Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11](O)=O)=[CH:5][CH:4]=1.C1CCC(N=C=NC2CCCCC2)CC1.[N:29]1[C:33]2[CH:34]=[CH:35][C:36]([C:38]([NH:40][NH2:41])=O)=[CH:37][C:32]=2[NH:31][CH:30]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:51])=CC=1>>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[S:51][C:38]([C:36]3[CH:35]=[CH:34][C:33]4[NH:29][CH:30]=[N:31][C:32]=4[CH:37]=3)=[N:40][N:41]=2)=[CH:5][CH:4]=1
Reactant: CSc1ccc(CCC(=O)O)cc1
Reactant: NNC(=O)c1ccc2nc[nH]c2c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CSc1ccc(CCc2nnc(-c3ccc4[nH]cnc4c3)s2)cc1

Procedure:
The compound was synthesized starting from 3-(4-methylthiophenyl)propionic acid (197 mg; 1 mmol), DCC (206 mg; 1 mmol), benzimidazol-5-carbohydrazide (176 mg; 1 mmol) and Lawesson's reagent (606 mg; 1.5 mmol) as described in method 2; yield: 0.029 mg (8.2%);
Reaction SMILES: C1(C[O:8][C:9](=[O:64])[C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:13]=[C:12]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[C:44]([O:48]CC4C=CC=CC=4)[C:43]=3[O:56]CC3C=CC=CC=3)[CH:11]=2)C=CC=CC=1.[H][H].CCCCCC>[Pd].C1COCC1>[OH:56][C:43]1[C:44]([OH:48])=[CH:45][CH:46]=[CH:47][C:42]=1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][O:35][C:12]1[CH:11]=[C:10]([CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:13]=1)[C:9]([OH:64])=[O:8]
Reactant: [H][H]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(OCCCCCCc2cccc(OCc3ccccc3)c2OCc2ccccc2)cc(C(=O)OCc2ccccc2)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCCCCc2cccc(O)c2O)cc(C(=O)O)c1
Reaction time: 5 h
Yield: 87.1 %

Procedure:
A mixture of 2.0 g of 3-[[6-[2,3-bis(phenylmethoxy)phenyl]hexyl]oxy]-5-(octadecyloxy)benzoic acid phenylmethyl ester and 0.5 g of 10% palladium on carbon in 100 ml of THF was stirred in a hydrogen atmosphere until uptake ceased after 5 hours. The usual workup followed by trituration of the crude product with hexane gave 1.2 g (88% yield, mp 92°-94°) of 3-[[6-(2,3-dihydroxyphenyl) hexyl]oxy]-5-(octadecyloxy)benzoic acid.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[NH:15][CH:16]1[CH2:22][CH2:21][CH2:20][N:19](C(OCC)=O)[CH2:18][CH2:17]1)[CH3:2].[OH-:28].[K+].[CH2:30]([OH:33])[CH2:31][OH:32]>>[C:30]([OH:3])(=[O:33])[C:31]([OH:32])=[O:28].[CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[NH:15][CH:16]1[CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[CH3:2]
Reactant: OCCO
Reactant: CCOCCn1c(NC2CCCN(C(=O)OCC)CC2)nc2ccccc21
Reactant: [OH-]
Agent: [K+]
Product: CCOCCn1c(NC2CCCNCC2)nc2ccccc21
Product: O=C(O)C(=O)O
Reaction time: 8 h
Yield: 9.9 %

Procedure:
A mixture of 105 parts of ethyl 4-[[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]amino]hexahydro-1H-azepine-1-carboxylate, 79 parts of potassium hydroxide and 833 parts of 1,2-ethanediol was stirred overnight at reflux temperature. The reaction mixture was distilled in vacuo and the residue was taken up in dichloromethane. The organic phase was filtered and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the ethanedioate salt. The salt was filtered off and crystallized from 2-propanol. The product was filtered off and dried, yielding 16.4 parts (9.9%) of 1-(2-ethoxyethyl)-N-(hexahydro-1H-azepin-4-yl)-1H-benzimidazol-2-amine ethanedioate(1:3), monohydrate (compound 37).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([S:11](Cl)(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[I:15][C:16]1[C:21]([NH2:22])=[CH:20][CH:19]=[C:18]([C:23]([F:26])([F:25])[F:24])[N:17]=1>N1C=CC=CC=1.O>[CH3:2][C:1]([C:5]1[CH:6]=[C:7]([S:11]([NH:22][C:21]2[C:16]([I:15])=[N:17][C:18]([C:23]([F:25])([F:24])[F:26])=[CH:19][CH:20]=2)(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3]
Reactant: Nc1ccc(C(F)(F)F)nc1I
Reactant: CC(C)(C)c1cccc(S(=O)(=O)Cl)c1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)c1cccc(S(=O)(=O)Nc2ccc(C(F)(F)F)nc2I)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
9.07 g (38.96 mM) of 3-tert-butylbenzenesulfonyl chloride were added to a solution of 6.60 g (22.92 mM) of 2-iodo-6-trifluoromethylpyridin-3-ylamine in 10.0 mL of pyridine. This reaction mixture was stirred at room temperature overnight. The medium was diluted with water and then extracted with ethyl acetate. The organic phase was washed with 1N hydrochloric acid solution and then dried over magnesium sulfate, filtered and then concentrated under reduced pressure. 14.40 g of the evaporation residue were dissolved in 50.0 mL of 1,4-dioxane, 56.4 mL (169.28 mM) of 3M potassium hydroxide were added, and the reaction mixture was then refluxed for 1 hour. The medium was concentrated under reduced pressure. The residue was dissolved in water, and the solution was acidified with concentrated hydrochloric acid and then extracted twice with DCM. The organic phase was dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was washed with petroleum ether and then filtered on a Büchner funnel. The title product was obtained in the form of a white solid (8.80 g, yield=86%). m.p.=125° C.
Reaction SMILES: [F:1][C:2]1[C:3]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([CH:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)=[CH:32][CH:31]=2)=[C:4]([C:8]2[N:13]=[C:12]([N:14]3[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:16]=[N:15]3)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[CH:51]1([C:54](Cl)=[O:55])[CH2:53][CH2:52]1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH:51]1([C:54]([N:39]2[CH2:40][CH2:41][CH:36]([C:33]3[CH:32]=[CH:31][C:30]([CH2:29][O:28][C:3]4[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=4[C:8]4[N:13]=[C:12]([N:14]5[C:18]([C:19]([F:21])([F:22])[F:20])=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:16]=[N:15]5)[CH:11]=[CH:10][CH:9]=4)=[CH:35][CH:34]=3)[CH2:37][CH2:38]2)=[O:55])[CH2:53][CH2:52]1
Reactant: O=C(Cl)C1CC1
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3cccc(F)c3OCc3ccc(C4CCNCC4)cc3)n2)c1C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1cnn(-c2cccc(-c3cccc(F)c3OCc3ccc(C4CCN(C(=O)C5CC5)CC4)cc3)n2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the title compound from Example 5 Step C (40 mg, 0.07 mmol) in DCM (1 mL) were added diisopropyl ethyl amine (0.12 mL, 0.70 mmol) and cyclopropanecarbonyl chloride (0.02 mL, 0.21 mmol). The reaction mixture was stirred for 1 h at ambient temperature, then was diluted with sat. aq. NaHCO3 and extracted with DCM. The organic phase was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. The product was used in the subsequent step without further purification: LCMS m/z 636.8 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[S:26][C:25]([CH3:27])=[CH:24][N:19]3[C:20](=[O:23])[C:21]=2I)[CH2:3][CH2:2]1.[F:28][C:29]([F:41])([F:40])[O:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O>[CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[S:26][C:25]([CH3:27])=[CH:24][N:19]3[C:20](=[O:23])[C:21]=2[C:34]2[CH:33]=[CH:32][C:31]([O:30][C:29]([F:28])([F:40])[F:41])=[CH:36][CH:35]=2)[CH2:3][CH2:2]1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: COc1cccc(/C=C/c2nc3sc(C)cn3c(=O)c2I)c1OCC1CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cccc(/C=C/c2nc3sc(C)cn3c(=O)c2-c2ccc(OC(F)(F)F)cc2)c1OCC1CC1
Yield: 56.2 %

Procedure:
The title compound was prepared from Intermediate 16 (100 mg, 0.202 mmol) and 4-trifluoromethoxyphenylboronic acid (58 mg, 0.283 mmol) using Pd[(C6H5)3P]4 (90 mg, 0.008 mmol) and sodium carbonate (128 mg, 1.213 mmol) in toluene (10 ml) and ethanol (5 ml) and water (4 ml) according to the procedure outlined in Example 1 to afford crude residue which was purified by column chromatography to afford 60 mg of the desired product; 1H NMR (300 MHz, DMSO-d6) δ 0.22-0.27 (m, 2H), 0.46-0.52 (m, 3H), 0.98-1.01 (m, 1H), 2.44 (s, 3H), 3.67 (d, J=6.9 Hz, 2H), 3.76 (s, 3H), 6.86-6.92 (m, 2H), 6.99-7.00 (m, 2H), 7.45 (m, 1H), 7.84 (s, 1H), 8.12 (d, J=15.6 Hz, 1H); ESI-MS (m/z) 529.23 (M+H)+.
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:6]=1[C:12]([CH3:14])=[O:13].[Cl-].[NH4+]>O1CCCC1>[CH3:14][C:12]([C:6]1[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:5]=1[CH3:4])([OH:13])[CH3:1]
Reactant: CC(=O)c1ccc(O)cc1C
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc(O)ccc1C(C)(C)O
Temperature: -40 °C
Reaction time: 5 h
Yield: 80.2 %

Procedure:
To a solution of methylmagnesium bromide (30 ml, 90 mmol, 3M solution) dissolved in tetrahydrofuran (15 ml), a solution of compound (16) (4.5 g, 30 mmol) dissolved in tetrahydrofuran (10 ml) was slowly added dropwise at −78° C. When the dropping was completed, was slowly heated to −40° C., and stirred for 5 hours. After heating to 0° C., the solution was stirred for one hour, and then, ammonium chloride (50 ml) was slowly added dropwise thereto. The reaction solution was extracted with organic solvent, washed, dried and purified by using column chromatography (eluent: hexane/ethyl acetate=10/1) to obtain 4.0 g (80%) of pure compound (17).
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[NH:6][C:7]2[C:12]([C:13]=1[C:14]([NH2:16])=[O:15])=[CH:11][CH:10]=[C:9]([O:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1)[CH:8]=2)=[O:3].[C:25](O)(=[O:27])[CH3:26].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.O>[C:25]([NH:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][C:9]2[CH:8]=[C:7]3[C:12]([C:13]([C:14]([NH2:16])=[O:15])=[C:5]([NH:4][C:2]([NH2:1])=[O:3])[NH:6]3)=[CH:11][CH:10]=2)=[CH:19][CH:20]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)O
Reactant: NC(=O)Nc1[nH]c2cc(Oc3ccc(N)cc3)ccc2c1C(N)=O
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: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(Oc2ccc3c(C(N)=O)c(NC(N)=O)[nH]c3c2)cc1
Yield: 47.6 %

Procedure:
The solution of 2-aminocarbonylamino-6-(4-aminophenyloxy)indole-3-carboxamide (Compound No.5-1, 40 mg, 0.12 mmol), acetic acid (8 μL, 0.14 mmol), N,N-diisopropylethylamine (46 μL, 0.26 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (48 mg, 0.13 mmol) in anhydrous N,N-dimethylformamide (1 mL) was stirred overnight at room temperature. Water (10 mL) was added to the reaction solution, and the precipitated solid was filtered off and washed with water (10 mL). The solid was dried at 40° C. under reduced pressure to give the title compound (21 mg) as a purple solid (46%).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C@H:7]([NH:9][C:10]([C:12]2[CH:20]=[C:19]3[C:15]([C:16](C(C)=C)=[N:17][N:18]3[C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[CH:14][CH:13]=2)=[O:11])[CH3:8])[O:4][N:3]=1.C[N+]1([O-])CC[O:35]CC1.[CH3:39][C:40]([CH3:42])=[O:41]>O.[Os](=O)(=O)(=O)=O>[OH:35][CH2:39][C:40]([C:16]1[C:15]2[C:19](=[CH:20][C:12]([C:10]([NH:9][C@@H:7]([C:5]3[O:4][N:3]=[C:2]([CH3:1])[N:6]=3)[CH3:8])=[O:11])=[CH:13][CH:14]=2)[N:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)[N:17]=1)([OH:41])[CH3:42]
Reactant: C=C(C)c1nn(-c2ccc(C)cc2)c2cc(C(=O)N[C@H](C)c3nc(C)no3)ccc12
Reactant: C[N+]1([O-])CCOCC1
Reactant: CC(C)=O
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: Cc1ccc(-n2nc(C(C)(O)CO)c3ccc(C(=O)N[C@H](C)c4nc(C)no4)cc32)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 74.7 %

Procedure:
N-[(1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]-1-(4-methylphenyl)-3-(prop-1-en-2-yl)-1H-indazole-6-carboxamide (40.6 mg, 0.101 mmol) was dissolved in acetone (919 μl)/water (92 μl). N-methylmorpholine oxide (15.2 mg, 0.130 mmol) was added. Osmium tetroxide (2.5% in n-butanol, 32 μl, 2.55 mmol) was added. The reaction mixture was stirred at room temperature for 2.5 h. The reaction was stopped, quenched by addition of saturated aqueous sodium sulfite (5 mL), and extracted with ethyl acetate (3×10 mL). The combined organic phases were washed with saturated aqueous sodium chloride (1×5 mL), dried (sodium sulfate), filtered, and the solvent evaporated under reduced pressure. The residue was purified by preparative HPLC (reverse phase, C-18), eluting with acetonitrile/water+0.1% trifluoroacetic acid. The product fraction was diluted with ethyl acetate (15 mL), washed with saturated aqueous sodium bicarbonate (2×15 mL) and saturated aqueous sodium chloride (1×10 mL), dried (sodium sulfate), and the solvent evaporated under reduced pressure to give the title compound (1:1 mixture of diastereomers) (32.9 mg, 0.076 mmol, 74.7% yield) as a white solid. HRMS: [M+1]=436.2001. 1H NMR (500 MHz, CDCl3): δ 8.15 (s, 1H); 8.00 (dd, J=8.5, 4.7 Hz, 1H); 7.53-7.46 (m, 3H); 7.30 (d, J=7.9 Hz, 2H); 7.13 (d, J=8.0 Hz, 1H); 5.58 (t, J=7.3 Hz, 1H); 4.22 (dd, J=11.3, 3.3 Hz, 1H); 3.78 (d, J=11.4 Hz, 1H); 2.42 (s, 3H); 2.45-2.28 (m, 3H); 1.71-1.65 (m, 6H).
Reaction SMILES: Cl[C:2]1[N:3]([CH2:21][CH2:22][CH3:23])[C:4](=[O:20])[C:5]2[NH:6][C:7]([C:11]34[CH2:18][CH:17]5[CH2:19][CH:13]([CH2:14][CH:15]3[CH2:16]5)[CH2:12]4)=[N:8][C:9]=2[N:10]=1.[C:24]([O-:27])([O-])=[O:25].[K+].[K+].FC(F)(F)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1>CN1CCCC1=O.C(OCC)(=O)C.O>[CH2:14]1[CH:15]2[C:11]3([C:7]4[NH:6][C:5]5[C:4](=[O:20])[N:3]([CH2:21][CH2:22][CH3:23])[C:2]([O:38][C:35]6[CH:36]=[CH:37][C:32]([C:24]([OH:27])=[O:25])=[CH:33][CH:34]=6)=[N:10][C:9]=5[N:8]=4)[CH2:18][CH:17]([CH2:19][CH:13]1[CH2:12]3)[CH2:16]2
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: O=C([O-])[O-]
Reactant: CCCn1c(Cl)nc2nc(C34CC5CC(CC3C5)C4)[nH]c2c1=O
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCn1c(Oc2ccc(C(=O)O)cc2)nc2nc(C34CC5CC(CC3C5)C4)[nH]c2c1=O
Temperature: 130 °C
Yield: 9 %

Procedure:
To a solution of 2-chloro-8-(hexahydro-2,5-methano-pentalen-3a-yl)-1-propyl-1,7-dihydro-purin-6-one (0.10 g, 0.30 mmol) in N-methyl-2-pyrrolidone (0.3 ml) was added K2CO3 (0.062 g, 0.45 mmol) followed by 4-trifluoromethyl phenol and the reaction mixture was heated at 130° C. overnight. The reaction mixture was diluted with ethyl acetate and water. The layers were separated and ethyl acetate layer was washed with water. The ethyl acetate layer was dried over anhydrous sodium sulphate and concentrated under vacuum. The crude product was purified by column chromatography using 5% methanol in DCM as the eluant to give the product (0.013 g, 9%) as a brown solid.
Reaction SMILES: C(=O)=O.[P:4]([Cl:7])(Cl)Cl.[C:8]([NH:12][CH2:13][CH:14]([OH:29])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C>ClCCl.CC(C)=O>[C:8]([N:12]1[CH2:13][CH:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[O:29][P:4]1[Cl:7])([CH3:10])([CH3:11])[CH3:9]
Reactant: CCCCCCCCCCCCCCC(O)CNC(C)(C)C
Reactant: ClP(Cl)Cl
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCC1CN(C(C)(C)C)P(Cl)O1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a CO2 (s)/acetone cooled solution of 10.5 ml (0.077 mol) of phosphorus trichloride in 150 ml of dichloromethane is added dropwise a solution of 24.0 g (0.077 mol) of 1-tert-butylamino-2-hexadecanol and 21.3 mol (0.153 mol) of triethylamine in 37.5 ml of dichloromethane over a five minute period. When the addition is completed, the cooling bath is replaced with a 50° C. water bath for 1 hour. This is then stirred at room temperature for 16 hours.
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[CH:2]=[CH2:3].[CH3:10][CH2:11][C:12](C)=O>>[CH:6]12[CH2:7][CH:11]([CH2:12][CH2:8]1)[CH:10]=[CH:9]2.[CH2:1]=[CH2:2].[C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[CH:2]=[CH2:3]
Reactant: CCC(C)=O
Agent: C=CC(=O)OC(C)(C)C
Product: C1=CC2CCC1C2
Product: C=C

Procedure:
The procedure of Example 11 was followed using 23.5 g (0.25 mol) norbornene, 6.4 g (0.05 mole) tert-butyl acrylate, 100 mL CFC-113, 1.5 g Perkadox® 16N, 2.8 g (0.10 mol) ethylene and 60 g (0.6 mol) tetrafluoroethylene. The product mixture was a clear liquid which was added to excess methanol to precipitate the polymer. There was isolated 35.8 g (39%) of white polymer; GPC (MEK) Mw 13700, Mn 7000, Mw/Mn 1.96; Inh. Visc. 0.0830; Tg 108° C. Anal. Found: C, 57.47; H, 6.11; F, 24.40. Full polymer composition could not be determined by 13C NMR due to overlapping resonances. However, the mole ratio of TFE to tert-butyl acrylate was found to be 3.0 to 1.0 from integration of peaks at 112 to 124 ppm (CF2) versus 80 ppm (CH).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Cl.[NH2:11][CH2:12][C:13]#[N:14].O.N1(O)C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(C(C)C)C(C)C)C.ClCCl>>[C:12]([CH2:13][NH:14][C:1](=[O:9])[C:2]1[CH:3]=[CH:4][N:5]=[CH:6][CH:7]=1)#[N:11]
Reactant: N#CCN
Reactant: O=C(O)c1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: N#CCNC(=O)c1ccncc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of isonicotinic acid (1.00 g, 8.12 mmol), 2-aminoacetonitrile hydrochloride (0.902 g, 9.75 mmol), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (1.24 g, 8.12 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (1.71 g, 8.94 mmol) and N-ethyl-N-isopropylpropan-2-amine (4.95 ml, 28.4 mmol) in dichloromethane (20.3 ml, 8.12 mmol) was allowed to stir at room temperature for 24 hours. The mixture was concentrated and the residue was purified by CombiFlash using 0-10% methanol/DCM as the eluent to 1.31 g of N-(cyanomethyl)isonicotinamide 5.3B. 400 MHz 1H NMR (CDCl3) δ: 9.62 (br s, 1H), 8.87 (d, J=8.0 Hz, 2H), 7.94 (d, J=8.0 Hz, 2H), 4.30 (d, J=2H). LCMS (ES+) m/z 162.
Reaction SMILES: [C:1]1([B-:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].O.S(O)(O)(=O)=O.[C:33]([P:37]([C:42]([CH3:45])([CH3:44])[CH3:43])[C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:36])([CH3:35])[CH3:34]>C1(C)C=CC=CC=1>[C:20]1([B-:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1.[C:42]([PH+:37]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:43])([CH3:44])[CH3:45]
Reactant: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: c1ccc([B-](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Temperature: 25 °C

Procedure:
A 300-ml four-necked flask was equipped with a stirrer, a thermometer and a reflux condenser. 16.4 g (48 mmol) of sodium tetraphenylborate and 66 ml of water were weighed in the flask, followed by stirring to dissolve sodium tetraphenylborate. While the stirring was continuously carried out, the aqueous solution of tri-tert-butylphosphine sulfate was added to the solution, and the mixture was stirred at 25° C. for 3 hours. After the completion of the reaction, the precipitated product was filtered off. The so obtained crystal was suspended in 100 ml of toluene at 50° C., and the suspension was cooled to 25° C. and filtered. The product filtered off was washed with 100 ml of toluene. The crystal was then suspended in 100 ml of methanol at 50° C., and the suspension was cooled to 25° C. and filtered. The product filtered off was washed with 100 ml of methanol. The crystal obtained was dried to give 19.4 g of objective tri-tert-butylphosphonium tetraphenylborate as white crystal. The yield (mol %) was 93% based on tri-tert-butylphosphine.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11](O)=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:14][C:15]1[CH:22]=[CH:21][C:18](C=O)=[CH:17][CH:16]=1>>[C:1]1([S:7](/[CH:10]=[CH:11]/[C:18]2[CH:21]=[CH:22][C:15]([Br:14])=[CH:16][CH:17]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CS(=O)(=O)c1ccccc1
Reactant: O=Cc1ccc(Br)cc1
Product: O=S(=O)(/C=C/c1ccc(Br)cc1)c1ccccc1
Yield: 78 %

Procedure:
A solution of phenyl sulfonylacetic acid (0.01 mol) and 4-bromobenzaldehyde (0.01 mol) was subjected to Procedure 1, Part B. The title compound was obtained in 78-80% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@@H:15]([NH:24][C:25]([C:27]3[NH:31][C:30](=[O:32])[O:29][N:28]=3)=[O:26])[CH2:16][C@@H:17]([CH3:23])[C:18]([O:20]CC)=[O:19])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][C@@H:15]([NH:24][C:25]([C:27]3[NH:31][C:30](=[O:32])[O:29][N:28]=3)=[O:26])[CH2:16][C@@H:17]([CH3:23])[C:18]([OH:20])=[O:19])=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1noc(=O)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@H](C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1noc(=O)[nH]1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
To a solution of (2R,4S)-ethyl 5-(3′-chlorobiphenyl-4-yl)-2-methyl-4-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamido)pentanoate (25 mg, 0.055 mmol) in MeOH (2 mL) is added aqueous 1 N NaOH (4 mL). After stirring at room temperature for 2 hours, the crude is quenched with 1N HCl and concentrated under reduced pressure to remove MeOH. The crude is diluted with EtOAc. The organic layer is washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The obtained residue is purified by RP-HPLC (SunFire C18, H2O(0.1% TFA)/CH3CN), and then lyophilized to give (2R,4S)-5-(3′-chlorobiphenyl-4-yl)-2-methyl-4-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamido)pentanoic acid (22 mg). HPLC retention time=1.64 minutes (condition B); MS (m+1)=430.2; 1H NMR (400 MHz, CD3OD) δ ppm 1.18 (d, J=7.1 Hz, 3 H) 1.68 (ddd, J=14.3, 10.5, 4.0 Hz, 1H) 1.99-2.05 (m, 1H) 2.55 (ddd, J=10.2, 6.8, 3.9 Hz, 1H) 2.80-2.97 (m, 2H) 4.27-4.44 (m, 1H) 7.28-7.35 (m, 3H) 7.39 (t, J=7.8 Hz, 1H) 7.49-7.55 (m, 3H) 7.58 (t, J=1.9 Hz, 1H)
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[C:30](OC(=O)C)(=[O:32])[CH3:31].O>C(Cl)Cl>[F:20][C:2]([F:1])([F:19])[C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][N:10]2[C:30](=[O:32])[CH3:31])=[CH:7][CH:8]=1
Reactant: CC(=O)OC(C)=O
Reactant: FC(F)(F)c1ccc([C@H]2NCCc3ccccc32)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (R)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (100 mg, 361 μmol, example 30 (step 1) in DCM (2 mL) was added DIEA (62.8 μL, 361 μmol) and acetic acid anhydride (34.0 μL, 361 mop. The resulting mixture was then stirred at RT for 16 h. Then, H2O (1 mL) was added and the mixture was extracted with DCM (2×5 mL). The combined organic extracts were dried over MgSO4 and concentrated. The residue was purified by silica gel flash column chromatography (0%-100% EtOAc/hexane) to give the title compound as a white solid. MS (ESI, positive ion) m/z: 320 (M+H).