Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[F:13][C:14]([F:24])([F:23])[C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[C:17]#N.Cl.[O:26](CC)CC>CCCCCC>[N:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:17]([C:16]2[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=2[C:14]([F:24])([F:23])[F:13])=[O:26])[CH:8]=1
Reactant: Brc1cccnc1
Reactant: N#Cc1ccccc1C(F)(F)F
Reactant: CCOCC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Product: O=C(c1cccnc1)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63 %

Procedure:
To a stirred and cooled (-70°~-80° C.) solution of 71.4 parts of a 1-butyllithium solution 1.6M in hexane in 105 parts of 1,1'-oxybisethane was added dropwise a solution of 40.6 parts of 3-bromopyridine in 70 parts of 1,1'-oxybisethane. Upon complete addition, stirring was continued for 15 minutes and a solution of 30 parts of 2-(trifluoromethyl)benzonitrile in 35 parts of 1,1'-oxybisethane was added dropwise at this low temperature. Upon completion, the mixture was stirred for 3 hours at this low temperature. The mixture was heated to room temperature and poured into 84 parts of a hydrochloric acid solution 10N and some crushed ice. The aqueous layer was separated and heated to the boiling point. After cooling, the mixture was made alkaline with an ammonium hydroxide solution and the product was extracted with dichloromethane. The extract was dried, filtered and concentrated. The residue was purified by filtration over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was concentrated, yielding 27.8 parts (63%) of (3-pyridinyl) [2-(trifluoromethyl)phenyl]methanone as an oily residue (intermediate 3).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH:6]([N:9]([C:11]1[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=1)[CH3:10])([CH3:8])[CH3:7].CN([CH:21]=[O:22])C>>[CH:6]([N:9]([C:11]1[CH:12]=[C:13]([OH:17])[C:14](=[CH:15][CH:16]=1)[CH:21]=[O:22])[CH3:10])([CH3:8])[CH3:7]
Reactant: CC(C)N(C)c1cccc(O)c1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)N(C)c1ccc(C=O)c(O)c1
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
11 g (0.118 mol) of phosphorus oxychloride are cautiously added to 33 ml of dry DMF at −5° C. within a period of 5 minutes, during the course of which the temperature of the reaction solution should not exceed 10° C. Subsequently, a solution of 19.4 g (0.1176 mol) of 3-(N-isopropyl-N-methylamino)phenol in 25 ml of dry DMF is added thereto within a period of 10 minutes, during the course of which the temperature of the reaction solution should not exceed 20° C. When the addition is complete, the reaction solution is heated for 2 hours at 90° C. and then immediately poured onto 150 g of ice. The crude mixture is extracted three times with 100 ml of chloroform. The combined organic phases are concentrated under a high vacuum. The oily residue is purified by column chromatography on silica gel (eluant n-hexane/chloroform 95:5). Yield: 5.8 g (26%), colourless liquid.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH2:23]([O:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([O:42][CH2:43][CH3:44])[C:34]=1[C:35]1[CH:36]=[N:37][C:38]([F:41])=[CH:39][CH:40]=1)[C:29]([OH:31])=O)[CH3:24].Cl.[NH:46]1[C:50]([C:51]2[CH:52]=[C:53]3[C:63](=[CH:64][CH:65]=2)[O:62][C:56]2([CH2:61][CH2:60][NH:59][CH2:58][CH2:57]2)[CH2:55][C:54]3=[O:66])=[N:49][N:48]=[N:47]1>O.CN(C=O)C.CCN(CC)CC>[CH2:43]([O:42][C:33]1[CH:32]=[C:28]([C:29]([N:59]2[CH2:60][CH2:61][C:56]3([CH2:55][C:54](=[O:66])[C:53]4[C:63](=[CH:64][CH:65]=[C:51]([C:50]5[NH:49][N:48]=[N:47][N:46]=5)[CH:52]=4)[O:62]3)[CH2:57][CH2:58]2)=[O:31])[CH:27]=[C:26]([O:25][CH2:23][CH3:24])[C:34]=1[C:35]1[CH:36]=[N:37][C:38]([F:41])=[CH:39][CH:40]=1)[CH3:44]
Reactant: O=C1CC2(CCNCC2)Oc2ccc(-c3nnn[nH]3)cc21
Reactant: CCOc1cc(C(=O)O)cc(OCC)c1-c1ccc(F)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4nnn[nH]4)ccc2O3)cc(OCC)c1-c1ccc(F)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Et3N (200 μL), HOBT (110 mg) and WSC hydrochloride (138 mg) were added to a DMF (4 mL) solution of 3,5-diethoxy-4-(6-fluoropyridin-3-yl)benzoic acid (186 mg) and 6-(tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one hydrochloride (231 mg), and stirred overnight at room temperature. Water was added to the reaction liquid, the formed solid was taken out through filtration, and the solid was washed with water and ether. The solid was dried under reduced pressure to obtain the title compound. 1H-NMR (400 MHz, DMSO-d6) δ: 8.42 (1H, d, J=4.0 Hz), 8.24 (1H, dd, J=8.0, 4.0 Hz), 8.13 (1H, s), 7.89 (1H, dt, J=8.0, 4.0 Hz), 7.32 (1H, d, J=8.0 Hz), 7.18 (1H, dd, J=8.0, 4.0 Hz), 6.75 (2H, s), 4.32-4.18 (1H, m), 4.08 (4H, q, J=8.0 Hz), 3.64-3.20 (3H, m), 2.98 (2H, s), 2.10-1.75 (4H, m), 1.17 (6H, t, J=8.0 Hz). MS [M+H]+=573.
Reaction SMILES: [C:1]1([P:7]([CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[C:20]3[C:25]=2[C:24]([C:26]2[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][C:34]=4[CH2:36][P:37]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=O)[CH:29]=[CH:28][CH:27]=2)=[CH:23][CH:22]=[CH:21]3)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CCCC)CCCC)CCC.C[SiH](Cl)Cl>C1(C)C(C)=CC=CC=1>[C:45]1([P:37]([CH2:36][C:34]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:35]=2[C:26]([C:24]2[C:25]4[C:20](=[CH:19][CH:18]=[CH:17][C:16]=4[CH2:15][P:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)[CH:21]=[CH:22][CH:23]=2)=[CH:27][CH:28]=[CH:29]3)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: O=P(Cc1cccc2cccc(-c3cccc4cccc(CP(=O)(c5ccccc5)c5ccccc5)c34)c12)(c1ccccc1)c1ccccc1
Agent: C[SiH](Cl)Cl
Solvent: CCCCN(CCCC)CCCC
Solvent: Cc1ccccc1C
Product: c1ccc(P(Cc2cccc3cccc(-c4cccc5cccc(CP(c6ccccc6)c6ccccc6)c45)c23)c2ccccc2)cc1

Procedure:
20.48 g (0.03 mol) of 8,8'-bis(diphenylphosphinylmethyl)-1,1'-binaphthyl are suspended in 75 ml of xylene and 36 ml (0.15 mol) of tri-n-butylamine in the absence of air and moisture, and 16.57 g (0.144 mol) of methyldichlorosilane are added dropwise with stirring. The mixture is then refluxed for 14 hours to give a clear solution. Xylene is distilled off at atmospheric pressure, and the mixture is allowed to cool with stirring. This results in the formation of 8,8'-bis(diphenylphosphinomethyl)-1,1'-binaphthyl as a colorless solid, which is filtered off under an inert gas and washed with 20 ml of degassed acetone. 16.7 g (87%) of colorless crystals of melting point 168° to 170° C. are obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[O:8].[Cl:9][C:10]1[C:15]([C:16]#[N:17])=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=[C:12]([NH:22][CH:23]([CH2:27]O)[CH:24]([CH3:26])[CH3:25])[N:11]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:9][C:10]1[C:15]([C:16]#[N:17])=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=[C:12]([N:22]2[CH:23]([CH:24]([CH3:26])[CH3:25])[CH2:27][O:8][CH:7]2[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[N:11]=1
Reactant: CC(C)C(CO)Nc1cc(C(F)(F)F)c(C#N)c(Cl)n1
Reactant: O=Cc1ccccn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)C1COC(c2ccccn2)N1c1cc(C(F)(F)F)c(C#N)c(Cl)n1

Procedure:
Pyridine-2-carboxaldehyde (207 mg, 1.9 mmol) was added to a toluene solution (15 mL) of 2-chloro-6-[[1-(hydroxymethyl)-2-methyl-propyl]amino]-4-(trifluoromethyl)pyridine-3-carbonitrile (400 mg, 1.3 mmol) (Compound 13) followed by a catalytic amount of para-toluene sulfonic acid (50 mg). The reactants were refluxed for 6 hours in a Dean-Stark apparatus, concentrated under reduced pressure, adsorbed onto silica and purified using a neutral alumina column, eluting with a mobile phase of 10% ethyl acetate in hexane. 2-Chloro-6-[4-isopropyl-2-(2-pyridyl)oxazolidin-3-yl]-4-(tri fluoromethyl) pyridine-3-carbonitrile (Compound 12) was isolated as a solid in 20% yield. mp 112-115° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH:4](Br)[CH2:5][CH2:6][CH2:7][CH3:8].[F:11][C:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][C:13]=1[CH3:19].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3](=[O:10])[CH:4]([S:18][C:15]1[CH:16]=[CH:17][C:12]([F:11])=[C:13]([CH3:19])[CH:14]=1)[CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCC(Br)C(=O)OC
Reactant: Cc1cc(S)ccc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC(Sc1ccc(F)c(C)c1)C(=O)OC
Temperature: 25 °C
Reaction time: 46 h
Yield: 91.7 %

Procedure:
To a solution of 2-bromo-hexanoic acid methyl ester (0.500 g, 2.404 mmol) and 4-fluoro-3-methyl-benzenethiol (0.340 g, 2.404 mmol) in 20 mL of dichloromethane, was added triethylamine (3.3 mL, 12.020 mmol). After stirring at room temperature under N2 for 46 h, the reaction mixture was diluted with dichloromethane and washed with 1N HCl and brine. The organic layer dried over anhydrous Na2SO4. After removing the solvent under reduced pressure, the product was isolated by Flash chromatography (silica gel) eluting with 0-20% ethyl acetate/hexanes to give the title compound as colorless oil (0.596 g, 92% yield). LC-MS: tR=11.2 min; m/z 271 (M+H)+.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1>C(O)(=O)C.C1COCC1.O>[OH:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: c1cncc(OCCOC2CCCCO2)c1
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: OCCOc1cccnc1
Yield: 84.2 %

Procedure:
A solution of 3-(2-(tetrahydropyran-2-yloxy)ethoxy)pyridine (1.54 g, 7 mmol) in acetic acid (8 ml), THF (4 ml) and water (2 ml) was heated at 50° C. for 4 hours. The volatiles were removed by evaporation and the residue azeotroped with toluene to give 3-(2-hydroxyethoxy)pyridine (820 mg, 86%) as an off-white solid. 1H NMR Spectrum: (DMSOd6) 3.70(t, 2H); 4.05(t, 2H); 4.85(s, 1H); 7.25(dd, 1H); 7.37(dd, 1H); 8.10(d, 1H); 8.24(d, 1H) MS-ESI: 140 [MH]+
Reaction SMILES: [NH:1]1[C:11]2[C:12]3[CH:3]([CH2:4][C:5](=[O:13])[NH:6][C:7]=3[CH:8]=[CH:9][CH:10]=2)[C:2]1=[O:14].[H-].[Na+].Br[CH2:18][N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29]>CN(C=O)C>[O:29]=[C:20]1[C:21]2[C:22](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](=[O:24])[N:19]1[CH2:18][C:3]12[C:2](=[O:14])[NH:1][C:11]3[C:12]1=[C:7]([CH:8]=[CH:9][CH:10]=3)[NH:6][C:5](=[O:13])[CH2:4]2
Reactant: O=C1c2ccccc2C(=O)N1CBr
Reactant: O=C1CC2C(=O)Nc3cccc(c32)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CC2(CN3C(=O)c4ccccc4C3=O)C(=O)Nc3cccc(c32)N1
Reaction time: 0.17 h

Procedure:
To a stirred solution of (±)-2a,5-dihydropyrrolo[4,3,2-de]quinoline-2,4(1H,3H)-dione (2.00 g, 10.6 mmol, described in Intermediate 17) in degassed DMF (30 mL) at 0° C. was added sodium hydride (468 mg of a 60% dispersion in mineral oil, 11.7 mmol). The mixture was stirred for 10 min, then N-(bromomethyl)phthalimide (2.55 g, 10.6 mmol) was added and stirring was continued for 2 h. An additional portion of N-(bromomethyl)phthalimide (500 mg) was added and stirring was continued for 1 h. The reaction mixture was quenched with saturated aqueous NaHCO3 (100 mL) and extracted with EtOAc (3×50 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH—100:0 to 90:10, to give the title compound. MS: m/z=348 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:21]=[C:11]3[NH:12][C:13](=[O:20])[C:14]4[C:19]([N:10]3[N:9]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:5]=[CH:6][CH:7]=1.[N:22]1([CH2:28][CH2:29][C:30](O)=[O:31])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[O:20]=[C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:10]2[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([NH:1][C:30](=[O:31])[CH2:29][CH2:28][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)[CH:7]=[CH:6][CH:5]=3)[CH:21]=[C:11]2[NH:12]1
Reactant: Nc1cccc(-c2cc3[nH]c(=O)c4ccccc4n3n2)c1
Reactant: O=C(O)CCN1CCCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCN1CCCCC1)Nc1cccc(-c2cc3[nH]c(=O)c4ccccc4n3n2)c1

Procedure:
A solution of EXAMPLE 12 (0.1 g, 0.4 mmol), 3-piperidinopropionic acid (60 mg, 0.4 mmol), 1-hydroxybenzotriazole (0.098 g, 0.7 mmol), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (0.377 g, 0.7 mmol) and diisopropylethylamine (0.4 mL, 2.2 mmol) in N,N′-dimethylformamide (4 mL) was heated in a microwave at 100° C. for 15 minutes. The mixture was concentrated and purified by flash chromatography on silica gel with 10% methanol/dichloromethane to provide the title compound. 1H NMR (CD3OD) δ 8.23-8.27 (m, 3H), 7.89 (td, J=7.8, 1.5 Hz, 1H), 7.68 (d, J=8.3 Hz, 1H), 7.59 (dd, J=7.1, 2.2 Hz, 1H), 7.48-7.56 (m, 1H), 7.42 (t, J=8.0 Hz, 1H), 6.33 (s, 1H), 3.62 (s, 2H), 3.51 (t, J=6.6 Hz, 2H), 3.04 (s, 2H), 2.96 (t, J=6.8 Hz, 2H), 1.98 (d, J=3.4 Hz, 2H), 1.82 (s, 3H), 1.58 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].C(Cl)CCl.Cl.[CH3:33][N:34]([CH3:57])[CH2:35][CH2:36][N:37]([C:42]1[CH:43]=[C:44]2[C:48](=[CH:49][CH:50]=1)[C:47](=[O:51])[N:46]([CH2:52][C:53](O)=[O:54])[C:45]2=[O:56])[S:38]([CH3:41])(=[O:40])=[O:39]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[O:10][C:53](=[O:54])[CH2:52][N:46]1[C:45](=[O:56])[C:44]2[C:48](=[CH:49][CH:50]=[C:42]([N:37]([CH2:36][CH2:35][N:34]([CH3:33])[CH3:57])[S:38]([CH3:41])(=[O:39])=[O:40])[CH:43]=2)[C:47]1=[O:51]
Reactant: CN(C)CCN(c1ccc2c(c1)C(=O)N(CC(=O)O)C2=O)S(C)(=O)=O
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: CN(C)CCN(c1ccc2c(c1)C(=O)N(CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC3CC3)c1)C2=O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 76.6 %

Procedure:
To a solution of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (180 mg, 0.428 mmol), DMAP (52.3 mg, 0.428 mmol) and EDC (164 mg, 0.857 mmol) in DCM (10 ml), 2-(5-(N-(2-(dimethylamino)ethyl)methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetic acid hydrochloride (191 mg, 0.471 mmol) was added portion wise within 4 hours, and the reaction was stirred at room temperature for 24 hours. The solvent was evaporated and the crude was purified by flash silica gel chromatography (DCM/MeOH 10/0.2) affording (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(5-(N-(2-(dimethylamino)ethyl)methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetoxy)ethyl)pyridine 1-oxide as a white solid (253 mg, 0.328 mmol, 77% yield). MS/ESI+ 771.15 [MH]+, [αD]=−32.18, c=0.353, DCM). 1H NMR (300 MHz, DMSO-d6) δ ppm 8.43 (s, 2H), 7.93-8.00 (m, 2H), 7.89 (dd, 1H), 7.19 (d, 1H), 7.09 (d, 1H), 6.97 (dd, 1H), 7.08 (t, 1H), 6.02 (dd, 1H), 4.43 (s, 2H), 3.92-4.05 (m, 2H), 3.88 (t, 2H), 3.39 (dd, 1H), 3.23 (dd, 1H), 3.13 (s, 3H), 2.31 (t, 2H), 2.10 (s, 6H), 1.07-1.33 (m, 1H), 0.49-0.71 (m, 2H), 0.27-0.49 (m, 2H)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[C@@H:4]1[CH2:8][CH2:7][C:6](=[O:9])[NH:5]1.[H-].[Na+].[C:13]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1)#[N:14]>C1COCC1>[CH3:1][O:2][C:3](=[O:10])[C@@H:4]1[CH2:8][CH2:7][C:6](=[O:9])[N:5]1[CH2:19][C:18]1[CH:21]=[CH:22][C:15]([C:13]#[N:14])=[CH:16][CH:17]=1
Reactant: COC(=O)[C@@H]1CCC(=O)N1
Reactant: N#Cc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1CCC(=O)N1Cc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
L-Pyroglutamic acid methyl ester (1.36 g, 0.0095 mol) was dissolved in dry THF (20 mL) under Ar, treated with NaH (60% oil dispersion) (0.58 g, 0.0145 mol) with stirring for 5 min, then the mixture was cooled to 0° C. p-Cyanobenzylbromide (1.78 g, 0.0091 mol) was added, and the mixture left to slowly warm to ambient temperature. After 48 h the reaction mixture was partitioned between EtOAc and satd NaHCO3 solution, the aqueous layer separated and washed with CH2Cl2, the organics combined, washed with brine and dried (MgSO4). Filtration and concentration to dryness followed by trituration with ether gave the white solid product. 1H NMR(CDCl3, 400 MHz) δ 7.62(2H, d, J=8 Hz), 7.33(2H, d, J=8 Hz), 4.98(1H, d, J=15.4 Hz), 4.13(1H, d, J=15.4 Hz), 3.99(1H, dd, J=3, 9 Hz) and 2.5-2.6 (1H, m), 2.4-2.5 (1H, m), 2.2-2.45 (1H, m), 2.1-2.2 (1H, m) ppm.
Reaction SMILES: C(Cl)(Cl)=O.[C:5]([OH:12])(=[O:11])/[CH:6]=[CH:7]/[CH:8]=[CH:9]/[CH3:10].C(N([CH2:18][CH3:19])CC)C.Cl.C(N([CH2:26][CH3:27])CC)C.[C:28](OCC)(=[O:30])[CH3:29]>>[C:5]([O:12][C:28](=[O:30])/[CH:29]=[CH:26]/[CH:27]=[CH:18]/[CH3:19])(=[O:11])/[CH:6]=[CH:7]/[CH:8]=[CH:9]/[CH3:10]
Reactant: C/C=C/C=C/C(=O)O
Reactant: CCN(CC)CC
Reactant: CCOC(C)=O
Agent: Cl
Agent: O=C(Cl)Cl
Product: C/C=C/C=C/C(=O)OC(=O)/C=C/C=C/C
Yield: 85.6 %

Procedure:
In a 1000 ml four-neck flask, equipped with thermometer, intense cooler, submerged tube for phosgene and KPG agitator, 100 g (0.88 mol) of all-E-sorbic acid and 600 g of ethyl acetate are charged. To the resultant suspension are added 101.2 g (1 mol) of triethylamine, whereupon a clear yellow solution forms. The batch was then cooled using a cooling bath to 0-5° C. Then, in the course of 4 hours at 0-5° C., 50.7 g (0.51 mol) of phosgene were introduced, wherein the deposition of the triethylamine hydrochloride is immediately observed. After completion of phosgene metering, the batch was stirred overnight at RT. After examination for freedom from phosgene, the batch was filtered and the suction filter residue was washed with 200 ml of ethyl acetate. The resultant brownish-yellow filtrate was concentrated on a rotary evaporator in a vacuum. The resultant brown oil (90.7 g) was placed under nitrogen into a clear glass bottle and rapidly solidified at room temperature. A GC analysis gave a content of 85.9 weight % of all-E-sorbic anhydride; 9.13 weight % unreacted sorbic acid and 0.31% sorbyl chloride. In 1H-NMR, a content of 94.5 weight % anhydride and 2.9 weight % of triethylamine was observed. Isomerization was not observed. Based on the GC content, a yield of 85.6% of theory was determined, based on sorbic acid used.
Reaction SMILES: C([N:8]1[CH:13]2[CH:14]([N:16]3[CH:20]=[N:19][N:18]=[N:17]3)[CH2:15][C:9]1([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH:10]([O:21][CH2:22][C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=1)[CH2:11][CH2:12]2)C1C=CC=CC=1.[ClH:43]>CO.C(OCC)C.[OH-].[Pd+2].[OH-]>[ClH:43].[F:31][C:29]([F:30])([F:32])[C:27]1[CH:28]=[C:23]([CH2:22][O:21][C@@H:10]2[CH2:11][CH2:12][C@@H:13]3[NH:8][C@@:9]2([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:15][C@H:14]3[N:16]2[CH:20]=[N:19][N:18]=[N:17]2)[CH:24]=[C:25]([C:33]([F:34])([F:36])[F:35])[CH:26]=1
Reactant: FC(F)(F)c1cc(COC2CCC3C(n4cnnn4)CC2(c2ccccc2)N3Cc2ccccc2)cc(C(F)(F)F)c1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Product: FC(F)(F)c1cc(CO[C@@H]2CC[C@@H]3N[C@@]2(c2ccccc2)C[C@H]3n2cnnn2)cc(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
1R*,2R*,5S*,6R*)-8-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-6-(1H-tetrazol-1-yl)-8-azabicyclo[3.2.1]octane. (Example 116; 154 mg, 0.26 mmol) was dissolved in methanol (30 ml) and 2N hydrochloric acid (0.5 ml) and 10% palladium hydroxide (40 mg, 10%) added. The mixture was hydrogenated at 35 psi for 1 hour. The reaction mixture was then filtered and concentrated in vacuo and the oil partitioned between saturated sodium hydrogen carbonate solution and dichloromethane. The organics were collected, dried (MgSO4) and concentrated in vacuo to give an orange foam which was purified by flash column chromatography [7.5% methanol in dichloromethane] then further isolated by thin layer chromatography [7.5% methanol in dichloromethane] to give a clear oil. The hydrochloride salt was made by adding 1 equivalent of hydrogen chloride in diethyl ether (1.0M) to a solution in diethyl ether and the title compound filtered and dried in vacuo at 60° C. (25 mg, 18%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[CH2:13][CH3:14].[CH3:15][CH2:16][C:17](=O)[CH2:18][CH3:19]>[Pt].CCOCC.C1C2C(=CC=CC=2)C=CC=1S(O)(=O)=O>[CH2:13]([C:5]1[CH:6]=[CH:7][C:8]([NH:10][CH:17]([CH2:18][CH3:19])[CH2:16][CH3:15])=[CH:9][C:4]=1[CH2:3][O:2][CH3:1])[CH3:14]
Reactant: CCC(=O)CC
Reactant: CCc1ccc([N+](=O)[O-])cc1COC
Agent: [Pt]
Agent: O=S(=O)(O)c1ccc2ccccc2c1
Solvent: CCOCC
Product: CCc1ccc(NC(CC)CC)cc1COC
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.2 %

Procedure:
A mixture of 10.0g of 2-ethyl-5-nitrobenzyl methyl ether, 10.38g of 3-pentanone, 0.23g of 2-naphthalene sulfonic acid, and 0.60g of 5% platinum on carbon catalyst was shaken under hydrogen for 2 hours at room temperature and for 4 hours at 48° C. to 60° C. The mixture was diluted with 200 ml of ether, filtered and the filtrate shaken with 2.5% aqueous sodium hydroxide, washed with water, filtered through sodium sulfate and stirred over magnesium sulfate. The filtered solution was concentrated under vacuum to yield 10.76 grams of an amber liquid, pure by glc and tlc analyses.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[C:3]=1[OH:9].[Br:10]Br>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[Br:10][C:8]1[C:2]([F:1])=[C:3]([OH:9])[C:4](=[CH:6][CH:7]=1)[OH:5]
Reactant: BrBr
Reactant: Oc1cccc(F)c1O
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Oc1ccc(Br)c(F)c1O
Temperature: -10 °C
Reaction time: 1 h

Procedure:
3-Fluorocatechol (7.2 g) in 50 ml of carbon tetrachloride and 40 ml of chloroform are treated at -10° C. within 10 minutes with a solution of 2.88 ml of bromine in 30 ml of carbon tetrachloride. After stirring at -10° C. for 1 hour the reaction mixture is filtered. The residual solid is washed with a small amount of cold carbon tetrachloride and dried. There are obtained 6.30 g of 4-bromo-3-fluorocatechol as a white powder. This is treated with 6.0 ml of diphenylchloromethane and heated to 130° C. within 1 hour. Subsequently, the product is distilled at 135° C./0.05 Torr and recrystallized from ethanol. There are obtained 6.40 g of 5-bromo-4-fluoro-2,2-diphenyl-1,3-benzodioxol as a white crystalline powder of m.p. 61.5°-63° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5](Br)=[CH:4][N:3]=1.[N:10]1([S:16]([C:19]2[CH:24]=[CH:23][C:22]([SH:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[C:30]([CH3:34])=[CH:29][C:28]=1[S:35](Cl)(=[O:37])=[O:36]>>[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[C:30]([CH3:34])=[CH:29][C:28]=1[S:35]([NH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:25][C:22]2[CH:21]=[CH:20][C:19]([S:16]([N:10]3[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]3)(=[O:18])=[O:17])=[CH:24][CH:23]=2)=[CH:4][N:3]=1)(=[O:37])=[O:36]
Reactant: Cc1cc(S(=O)(=O)Cl)c(Cl)cc1Cl
Reactant: O=S(=O)(c1ccc(S)cc1)N1CCCCC1
Reactant: Cc1cc(N)ncc1Br
Product: Cc1cc(S(=O)(=O)Nc2cc(C)c(Sc3ccc(S(=O)(=O)N4CCCCC4)cc3)cn2)c(Cl)cc1Cl

Procedure:
2,4-Dichloro-5-methyl-N-{4-methyl-5-[4-(piperidine-1-sulfonyl)-phenylsulfanyl]-pyridin-2-yl}-benzenesulfonamide was prepared from 2-amino-5-bromo-4-methylpyridine and 4-(N-piperidinylsulfonyl)thiophenol according to General Method 11 step 1 followed by reaction with 2,4-dichloro-5-methylphenylsulfonyl chloride according to General Method 11 step 2. 1H NMR (CDCl3): 13.20 (1H, br s, NH), 8.40 (1H, s, A-ring CH ortho to 2×Cl), 8.03 (1H, s, A-ring CH ortho to SO2NH), 7.53 & 7.04 (2×2H, 2×d, 2×J 10 Hz, Ar CH's of C-ring), 7.41 & 7.15 (2×1H, 2×s, pyridyl CH's), 2.91-2.83 (4H, m, CH2NCH2), 2.38 & 2.23 (2×3H, 2×s, 2×CH3), 1.61-1.48 (4H, m, CH2CH2CH2CH2CH2), 1.39-1.28 (2H, m, CH2CH2CH2CH2CH2). Hplc (Luna 2, Gradient 5): rt=6.73 minutes. LC/MS rt=7.43 minutes, 586/588 (MH+).