Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[N:14]=[C:13]([C:21]([CH3:24])([CH3:23])[CH3:22])[N:12]=2)[CH2:7][CH2:6]1.[I-].[Na+].[C:27]1([P:33]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CC(C)=O>[Cl-:1].[C:21]([C:13]1[N:12]=[C:11]([N:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][CH2:2][P+:33]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:6][CH2:7]2)[CH:16]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[N:14]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)c1cc(N2CCN(CCCCl)CC2)nc(C(C)(C)C)n1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)c1cc(N2CCN(CCC[P+](c3ccccc3)(c3ccccc3)c3ccccc3)CC2)nc(C(C)(C)C)n1
Product: [Cl-]

Procedure:
3.52 g (10 mmol) of 1-chloro-3-[4-(2,6-di-t-butylpyrimidin-4-yl)piperazin-1-yl]propane (prepared by a method similar to Example 1, A.3) were dissolved, together with 1.8 g of sodium iodide (12 mmol) and 3.41 g (13 mmol) of triphenylphosphine in 75 ml of acetone and the solution was refluxed for 24 h.
Reaction SMILES: [CH3:1][C:2]1[N:6](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:5]=[N:4][C:3]=1/[CH:26]=[CH:27]/[C:28]([C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=1)=[O:29].[C:40]([O-:47])(=[O:46])/[CH:41]=[CH:42]\[C:43]([O-:45])=[O:44]>>[C:40]([OH:47])(=[O:46])/[CH:41]=[CH:42]\[C:43]([OH:45])=[O:44].[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1/[CH:26]=[CH:27]/[C:28]([C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=1)=[O:29]
Reactant: Cc1c(/C=C/C(=O)c2ccc3ccccc3c2)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C([O-])/C=C\C(=O)[O-]
Product: Cc1[nH]cnc1/C=C/C(=O)c1ccc2ccccc2c1
Product: O=C(O)/C=C\C(=O)O

Procedure:
The deprotection of (E)-3-[5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl]-1- (2-naphthalenyl)-2-propen-1-one (1.25 g) followed by maleate formation gave the title compound (0.75 g), m.p. 190°-191° (decomp.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.[C:13](Cl)(=O)[C:14](Cl)=O.Br[C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[C:22]([N+:34]([O-])=O)[CH:21]=1>C(Cl)Cl.CN(C=O)C.N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([NH:34][C:22]1[CH:21]=[C:20]([C:14]2[CH:13]=[CH:27][N:26]=[CH:23][CH:22]=2)[CH:25]=[CH:24][C:23]=1[NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:7]
Reactant: COc1ccc(C(=O)O)cc1F
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)cc1[N+](=O)[O-]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2cc(-c3ccncc3)ccc2NC(=O)OC(C)(C)C)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 18 %

Procedure:
To a suspension of 3-fluoro-4-methoxybenzoic acid (125 mg, 0.736 mmol) in DCM (10 mL), oxalyl chloride (0.442 mL, 0.883 mmol) and DMF (2 drops) were added. The reaction was stirred at room temperature for 30 min and a solution was obtained. A solution of compound 390 (210 mg, 0.736 mmol) (390 was synthesized following general procedures B and C starting from compound 2 and pyridin-4-ylboronic acid) in pyridine (10 mL) was added and the reaction was stirred for an additional hour, quenched with water, dissolved in AcOEt and washed with water. The organic layer was separated and dried with Na2SO4, filtered and concentrated under vacuum. The residue was purified via Isco (12 g column, 40-100% EtOAc/hexanes solvent gradient) to give the title compound 391 as a light yellowed (60 mg, 18% yield).
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11]([C:13]#[C:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[O:21][C:20]([CH3:26])([CH3:25])[CH:19]=[C:18]3[C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)[CH:10]=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].[OH-].[Na+].Cl>C1COCC1.CCO>[F:1][C:2]1[CH:12]=[C:11]([C:13]#[C:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[O:21][C:20]([CH3:26])([CH3:25])[CH:19]=[C:18]3[C:27]2[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=2)[CH:10]=[CH:9][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C)cc2)=CC(C)(C)O3)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc(C2=CC(C)(C)Oc3ccc(C#Cc4ccc(C(=O)O)c(F)c4)cc32)cc1
Temperature: 35 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
To a solution of ethyl 2-fluoro-4-[[4-(4-methylphenyl)-2,2-dimethyl-(2H)-chromen-6-yl]-ethynyl]-benzoate (Compound 272, 60.0 mg, 0.136 mmol) in 2.0 mL THF and 1.0 mL EtOH was added NaOH (120.0 mg, 3.0 mmol, 3.0 mL of a 1M aqueous solution). The resulting solution was heated to 35° C., cooled to room temperature and stirred overnight. The reaction mixture was acidified with 10% aqueous HCl and extracted with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NaCl, and dried (Na2SO4) before the solvent was removed under reduced pressure. The residual solid was recrystallized from CH3CN to give 53.0 mg (94%) the title compound as a colorless solid. 1H NMR (300 MHz, d6 -acetone) δ: 7.93 (1H, d, J=7.8 Hz), 7.43-7.16 (8H, m), 6.91 (1H, d, J=8.3 Hz), 5.77 (1H, s), 2.38 (3H, s), 1.49 (6H, s).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.CC(C)([O-])C.[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[CH2:19]([O:12][C:9]1[CH:10]=[CH:11][C:6]([S:5][CH2:4][CH2:3][CH2:2][OH:1])=[CH:7][CH:8]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: OCCCSc1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Product: OCCCSc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(3-Hydroxy-propylsulfanyl)-phenol (CAB02029, 3.686 g, 20 mmol) was dissolved in ethanol (50 mL) and potassium tert-Butoxide (2.80 g, 25 mmol) and benzyl bromide (3.0 mL, ca. 25 mmol) were added. The mixture was stirred overnight at room temperature, the precipitated potassium bromide was filtered off and the filtrate was concentrated under reduced pressure. The resulting yellow solid was dissolved in ethyl acetate (1.00 mL), the solution was washed with water (100 mL) and brine (100 mL), dried over sodium sulphate and concentrated under reduced pressure. The residue was dissolved in dichloromethane (ca. 10 mL) and the product was precipitated by addition of hexane (ca. 200 mL). The crystalline product was collected and dried under high vacuum. Yield: 4.481 g (82%) colourless, small plates. 1H-NMR (400 MHz, CDCl3) δ=1.45 (br s, 1H, —OH), 1.82-1.87 (m, 2H), 2.84 (t, J=7.4 Hz, 2H), 3.74-3.78 (m, 2H), 5.05 (s, 2H, —OCH2Ph), 6.90-6.93 (m, 2H, 7.31-7.44 (m, 7H).
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:13])=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.[OH:14][C:15]1[CH:32]=[CH:31][C:18]([O:19][CH:20]([CH3:30])[C:21]([O:28][CH3:29])=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[Cl:13])[N:3]=[C:2]([O:14][C:15]1[CH:16]=[CH:17][C:18]([O:19][CH:20]([CH3:30])[C:21]([O:28][CH3:29])=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:31][CH:32]=1)[CH:11]=[N:10]2
Reactant: CCOC(=O)C=C(OC)C(C)Oc1ccc(O)cc1
Reactant: Clc1cnc2cc(Cl)c(Cl)cc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C=C(OC)C(C)Oc1ccc(Oc2cnc3cc(Cl)c(Cl)cc3n2)cc1

Procedure:
A mixture of 2,6,7-trichloroquinoxaline (0.8 eq, 3.43 ml.), ethyl 4-(4-hydroxyphenoxy)-3-methoxy-2-pentenoate (1.09 g, 1.2 eq), K2CO3 (568 mg) and CH3CN (20 ml) is refluxed overnight and then filtered. The filtrate is concentrated and taken up in CH2Cl2. The CH2Cl2 solution is washed, dried and evaporated to dryness to yield crystalline enol ether, i.e., ethyl 4-[4-(6,7-dichloro-2-quinoxalyloxy)phenoxy]-3-methoxy-2-pentenoate.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1.S(=O)(=O)(O)O>C1COCC1.ClCCl.[O-2].[O-2].[Mn+4]>[Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccc(CCl)cc1
Agent: [Mn+4]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=Cc1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
Under an argon atmosphere, 4-chloromethylbenzoic acid (15.08 g, 88.40 mmol) was dissolved in THF (150 ml), and 1M borane-THF complex (135 ml, 135.00 mmol) was slowly added dropwise under ice-cooling. The mixture was stirred at room temperature for 2 hours, 1N sulfuric acid (160 ml) was added, and the mixture was stirred for 1 hour and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained crude product was dissolved in dichloromethane (300 ml). Manganese dioxide (76.94 g, 885.0 mmol) was added, and the mixture was stirred overnight at room temperature. After filtration through celite, the filtrate was concentrated under reduced pressure to give the title compound (11.93 g, 87%).
Reaction SMILES: Cl.C[C@@H](O)[C@H](NC(CNC([C@@H](NC([C@@H](NC([C@@H](N)CC1N=CNC=1)=O)CO)=O)CCC(N)=O)=O)=O)C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H:210]([C:214]([OH:216])=[O:215])[C@H:211]([OH:213])[CH3:212])=O)CC(N)=O)=O)CCSC)=O)CC(C)C)=O)CC1C2C=CC=CC=2NC=1)=O)CCC(N)=O)=O)C(C)C)=O)CC1C=CC=CC=1)=O)CC(O)=O)=O)CCC(N)=O)=O)C)=O)CCCN=C(N)N)=O)CCCN=C(N)N)=O)CO)=O)CC(O)=O)=O)CC(C)C)=O)CC1C=CC(O)=CC=1)=O)CCCCN)=O)CO)=O)CC1C=CC(O)=CC=1)=O)CC(O)=O)=O)CO)=O)[C@H](O)C)=O)CC1C=CC=CC=1)=O.C(O)[C@H]1[O:254][C@H:253]([O:255][C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@H:252](O)[C@@H](O)[C@@H]1O.[CH2:271](N)[C:272](O)=[O:273]>CS(C)=O>[CH3:252][C:253]([O:255][C@H:212]1[C@H:211]([OH:213])[C@@H:210]([C:214]([OH:216])=[O:215])[O:273][CH:272]=[CH:271]1)=[O:254]
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)Cc1c[nH]cn1)[C@@H](C)O)[C@@H](C)O)C(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)O)[C@@H](C)O
Reactant: OC[C@H]1O[C@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: NCC(=O)O
Agent: Cl
Solvent: CS(C)=O
Product: CC(=O)O[C@@H]1C=CO[C@H](C(=O)O)[C@H]1O

Procedure:
Glucagon acetate was prepared at 1.0 mg/mL via dissolution in 2 mM L-glycine, pH 3.0 (titrated with concentrated HCl). The glucagon formulations were lyophilized and reconstituted in DMSO at a nominal concentration of 5 mg/mL glucagon. Solution samples were divided and trehalose was added to one solution to a concentration of 5%. These formulations were aliquoted into vials and placed in a stability incubator at 5° C. At 5° C., these solutions were observed to freeze. The glucagon solutions were thawed at various intervals and turbidity was determined using the absorbance at 630 nm.
Reaction SMILES: [O:1]1[CH2:15][CH:2]1[CH2:3][O:4][C:5]1[C:14]2[CH2:13][CH:12]=[CH:11][CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.ClC1C=CC=C(C(OO)=[O:24])C=1>C(Cl)Cl>[O:24]1[CH:12]2[CH:11]1[CH2:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]([O:4][CH2:3][CH:2]3[O:1][CH2:15]3)[C:14]=1[CH2:13]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C1=CCc2c(cccc2OCC2CO2)C1
Solvent: ClCCl
Product: c1cc2c(c(OCC3CO3)c1)CC1OC1C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a well-stirred solution of 7 g. (0.03 m.) of 1-(2,3-epoxy-propoxy)-5,8-dihydro-naphthalene (prepared as described in application Ser. No. 768,176, filed Oct. 16, 1968, issued Oct. 13, 1970, as U.S. Pat. No. 3,534,085) in 60 ml. of CH2Cl2, 7.1 g. (0.03 m.) of 85% m-chloroperbenzoic acid in 100 ml. CH2Cl2 is added dropwise at such a rate that the temperature is maintained between 25° to 30° C. The mixture is stirred overnight at room temperature. The resulting precipitate (m-chlorobenzoic acid) is filtered off and the CH2Cl2 extract is washed successively with sat. NaHCO3 solution, and water. After drying (MgSO4), the solution is evaporated in vacuo to give 7.2 g. (95%) of oil which solidifies. A sample recrystallized from ether gives white needles, m.p. 85°-87°; λ Nujolmax 1330-1350 cm-1 (epoxy), τ CDCl3 absence of vinyl protons 4.0-4.2 region.
Reaction SMILES: [OH:1][C@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:23])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.[O:24]=[O:25]>>[O:24]([C@:4]12[CH2:3][C@@H:2]([OH:1])[CH2:21][CH2:20][C@:19]1([CH3:22])[C@@H:18]1[C@H:7]([C@H:8]3[C@:15]([CH3:23])([CH2:16][CH2:17]1)[C@@H:11]([C:12](=[O:14])[CH3:13])[CH2:10][CH2:9]3)[CH:6]=[CH:5]2)[OH:25]
Reactant: O=O
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3C=C[C@@]4(OO)C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
3β-Hydroxy-5-pregnen-20-one 1 reacts with singlet oxygen to yield 5α-hydroperoxy-3β-hydroxy-6-pregnene-20-one 2. This hydroperoxide undergoes a rearrangement when in chloroform solution to yield 7α-hydroperoxy-3β-hydroxy-5-pregnene-17-one, 3. Treatment of the hydroperoxide with zinc and acetic acid yields 3β,7α-dihydroxy-5-pregnen-20-one 4. ##STR27##
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]([OH:12])=[O:11])=[C:4]([CH3:13])[CH:3]=1.CN(C([O:21]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:38][CH2:39][N:40](CC)[CH2:41][CH3:42].FC1C=C(C=C(F)C=1)CN>C1COCC1.CCOC(C)=O>[CH3:9][O:8][C:6]1[C:5]([C:10]([OH:12])=[O:11])=[C:4]([CH3:13])[CH:3]=[C:2]([N:40]2[CH2:41][CH2:42][O:21][CH2:38][CH2:39]2)[N:7]=1
Reactant: CCN(CC)CC
Reactant: COc1nc(Cl)cc(C)c1C(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NCc1cc(F)cc(F)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1nc(N2CCOCC2)cc(C)c1C(=O)O
Temperature: 50 °C
Reaction time: 3 h
Yield: 46.7 %

Procedure:
To a solution of 302 mg crude 6-chloro-2-methoxy-4-methyl-pyridine-3-carboxylic acid in THF (12 ml) were added 568 mg (1.5 mmol) HATU and 934 μl (6.8 mmol) NEt3. The RM was stirred at 50° C. for 3 h followed by the addition of 268 mg (1.9 mmol) 3,5-difluorobenzylamine. Stirring was continued at 50° C. for 72 h. The RM was then diluted with EtOAc (50 ml) and subsequently washed with a 4M aq. NH4Cl sol., a 1M aq. NaHCO3 sol. and brine. The organic layer was dried over MgSO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 3:1) provided 237 mg (0.7 mmol, 54% over 2 steps) 2-methoxy-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[N:19]=[C:18]([N:20]([CH3:22])[CH3:21])[CH:17]=[CH:16][CH:15]=1.[B:23](OC(C)C)([O:28]C(C)C)[O:24]C(C)C.[Cl-].[NH4+]>C1COCC1>[CH3:21][N:20]([CH3:22])[C:18]1[N:19]=[C:14]([F:13])[C:15]([B:23]([OH:28])[OH:24])=[CH:16][CH:17]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CN(C)c1cccc(F)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CN(C)c1ccc(B(O)O)c(F)n1
Reaction time: 0.5 h
Yield: 84 %

Procedure:
In a microwave tube was placed 2,6-difluoropyridine (0.500 mL, 5.47 mmol), dimethylamine, (2.0 M solution in THF, 4.11 mL, 8.21 mmol). The mixture was heated at 150° C. for 20 min. Water was added and the mixture was extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give 536 mg of a crude yellow oil, which was purified by column chromatography (3/1 Hex/ethyl acetate) to give 500 mg of 6-fluoro-N,N-dimethylpyridin-2-amine as a light yellow oil. To a solution of diisopropylamine (0.15 mL, 1.1 mmol) in 2 mL of THF at 0° C. was added butyllithium (1.6 M in hexane, 0.69 mL, 1.1 mmol). The reaction stirred for 30 minutes and was then cooled to 60° C. at which time 6-fluoro-N,N-dimethylpyridin-2-amine (0.124 g, 0.88 mmol) was added in 1 mL of THF. The reaction stirred at −60° C. for 45 min. Then triisopropyl borate (0.25 mL, 1.1 mmol) was added and the reaction was allowed to stir for 1 h at 23° C. Ammonium chloride (sat.) was added and the mixture was extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give 136 mg of a brown oil, which was purified by column chromatography (3/1 hexanes/ethyl acetate to 1/1 EtOAc/hexanes) to give 46 mg of a white solid. ES+=185.1 (M+H)
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][N:16]=2)[CH2:11][CH:10]([NH:24]C(=O)OCC2C=CC=CC=2)[C:9]1=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.CO.[Pd]>[NH2:24][CH:10]1[CH2:11][C:12]2[C:17](=[N:16][CH:15]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:13]=2)[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]1=[O:35]
Reactant: O=C(NC1Cc2cc(-c3ccccc3)cnc2N(Cc2ccccc2)C1=O)OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: NC1Cc2cc(-c3ccccc3)cnc2N(Cc2ccccc2)C1=O
Yield: 99.3 %

Procedure:
To a solution of 1I (170 mg, 0.367 mmol) in THF (5 mL) and MeOH (5 mL) at RT was added palladium 5% wt. on activated carbon (85 mg). The reaction mixture was stirred under a hydrogen balloon for lh. The reaction was filtered and the filtrate concentrated to give the title compound as a light yellowish oil (120 mg, 100%). LC/MS (method A): retention time=3.07 min, (M+H)+=330.
Reaction SMILES: S([O:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])(C(F)(F)F)(=O)=O.[CH3:16][C:17]([N+:22]([O-:24])=[O:23])([CH2:20]O)[CH2:18][OH:19].N1C=CC=CC=1>C(Cl)(Cl)Cl>[S:9]([O:19][CH2:18][C:17]([CH3:20])([N+:22]([O-:24])=[O:23])[CH2:16][O:8][S:9]([C:12]([F:13])([F:14])[F:15])(=[O:10])=[O:11])([C:12]([F:15])([F:14])[F:13])(=[O:10])=[O:8]
Reactant: CC(CO)(CO)[N+](=O)[O-]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(COS(=O)(=O)C(F)(F)F)(COS(=O)(=O)C(F)(F)F)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of triflic anhydride (16.5 ml, 0.1 mol) in chloroform (50 ml) is added a solution of 2-methyl-2-nitro-1,3-propanediol (6.75 g, 0.05 mol) and pyridine (8.85 ml, 0.11 mol) in chloroform (50 ml) with external cooling to ensure a temperature of between 0° and 5° C. during the addition. After the addition the cooling bath is removed and the reaction stirred for 18 hours at ambient temperature. The reaction mixture is transferred to a separating funnel and washed with water. The organic layer is dried (Na2SO4), filtered and evaporated to dryness. The crude product is purified by chromatography using a 4:1 mixture of Hexane:Ethyl acetate as eluant; the product is obtained as a solid with melting point 50-52° C.
Reaction SMILES: [C:1]([C:4]1[CH:24]=[CH:23][C:7]([C:8]([NH:10][C:11]2[CH:21]=[C:20]([NH2:22])[CH:19]=[CH:18][C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:9])=[CH:6][CH:5]=1)([OH:3])=[O:2].[C:25](Cl)(=[O:28])[CH2:26][CH3:27].O.Cl>N1C=CC=CC=1>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][C:11]2[CH:21]=[C:20]([NH:22][C:25](=[O:28])[CH2:26][CH3:27])[CH:19]=[CH:18][C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:9])=[CH:23][CH:24]=1)([OH:3])=[O:2]
Reactant: CCOC(=O)c1ccc(N)cc1NC(=O)c1ccc(C(=O)O)cc1
Reactant: CCC(=O)Cl
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc(NC(=O)CC)cc1NC(=O)c1ccc(C(=O)O)cc1
Reaction time: 3 h
Yield: 62.6 %

Procedure:
A solution of 3 g of ethyl 2-(4-carboxybenzamido)-4-aminobenzoate in 30 ml of pyridine was mixed with 3 g of propionyl chloride, and the mixture was held at 40° to 50° C. for a period of 3 hours. Subsequently, 20 ml of water was gradually added to the mixture which was held at the temperature for a period of one hour. After further addition of 100 ml of water, hydrochloric acid was used to control the pH of the reaction mixture between 1 and 2, and the precipitating crystal was filtered, washed with water, and recrystallized from a solvent mixture of ethanol and water to thereby produce 2.2 g of ethyl 2-(4-carboxybenzamido)-4-propionamidobenzoate having a melting point in the range of from 246° to 248° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](O)=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17].C(Cl)(=O)C([Cl:21])=O.CN(C=O)C>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([Cl:21])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1C
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccccc1-c1ccc(C(=O)Cl)cc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under Argon atmosphere, Intermediate 3 (147.08 mg; 0.65 mmol) was stirred in anhydrous DCM (5 mL). Oxalyl chloride (57.75 μL; 0.68 mmol) was added followed by DMF (0.50 μL; 0.01 mmol). The reaction mixture was stirred 3 hours at RT. Solvents were evaporated to give 2,2′-dimethylbiphenyl-4-carbonyl chloride as a yellow oil. The latter was dissolved in anhydrous THF (3 mL), Intermediate 46 (136.62 mg; 0.65 mmol) and DIEA (221.08 μL; 1.30 mmol) were added under argon. The mixture was heated in the microwave at 150° C. for 15 min. The reaction mixture was diluted in water and extracted with EtOAc, the organic phase was then washed with NH4Cl, NaHCO3 and NaCl sat. solution. The organic layer was then dried over magnesium sulfate, filtered and concentrated, the crude product was purified by flash chromatography (c-hex/EtOAc: 9.5/0.5), affording the title compound. LC/MS (Method A): 398.9 (M−H)−, 400.8 (M+H)+. HPLC (Method A) Rt 6.37 min (Purity: 98.8%).
Reaction SMILES: [Na].Cl[C:3]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:6][S:5][N:4]=1.[CH2:14]([OH:18])[CH2:15][CH2:16][CH3:17]>>[CH2:14]([O:18][C:3]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:6][S:5][N:4]=1)[CH2:15][CH2:16][CH3:17]
Reactant: Clc1nsnc1-c1cccnc1
Reactant: CCCCO
Agent: [Na]
Product: CCCCOc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
To a solution of sodium (290 mg, 12.5 mmol) in n-butanol (10 ml) was added 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (490 mg, 2.5 mmol). The mixture was stirred at 25° C. for 18 h and evaporated. The residue was dissolved in water and extracted with methylene chloride. The combined organic phases were dried and evaporated to yield 580 mg (100%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([C:8]2[C:9]([CH3:19])=[C:10]([CH2:14][CH2:15][C:16](O)=[O:17])[CH:11]=[CH:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1.S(Cl)([Cl:24])=O>>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([C:8]2[C:9]([CH3:19])=[C:10]([CH2:14][CH2:15][C:16]([Cl:24])=[O:17])[CH:11]=[CH:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1c(CCC(=O)O)cccc1C(=O)c1ccc(Cl)cc1
Product: Cc1c(CCC(=O)Cl)cccc1C(=O)c1ccc(Cl)cc1

Procedure:
830 mg of 3-(3'-p-chlorobenzoyl-2'-methyl-phenyl)propionic acid and 4.2 ml of thionyl chloride were refluxed for 3 hours and then excess thionyl chloride was distilled off and the last traces were removed by entrainment with benzene to obtain 876 mg of 3-(3'-p-chlorobenzoyl-2'-methyl-phenyl)propionyl chloride which was used as is for the next step.