Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH2:23]([C@@:26]1([CH3:53])[CH2:31][C@H:30]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=2)[C@@H:29]([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=2)[N:28]([C@@H:46]([CH:49]([CH3:51])[CH3:50])[CH2:47][OH:48])[C:27]1=[O:52])[CH:24]=[CH2:25].O>ClCCl>[CH2:23]([C@@:26]1([CH3:53])[CH2:31][C@H:30]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=2)[C@@H:29]([C:39]2[CH:40]=[CH:41][C:42]([Cl:45])=[CH:43][CH:44]=2)[N:28]([C@@H:46]([CH:49]([CH3:50])[CH3:51])[CH:47]=[O:48])[C:27]1=[O:52])[CH:24]=[CH2:25]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CO)C(C)C)C1=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O
Solvent: ClCCl
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](C=O)C(C)C)C1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Dess-Martin periodinane (938 mg, 2.212 mmol) was added as a solid to a solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxy-3-methylbutan-2-yl)-3-methylpiperidin-2-one (Example 261, Step H, 365.4 mg, 0.794 mmol) in dichloromethane (8 mL) and water (0.04 mL, 2.220 mmol). The resulting suspension was vigorously stirred at ambient temperature for 1.5 h. The reaction was quenched with sodium thiosulfate solution (1M aq, 6 mL). Additional sodium thiosulfate solution (1M aq, 6 mL) was added and stirred until the chalky suspension became a slightly cloudy biphasic mixture. The aqueous phase was separated and back extracted with dichloromethane. The organic layer was washed with sodium thiosulfate solution, saturated aqueous sodium bicarbonate and sat. aq. NaCl solution. After drying over sodium sulfate and concentration, the residue was purified on silica gel, eluting with a gradient of 0 to 30% ethyl acetate in hexanes. Fractions containing the desired product were pooled to give the title compound as a white foam. MS (ESI) m/z=458 [M+H]+.
Reaction SMILES: O.[NH2:2][NH2:3].[F:4][C:5]1[CH:6]=[CH:7][C:8]2[N:14]3[CH:15]=[N:16][C:17]([C:18]([O-])=[O:19])=[C:13]3[CH2:12][N:11]([CH3:21])[C:10](=[O:22])[C:9]=2[CH:23]=1>C(O)C>[F:4][C:5]1[CH:6]=[CH:7][C:8]2[N:14]3[CH:15]=[N:16][C:17]([C:18]([NH:2][NH2:3])=[O:19])=[C:13]3[CH2:12][N:11]([CH3:21])[C:10](=[O:22])[C:9]=2[CH:23]=1
Reactant: NN
Reactant: CN1Cc2c(C(=O)[O-])ncn2-c2ccc(F)cc2C1=O
Solvent: CCO
Solvent: O
Product: CN1Cc2c(C(=O)NN)ncn2-c2ccc(F)cc2C1=O
Yield: 96 %

Procedure:
13 ml of hydrazine hydrate were added to a suspension of 7.0 g (23 mmol) of 8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-3-carboxylate in 70 ml of ethanol and the mixture was heated at reflux for 3 hours. After cooling to 0° the crystals obtained were filtered off and there were obtained 6.43 g (96%) of 8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid hydrazide as colourless needles of m.p. 288°-290°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B2OCC(C)(C)CO2)[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.Br[C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[C:22]#[N:23]>COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>[F:1][C:2]1[CH:3]=[C:4]([C:20]2[C:21]([C:22]#[N:23])=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: CC1(C)COB(c2cc(F)cc([N+](=O)[O-])c2)OC1
Reactant: N#Cc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: N#Cc1ccccc1-c1cc(F)cc([N+](=O)[O-])c1
Temperature: 90 °C
Yield: 72.1 %

Procedure:
A mixture of 2-(3-fluoro-5-nitrophenyl)-5,5-dimethyl-[1,3,2]dioxaborinane (15 g, 59 mmol) and 2-bromobenzonitrile (12.4 g, 68.2 mmol) in 1,2-dimethoxyethane (125 mL) and 2 M aqueous sodium carbonate (50 mL) was degassed with nitrogen for 30 min then treated with tetrakis-(triphenylphosphine)palladium(0) (2.06 g, 1.8 mmol). The reaction was then heated at 90° C. for 16 h, cooled to ambient temperature and partitioned between ethyl acetate and water. The organics were washed with brine, dried over anhydrous magnesium sulfate, filtered and pre-adsorbed onto silica gel. Purification by dry flash chromatography on silica gel, eluting with isohexane (containing 1% methanol) on a gradient of ethyl acetate (10-40%) afforded 3′-fluoro-5′-nitrobiphenyl-2-carbonitrile as a cream-coloured solid (10.3 g, 72%): δH (400 MHz, CDCl3) 7.54-7.61 (2H, m), 7.65 (1H, ddd, J 8, 2 and 2), 7.74 (1H, ddd, J 8, 8 and 2), 7.84 (1H, dd, J 8 and 2), 8.03 (1H, ddd, J 8, 8 and 2), 8.22-8.24 (1H, m).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH2:9].[OH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH2:26][CH:27]([CH3:30])[CH2:28][CH3:29])=[O:24])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.ClCCl>[CH2:2]([O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH2:26][CH:27]([CH3:30])[CH2:28][CH3:29])=[O:24])=[CH:19][CH:18]=2)=[CH:15][CH:16]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH2:9]
Reactant: C=CCCCCCCBr
Reactant: CCC(C)COC(=O)c1ccc(-c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: C=CCCCCCCOc1ccc(-c2ccc(C(=O)OCC(C)CC)cc2)cc1
Yield: 76.9 %

Procedure:
5.1 g of 8-bromo-1-octene, 8.2 g of 2-methylbutyl 4'-hydroxybiphenyl-4-carboxylate, and 4.0 g of potassium carbonate were refluxed in acetone for 20 hours. After the conclusion of the reaction, the reaction product was diluted with dichloromethane, and the inorganic matters were removed by filtration. The solvent was distilled out under reduced pressure, and the residue was purified by column chromatography to obtain 8.1 g of the objective 2-methylbutyl 4'-(7-octenyloxy)biphenyl-4-carboxylate. (Yield: 77%)
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:3]=1[C:4]([C:6]1[C:11]([CH3:12])=[CH:10][C:9]([O:13][CH3:14])=[C:8]([O:15][CH3:16])[C:7]=1[OH:17])=[O:5].[K].Br[CH2:25][CH2:26][CH2:27][CH3:28]>CN(C)C=O>[CH2:25]([O:17][C:7]1[C:8]([O:15][CH3:16])=[C:9]([O:13][CH3:14])[CH:10]=[C:11]([CH3:12])[C:6]=1[C:4](=[O:5])[C:3]1[C:2]([Cl:1])=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:22])[CH2:26][CH2:27][CH3:28]
Reactant: CCCCBr
Reactant: COc1cc(C)c(C(=O)c2c(Cl)cccc2Cl)c(O)c1OC
Agent: [K]
Solvent: CN(C)C=O
Product: CCCCOc1c(OC)c(OC)cc(C)c1C(=O)c1c(Cl)cccc1Cl
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of 2,6-dichloro-3',4'-dimethoxy-2'-hydroxy-6'-methyl-benzophenone, potassium salt (1.13 g; 3 mmol), 1-bromobutane (0.69 g, 5 mmol) and dimethyl formamide (5 ml) are stirred at 100° C. for 8 h, and concentrated in vacuo. The residue is dissolved by shaking with a toluene/water mixture, after separation, the organic layer is collected washed with water and dried. After addition of silica gel (5 g), the solvent is evaporated. A flash chromatography column is packed with silica gel (25 g) and the charged silica gel is layered on top of that. Elution with petrol ether/ethyl acetate (95/5, 500 ml) gives the title compound, 0.82 g, (69% y) as colourless crystals, mp. 70° C.
Reaction SMILES: FS([C:5]([F:14])([F:13])[C:6](O[Si](C)(C)C)=O)(=O)=O.[Br:15][C:16]1[C:17]([N:31]([CH3:36])[S:32]([CH3:35])(=[O:34])=[O:33])=[CH:18][C:19]2[O:23][C:22]([CH:24]=C)=[C:21]([C:26]([NH:28][CH3:29])=[O:27])[C:20]=2[CH:30]=1.[F-].[Na+]>C1(C)C=CC=CC=1.COCCOCCOC>[Br:15][C:16]1[C:17]([N:31]([CH3:36])[S:32]([CH3:35])(=[O:33])=[O:34])=[CH:18][C:19]2[O:23][C:22]([CH:24]3[CH2:6][C:5]3([F:13])[F:14])=[C:21]([C:26]([NH:28][CH3:29])=[O:27])[C:20]=2[CH:30]=1
Reactant: C[Si](C)(C)OC(=O)C(F)(F)S(=O)(=O)F
Reactant: C=Cc1oc2cc(N(C)S(C)(=O)=O)c(Br)cc2c1C(=O)NC
Agent: [F-]
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: Cc1ccccc1
Product: CNC(=O)c1c(C2CC2(F)F)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Temperature: 120 °C
Reaction time: 2 h
Yield: 22.9 %

Procedure:
A solution of trimethylsilyl 2-fluorosulfonyl-2,2-difluoroacetate (31 mg, 0.12 mmol) in toluene (0.5 mL) was added dropwise to a solution of 5-bromo-N-methyl-6-(N-methylmethylsulfonamido)-2-vinylbenzofuran-3-carboxamide (30 mg, 0.07 mmol) and NaF (1 mg, 0.02 mmol) in diglyme (1 mL) at 120° C. over 15 min. The mixture was then stirred at 120° C. for 2 h. The mixture was concentrated in vacuum and the residue was purified by prep-TLC (PE:EA=1:1) to give the product of 5-bromo-2-(2,2-difluorocyclopropyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (7 mg, yield: 22%). 1H-NMR (DMSO-d6, 400 MHz) δ 8.13 (s, 1H), 8.02 (s, 1H), 3.74˜3.66 (m, 1H), 3.19 (s, 3H), 3.18 (s, 3H), 2.84 (s, 3H), 2.38˜2.39 (m, 1H), 2.21˜2.17 (m, 1H). MS (M+H)+: 437/439.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:5]=[C:4]([NH:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:47]1([CH2:53][CH2:54][NH2:55])[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1.C(N(CC)CC)C>O1CCCC1>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:5]=[C:4]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([NH:55][CH2:54][CH2:53][N:47]3[CH2:52][CH2:51][O:50][CH2:49][CH2:48]3)=[O:20])=[CH:21][CH:22]=2)[N:3]=1
Reactant: Nc1nc(Nc2ccc(C(=O)O)cc2)nn1-c1ccccn1
Reactant: NCCN1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1nc(Nc2ccc(C(=O)NCCN3CCOCC3)cc2)nn1-c1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.3 %

Procedure:
To 4-(5-amino-1-pyridin-2-yl-1H-[1,2,4]triazol-3-ylamino)-benzoic acid (4.635 g, 15.643 mmole) in tetrahydrofuran (50 mL) was added (7.12 g, 1.2 equivalents) of HBTU, followed by 2-morpholin-4-yl-ethylamine (2.24 g, 1.1 equivalents) and triethylamine (5.45 mL, 2.5 equivalents). The reaction was stirred overnight at room temperature. The solid was filtered, washing with tetrahydrofuran, cold ethanol, water, ethanol, and finally ether. The compound was dried to provide 4-(5-amino-1-pyridin-2-yl-1H-[1,2,4]triazol-3-ylamino)-N-(2-morpholin-4-yl-ethyl)-benzamide (1.17 g, 18% yield) as a white solid. The organic phases contained product also but was not further isolated.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([F:10])[F:9])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:16]([O:18]CC)=[CH2:17])CCC.Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:9][CH:8]([F:10])[C:4]1[CH:3]=[C:2]([C:16](=[O:18])[CH3:17])[CH:7]=[CH:6][CH:5]=1
Reactant: FC(F)c1cccc(Br)c1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)c1cccc(C(F)F)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
A mixture of 1-bromo-3-(difluoromethyl)benzene (0.72 g, 3.48 mmol), tributyl(1-ethoxyvinyl)tin (1.38 g, 3.83 mmol), dichlorobis(triphenylphosphine)-palladium(II) (0.24 g, 0.35 mmol) in toluene (12 mL) is heated at 100° C. under nitrogen atmosphere for 16 hours. After cooling to room temperature, 2M hydrochloric acid (12 mL) is added to the mixture. Then the resulting mixture is stirred at room temperature for 1 hour. The mixture is diluted with ethyl acetate (100 mL) and washed with water (100 mL). The organic layer is dried over sodium sulfate, and concentrated under reduced pressure. The residue is purified by column chromatography on silica-gel eluting with n-hexane/ethyl acetate (30:1) to give 0.58 g (98% yield) of the title compound as colorless oil.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][N:3]=1.[CH3:9][O-:10].[Na+].O>CO>[I:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([O:10][CH3:9])[CH:7]=1
Reactant: Fc1cc(I)ccn1
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(I)ccn1
Yield: 95.4 %

Procedure:
500 ml of methanol was added to 59.4 g (253 mmol) of crude 2-fluoro-4-iodopyridine obtained in Step (b) so that it was dissolved in methanol, and 21.5 g (398 mmol) of sodium methoxide was added, followed by reflux with heating for 3 hours. 300 ml of water was added to terminate the reaction, and methanol was distilled off under reduced pressure. After extraction with ethyl ether, the organic layer was dried over sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure to obtain 56.7 g (crude yield: 91%) of crude 4-iodo-2-methoxypyridine.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C@@H:22]([NH:24]C(=O)OC(C)(C)C)[CH3:23])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[S:18]([CH3:21])(=[O:20])=[O:19])=[N:9]2)=[CH:4][CH:3]=1.Cl.FC1C=C2C(C=C([C@@H](N)C)C(C3C=CC=CC=3S(C)(=O)=O)=N2)=CC=1.[NH2:57][C:58]1[C:63]([C:64]#[N:65])=[C:62](Cl)[N:61]=[CH:60][N:59]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:57][C:58]1[C:63]([C:64]#[N:65])=[C:62]([NH:24][C@H:22]([C:7]2[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[S:18]([CH3:21])(=[O:20])=[O:19])=[N:9][C:10]3[C:5]([CH:6]=2)=[CH:4][CH:3]=[C:2]([F:1])[CH:11]=3)[CH3:23])[N:61]=[CH:60][N:59]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1cc2ccc(F)cc2nc1-c1ccccc1S(C)(=O)=O
Agent: C[C@H](N)c1cc2ccc(F)cc2nc1-c1ccccc1S(C)(=O)=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc(N)c1C#N)c1cc2ccc(F)cc2nc1-c1ccccc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 5.1 %

Procedure:
To (S)-tert-butyl (1-(7-fluoro-2-(2-(methylsulfonyl)phenyl)quinolin-3-yl)ethyl)-carbamate (440 mg, 1.0 mmol) was added HCl, 4M (1 mL). The resulting mixture was stirred at rt for 1 h. Solvent was removed and the crude (S)-1-(7-fluoro-2-(2-(methylsulfonyl)phenyl)quinolin-3-yl)ethanamine was used without further workup. A solution of (1S)-1-(7-fluoro-2-(2-(methylsulfonyl)phenyl)-quinolin-3-yl)ethanamine (100 mg, 290 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (45 mg, 290 μmol) and DIEA (101 μl, 581 mol) in DMF (4 mL) was heated to 100° C. overnight. Solvent was removed under reduce pressure and purified via preparatory. TLC using 3% of MeOH/DCM to afford a white powder of (S)-4-amino-6-((1-(7-fluoro-2-(2-(methylsulfonyl)phenyl)quinolin-3-yl)ethyl)-amino)pyrimidine-5-carbonitrile (6.9 mg, 5.1%). 1H NMR (500 MHz, CD3OD) δ ppm 1.51 (d, J=7.09 Hz, 3H) 3.17 (s, 3H) 5.43 (d, J=6.85 Hz, 1H) 7.48 (d, J=2.45 Hz, 1H) 7.60-7.63 (m, 1H) 7.66-7.69 (m, 2H) 7.73 (d, J=1.47 Hz, 1H) 7.81 (s, 1H) 8.07 (dd, J=9.05, 6.11 Hz, 1H) 8.13-8.17 (m, 1H) 8.49 (s, 1H). Mass Spectrum (ESI) m/e=463 (M+1).
Reaction SMILES: [C:1]1([C:13]2[C:14](=[O:28])[NH:15][C:16](=[O:27])[C:17]=2[C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.[H][H]>[Pd].CO>[C:1]1([C@H:13]2[C@@H:17]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[C:16](=[O:27])[NH:15][C:14]2=[O:28])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1
Reactant: [H][H]
Reactant: O=C1NC(=O)C(c2cn3c4c(cccc24)CCC3)=C1c1c[nH]c2ccccc12
Agent: [Pd]
Solvent: CO
Product: O=C1NC(=O)[C@@H](c2cn3c4c(cccc24)CCC3)[C@H]1c1c[nH]c2ccccc12
Yield: 57.1 %

Procedure:
A suspension of 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4(1H-indol-3-yl)pyrrole-2,5-dione (16 g, 43.6 mmol) and 10% palladium on carbon (Pd/C, wet catalyst) (8 g) were stirred under 1 atmosphere of hydrogen in methanol (600 ml) at room temperature for 48 hours. The catalyst was then filtered through a bed of C elite and the filtrate evaporated to dryness. The residue was re-dissolved in methanol and the product precipitated by the addition of cold water. The precipitate was filtered, washed with water and dried under vacuum to yield (±)-cis-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4(1H-indol-3-yl)pyrrolidine-2,5-dione (9.2 g). 1H NMR (DMSO-d6) 400 MHz δ: 11.56 (s, 1H), 10.66 (s, 1H), 7.43 (d, 1H, J=7.6 Hz), 7.14 (d, 2H, J=8 Hz), 6.86-6.97 (m, 4H), 6.78 (t, 1H, J=7.2 Hz), 6.69 (d, 1H, J=6.8 Hz), 4.88 (dd, 2H, J=9.2 and 45.6 Hz), 3.88 (m, 2H), 2.76 (t, 2H, J=5.6 Hz), 1.94 (t, 2H, J=6 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][CH2:12][O:11][C:10]([CH3:15])([CH3:14])[O:9]2)[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[C:21](=[O:23])=[O:22].[Cl-].[NH4+]>C1COCC1.CCCCCC>[CH3:14][C:10]1([CH3:15])[O:9][CH:8]([C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[C:21]([OH:23])=[O:22])[CH2:13][CH2:12][O:11]1
Reactant: O=C=O
Reactant: CC1(C)OCCC(c2cccc(Br)c2)O1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1(C)OCCC(c2cccc(C(=O)O)c2)O1
Temperature: -78 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
A 1 g portion of 4-(3-bromophenyl)-2,2-dimethyl-1,3-dioxane was dissolved in 18 ml of THF solution and cooled to −78° C., and then 2.35 ml of hexane solution containing 1.57 M n-butyl lithium was added dropwise thereto spending 1 hour. After completion of the dropwise addition, this was further stirred for 30 minutes. After adding excess amount of carbon dioxide thereto at −78° C., the mixture was risen to room temperature. The reaction solution was mixed with ammonium chloride aqueous solution and extracted 10 times with chloroform-methanol (5:1), the organic layer was dried with sodium sulfate and concentrated, and then the thus formed residue was purified by a silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain 550 mg (63%) of 3-(2,2-dimethyl-1,3-dioxan-4-yl)benzoic acid (Reference Example 15-1). FA: 237
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].F[C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=1.O>CS(C)=O>[F:25][C:24]([F:27])([F:26])[C:22]1[CH:21]=[CH:20][N:19]=[C:18]([O:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=2)[CH:23]=1
Reactant: Fc1cc(C(F)(F)F)ccn1
Reactant: OCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: OCCc1ccc(Oc2cc(C(F)(F)F)ccn2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.4 %

Procedure:
2-(4-Hydroxyphenyl)ethanol (4.0 g, 29 mmol), K2CO3 (8.0 g, 58 mmol) and 2-fluoro-4-trifluoromethylpyridine (3.6 g, 22 mmol) were combined in DMSO (30 mL) and stirred at 25° C. for 20 h. The mixture was poured into H2O and extracted twice with Et2O. The combined Et2O extracts were washed with 1M NaOH, H2O, brine, and concentrated in vacuo to give 2-[4-(4-trifluoromethylpyridin-2-yloxy)-phenyl]-ethanol (4.7 g; 57%), mp 78-79° C.; EIMS m/z 283; 1H NMR (300 MHz, DMSO-d6) δ 8.38 (d, J=5.3 Hz, 1H), 7.0-7.5 (m, 8H), 4.67 (t, J=5.0 Hz, 2H), 2.74 (t, J=5.2 Hz, 2H).
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]([CH2:16][CH2:17][CH3:18])[C:12]([O:14][CH3:15])=[O:13])=[CH:3]1.[Br:19]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl>[Br:19][C:3]1[N:2]([CH3:1])[C:10]2[C:5]([C:4]=1[CH:11]([CH2:16][CH2:17][CH3:18])[C:12]([O:14][CH3:15])=[O:13])=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCC(C(=O)OC)c1cn(C)c2ccccc12
Solvent: ClC(Cl)(Cl)Cl
Product: CCCC(C(=O)OC)c1c(Br)n(C)c2ccccc12

Procedure:
A solution of methyl 2-(1-methyl-1H-indol-3-yl)pentanoate (12b) (860 mg, 3.44 mmol) and N-bromosuccinimide (623 mg, 3.5 mmol) in tetrachloromethane (20 mL) was stirred at room temperature for 5 hours. The mixture was then filtered and the filtrate was washed with water (10 mL), brine (10 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure to afford the desired product (12c) as a brown oil without further purification (1.13 g, 3.44 mmol, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][C:4]=1[CH2:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH2:21][CH:20]1[C:32]([NH2:34])=[O:33])=[O:18].[NH:35]1[CH:39]=[C:38]([CH2:40][C:41](O)=[O:42])[N:37]=[CH:36]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH:10]2[CH2:15][CH2:14][N:13]([C:41]([CH2:40][C:38]3[N:37]=[CH:36][NH:35][CH:39]=3)=[O:42])[CH2:12][CH2:11]2)[CH:6]=[CH:5][C:4]=1[CH2:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH2:21][CH:20]1[C:32]([NH2:34])=[O:33])=[O:18]
Reactant: O=C(O)Cc1c[nH]cn1
Reactant: COc1cc(OC2CCNCC2)ccc1CC(=O)N1CCN(c2ccccc2C)CC1C(N)=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(OC2CCN(C(=O)Cc3c[nH]cn3)CC2)ccc1CC(=O)N1CCN(c2ccccc2C)CC1C(N)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(2-Methoxy-4-(4-piperidyloxy)phenylacetyl)-4-(2-methylphenyl) piperazine-2-carboxamide (200 mg, 0.429 mmole) and 4-imidazoleacetic acid (70 mg, 0.429 mmole) were dissolved in 4 ml of dry N,N-dimethylformamide at room temperature. To this solution was added 209 mg (0.472 mmole) of benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP). The pH of the reaction mixture was adjusted to 9 with the addition of diisopropylethylamine (DEA) in 100 μL increments. The reaction mixture was stirred at ambient temperature for 2 hr whereupon all volatiles were removed under reduced pressure. The residue was suspended in ethyl acetate and this suspension was washed with water. The organic phase and some insoluble material were combined, concentrated, and azeotropically dried with toluene. The resulting semi-solid was purified via preparative thick layer chromatography on precoated silica gel plates (85:15:1.5 chloroform-methanol-concentrated ammonium hydroxide elution) to give the title compound in homogeneous form: m.p. 120°-124° C.
Reaction SMILES: [C:1]1([Si:7](Cl)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:21]=[N+:22]=[N-:23].[Li+]>O1CCCC1>[C:1]1([Si:7]([N:21]=[N+:22]=[N-:23])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cl[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Li+]
Solvent: C1CCOC1
Product: [N-]=[N+]=N[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 86.3 %

Procedure:
Following the method of Wiberg et al [Wiberg et al, Angew. Chem. Internat'l Ed. Engl., 1, 335 (1962)] in an inert atmosphere enclosure a solution of triphenylsilylchloride (73.9 g, 0.251 mol) in tetrahydrofuran (400 ml) was stirred with lithium azide (15.3 g, 0.312 mol) at room temperature over a period of 115 hr. After filtration, the solvent was removed in vacuo. The resulting white solid was boiled with heptane (350 ml), filtered hot and allowed to crystalline. Triphenylsilyl azide, 65.5 g (86.3% yield), mp 82°-84° C was obtained. The melting point and infrared spectrum were identical with that of an authentic sample.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[OH:15].[Cl:16][C:17]1[N:18]=[C:19]([C:24](O)=[O:25])[NH:20][C:21]=1[CH2:22][CH3:23].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[Cl:16][C:17]1[N:18]=[C:19]([C:24]([NH:1][C@@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[CH2:4][C@H:3]2[OH:15])=[O:25])[NH:20][C:21]=1[CH2:22][CH3:23]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCc1[nH]c(C(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2O)nc1Cl
Yield: 76 %

Procedure:
The same operation as in Example (1g) was performed using tert-butyl trans(±)-4-amino-3-hydroxypiperidine-1-carboxylate obtained in Example (77a) (510 mg, 2.36 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained by the method described in Example (1d) (440 mg, 2.14 mmol), WSC hydrochloride (1.2 g, 6.26 mmol) and HOBT (284 mg, 2.10 mmol), to obtain 604.1 mg of the title compound as a white solid (76%).