracted three times with 200 mL of chloroform. The obtained organic layers were mixed and dried with magnesium sulfate. After removing magnesium sulfate by filtration, the filtrate was concentrated to obtain a crude product. The crude product was purified with silica gel column chromatography followed by further recrystallization with diethyl ether to obtain 1.92 g of 5-methyltriphenylsilyl-2,2′-bipyridine.