Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:34][CH2:35][C:36]1[C:37]([F:53])=[C:38]([O:43][C:44]2[CH:45]=[C:46]([CH:49]=[C:50]([Cl:52])[CH:51]=2)[C:47]#[N:48])[C:39]([Cl:42])=[CH:40][CH:41]=1.C[Si](C)(C)CCOC[N:60]1[C:64]2[CH:65]=[C:66]([C:68](O)=[O:69])[NH:67][C:63]=2[N:62]=[CH:61]1.[C:73]([OH:79])([C:75]([F:78])([F:77])[F:76])=[O:74]>CN(C=O)C.C(Cl)Cl>[F:76][C:75]([F:78])([F:77])[C:73]([OH:79])=[O:74].[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([CH2:35][NH:34][C:68]([C:66]2[NH:67][C:63]3[N:62]=[CH:61][NH:60][C:64]=3[CH:65]=2)=[O:69])=[C:37]([F:53])[C:38]=1[O:43][C:44]1[CH:45]=[C:46]([C:47]#[N:48])[CH:49]=[C:50]([Cl:52])[CH:51]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: C[Si](C)(C)CCOCn1cnc2[nH]c(C(=O)O)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cc4[nH]cnc4[nH]3)c2F)c1
Reaction time: 8 h
Yield: 6 %

Procedure:
HATU (0.092 g, 0.241 mmol) was added to a solution of DIPEA (0.042 ml, 0.241 mmol), 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.050 g, 0.161 mmol) and 1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1,4-dihydropyrrolo[2,3-d]imidazole-5-carboxylic acid (0.045 g, 0.161 mmol) dissolved in DMF (2 ml). The resulting solution was stirred overnight. The reaction mixture was partitioned between water and EtOAc. The organic layer was separated, dried over MgSO4 and evaporated to a residue. Purification was accomplished by reverse-phase HPLC (water/acetonitrile with 0.1% TFA) to afford a residue which was dissolved in DCM and TFA. This was stirred until LCMS showed complete removal of the SEM group. The solvent and acid were evaporated and the resulting solid washed with DCM and acetone to afford the title compound (0.0052 g, 6%) as a tan solid. 1H NMR (400 MHz, CD3OD) δ ppm 8.65 (s, 1H), 7.55 (t, 1H), 7.36-7.43 (m, 2H), 7.27 (t, 1H), 7.20 (dd, 1H), 6.95 (s, 1H), 4.63 (s, 2H). 19F NMR (376 MHz, CD3OD) δ ppm −77.52 (s, 3F), −133.01 (s, 1F). LCMS: m/z=442.0 (M−1).
Reaction SMILES: O[Li].O.[CH2:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[C@H:14]1[CH2:18][CH2:17][CH2:16][N:15]1[C:19]1[CH:24]=[CH:23][N:22]2[N:25]=[CH:26][C:27]([C:28]([O:30]CC)=[O:29])=[C:21]2[CH:20]=1)[CH3:5].Cl>C(O)C.O>[CH2:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[C@H:14]1[CH2:18][CH2:17][CH2:16][N:15]1[C:19]1[CH:24]=[CH:23][N:22]2[N:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[C:21]2[CH:20]=1)[CH3:5]
Reactant: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3OCC)cc12
Agent: Cl
Agent: [Li]O
Solvent: CCO
Solvent: O
Product: CCOc1ccc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2c1
Reaction time: 8 h

Procedure:
1M aq. solution of LiOH.H2O (0.4 mL) was added to a stirred solution of (R)-ethyl 5-(2-(2-ethoxy-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (Int-77) (0.12 g, 0.32 mmol) in ethanol (5 mL) and the stirring was continued at 90° C. for 8 h. The reaction mixture was concentrated under reduced pressure to afford the crude, which was diluted with cold water (20 mL) and acidified with 2N HCl solution to pH=2, solid precipitated out was filtered and dried to afford the desired compound (Int-78) as yellow solid. MS (ESI): m/z 370.3 (M+H).
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=[O:5].C(O)=O.S(=O)(=O)(O)O.[CH2:17]=[CH:18][CH2:19][CH2:20][CH3:21].C=CCC>C(CC(C)(C)C)(C)C>[C:1]([O:8][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])(=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=[O:5]
Reactant: C=CCCC
Reactant: CC(=O)CCC(=O)O
Agent: C=CCC
Agent: O=S(=O)(O)O
Solvent: O=CO
Solvent: CC(C)CC(C)(C)C
Product: CCCCCOC(=O)CCC(C)=O
Temperature: 75 °C

Procedure:
A 5 cc autoclave is charged with 1 cc of iso-octane and 1 cc of an aqueous solution containing 2 mmoles of levulinic acid and 2 mmoles of formic acid. 5 wt. % sulfuric acid is added as a catalyst. The reactor is pressurized to 0.69 MPa with 1-pentene and heated to 75° C. for 5 hours while maintaining a constant pressure of 1-butene. After cooling, the organic phase is separated. A mixture of pentyl formate and pentyl levulinate is formed as product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:10][CH:9]([NH:11]C(=O)OC(C)(C)C)[CH2:8]1.ClC1C(N2CC(N)C2)=NC=C(C(F)(F)F)C=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:8][CH:9]([NH2:11])[CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1CN(c2ccccn2)C1
Agent: NC1CN(c2ncc(C(F)(F)F)cc2Cl)C1
Product: NC1CN(c2ccccn2)C1

Procedure:
The title compound was prepared from tert-butyl (1-pyridin-2-ylazetidin-3-yl)carbamate in a similar manner as described for 1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]azetidin-3-amine. 1H NMR (500 MHz CDCl3): δ 1.96 (bs, 2H), 3.59-3.63 (m, 2H), 3.89-3.95 (m, 1H), 4.22-4.27 (m, 2H), 6.26 (d, 1H), 6.55-6.58 (m, 1H), 7.38-7.43 (m, 1H), 8.11 (s, 1H).
Reaction SMILES: C(O)(C(F)(F)F)=O.C([Cl:11])(=O)C.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=O)=[CH:15][CH:14]=1>>[Br:12][C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[C:20](\[Cl:11])/[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[CH:15][CH:14]=1
Reactant: CC(=O)Cl
Reactant: O=C(Cc1ccc(Br)cc1)c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cl/C(=C\c1ccc(Br)cc1)c1ccc(Cl)cc1
Yield: 74.5 %

Procedure:
In a 250 mL flask, TFA (24.7 mL; 322.8 mmol) and acetyl chloride (18.34 mL; 258.23 mmol) were added in one portion into 2-(4-bromophenyl)-1-(4-chlorophenyl) ethanone (Vd) (10.0 g; 32.30 mmol) at RT. Protocol and work-up was then similar with those described above. The title compound (m=7.89 g) was obtained in a 74.5% yield. Melting point: 108° C.
Reaction SMILES: C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:54]1[N:59]=[C:58]([N:60]2[CH2:65][CH2:64][O:63][CH2:62][CH2:61]2)[N:57]=[C:56]([C:66]2[CH:67]=[N:68][C:69]([NH2:72])=[N:70][CH:71]=2)[CH:55]=1.[CH3:73][O:74][C:75]1[CH:84]=[CH:83][CH:82]=[C:81]2[C:76]=1[CH:77]=[C:78]([NH2:85])[CH:79]=[N:80]2>CC([O-])=O.CC([O-])=O.[Pd+2].C1COCC1>[NH2:72][C:69]1[N:68]=[CH:67][C:66]([C:56]2[N:57]=[C:58]([N:60]3[CH2:65][CH2:64][O:63][CH2:62][CH2:61]3)[N:59]=[C:54]([NH:85][C:78]3[CH:79]=[N:80][C:81]4[C:76]([CH:77]=3)=[C:75]([O:74][CH3:73])[CH:84]=[CH:83][CH:82]=4)[CH:55]=2)=[CH:71][N:70]=1
Reactant: Nc1ncc(-c2cc(Cl)nc(N3CCOCC3)n2)cn1
Reactant: COc1cccc2ncc(N)cc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: COc1cccc2ncc(Nc3cc(-c4cnc(N)nc4)nc(N4CCOCC4)n3)cc12
Temperature: 110 °C

Procedure:
The desired compound was prepared as described in Example 2: Pd(OAc)2, BINAP, cesium carbonate, THF (0.8 mL) were mixed with 5-(6-chloro-2-morpholinopyrimidin-4-yl)pyrimidin-2-amine (1 eq.) and 5-methoxyquinolin-3-amine (2 eq), which was prepared as shown in Method 20. The mixture was heated under microwave irradiation for 10 minutes at 110° C. The solution was filtered and concentrated under reduced pressure. The crude product was purified by preparative reverse phase HPLC. LC/MS (m/z): 431.2 (MH+), Rt 2.03 minutes.
Reaction SMILES: OC(C(F)(F)F)=O.[F:8][C:9]1[N:14]=[CH:13][C:12]([N:15]2[CH2:19][CH:18]([C:20]([OH:22])=O)[N:17]([CH3:23])[C:16]2=[O:24])=[CH:11][CH:10]=1.C(N1CCOCC1)C.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl:56][C:57]1[CH:62]=[C:61]([Cl:63])[CH:60]=[CH:59][C:58]=1[CH2:64][NH2:65]>ClCCl>[Cl:56][C:57]1[CH:62]=[C:61]([Cl:63])[CH:60]=[CH:59][C:58]=1[CH2:64][NH:65][C:20]([CH:18]1[CH2:19][N:15]([C:12]2[CH:13]=[N:14][C:9]([F:8])=[CH:10][CH:11]=2)[C:16](=[O:24])[N:17]1[CH3:23])=[O:22]
Reactant: NCc1ccc(Cl)cc1Cl
Reactant: CN1C(=O)N(c2ccc(F)nc2)CC1C(=O)O
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CN1C(=O)N(c2ccc(F)nc2)CC1C(=O)NCc1ccc(Cl)cc1Cl
Reaction time: 0.17 h
Yield: 18.1 %

Procedure:
To a solution of 1-(6-fluoro-3-pyridinyl)-3-methyl-2-oxo-4-imidazolidinecarboxylic acid TFA salt (200 mg, 0.836 mmol) and N-ethylmorpholine (0.635 ml, 5.02 mmol) in dichloromethane (10 ml) was added 1-hydroxybenzotriazole hydrate (128 mg, 0.836 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (160 mg, 0.836 mmol) and the mixture was stirred for 10 minutes. 1-(2,4-Dichlorophenyl)methanamine (147 mg, 0.836 mmol) was added and the reaction stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and washed with saturated sodium hydrogen carbonate solution, water and brine, separated through a hydrophobic frit and the organic layer was reduced under vacuum. The residue was purified by FFlashmaster automated silica gel chromatography eluting with 10-100% ethyl acetate in isohexane to give N-[(2,4-dichlorophenyl)methyl]-1-(6-fluoro-3-pyridinyl)-3-methyl-2-oxo-4-imidazolidinecarboxamide (60 mg, 18% yield). LC/MS [M+H]+=397, retention time=2.63 minutes.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([CH2:9][NH2:10])[C:5]([Cl:11])=[C:4]([Cl:12])[C:3]=1[CH2:13][NH2:14].[C:15]1(=[O:25])O[C:18](=[O:19])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12>CN1CCCC1=O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([CH2:9][N:10]2[C:18](=[O:19])[C:17]3=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]3[C:15]2=[O:25])[C:5]([Cl:11])=[C:4]([Cl:12])[C:3]=1[CH2:13][N:14]1[C:15](=[O:25])[C:16]2=[CH:24][CH:23]=[CH:22][CH:21]=[C:17]2[C:18]1=[O:19]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCc1c(Cl)c(Cl)c(CN)c(Cl)c1Cl
Solvent: CN1CCCC1=O
Product: O=C1c2ccccc2C(=O)N1Cc1c(Cl)c(Cl)c(CN2C(=O)c3ccccc3C2=O)c(Cl)c1Cl

Procedure:
In a 3 liter, round-bottom flask equipped with a heating mantle, mechanical stirrer, thermometer, nitrogen inlet and condenser, 137 gms (0.5 mole) of 2,3,5,6-tetrachloro-p-xylylenediamine was dissolved at room temperature in 1 liter N-methyl-2-pyrrolidone (NMP). While stirring, 150 gms (1.0 mole) solid phthalic anhydride was added, the temperature rising to 47° C. The resulting greenish solution was heated to 180°-185° C. for 30 minutes, after which period crystallization took place. The hot mixture was poured into a 2 liter beaker when mass crystallization occurred.
Reaction SMILES: Br[C:2]1[C:3]([F:25])=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:15]4[N:16]([CH:21]([CH3:23])[CH3:22])[N:17]=[C:18]([CH3:20])[N:19]=4)=[CH:10]3)[C:6]=2[CH:24]=1.[CH3:26][O:27][C:28](=[O:39])[C:29]([N:32]1[CH2:37][CH2:36][CH:35]([SH:38])[CH2:34][CH2:33]1)([CH3:31])[CH3:30].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C>O1CCOCC1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:26][O:27][C:28](=[O:39])[C:29]([N:32]1[CH2:33][CH2:34][CH:35]([S:38][C:2]2[C:3]([F:25])=[CH:4][C:5]3[O:14][CH2:13][CH2:12][N:11]4[C:7](=[N:8][C:9]([C:15]5[N:16]([CH:21]([CH3:23])[CH3:22])[N:17]=[C:18]([CH3:20])[N:19]=5)=[CH:10]4)[C:6]=3[CH:24]=2)[CH2:36][CH2:37]1)([CH3:31])[CH3:30]
Reactant: COC(=O)C(C)(C)N1CCC(S)CC1
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(Br)c(F)cc2OCC3)n(C(C)C)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C)(C)N1CCC(Sc2cc3c(cc2F)OCCn2cc(-c4nc(C)nn4C(C)C)nc2-3)CC1
Temperature: 120 °C

Procedure:
A mixture of 9-bromo-8-fluoro-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (320 mg, 0.788 mmol), 2-(4-mercaptopiperidin-1-yl)-2-methylpropionic acid methyl ester (257 mg, 1.18 mmol), Pd2(dba)3 (36 mg, 0.039 mmol, mol %), XantPhos (46 mg, 0.079 mmol, 10 mol %) and DIPEA (0.55 mL, 3.15 mmol) in dioxane (10 mL) was purged with nitrogen and then heated at 120° C. for 2 h using microwave irradiation. The crude reaction mixture was diluted with DCM (150 mL) and purified by column chromatography (Si-PCC, gradient 0-6% MeOH in DCM) affording 2-{4-[8-Fluoro-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-9-ylsulfanyl]piperidin-1-yl}-2-methylpropionic acid methyl ester (quantitative yield), impure but taken forward to the next step without further purification. LCMS: RT 2.29 and 2.36 min [M+H]+ 543.2
Reaction SMILES: [CH2:1]([C:10]1([OH:24])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]1[NH:19][CH2:20][CH2:21][CH2:22]O)[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.S(Cl)([Cl:27])=O>>[CH2:1]([C:10]1([OH:24])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]1[NH:19][CH2:20][CH2:21][CH2:22][Cl:27])[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1
Reactant: COc1cccc(CC2(O)C(NCCCO)=Nc3ccccc32)c1
Reactant: O=S(Cl)Cl
Product: COc1cccc(CC2(O)C(NCCCCl)=Nc3ccccc32)c1

Procedure:
Reaction of 3-(m-anisyl)-2-(3-hydroxypropylamino)-3H-indol-3-ol with thionylchloride by a procedure analogous to that described in Example 2 gives 3-(m-anisyl)-2-(3-chloropropylamino)-3H-indol-3-ol.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[OH:14])/[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:22][C:23]#[N:24]>CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH2:22][C:23]#[N:24])/[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1
Reactant: N#CCCl
Reactant: CCOC(=O)/C(=N\O)c1csc(N)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C(=N\OCC#N)c1csc(N)n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
54 g of ethyl 2-(2-amino-4-thiazolyl)-2-(Z)-hydroxyimino-acetate are dissolved in 500 ml of dimethylformamide. After the addition of 138 g of potassium carbonate, there are added dropwise within 1 hour 47 ml of chloroacetonitrile and the mixture is then stirred at room temperature for 20 hours. The dark solution obtained is poured into ice-water and extracted with ethyl acetate. The organic phase is washed with water, treated with active carbon, dried over magnesium sulphate and concentrated. After recrystallization from toluene, there are obtained 38 g of ethyl 2-(2-amino-4-thiazolyl)-2-[(Z)-(cyanomethoxy)imino]-acetate of melting point 167°-168° C.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH:25]([CH3:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C1CCCCC=1.B(Br)(Br)Br.ClCCl>>[CH3:26][CH:25]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]1[S:9]([C:6]1[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=1)(=[O:11])=[O:10]
Reactant: COc1ccc(S(=O)(=O)N2c3ccccc3-c3ccccc3C2C)cc1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Solvent: ClCCl
Product: CC1c2ccccc2-c2ccccc2N1S(=O)(=O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
A stirred suspension of 5-[(4-methoxyphenyl)sulfonyl]-6-methyl-5,6-dihydrophenanthridine (0.73 g, 2.0 mmol) and cyclohexene (3.28 g, 40 mmol) was treated at room temperature under nitrogen with a solution of 1.0 M boron tribromide in dichloromethane (12 mL, 12 mmol). After stirring for approximately four hours at room temperature, the reaction was quenched with methanol (20 mL) and diluted with dichloromethane. The mixture was washed sequentially with an aqueous potassium carbonate solution, a saturated, aqueous sodium chloride solution, and water. The organic phase was dried over anhydrous sodium sulfate, filtered through a short column of silica gel, and eluted with ethyl acetate. The ethyl acetate phase was evaporated in vacuo to a crude residue (1.0 g). The crude residue was purified by preparative chromatography on a Biotage® 40 Mi column of pre-packed silica gel (90 g) with gradient elution of between 10% to 30% methyl tert-butyl ether in hexane at a flow rate of 50 mL/min and afforded, after evaporation of the solvent, a colorless oil. Crystallization of the colorless oil from a mixture of diethyl ether-hexane yielded the title compound (0.525 g, 1.5 mmol, 75%) as a homogeneous, colorless, crystalline solid,
Reaction SMILES: [CH2:1]([C@H:8]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:9][C@H:10]([OH:42])[C@@H:11]([N:27](CC1C=CC=CC=1)CC1C=CC=CC=1)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19]CC2C=CC=CC=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])=O.[NH4+]>C1COCC1.[Pd]>[NH2:27][C@@H:11]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=1)[C@@H:10]([OH:42])[CH2:9][C@@H:8]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccc(OCc2ccccc2)cc1)N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccc(O)cc1
Yield: 82.8 %

Procedure:
A solution containing the product from Example 23E (12.3 g, 18.4 mmol) in THF (169 mL) was treated with 10% Pd on carbon (2.5 g) and ammonium formate (6.9 g, 109.4 mmol) and the mixture was heated at reflux for 1.5 hours. Additional 10% Pd on carbon (1.25 g) and NH4CO2H (3.45 g) were added and the mixture was heated at reflux for 2.5 hours. The reaction was concentrated and partitioned between chloroform and water and the solution was adjusted to pH 10 with NaHCO3 solution. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated to give the title compound (6.1 g, 82% yield), which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:22])=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][C@@H:12]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH3:13])[N:8]=[CH:7]2.C(=O)([O-])[O-].[K+].[K+].[CH2:29]([CH:31]1[O:33][CH2:32]1)Br>CC(C)=O>[Br:1][C:2]1[C:3]([O:22][CH2:29][CH:31]2[CH2:32][O:33]2)=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][C@@H:12]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:17])[CH3:13])[N:8]=[CH:7]2
Reactant: C[C@@H](Cn1ncc2ccc(O)c(Br)c21)O[Si](C)(C)C(C)(C)C
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C[C@@H](Cn1ncc2ccc(OCC3CO3)c(Br)c21)O[Si](C)(C)C(C)(C)C
Yield: 471.5 %

Procedure:
A suspension of the product from Step C (3.66 g, 9.51 mmol), potassium carbonate (1.92 g, 1.46 mmol), and epibromohydrine (1.32 mL, 1.60 mmol) in acetone (200 mL) was heated at reflux for 30 h. The solid was removed by filtration and the filtrate was concentrated to an oil that was purified by chromatography (silica, 2% to 10% EtOAc/hexane) to afford an oil (3.33 g, 79%): LC/MS (+APCI) m/z 441, 443 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[C:6]([CH:11]=[N:12][OH:13])[C:5]=1[F:14].[Cl:16]N1C(=O)CCC1=O.O.CCOC(C)=O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[C:6]([C:11]([Cl:16])=[N:12][OH:13])[C:5]=1[F:14]
Reactant: COC(=O)c1c(Cl)ccc(C=NO)c1F
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1c(Cl)ccc(C(Cl)=NO)c1F
Temperature: 50 °C

Procedure:
To a solution of methyl-6-chloro-2-fluoro-3-((hydroxyimino)methyl)benzoate (553 mg, 2388 μmol) in DMF (5.3 ml) at 0° C. was added N-chlorosuccinimide (351 mg, 2626 μmol). The mixture was heated to 50° C. for 10 min after which time LCMS analysis indicated the reaction was complete. The mixture was cooled to RT, water was added followed by EtOAc, the layers were separated, and the aqueous was extracted with EtOAc (3×). The combined organic layers were washed with brine (2×), dried over MgSO4, filtered and concentrated to yield the title compound as a yellow viscous oil, which solidified under reduced pressure.
Reaction SMILES: [NH2:1][C@@:2]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[CH2:6][O:5][CH2:4][C@H:3]1[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[CH3:22]O>>[NH2:1][C@@:2]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[CH2:6][O:5][CH2:4][C@H:3]1[C:7]([O:9][CH3:22])=[O:8]
Reactant: CO
Reactant: N[C@@]1(c2ccccc2F)COC[C@H]1C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)[C@@H]1COC[C@@]1(N)c1ccccc1F
Temperature: 70 °C
Reaction time: 8 h

Procedure:
(±)-(3S*,4S*)-4-Amino-4-(2-fluorophenyl)tetrahydrofuran-3-carboxylic acid (0.22 g) was transferred into the reaction vessel. Methanol (15 mL) was transferred into the reaction vessel. Sulphuric acid (1 mL) was transferred into the reaction vessel. The reaction was stirred at 70° C. for 8 h. The reaction mixture was concentrated under reduced pressure. Saturated sodium bicarbonate (40 mL) was then added followed by an extraction with DCM (3×40 mL). The combined organic phases were dried over MgSO4, filtered and concentrated. The crude product was purified by preparative HPLC (Method B) to give the title compound (120 mg). 1H NMR (400 MHz, CDCl3) δ ppm 3.73 (s, 3H) 3.78 (t, J=8.21 Hz, 1H) 4.02 (dd, J=8.91, 2.97 Hz, 1H) 4.15 (d, J=8.97 Hz, 1H) 4.22 (t, J=8.72 Hz, 1H) 4.36-4.44 (m, 1H) 7.09 (ddd, J=12.41, 8.12, 1.20 Hz, 1H) 7.18 (td, J=7.64, 1.14 Hz, 1H) 7.29-7.35 (m, 1H) 7.63 (td, J=8.05, 1.45 Hz, 1H).
Reaction SMILES: C1(N=C=O)C=CC(N=C=O)=CC=1.[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22])#[CH:14].[CH2:23]([O:25][C:26](=[O:35])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][N+:32]([O-])=[O:33])[CH3:24].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:23]([O:25][C:26](=[O:35])[CH2:27][CH2:28][CH2:29][CH2:30][C:31]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])[O:33][N:32]=1)[CH3:24]
Reactant: CCOC(=O)CCCCC[N+](=O)[O-]
Reactant: C#Cc1ccccc1OC
Agent: O=C=Nc1ccc(N=C=O)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCCc1cc(-c2ccccc2OC)on1
Reaction time: 2.5 h
Yield: 97.9 %

Procedure:
Add 1,4-phenylenediisocyanate (14.5 g, 90.8 mmol) to a stirred solution of 1-ethynyl-2-methoxy-benzene (4.0 g, 30.3 mmol) and 6-nitro-hexanoic acid ethyl ester (8.6 g, 45.4 mmol) in toluene (300 mL, anhydrous) and stir under N2. Add triethylamine (12.7 mL, 90.8 mmol) and heat to reflux under N2. After 2.5 hours, filter mixture through a pad of Celite® and rinse with toluene. Concentrate to get 9 grams of a orange oil. Adsorb on SiO2 and purify the residue by flash chromatography on silica gel eluting with 0-20% EtOAc/hexanes to afford the title compound (14.0 g, 74%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][NH:25][CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH3:29][C:30]([CH3:35])([CH3:34])[C:31](Cl)=[O:32]>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][C:15]=2[CH2:24][N:25]([C:31](=[O:32])[C:30]([CH3:35])([CH3:34])[CH3:29])[CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OCC)ccc1OC
Reactant: CC(C)(C)C(=O)Cl
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)C(C)(C)C)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester and trimethylacetyl chloride.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[C:4]([Cl:10])[C:3]=1[Cl:11].[I-]>>[Cl:11][C:3]1[C:4]([Cl:10])=[C:5]([Cl:9])[C:6]([Cl:8])=[N:7][CH:2]=1
Reactant: Clc1nc(Cl)c(Cl)c(Cl)c1Cl
Agent: [I-]
Product: Clc1cnc(Cl)c(Cl)c1Cl

Procedure:
The reaction of pentachloropyridine with a source of iodide ions and a proton donor in a solvent to form symmetrical tetrachloropyridine takes place in high yield and in a reasonable time period provided the reactants are heated sufficiently. The product is recovered by known techniques such as distillation.