Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([OH:15])[CH2:12][CH2:13]Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N-:22]=[N+:23]=[N-:24].[Na+]>CN(C=O)C.CCOC(C)=O>[N:22]([CH2:13][CH2:12][C:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([OH:15])[CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)[Si](C)(C)OCCC(O)(CCCl)c1ccccc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCC(O)(CCN=[N+]=[N-])c1ccccc1

Procedure:
A solution of 1-{[tert-butyl(dimethyl)silyl]oxy}-5-chloro-3-phenylpentan-3-ol ((5.2 g, 15.7 mmol) and NaN3 (7.8 g, 120 mmol) in 50 mL DMF was stirred for 24 h at 65° C. The reaction mixture was then diluted with EtOAc, washed with water, dried, filtered and evaporated in vacuo to provide 1-azido-5-{[tert-butyl(dimethyl)silyl]oxy) 3-phenylpentan-3-ol in quantitative yield as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.40-7.32 (m, 4H), 7.24 (m, 1H), 4.89 (s, 1H), 3.72 (dt, 1H, J=10.3, 3.9 Hz), 3.47-3.36 (m, 2H), 2.97 (ddd, 1H, J=12.3, 10.1, 5.5 Hz), 2.24-2.10 (m, 2H), 2.07-1.93 (m, 2H), 0.86 (s, 9H), −0.02, (s, 3H), −0.09 (s, 3H); ESI-MS 358 (M+Na).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:35][CH2:36][CH:37]([OH:41])[CH2:38][C:39]#[CH:40].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:24](=[O:26])[O:41][CH:37]([CH2:36][CH3:35])[CH2:38][C:39]#[CH:40])=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: C#CCC(O)CC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C#CCC(CC)OC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Yield: 42.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 5-hexyn-3-ol (26 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (30 mg, yield 39%).
Reaction SMILES: [S:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.B(F)(F)F.[CH3:12]COCC.[N+]([C:22]([O:24][CH2:25][CH3:26])=[O:23])(C([O-])=O)=[N-]>CCOCC>[O:7]=[C:4]1[CH2:5][CH2:6][S:1][CH2:12][CH2:2][CH:3]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: O=C1CCSCC1
Reactant: CCOC(=O)[N+](=[N-])C(=O)[O-]
Reactant: CCOCC
Agent: FB(F)F
Product: CCOC(=O)C1CCSCCC1=O
Temperature: -30 °C

Procedure:
To a cold solution (−30° C.) of tetrahydrothiopyran-4-one (5.0 g, 43.0 mmol) in anhydrous ether, were simultaneously added a solution of boron trifluoride etherate (5.4 ml, 43.0 mmol) in diethyl ether (4.6 ml) and a solution of ethyl diazodicarboxylate (5.8 ml, 55.9 mmol) in diethyl ether (4.6 ml) over 1.5 hours via a syringe pump. Upon completion of additions, the reaction mixture was allowed to stir for an additional hour at −30° C. and then warmed to room temperature. The reaction mixture was washed with 30% potassium carbonate and the organic phase was dried over Na2SO4 and concentrated in vacuo to give ethyl 5-oxothiepane-4-carboxylate as a white solid.
Reaction SMILES: CN1CCN(C2C=CC(NC3C4N(N=CN=4)C(C4C=C(C(N)=O)SC=4)=CN=3)=CC=2)CC1.[Br:32][C:33]1[N:38]2[N:39]=[CH:40][N:41]=[C:37]2[C:36](Br)=[N:35][CH:34]=1.[F:43][C:44]1[CH:49]=[C:48]([N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)[CH:47]=[CH:46][C:45]=1[NH2:56].CCN(C(C)C)C(C)C.N12CCN(CC1)CC2>CC(O)C>[Br:32][C:33]1[N:38]2[N:39]=[CH:40][N:41]=[C:37]2[C:36]([NH:56][C:45]2[CH:46]=[CH:47][C:48]([N:50]3[CH2:51][CH2:52][O:53][CH2:54][CH2:55]3)=[CH:49][C:44]=2[F:43])=[N:35][CH:34]=1
Reactant: Brc1ncc(Br)n2ncnc12
Reactant: Nc1ccc(N2CCOCC2)cc1F
Agent: C1CN2CCN1CC2
Agent: CN1CCN(c2ccc(Nc3ncc(-c4csc(C(N)=O)c4)n4ncnc34)cc2)CC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cc(N2CCOCC2)ccc1Nc1ncc(Br)n2ncnc12

Procedure:
This compound may be prepared using methods as described for Compound 6, step 1, using 5,8-dibromo-[1,2,4]triazolo[1,5-a]pyrazine (0.105 g, 0.89 mmol), 2-fluoro-4-morpholin-4-yl-phenylamine (93 mg, 0.474 mmol), DIPEA (0.123 mL, 0.706 mmol) and 1,4-diazabicyclo[2.2.2]octane (53 mg, 0.472 mmol) in 2-propanol (2 mL). The reaction mixture is partitioned between DCM and 10% citric acid (aq) solution, the organic layer is separated and washed with 10% citric acid solution, water and brine, dried over MgSO4, filtered and concentrated in vacuo. The title compound is isolated as a pale red solid (77 mg, 42%) and used in the next step without further purification. LCMS: Rt 3.48 min (89%).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:14])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12]C)[CH:6]=2.B(Br)(Br)[Br:16].CO>C(Cl)Cl>[BrH:16].[F:1][C:2]1[C:3]([CH3:14])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([OH:12])[CH:6]=2
Reactant: COc1ccc2cc(F)c(C)nc2c1
Reactant: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: Br
Product: Cc1nc2cc(O)ccc2cc1F
Temperature: 0 °C
Reaction time: 3 h
Yield: 107.5 %

Procedure:
To a solution of 3-fluoro-7-methoxy-2-methylquinoline (0.255 g, 1.33 mmol) in DCM (5 mL) was added BBr3 (6.67 mL, 6.67 mmol) at 0° C. The mixture was stirred at 0° C. for 2 hours and at ambient temperature for 3 hours. Methanol (10 mL) was added slowly and the resulting mixture was stirred at ambient temperature for 1 hour. The solvent was removed under reduced pressure. The resulting solid was suspended in 1:1 ether/hexane and stirred at ambient temperature for 10 minutes. The solid was collected by filtration to give 3-fluoro-2-methylquinolin-7-ol hydrobromide (0.37 g, 1.43 mmol, 107% yield) as a solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:20])=O>ClCCl.CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([Cl:20])=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(OCc2ccccc2)cc1

Procedure:
To a mixture of 4-benzyloxybenzoic acid (2.28 g, 10 mmole) in 20 ml dried dichloromethane were added five drops of DMF and 2.5 ml thionyl chloride. The mixture was refluxed for three hours and evaporated under reduced pressure. Yield: 2.45 g=100%
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[F:13][C:14]([F:27])([O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=O)[CH:15]([F:17])[F:16].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[F:13][C:14]([F:27])([O:18][C:19]1[CH:20]=[C:21]([CH2:22][NH:1][C:2]2[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=2)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:24]=[CH:25][CH:26]=1)[CH:15]([F:16])[F:17]
Reactant: O=Cc1cccc(OC(F)(F)C(F)F)c1
Reactant: CCOC(=O)c1cccc(N)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1cccc(NCc2cccc(OC(F)(F)C(F)F)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
EX-456A) Ethyl 3-aminobenzoate (6.75 mL, 0.045 mol) and 3-(1,1,2,2-tetrafluoro-ethoxy)benzaldehyde (10 g, 45 mmol) were dissolved in 100 mL of dichloroethane and acetic acid (2.7 mL, 47 mmol), then solid NaBH(OAc)3 (14.3 g, 67 mmol) was added. The mixture was stirred at room temperature for 3 hours, then quenched with aqueous sodium bicarbonate and extracted with dichloromethane. The organic layer was washed with brine, then dried over MgSO4, and evaporated to give 16.7 g (98%) of the desired ethyl 3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]benzoate product as a yellow oil. 1H NMR (CDCl3) δ 1.3 (t, 3H), 4.3 (q, 2H), 4.5 (s, 2H), 6.5 (tt, 1H), 6.9 (d, 1H), 7.1-7.4 (m, 7H).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][C:5]2[CH:9]=[CH:10][S:11][C:4]=2[S:3]1(=[O:13])=[O:12].[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[O:23].C(N(CC)CC)C.Cl>CS(C)=O>[OH:8][C:7]1[N:2]([CH3:1])[S:3](=[O:13])(=[O:12])[C:4]2[S:11][CH:10]=[CH:9][C:5]=2[C:6]=1[C:22](=[O:23])[NH:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[Cl:14]
Reactant: CN1C(=O)Cc2ccsc2S1(=O)=O
Reactant: O=C=Nc1ccccc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CN1C(O)=C(C(=O)Nc2ccccc2Cl)c2ccsc2S1(=O)=O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
1 g (4.6 mmol) of 3,4-dihydro-2-methyl-3-oxo-2H-thieno[3,2-e]-1,2-thiazine 1,1-dioxide are sitrred at room temperature for 3 hours under nitrogen with 0.71 g (4.6 mmol) of o-chlorophenylisocyanate and 0.47 g (4.6 mmol) of triethylamine in 10 ml of absolute dimethylsulfoxide. Thereafter, the mixture is poured into 40 ml of 2-N hydrochloric acid and 25 g of ice and stirred for 20 minutes. The separated precipitate is filtered off under suction and washed neutral with water. The precipitate is dissolved in 200 ml of methylene chloride, the turbid solution is dried over sodium sulfate, stirred with 0.3 g of active carbon and filtered. The filtrate is extracted with five 100 ml portions of saturated sodium carbonate solution, each of the aqueous phases being re-extracted with a small amount of methylene chloride. The combined aqueous phases are acidified to pH 1 with concentrated hydrochloric acid. The separated product is extracted with two 150 ml portions of methylene chloride. The combined organic phases are dried over sodium sulfate, whereupon the solvent is distilled off. For purification, the product is recrystallized from ca 50 ml of methanol. There is obtained 3-hydroxy-2-methyl-4-(2-chlorophenylcarbamoyl)-2H-thieno[3,2-e]-1,2-thiazine 1,1-dioxide of melting point 168°-170° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1.[C:11](=O)(OC1C=CC=CC=1)[O:12]C1C=CC=CC=1.[NH2:27][S:28]([C:31]1[CH:40]=[C:39]([I:41])[CH:38]=[CH:37][C:32]=1[C:33]([O:35][CH3:36])=[O:34])(=[O:30])=[O:29]>CC(N(C)C)=O>[CH3:9][O:8][C:6]1[N:5]=[C:4]([CH3:10])[N:3]=[C:2]([NH:1][C:11]([NH:27][S:28]([C:31]2[CH:40]=[C:39]([I:41])[CH:38]=[CH:37][C:32]=2[C:33]([O:35][CH3:36])=[O:34])(=[O:30])=[O:29])=[O:12])[N:7]=1
Reactant: COc1nc(C)nc(N)n1
Reactant: COC(=O)c1ccc(I)cc1S(N)(=O)=O
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccc(I)cc1S(=O)(=O)NC(=O)Nc1nc(C)nc(OC)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 55.4 %

Procedure:
0.96 g of sodium tert-butylate was added to a suspension of 1.05 g of 2-amino-4-methoxy-6-methyl-1,3,5-triazine in 20 ml of dimethylacetamide (DMA) at room temperature, with vigorous stirring, to form a first mixture. A solution of 1.12 g of diphenyl carbonate in 10 ml of DMA was then added to the first mixture, in the course of 7 minutes, while it was cooled in an ice bath, to form a second mixture. The second mixture was subsequently stirred for another 15 minutes while cooled in the ice bath, and a solution of 1.84 g of methyl 2-aminosulfonyl-4-iodobenzoate (92.5% pure) in DMA was then added dropwise in the course of 7 minutes. When the reaction ended, the product was worked up as described in Example 1. 1.47 g of the desired product (58% of theory) was thus obtained.
Reaction SMILES: [OH:1][C@H:2]([C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH:28]=1)[CH2:3][NH:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:26]=[CH:25][C:14]([NH:15][C:16]([NH:18][CH2:19][C:20]([O:22]CC)=[O:21])=[O:17])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[OH-].[Na+]>>[OH:1][C@H:2]([C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([NH:34][S:35]([CH3:38])(=[O:36])=[O:37])[CH:28]=1)[CH2:3][NH:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[CH:13][C:14]([NH:15][C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[CH:25][CH:26]=2)[CH2:7][CH2:6]1
Reactant: CCOC(=O)CNC(=O)Nc1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(NC(=O)NCC(=O)O)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from ethyl {[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)carbonyl]-amino}acetate (which was obtained in Example 377) by NaOH hydrolysis as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.35–1.55 (m, 2 H), 1.80–2.00 (m, 2 H), 2.50–2.90 (m, 5 H), 2.92 (s, 3 H), 3.30–3.50 (m, 2 H), 3.59 (d, J=5.9 Hz, 2 H), 4.60 (dd, J=8.8, 3.5 Hz, 1 H), 6.14 (t, J=5.0 Hz, 1 H), 6.80 (d, J=9.1 Hz, 2 H), 6.84 (d, J=8.3 Hz, 1 H), 7.03 (dd, J=8.3, 2.0 Hz, 1 H), 7.15–7.25 (m, 3 H), 8.54 (s, 1 H); MS (ES) m/z: 520.3 (M−H)−; HRMS Calcd. for C23H32N5O7S (MH+): 522.2017. Found: 522.2000.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:11]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([C:28]#[N:29])[CH:22]=2)[CH2:10]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:28]([C:23]1[CH:22]=[C:21]([C@H:11]2[CH2:10][C@@H:9]([OH:8])[CH2:13][N:12]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:26]=[C:25]([F:27])[CH:24]=1)#[N:29].[C:28]([C:23]1[CH:22]=[C:21]([C@@H:11]2[CH2:10][C@@H:9]([OH:8])[CH2:13][N:12]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:26]=[C:25]([F:27])[CH:24]=1)#[N:29]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)CC1c1cc(F)cc(C#N)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@@H]1c1cc(F)cc(C#N)c1
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1c1cc(F)cc(C#N)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (4R)-tert-butyl 4-((tert-butyldimethylsilyl)oxy)-2-(3-cyano-5-fluorophenyl)pyrrolidine-1-carboxylate (I-12) (2.7 g, 6.4 mmol) in THF (25 mL) at room temperature was added TBAF (7.1 mL of a 1.0 M solution in THF, 7.0 mmol). The mixture was stirred at room temperature for 1 hour then concentrated. The mixture was purified by column chromatography on silica gel with EtOAc/hexanes gradient as eluant to yield the desired isomer (2R,4R)-tert-butyl 2-(3-cyano-5-fluorophenyl)-4-hydroxypyrrolidine-1-carboxylate (I-13A) and (2S,4R)-tert-butyl 2-(3-cyano-5-fluorophenyl)-4-hydroxypyrrolidine-1-carboxylate (I-13B). 1H NMR (400 MHz, CDCl3) δ 7.41 (s, 1 H), 7.35-7.26 (m, 1 H), 7.24-7.16 (m, 1 H), 4.89 (d, J=48.8 Hz, 1 H), 4.56-4.50 (m, 1 H), 3.85-3.70 (m, 1 H), 3.66-3.55 (m, 1 H), 2.59 (bs, 1 H), 2.00-1.90 (m, 1 H), 1.45 (bs, 3 H), 1.22 (bs, 6 H). MS m/z 304.1 (M+23)+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([O:8][CH2:9][C:10]2[NH:11][C:12]3[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:6][CH:5]=1.[CH2:22]([O:24][C:25]([CH:27]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:28][CH2:29]Br)=[O:26])[CH3:23].O>CN(C)C=O>[CH2:22]([O:24][C:25]([CH:27]([CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH2:28][CH2:29][N:14]1[C:13]2[CH:15]=[CH:16][CH:17]=[C:18]([CH3:19])[C:12]=2[N:11]=[C:10]1[CH2:9][O:8][C:7]1[CH:20]=[CH:21][C:4]([Cl:3])=[CH:5][CH:6]=1)=[O:26])[CH3:23]
Reactant: CCOC(=O)C(CCBr)Cc1ccccc1
Reactant: Cc1cccc2nc(COc3ccc(Cl)cc3)[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(CCn1c(COc2ccc(Cl)cc2)nc2c(C)cccc21)Cc1ccccc1
Temperature: 25 °C
Yield: 117.8 %

Procedure:
A sodium hydride solution (60% in oil, 810 mg, 20.3 mmol) was washed with hexanes (2×50 ml) and then diluted with N,N-dimethylformamide (100 ml). At room temperature, under a nitrogen atmosphere, 2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole (5.0 g, 18.3 mmol) was then added in one portion. The resulting mixture was then stirred at room temperature for thirty minutes, and then 3-(ethoxycarbonyl)-4-phenylbutyl bromide (5.79 g, 20.3 mmol) in N,N-dimethylformamide (10 ml) was added dropwise. Upon completion of this addition, the reaction mixture was stirred for about six hours at a temperature of 70-80° C. The reaction mixture was then cooled to room temperature, poured into water (500 ml), and then extracted with ethyl acetate (500 ml). The organic fraction was washed once with water (500 ml) and then dried over potassium carbonate. The solvents were removed in vacuo, yielding 10.28 grams of a dark oil. The crude material was further purified by flash silica gel chromatography, eluting with a gradient solvent of methylene chloride to 9:1 methylene chloride:ethyl acetate. The fractions containing the desired title product were combined and concentrated in vacuo to yield 8.08 grams (93%) of a viscous yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH3:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][NH:28]1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:28]1[CH2:29][CH2:30][CH2:31][CH2:32][CH:27]1[CH3:26])=[O:5])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: CC1CCCCN1
Agent: ClCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(NC(=O)c1ccc(C(=O)N2CCCCC2C)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, rac.-2-methylpiperidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 4.58 minutes; C23H24Cl2N4O2 (459.38); mass spectrum: (M−H)−=458/460/462 (chlorine isotope).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].[BrH:11].O.C(=O)(O)[O-].[Na+]>C1CCCCC1>[Br:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9]
Reactant: Br
Reactant: OCCCCCCCCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCCCC1
Product: OCCCCCCCCBr

Procedure:
25 g of octane-1,8-diol was boiled in 250 ml of cyclohexane with 22.6 ml of 47% aqueous hydrobromic acid for six hours in a water separator. The reaction mixture was then poured onto saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was washed with saturated, aqueous sodium chloride solution, dried on sodium sulfate, filtered and concentrated by evaporation in a vacuum. Column chromatography on silica gel with a mixture that consists of hexane/ethyl acetate yielded 21.6 g of the title compound as a yellowish oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([NH:16][C:17]([O:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][C:23]=2[Cl:31])=[O:18])[CH:13]=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][CH:42]=1)[C:39]([N:43]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[N:38][CH:37]=[CH:36]2.O.[C:59]([OH:63])(=[O:62])[CH:60]=O>>[C:54]([O:53][C:51]([N:43]([C:44]([O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:45])[C:39]1[C:40]2[C:35](=[CH:34][C:33]([NH:32][CH:60]([C:25]3[CH:26]=[CH:27][C:22]([CH2:21][CH2:20][O:19][C:17](=[O:18])[NH:16][C:12]4[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:11]=4)=[C:23]([Cl:31])[CH:24]=3)[C:59]([OH:63])=[O:62])=[CH:42][CH:41]=2)[CH:36]=[CH:37][N:38]=1)=[O:52])([CH3:57])([CH3:56])[CH3:55]
Reactant: O=CC(=O)O
Reactant: CC(C)(C)OC(=O)NCc1cccc(NC(=O)OCCc2ccc(B(O)O)cc2Cl)c1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(N)ccc12
Solvent: O
Product: CC(C)(C)OC(=O)NCc1cccc(NC(=O)OCCc2ccc(C(Nc3ccc4c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc4c3)C(=O)O)cc2Cl)c1
Yield: 86 %

Procedure:
Using a procedure analogous to that used to prepare 2D, 61E (350 mg, 0.781 mmol) was reacted with Intermediate 1 and glyoxylic acid monohydrate to afford 61F (547 mg, 86%) as an oil. MS (ESI) m/z 822.0 (M+2 H)+.
Reaction SMILES: C([NH:5][C:6]1[C:11]([F:12])=[C:10]([N:13]2[C:17](=[O:18])[C:16]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]3[C:14]2=[O:23])[C:9]([Cl:24])=[C:8]([F:25])[N:7]=1)(C)(C)C>FC(F)(F)C(O)=O>[NH2:5][C:6]1[C:11]([F:12])=[C:10]([N:13]2[C:14](=[O:23])[C:15]3=[CH:22][CH:21]=[CH:20][CH:19]=[C:16]3[C:17]2=[O:18])[C:9]([Cl:24])=[C:8]([F:25])[N:7]=1
Reactant: CC(C)(C)Nc1nc(F)c(Cl)c(N2C(=O)c3ccccc3C2=O)c1F
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(F)c(Cl)c(N2C(=O)c3ccccc3C2=O)c1F
Temperature: 70 °C

Procedure:
To 80 ml of trifluoroacetic acid was added all amount of the N-[2-(t-butylamino)-5-chloro-3,6-difluoropyridin-4-yl]phthalimide, and the mixture was stirred at 70° C. for 5 and half hours. The solution was concentrated under reduced pressure. The precipitate was dispersed in chloroform, and collected by filtration to obtain 19.5 g of the title compound as a colorless powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Br.Br[CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][CH:3]=1
Reactant: BrCc1cccnc1
Reactant: Sc1ccc(Br)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Brc1ccc(SCc2cccnc2)cc1
Yield: 85.9 %

Procedure:
Following method of example 9a, reaction of 4-bromo-benzenethiol (4.8 g, 24.1 mmol) with hydrobromic acid salt of 3-bromomethyl-pyridine (6.9 g, 26.5 mmol) and potassium carbonate (7.3 g, 53 mmol) in 91 ml acetone gives the title compound as a yellow solid (5.8 g). MS (m/e): 281 (M+H).
Reaction SMILES: [CH2:1]([N:5]1[CH2:9][CH2:8][CH2:7][CH:6]1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].O.O.[Sn](Cl)Cl>C(O)C>[CH2:1]([N:5]1[CH2:9][CH2:8][CH2:7][CH:6]1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CCCC1COc1ccc([N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: CCCCN1CCCC1COc1ccc(N)cc1

Procedure:
In a manner similar to Preparation 44 react 1-butyl-2-[(4-nitrophenoxy)methyl]pyrrolidine with tin(II) chloride dihydrate in ethanol to obtain the title compound.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]2[N:6]([CH:9]3[CH2:14][CH2:13][CH2:12][CH2:11][O:10]3)[CH:7]=[N:8][C:4]=2[C:3]=1[O:17][CH3:18].[CH:19](/B(O)O)=[CH:20]\[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O>[CH3:18][O:17][C:3]1[C:4]2[N:8]=[CH:7][N:6]([CH:9]3[CH2:14][CH2:13][CH2:12][CH2:11][O:10]3)[C:5]=2[CH:15]=[CH:16][C:2]=1[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OB(O)/C=C/c1ccccc1
Reactant: COc1c(Br)ccc2c1ncn2C1CCCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: COc1c(C=Cc2ccccc2)ccc2c1ncn2C1CCCCO1
Temperature: 100 °C
Reaction time: 6 h
Yield: 77.9 %

Procedure:
A 1 L three-necked round bottom flask fitted with an overhead stirrer was dried and cooled under a stream of nitrogen then charged with 5-bromo-4-methoxy-1-(tetrahydro-pyran-2-yl)-1H-benzoimidazole (30 g, 0.096 mol, 1.0 equiv.) in 1,4-dioxane (300 mL) and water (60 mL). The mixture was degassed with nitrogen. To the degassed solution at RT was added sequentially trans-β-styrene boronic acid (14.26 g, 0.096 mol, 1.0 equiv.), Cs2CO3 (62.82 g, 0.19 mol, 2.0 equiv.), Pd(II)Cl2(PPh3)2 (3.38 g, 0.004 mol, 0.05 equiv.) then the reaction was heated with stirring at 100° C. for 6 h. The reaction mixture was quenched with ice cold water (1 L) and extracted with EtOAc (2×1 L). The organic layers were combined, washed with brine solution (500 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude material was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (40-50% EtOAc) to afford 4-methoxy-5-styryl-1-(tetrahydro-pyran-2-yl)-1H-benzoimidazole (25 g, 77%) as a brown solid.