Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[C:2]1([CH3:12])[CH:7]=[CH:6][C:5](S(O)(=O)=O)=[CH:4][CH:3]=1.[C:13]([O-:16])(O)=O.[Na+]>C1CCCCC1>[CH3:12][C@@H:2]1[CH:7]=[CH:6][CH2:5][C:4]2([CH2:7][CH2:6][CH2:5][CH2:4]2)[C@H:3]1[C:13](=[O:16])/[CH:3]=[CH:2]/[CH3:12]
Reactant: O=C([O-])O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: O
Solvent: C1CCCCC1
Product: C/C=C/C(=O)[C@H]1[C@H](C)C=CCC12CCCC2
Temperature: 0 °C
Yield: 79 %

Procedure:
At −70° C., a solution of diisopropylamine (0.5 g, 4.93 mmol) in tetrahydrofuran (4 ml) was treated with n-butyl lithium (3.3 ml, 1.6M in hexane, 5.14 mmol). The resulting solution was stirred at −70° C. for 20 min. and treated with a solution of 1-(rel-(6S,7R)-7-methylspiro[4.5]dec-8-en-6-yl)ethanone (0.79 g, 4.11 mmol) in tetrahydrofuran (4 ml). The resulting solution was stirred 20 min. at −70° C. warmed to 0° C., cooled to −70° C., and treated with a solution of acetaldehyde (0.9 g, 20.5 mmol) in tetrahydrofuran (4 ml). After 20 min. stirring, the reaction mixture was warmed to −5° C., treated with a 1:1 mixture of a 2N aqueous HCl solution and saturated aqueous NaCl solution (25 ml) and extracted three times with MTBE (60 ml). The combined organic phases were washed with a saturated solution of NaHCO3, with a saturated solution of NH4Cl, and with water, dried (MgSO4), and concentrated. Fluid chromatography (FC, SiO2, hexane/MTBE 35:1) of the crude product (1.3 g) gave the desired intermediate β-hydroxyketone (0.47 g, 1.98 mmol, 48%) which was dissolved in cyclohexane (1 ml). The resulting solution was treated with para-toluene sulfonic acid monohydrate (13 mg, 6.7 mmol) and refluxed 1.5 h. The reaction mixture was cooled to 0° C., treated with a saturated aqueous solution of NaHCO3 and the aqueous phase was extracted twice with MTBE. The combined organic phases were washed with water, dried (MgSO4) and concentrated. FC (SiO2, hexane/MTBE 50:1) of the crude product (0.42 g) gave (E)-1-(rel-(6S,7R)-7-Methylspiro[4.5]dec-8-en-6-yl)but-2-en-1-one (0.34 g, 79%).
Reaction SMILES: Cl[S:2]([N:5]=C=O)(=[O:4])=[O:3].C(O)=O.[OH:11][CH2:12][CH:13]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1.N1C=CC=CC=1>ClCCl>[S:2]([O:11][CH2:12][CH:13]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:30])[CH3:29])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)(=[O:4])(=[O:3])[NH2:5]
Reactant: CC(C)(C)OC(=O)NC(CO)c1cccc(C(F)(F)F)c1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O=CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(COS(N)(=O)=O)c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A quantity of 171 μl (1.97 mmol) of chlorosulphonyl isocyanate was admixed under argon at 0° C., with vigorous stirring, with 74 μl (1.97 mmol) of anhydrous formic acid. Following the addition, the reaction mixture solidified within seconds. A quantity of 2 ml of dichloromethane was added. The reaction mixture was then stirred further at 0° C. for 1 h and then RT for 8 h. Thereafter it was cooled to 0° C. again and admixed with a solution of 400 mg (1.31 mmol) of the compound from Example 59A and 159 μl (1.97 mmol) of pyridine in 2 ml of dichloromethane. The cooling bath was removed and the reaction mixture was stirred overnight at RT. For work-up, 5 ml of water and 5 ml of ethyl acetate were added. After 10 min, the mixture was diluted with 100 ml of ethyl acetate, and washed twice with water and once with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulphate and freed from the solvent on a rotary evaporator. The residue was purified by preparative HPLC [Method 10]. The product fraction was freed from the solvent on a rotary evaporator. Drying in an HV gave 260 mg (52% of theory) of the title compound.
Reaction SMILES: O1CCOCC1.CO.C([O:11][C:12](=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][S:17][C:18]1[S:19][C:20]2[C:26]([F:27])=[CH:25][C:24]([F:28])=[C:23]([F:29])[C:21]=2[N:22]=1)C.[OH-].[Na+]>O>[F:29][C:23]1[C:21]2[N:22]=[C:18]([S:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]([OH:30])=[O:11])[S:19][C:20]=2[C:26]([F:27])=[CH:25][C:24]=1[F:28]
Reactant: CCOC(=O)CCCCSc1nc2c(F)c(F)cc(F)c2s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CCCCSc1nc2c(F)c(F)cc(F)c2s1
Yield: 26.5 %

Procedure:
To a mixture of dioxane (5 ml), methanol (2.5 ml) and water (2.5 ml) was added 5-(4,5,7-trifluorobenzothiazol-2-ylthio)pentanoic acid ethyl ester (590 mg, 2 mmol) and sodium hydroxide (100 mg, 2.5 mmol) and the resultant mixture was stirred for 15 hours at room temperature. The reaction mixture was diluted with water and washed with ether. The aqueous phase was then acidified with 7% hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with an aqueous saturated saline solution, dried and then evaporated. The resulting oily residue was purified on a silica gel column and crystallized from hexane-isopropyl ether to give 5-(4,5,7-trifluorobenzothiazol-2-ylthio)pentanoic acid (170 mg, 31%) as a colorless powder.
Reaction SMILES: CC1NC(C2C=C(C=CC=2C)C(O)=O)=C(C)N=1.[CH:18]1([C:21]2[C:30]([C:31]3[NH:35][C:34]([O:36][CH3:37])=[N:33][N:32]=3)=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[C:23]([CH3:38])[CH:22]=2)[CH2:20][CH2:19]1.CC1NC(C2C=C(C=CC=2C)C(OC)=O)=C(C)N=1>>[CH:18]1([C:21]2[C:30]([C:31]3[NH:35][C:34]([O:36][CH3:37])=[N:33][N:32]=3)=[CH:29][C:24]([C:25]([OH:27])=[O:26])=[C:23]([CH3:38])[CH:22]=2)[CH2:19][CH2:20]1
Reactant: COC(=O)c1cc(-c2nnc(OC)[nH]2)c(C2CC2)cc1C
Agent: COC(=O)c1ccc(C)c(-c2[nH]c(C)nc2C)c1
Agent: Cc1nc(C)c(-c2cc(C(=O)O)ccc2C)[nH]1
Product: COc1nnc(-c2cc(C(=O)O)c(C)cc2C2CC2)[nH]1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 5.7, except methyl 4-cyclopropyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoate (compound 91.5) was used in place of methyl 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoate (compound 5.6). m/z (ES+) 274 (M+H)+.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[N:16]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]([O:34][C:35]([N:37]1[CH2:42][CH2:41][C:40](=O)[CH2:39][CH2:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)(O)[O-].[Na+]>O.ClCCCl>[C:30]([O:34][C:35]([N:37]1[CH2:42][CH2:41][CH:40]([N:27]2[CH2:28][CH2:29][CH:24]([N:16]3[C:17]4=[N:18][CH:19]=[N:20][C:21]([NH2:23])=[C:22]4[C:14]([C:11]4[CH:10]=[CH:9][C:8]([O:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[CH:13][CH:12]=4)=[N:15]3)[CH2:25][CH2:26]2)[CH2:39][CH2:38]1)=[O:36])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(N2CCC(n3nc(-c4ccc(Oc5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.2 %

Procedure:
3-(4-phenoxyphenyl)-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Compound 2) (350 mg, 0.906 mmol), 1-tert-butoxycarbonyl-4-piperidone(198 mg, 0.996 mmol), sodium triacetoxyborohydride (288 mg, 1.358 mmol) and glacial acetic acid(60 ul, 0.996 mmol) were mixed with 5 ml of 1,2-dichloroethane. After stirring at room temperature overnight, 2 ml of water was added followed by solid sodium bicarbonate until the pH reached about 8. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed, dried and evaporated. The residue was purified via flash column chromatography to give 254 mg of 1-[1-(1-tert-butoxycarbonyl-4-piperidyl)-4-piperidyl]-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine. 1H NMR (DMSO) 1.39(m, 13H), 1.75(m, 2H), 1.91(m, 2H), 2.17(m, 2H), 2.35(m, 2H), 2.72(m, 2H), 3.0 (m, 2H), 3.63(m, 1H), 3.98(m, 2H), 4.63(m, 1H), 7.16(m, 5H), 7.44(m, 2H), 7.67(d, J=8.60 Hz, 2H), 8.23(s, 1H); LC/MS (MH+=484).
Reaction SMILES: C(OC([N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[C:8]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)=[CH:7]1)=O)C.[OH-].[K+]>C(O)(C)C>[C:24]([O:23][C:21]([N:18]1[CH2:17][CH2:16][CH:15]([C:8]2[C:9]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:6][CH:7]=2)[CH2:20][CH2:19]1)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: CCOC(=O)n1cc(C2CCN(C(=O)OC(C)(C)C)CC2)c2cccnc21
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ncccc23)CC1

Procedure:
4 g (10.72 mmol) of 3-(1-tert-butoxycarbonyl-piperidin-4-yl)-pyrrolo[2,3-b]pyridine-1-carboxylic acid ethyl ester were added to a solution of 3 g (53.6 mmol) of potassium hydroxide in 120 ml of isopropanol. The mixture was refluxed for 16 hours. The solvent was distilled off and cold water was added. This solution was acidified with concentrated hydrochloric acid and then basified with 8 N aqueous sodium hydroxide solution. This aqueous solution was extracted twice with ethyl acetate. The organic phase was washed with water and brine, dried over magnesium sulphate, filtered and evaporated under reduced pressure. 1.6 g (50% of yield) of the expected product were obtained as yellowish solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:38][CH3:39])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][CH2:26][N:27]3C(=O)C4C(=CC=CC=4)C3=O)[N:9]=2)[CH:7]=1.NN>C(O)C>[NH2:27][CH2:26][CH2:25][N:10]1[CH:11]=[C:12]([NH:13][C:14]([C:16]2[CH:17]=[N:18][N:19]3[CH:24]=[CH:23][CH:22]=[N:21][C:20]=23)=[O:15])[C:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:38][CH3:39])=[N:9]1
Reactant: COc1ccc(Cl)cc1-c1nn(CCN2C(=O)c3ccccc3C2=O)cc1NC(=O)c1cnn2cccnc12
Agent: NN
Solvent: CCO
Product: COc1ccc(Cl)cc1-c1nn(CCN)cc1NC(=O)c1cnn2cccnc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 15.4 %

Procedure:
To a solution of N-(3-(5-chloro-2-methoxyphenyl)-1-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (prepared following the synthetic procedures described for Example 14) (104.1 mg, 0.192 mmol) in 8 mL ethanol was added hydrazine (78 μL, 2.5 mmol). The reaction mixture was stirred at room temperature for 18 hours, and then concentrated. The crude product was purified by reverse phase HPLC and lyophilized to give 17.7 mg (15.4%) of N-(1-(2-aminoethyl)-3-(5-chloro-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m+H=412.1; 1H NMR (400 MHz, DMSO-d6) δ: 9.68 (s, 1H), 9.33 (dd, J=7.0, 1.6, 1H), 8.77 (dd, J=4.2, 1.6, 1H), 8.65 (s, 1H), 8.30 (s, 1H), 7.49 (dd, J=8.8, 2.7, 1H), 7.42 (d, J=2.7, 1H), 7.29 (m, 2H), 4.14 (t, J=6.2, 2H), 3.85 (s, 3H), 2.99 (t, J=6.2, 2H).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[CH:7]([NH:15][C:16](=[O:21])[O:17][CH:18]([CH3:20])[CH3:19])[CH2:6][CH:5]1[CH3:22])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].OB(O)[C:31]1[O:32][CH:33]=[CH:34][C:35]=1[C:36]([OH:38])=[O:37].[OH-].[Na+:41]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1.C(O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:31]3[O:32][CH:33]=[CH:34][C:35]=3[C:36]([O-:38])=[O:37])=[CH:11][CH:12]=2)[C@@H:7]([NH:15][C:16]([O:17][CH:18]([CH3:20])[CH3:19])=[O:21])[CH2:6][C@H:5]1[CH3:22])(=[O:3])[CH3:2].[Na+:41]
Reactant: CC(=O)N1c2ccc(Br)cc2C(NC(=O)OC(C)C)CC1C
Reactant: O=C(O)c1ccoc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(=O)N1c2ccc(-c3occc3C(=O)[O-])cc2[C@@H](NC(=O)OC(C)C)C[C@H]1C
Temperature: 25 °C
Yield: 15 %

Procedure:
A flask was charged with 1-methylethyl (1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl)carbamate (for a preparation see Example 61) (100 mg, 0.271 mmol), potassium carbonate (74.9 mg, 0.542 mmol), 2-(dihydroxyboranyl)-3-furancarboxylic acid (50.7 mg, 0.325 mmol) and tetrakis(triphenylphosphine)palladium(0) (15.65 mg, 0.014 mmol) then filled with ethanol (1 mL) and toluene (1 mL) and the resulting mixture was refluxed under nitrogen for 21 h then cooled to room temperature and partitioned between a 2M HCl aqueous solution (40 mL) and EtOAc (40 mL). The layers were separated and the aqueous phase was extracted with EtOAc (2×40 mL). The combined organic phases were washed with brine (80 mL), dried over Na2SO4 and concentrated in vacuo. Purification of the residue using MDAP (modifier; trifluoroacetic acid) gave a residue which was treated with a 2M NaOH aqueous solution (2.25×10−2 mL, 4.50 mmol). The precipitate formed was filtered off and dried under house vacuum to give sodium 2-[(2R,4S)-1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]-3-furancarboxylate (18 mg, 0.040 mmol, 15%) as a cream solid.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([C:15](=[O:16])[NH:14][C:13](=[O:17])[CH:12]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=[O:7].[CH3:35][N:36]([CH3:41])[CH2:37][CH2:38][CH2:39]O>>[F:32][C:29]([F:30])([F:31])[C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:28]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([C:15](=[O:16])[N:14]([CH2:39][CH2:38][CH2:37][N:36]([CH3:41])[CH3:35])[C:13](=[O:17])[CH:12]2[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:24][CH2:25]1)=[O:7]
Reactant: O=C1NC(=O)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)C1c1ccccc1
Reactant: CN(C)CCCO
Product: CN(C)CCCN1C(=O)C(c2ccccc2)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)C1=O

Procedure:
The title compound, MS: m/e=570.2 (M+H+), was prepared in accordance with the general method of example 121 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-4-phenyl-2,8-diaza-spiro[4.5]decane-1,3 -dione and 3-dimethylamino-1-propanol.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([Si](C(C)C)(C(C)C)[N:23]1[CH:27]=[CH:26][C:25]([CH:28]2[CH2:33][CH2:32][N:31]([S:34]([N:37]3[CH2:42][CH2:41][CH2:40][CH2:39][C@@H:38]3[C:43]([O:45][CH3:46])=[O:44])(=[O:36])=[O:35])[CH2:30][CH2:29]2)=[CH:24]1)(C)C>O1CCCC1.C(OCC)(=O)C>[NH:23]1[CH:27]=[CH:26][C:25]([CH:28]2[CH2:29][CH2:30][N:31]([S:34]([N:37]3[CH2:42][CH2:41][CH2:40][CH2:39][C@@H:38]3[C:43]([O:45][CH3:46])=[O:44])(=[O:36])=[O:35])[CH2:32][CH2:33]2)=[CH:24]1
Reactant: COC(=O)[C@H]1CCCCN1S(=O)(=O)N1CCC(c2ccn([Si](C(C)C)(C(C)C)C(C)C)c2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1CCCCN1S(=O)(=O)N1CCC(c2cc[nH]c2)CC1
Reaction time: 0.5 h
Yield: 31 %

Procedure:
Tetrabutylammonium fluoride (2.45 ml, 2.45 mmol) was added to a solution of methyl 1-[4-(1-triisopropylsilylpyrrol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxylate (2.5 g, 4.89 mmol) [prepared as described in Step 2 above] in tetrahydrofuran (48 ml) at 0° C. After 30 min., the reaction mixture was diluted with ethyl acetate, washed with water, brine, dried over MgSO4, and concentrated in vacuo. The residue was chromatographed (SiO2, 15-40% ethyl acetate/hexanes) to yield methyl 1-[4-(pyrrol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxylate (31%) as a clear oil. This material was converted to 1-[4-(pyrrol-3-yl)-piperidine-1-sulfonyl]piperidine-2-(R)-carboxylic acid (93%) by proceeding as described in Example 11, Step 1, but substituting methyl (R)-2-{[4-(5-chloropyridin-2-yloxy)piperidine-1 sulfonyl]amino}-3-methylbutyrate with methyl 1-[4-(pyrrol-3-yl)piperidine-1-sulfonyl]-piperidine-2-(R)-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:23]([O:25][CH3:26])=[O:24].[CH3:27][C:28]1[CH:32]=[C:31]([CH2:33][C:34](O)=[O:35])[O:30][N:29]=1>O=P(Cl)(Cl)Cl>[Cl:8][C:6]1[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]([C:23]([O:25][CH3:26])=[O:24])=[C:2]([NH:1][C:34](=[O:35])[CH2:33][C:31]2[O:30][N:29]=[C:28]([CH3:27])[CH:32]=2)[CH:7]=1
Reactant: COC(=O)c1cc(-c2ccc(-c3ccc(OC)cc3)cc2)c(Cl)cc1N
Reactant: Cc1cc(CC(=O)O)on1
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cc(-c2ccc(-c3ccc(OC)cc3)cc2)c(Cl)cc1NC(=O)Cc1cc(C)no1
Temperature: 80 °C
Yield: 30.5 %

Procedure:
A stirred suspension of methyl 4-amino-6-chloro-4″-methoxy-[1,1′:4′,1″-terphenyl]-3-carboxylate (Intermediate 49) (520 mg, 1.41 mmol)) and 2-(3-methylisoxazol-5-yl) acetic acid (Aldrich, 219 mg, 1.56 mmol) in POCl3 (6 mL) was heated at 80° C. for 2 h and then cooled to room temperature. The solution was concentrated under reduced pressure. The crude material was taken up with ethyl acetate and saturated NaHCO3, the organic phase was washed with water and dried over Na2SO4 and the solvent removed under reduced pressure. The crude material was purified on silica gel column chromatography using cyclohexane to cyclohexane/ethyl acetate 75:25 as eluant to give the title compound methyl 6-chloro-4″-methoxy-4-(2-(3-methylisoxazol-5-yl)acetamido)-[1,1′:4′,1″-terphenyl]-3-carboxylate (210 mg, 0.43 mmol, 30.4%). LCMS: (M+H)+=491; Rt=1.37 min.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:5]=2[CH3:14])[CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:18][C:19]1[C:24]([F:25])=[CH:23][C:22]([O:26][CH2:27][CH3:28])=[CH:21][C:20]=1[F:29].O>C1COCC1>[CH:1]1([C:4]2[N:8]([CH2:18][C:19]3[C:20]([F:29])=[CH:21][C:22]([O:26][CH2:27][CH3:28])=[CH:23][C:24]=3[F:25])[N:7]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:5]=2[CH3:14])[CH2:2][CH2:3]1
Reactant: CCOc1cc(F)c(CBr)c(F)c1
Reactant: CCOC(=O)c1n[nH]c(C2CC2)c1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1nn(Cc2c(F)cc(OCC)cc2F)c(C2CC2)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
46.9 g of ethyl 5-cyclopropyl-4-methyl-1H-pyrazole-3-carboxylate 1-15-1 (266 mmol, 1.0 eq.) in 588 mL THF were cooled to 0° C. and 11.6 g sodiumhydride (60%, 290 mmol, 1.2 eq.) were added in small portions. The resulting suspension was diluted with 250 mL THF. 66.7 g 2-(bromomethyl)-5-ethoxy-1,3-difluorobenzene (266 mmol, 1.1 eq., commercially available) were added slowly. The reaction mixture was stirred at rt for 2 hours. 300 mL water was added and the THF was evaporated in vacuum. The aqueous residue was extracted with ethylacetate three times. The combined organic layers were dried over a silicone filter and concentrated in vacuo. The residue was purified by flash chromatography to provide 79.8 g (195 mmol, 81%) of 89% pure target compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(O[N:44]1[C:49](=[O:50])[CH2:48][CH2:47][C:45]1=[O:46])=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[C:1]([O:5][C:6](=[O:26])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][N:44]2[C:49](=[O:50])[CH2:48][CH2:47][C:45]2=[O:46])=[O:24])=[CH:9][CH:8]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Reactant: CC(C)(C)OC(=O)c1ccc(OCCCCCCCCCC(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(OCCCCCCCCCC(=O)ON2C(=O)CCC2=O)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 28 %

Procedure:
4-(9-Carboxynonyloxy)benzoic acid tert-butyl ester (779 mg, 2.14 mmol) was dissolved in THF (15 mL), and DIEA (366 μl, 2.14 mmol) was added. The mixture was cooled to 0° C., and placed under nitrogen, and HSTU was added. The mixture was stirred at 0° C. for 30 min and at RT for 16 h. The sample was concentrated under vacuum and AcOEt (40 ml) was added. The mixture was washed with 0.2 N HCl (2×25 ml), dried over MgSO4, and concentrated under vacuum to yield a slightly yellow solid. The solid was recrystallized from AcOEt to yield a white powder (276 mg, 28% yield). The mother liquor was concentrated to yield crystalline residue (430 mg, 43% yield). Data for the white powder:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[CH:13]=[N:14][C:15](Cl)=[CH:16][CH:17]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19](=[NH:32])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.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.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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]>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[CH:13]=[N:14][C:15]([N:32]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:16][CH:17]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc(Cl)nc2)C1
Reactant: N=C(c1ccccc1)c1ccccc1
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
Product: CC(C)(C)OC(=O)N1CC(c2ccc(N=C(c3ccccc3)c3ccccc3)nc2)C1
Temperature: 80 °C
Yield: 70.9 %

Procedure:
A mixture of 3-(6-chloropyridin-3-yl)-azetidine-1-carboxylic acid tert-butyl ester (274 mg, 1.0 mmol), benzophenone imine (0.2 mL, 1.2 mmol), Pd2(dba)3 (22 mg, 0.025 mmol), Xantphos (58 mg, 0.10 mmol) and cesium carbonate (652 mg, 2.0 mmol) in dioxane (10 mL) was de-gassed and purged with nitrogen and the reaction mixture was heated at 80° C. in a sealed vial overnight. The resultant mixture was allowed to cool to room temperature, before being partitioned between ethyl acetate and water. The layers were separated and the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (30-40% ethyl acetate in cyclohexane) to afford the title compound as a yellow solid (293 mg, 70% yield). LCMS (Method C): RT=3.31 min, m/z: 269 [M+H+].
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:13])[NH:8][C:9]([CH3:12])=[N:10][CH:11]=1)=[O:5])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].Br[CH2:33][C:34]([C:36]1[CH:40]=[C:39]([CH3:41])[O:38][C:37]=1[CH3:42])=[O:35]>COCCOC>[CH3:42][C:37]1[O:38][C:39]([CH3:41])=[CH:40][C:36]=1[C:34](=[O:35])[CH2:33][N:8]1[C:7](=[O:13])[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:11][N:10]=[C:9]1[CH3:12]
Reactant: CCOC(=O)c1cnc(C)[nH]c1=O
Reactant: Cc1cc(C(=O)CBr)c(C)o1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: COCCOC
Product: CCOC(=O)c1cnc(C)n(CC(=O)c2cc(C)oc2C)c1=O
Yield: 31 %

Procedure:
5-Ethoxycarbonyl-2-methylpyrimid-4-one (3.5 g, 19 mmol) was dissolved in DME (110 mL) and TBAF (28.5 mL, 1 M solution in THF, 28.5 mmol) added dropwise at 0° C. The resulting solution was stirred ten minutes and a solution of 3-bromoacetyl-2,5-dimethylfuran (4.3 g, 20 mmol) in DME (10 mL) was added dropwise. The reaction was stirred at room temperature overnight. The solution was then concentrated in vacuo and partitioned between EtOAc and saturated aqueous NH4Cl. The EtOAc layer was separated and concentrated. The product was purified using flash silica chromatography (EtOAc/hexane=2:8 to 8:2), with the o-alkylated side product eluting at 4:6, and the desired N-alkylated product eluting at 8:2. The N-alkylated product was dried as a yellow solid, isolated in 31% yield; MS: 319 (M+H) and 273.